WO2024103016A1

WO2024103016A1 - 4'-halomethyl-cytidine phosphoramidates and related compounds and their use in treating medical conditions

Info

Publication number: WO2024103016A1
Application number: PCT/US2023/079400
Authority: WO
Inventors: Donna L. Romero; Oliver Saunders; Gregory Stuart Bisacchi; Shon Pulley; Harry R. Chobanian
Original assignee: Rome Therapeutics Inc
Current assignee: Rome Therapeutics Inc
Priority date: 2022-11-11
Filing date: 2023-11-10
Publication date: 2024-05-16
Anticipated expiration: 2025-05-11

Abstract

Substituted 4'-halomethyl-cytidine phosphoramidates 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

4'-HALOMETHYL-CYTIDINE PHOSPHORAMIDATES 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 63/582,728, filed September 14, 2023, and United States Provisional Patent Application serial number 63/383,420, filed November 11, 2022; the contents of each 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 November 9, 2023, is named 205645_seqlist.xml and is 2,695 bytes in size. FIELD OF THE DISCLOSURE [0003] Substituted 4'-halomethyl-cytidine phosphoramidates 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 4'-halomethyl-cytidine phosphoramidates 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 4'-halomethyl-cytidine phosphoramidates 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 4'-halomethyl-cytidine phosphoramidates 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 collection of substituted 4'-halomethyl- cytidine cyclic phosphoramidates and related compounds, such as a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of substituted 4'-halomethyl-cytidine cyclic phosphoramidates and related compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0008] Another aspect of the disclosure provides a collection of substituted 4'-halomethyl- cytidine phosphoramidates and related compounds, such as a compound represented by Formula VII:

or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of substituted 4'-halomethyl-cytidine phosphoramidates and related compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0009] 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 or II, to a subject in need thereof to treat the disorder, as further described in the detailed description. [0010] 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 an influenza viral infection. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula III or Formula IV to treat the disorder; wherein Formula III and Formula IV are represented by:

(III) (IV) or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Additional features of the method are described in the detailed description. [0011] 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 or II, in order to inhibit the activity of said LINE1 reverse transcriptase, as further described in the detailed description. [0012] 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 an influenza viral infection. The method comprises contacting a LINE1 reverse transcriptase with an effective amount of a compound described herein, such as a compound of Formula III or IV, in order to inhibit the activity of said LINE1 reverse transcriptase, as further described in the detailed description. [0013] 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 or II, in order to inhibit the activity of said HERV-K reverse transcriptase, as further described in the detailed description. [0014] 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 an influenza viral infection. The method comprises contacting a HERV-K reverse transcriptase with an effective amount of a compound described herein, such as a compound of Formula III or IV, in order to inhibit the activity of said HERV-K reverse transcriptase, as further described in the detailed description. BRIEF DESCRIPTION OF FIGURES [0015] Figure 1 is a graph depicting interferon levels over time in THP1-Dual^TM KO- TREX1 xenografts from mice treated with vehicle or decitabine (DAC) at 5mg/kg IP, once daily, for four days, as described in Example 15. DETAILED DESCRIPTION [0016] Substituted 4'-halomethyl-cytidine phosphoramidates 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); “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. [0017] 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 [0018] 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. [0019] 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. [0020] 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:

[0021] Exemplary bridged bicyclics include:

. [0022] The term “lower alkyl” refers to a C_1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0023] The term “lower haloalkyl” refers to a C_1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0024] 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)). [0025] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0026] As used herein, the term “bivalent C_1-8 (or C_1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0027] 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. [0028] 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. [0029] 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. [0030] The term “halogen” means F, Cl, Br, or I. [0031] 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

erm “arylene” refers to a bivalent aryl group. [0032] 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. [0033] 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.,

[0034] 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). [0035] 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. [0036] 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. [0037] 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. [0038] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH2)0–4R^o; –(CH2)0–4OR^o; -O(CH2)0-4R^o, –O–(CH2)0– 4C(O)OR°; –(CH2)0–4CH(OOR)°2; –(CH2)0–4SR^o; –(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^o)₂; –(CH₂)_0–4N(R^o)C(O)R^o; –N(R^o)C(S)R^o; –(CH₂)_0–4N(R^o)C(O)NR^o ₂; -N(R^o)C(S)NR^o2; –(CH2)0–4N(R^o)C(O)OR^o; –N(R^o)N(R^o)C(O)R^o; -N(R^o)N(R^o)C(O)NR^o2; -N(R^o)N(R^o)C(O)OR^o; –(CH₂)_0–4C(O)R^o; –C(S)R^o; –(CH₂)_0–4C(O)OR^o; –(CH₂)_0–4C(O)SR^o; -(CH2)0–4C(O)OSiR^o3; –(CH2)0–4OC(O)R^o; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^o; –(CH₂)_0–4C(O)NR^o ₂; –C(S)NR^o ₂; –C(S)SR°; –SC(S)SR°, -(CH₂)_0–4OC(O)NR^o ₂; -C(O)N(OR^o)R^o; –C(O)C(O)R^o; –C(O)CH2C(O)R^o; –C(NOR^o)R^o; -(CH2)0–4SSR^o; –(CH2)0– 4S(O)2R^o; –(CH2)0–4S(O)2OR^o; –(CH2)0–4OS(O)2R^o; –S(O)2NR^o2; –S(O)(NR^o)R^o; – S(O)₂N=C(NR^o ₂)₂; -(CH₂)_0–4S(O)R^o; -N(R^o)S(O)₂NR^o ₂; –N(R^o)S(O)₂R^o; –N(OR^o)R^o; – C(NH)NR^o2; –P(O)2R^o; -P(O)R^o2; -OP(O)R^o2; –OP(O)(OR^o)2; SiR^o3; –(C1–4 straight or branched alkylene)O–N(R^o)₂; or –(C_1–4 straight or branched alkylene)C(O)O–N(R^o)₂. [0039] Each R^o 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^o, 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^o selected from =O and =S; or each R^o is optionally substituted with a monovalent substituent independently selected from halogen, –(CH₂)_0–2R ^●, –(haloR ^●), –(CH₂)_0–2OH, –(CH₂)_0–2OR ^●, – (CH₂)_0–2CH(OR ^●)₂; -O(haloR ^●), –CN, –N₃, –(CH₂)_0–2C(O)R ^●, –(CH₂)_0–2C(O)OH, –(CH₂)_0– ₂C(O)OR ^●, –(CH₂)_0–2SR ^●, –(CH₂)_0–2SH, –(CH₂)_0–2NH₂, –(CH₂)_0–2NHR ^●, –(CH₂)_0–2NR ^● ₂, –NO₂, –SiR ^●3, –OSiR ^●3, -C(O)SR ^●, –(C1–4 straight or branched alkylene)C(O)OR ^●, or –SSR ^●. [0040] Each R ^● 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 ^● 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. [0041] When R^* is C1–6 aliphatic, R^* is optionally substituted with halogen, – R ^●, -(halo R ^●), -OH, –OR ^●, –O(haloR ^●), –CN, –C(O)OH, –C(O)OR ^●, –NH2, –NHR ^●, –NR ^●2, or –NO₂, wherein each R ^● 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 ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0042] 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 ^●, -(haloR ^●), -OH, –OR ^●, – O(haloR ^●), –CN, –C(O)OH, –C(O)OR ^●, –NH2, –NHR ^●, –NR ^●2, or –NO2, wherein each R ^● 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 ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0043] 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. [0044] 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. [0045] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C1–4alkyl)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. [0046] 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. [0047] 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. [0048] 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 an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this disclosure. [0049] 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. [0050] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. [0051] 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. [0052] 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. [0053] 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. [0054] 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. [0055] 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. [0056] 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. [0057] 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. [0058] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone. [0059] The symbol “

” indicates a point of attachment. [0060] 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

, 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,

. [0061] 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. [0062] 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. [0063] As used herein, the terms “subject” and “patient” are used interchangeable 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. [0064] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target. [0065] 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. [0066] 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. [0067] 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]. [0068] 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. [0069] 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. [0070] 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. [0071] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. I. Substituted 4'-Halomethyl-Cytidine Phosphoramidates and Related Compounds [0072] Substituted 4'-halomethyl-cytidine phosphoramidates 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. [0073] One aspect of the disclosure provides a compound represented by Formula I:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)) or -P(O)(OR⁴)₂; R² is halo, hydrogen, or -OH; R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, -CF₃, or C_1-3 aliphatic; R⁴ represents independently for each occurrence C_1-6 alkyl, -(C_1-4 alkylene)-OC(O)O-(C_1- ₁₀ alkyl), or hydrogen; R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰; R⁶ is hydrogen or C_1-4 alkyl; R⁷ is -C(R⁸)₂-CO₂R⁹; R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl; R¹¹ is hydrogen, halo, -CH3, or -CF3;

m is 0, 1, 2, or 3. [0074] The definitions of variables in Formula I above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0075] In certain embodiments, the compound is a compound of Formula I. [0076] As defined generally above, R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)) or -P(O)(OR⁴)2. In certain embodiments, R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)). In certain embodiments, R¹ is -P(O)(OR⁴)2. In certain embodiments, R¹ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0077] As defined generally above, R² is halo, hydrogen, or -OH. In some embodiments, R² is halo or hydrogen. In some embodiments, R² is hydrogen or -OH. In some embodiments, R² is halo or -OH. In some embodiments, R² is fluoro, hydrogen, or -OH. In some embodiments, R² is fluoro or hydrogen. [0078] In some embodiments, R² is halo. In some embodiments, R² is chloro, fluoro, or bromo. In some embodiments R² is chloro. In some embodiments, R² is fluoro. In some embodiments, R² is bromo. In some embodiments, R² is hydrogen. In some embodiments, R² is - OH. In certain embodiments, R² is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0079] As defined generally above, R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, -CF3, or C1-3 aliphatic. In some embodiments, R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, or -CF3. In some embodiments, R³ is -CH2F or -CF3. In some embodiments, R³ is -CH2Cl or -CH2F. [0080] In some embodiments, R³ is C1-3 aliphatic. In some embodiments, R³ is C2-3 aliphatic. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, -C≡CH, or cyclopropyl. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, or - C≡CH. In some embodiments, R³ is -CH₃ or -CH₂CH₃. In some embodiments, R³ is -C(H)=CH₂, -CH₂C(H)=CH₂, or -C≡CH. In some embodiments, R³ is -CH₃. In some embodiments, R³ is - CH2CH3. In some embodiments, R³ is -C(H)=CH2. In some embodiments, R³ is -CH2C(H)=CH2. In some embodiments, R³ is -C≡CH. In some embodiments, R³ is cyclopropyl. [0081] In some embodiments, R³ is -CH2Cl, -CH2F, -CH2Br, or -CH2I. In some embodiments, R³ is -CH2Cl. In some embodiments, R³ is-CH2F. In some embodiments, R³ is- CH₂Br. In some embodiments, R³ is-CH₂I. In some embodiments, R³ is -CF₃. In certain embodiments, R³ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0082] As defined generally above, R⁴ represents independently for each occurrence C_1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl), or hydrogen. In some embodiments, R⁴ represents independently for each occurrence C1-6 alkyl or -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl. In some embodiments, R⁴ represents independently for each occurrence C1-6 alkyl or hydrogen. In some embodiments, R⁴ represents independently for each occurrence -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl) or hydrogen. [0083] In some embodiments, R⁴ represents independently for each occurrence C1-6 alkyl. In some embodiments, R⁴ represents independently for each occurrence C_1-4 alkyl. In some embodiments, R⁴ represents independently for each occurrence C_3-6 alkyl. [0084] In some embodiments, R⁴ represents independently for each occurrence -(C_1-4 alkylene)-OC(O)O-(C1-10 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C1-4 alkylene)-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C1-4 alkylene)-OC(O)O-(C6-10 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C1-2 alkylene)-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ represents independently for each occurrence -CH₂-OC(O)O-(C_1-6 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C1-2 alkylene)-OC(O)O- (C6-10 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C2-4 alkylene)-OC(O)O-(C1-10 alkyl). [0085] In some embodiments, R⁴ is C1-6 alkyl. In some embodiments, R⁴ is C1-4 alkyl. In some embodiments, R⁴ is C_3-6 alkyl. [0086] In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl). In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C_1-6 alkyl). In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C_6-10 alkyl). In some embodiments, R⁴ is -(C_1-2 alkylene)-OC(O)O-(C_1-6 alkyl). In some embodiments, R⁴ is -CH2-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ is -(C1- 2 alkylene)-OC(O)O-(C6-10 alkyl). In some embodiments, R⁴ is -(C2-4 alkylene)-OC(O)O-(C1-10 alkyl). In certain embodiments, R⁴ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0087] As defined generally above, R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰. In certain embodiments, R⁵ is phenyl or naphthyl. [0088] In certain embodiments, R⁵ is phenyl substituted with m instances of R¹⁰. In certain embodiments, R⁵ is naphthyl substituted with m instances of R¹⁰. In certain embodiments, R⁵ is

. [0089] In certain embodiments, R⁵ is phenyl. In certain embodiments, R⁵ is naphthyl. In certain embodiments, R⁵ is 1-naphthyl. In certain embodiments, R⁵ is 2-naphthyl. In certain embodiments, R⁵ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0090] As defined generally above, R⁶ is hydrogen or C1-4 alkyl. In certain embodiments, R⁶ is hydrogen or methyl. [0091] In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is C_1-4 alkyl. In certain embodiments, R⁶ is methyl. In certain embodiments, R⁶ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0092] As defined generally above, R⁷ is -C(R⁸)₂-CO₂R⁹. In certain embodiments, R⁷ is - C(H)(R⁸)-CO2R⁹.

[0095] In certain embodiments,

,

. In certain embodiments,

. In certain embodiments,

certain embodiments,

. [0096] In certain embodiments, R⁷ is . In certain embodiments, R⁷ is

. , . certain embodiments, R⁷

is . In certain embodiments, R⁷ is

. In certain embodiments, R⁷ is

. , . [0097] In certain embodiments, R⁷ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0098] As defined generally above, R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. [0099] In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl. In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl; wherein said C_1-6 alkyl is optionally substituted with phenyl. [0100] In certain embodiments, R⁸ represents independently for each occurrence methyl, benzyl, or hydrogen. In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl optionally substituted with phenyl. In certain embodiments, R⁸ represents independently for each occurrence methyl or benzyl. In certain embodiments, R⁸ represents independently for each occurrence benzyl or hydrogen. [0101] In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. [0102] In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen. In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C1-4 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C1-3 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C2-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C3-6 alkyl. [0103] In certain embodiments, one occurrence of R⁸ is C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is C_1-6 alkyl optionally substituted with phenyl, and the other occurrence of R⁸ is hydrogen. [0104] In certain embodiments, one occurrence of R⁸ is C1-6 alkyl or hydrogen, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is C1-4 alkyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is methyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, R⁸ is methyl. In certain embodiments, R⁸ is hydrogen. [0105] In certain embodiments, two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. In certain embodiments, two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-membered saturated carbocyclic ring. [0106] In certain embodiments, R⁸ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0107] As defined generally above, R⁹ is C_1-6 alkyl or C_2-6 alkenyl; wherein said C_1-6 alkyl is optionally substituted with phenyl. [0108] In certain embodiments, R⁹ is C_1-6 alkyl, allyl, or -CH₂-phenyl. In certain embodiments, R⁹ is allyl or -CH2-phenyl. In certain embodiments, R⁹ is allyl. In certain embodiments, R⁹ is -CH2-phenyl. [0109] In certain embodiments, R⁹ is C1-6 alkyl or C2-6 alkenyl. [0110] In certain embodiments, R⁹ is C1-6 alkyl optionally substituted with phenyl. In certain embodiments, R⁹ is C1-6 alkyl substituted with phenyl. [0111] In certain embodiments, R⁹ is C1-6 alkyl. In certain embodiments, R⁹ is C1-4 alkyl. In certain embodiments, R⁹ is C1-2 alkyl or C4-6 alkyl. In certain embodiments, R⁹ is methyl, ethyl, or C₄ alkyl. In certain embodiments, R⁹ is methyl, ethyl, or isopropyl. In certain embodiments, R⁹ is methyl or ethyl. In certain embodiments, R⁹ is ethyl or isopropyl. [0112] In certain embodiments, R⁹ is C_2-6 alkenyl. [0113] In certain embodiments, R⁹ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0114] As defined generally above, R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl. In certain embodiments, R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, or C1-4 haloalkyl. [0115] In certain embodiments, R¹⁰ represents independently for each occurrence halo. In certain embodiments, R¹⁰ represents independently for each occurrence fluoro, chloro, or bromo. In certain embodiments, R¹⁰ is bromo. In certain embodiments, R¹⁰ represents independently for each occurrence C1-4 alkyl. In certain embodiments, R¹⁰ represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R¹⁰ represents independently for each occurrence C_1-4 alkoxyl. In certain embodiments, R¹⁰ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0116] As defined generally above, R¹¹ is hydrogen, halo, -CH₃, or -CF₃. [0117] In some embodiments, R¹¹ is hydrogen, fluoro, -CH₃, or -CF₃. In some embodiments, R¹¹ is halo, -CH₃, or -CF₃. In some embodiments, R¹¹ is hydrogen, -CH₃, or -CF₃. In some embodiments, R¹¹ is hydrogen, halo, or -CF3. In some embodiments, R¹¹ is hydrogen, halo, or - CH3. In some embodiments, R¹¹ is -CH3 or -CF3. In some embodiments, R¹¹ is hydrogen or halo. In some embodiments, R¹¹ is hydrogen or fluoro. In some embodiments, R¹¹ is hydrogen or - CH3. In some embodiments, R¹¹ is hydrogen or -CF3. In some embodiments, R¹¹ is halo or -CF3. In some embodiments, R¹¹ is halo or -CH₃. [0118] In some embodiments, R¹¹ is hydrogen. In some embodiments, R¹¹ is halo. In some embodiments, R¹¹ is chloro, bromo, or fluoro. In some embodiments, R¹¹ is bromo or fluoro. In some embodiments, R¹¹ is chloro or fluoro. In some embodiments, R¹¹ is chloro or bromo. In some embodiments, R¹¹ is chloro. In some embodiments, R¹¹ is bromo. In some embodiments, R¹¹ is fluoro. In some embodiments, R¹¹ is -CH3. In some embodiments, R¹¹ is -CF3. In certain embodiments, R¹¹ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0119] As defined generally above,

. some embodiments, B¹ is

. In some embodiments,

. [0120] In some embodiments, B¹ is

, and R¹¹ is hydrogen or halo. In some embodiments,

certain embodiments, B¹ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0121] 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 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Tables 1, 2, and 3, below. [0122] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments. [0123] Another aspect of the disclosure provides a compound represented by Formula I-A:

or a pharmaceutically acceptable salt thereof; wherein: R² is fluoro, hydrogen, or -OH; R³ is -CH₂Cl or -CH₂F; R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰; R⁶ is hydrogen or C_1-4 alkyl; R⁷ is -C(R⁸)₂-CO₂R⁹; R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl; R¹¹ is hydrogen, halo, -CH3, or -CF3;

m is 0, 1, 2, or 3. [0124] The definitions of variables in Formula I-A above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0125] In certain embodiments, the compound is a compound of Formula I-A. [0126] As defined generally above, R² is fluoro, hydrogen, or -OH. In some embodiments, R² is fluoro or hydrogen. In some embodiments, R² is hydrogen or -OH. In some embodiments, R² is fluoro or -OH. In some embodiments, R² is fluoro. In some embodiments, R² is hydrogen. In some embodiments, R² is -OH. In certain embodiments, R² is selected from the groups depicted in the compounds in Table 1, below. [0127] As defined generally above, R³ is -CH2Cl or CH2F. In some embodiments, R³ is - CH2Cl. In some embodiments, R³ is -CH2F. In certain embodiments, R³ is selected from the groups depicted in the compounds in Table 1, below. [0128] As defined generally above, R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰. In certain embodiments, R⁵ is phenyl or naphthyl. [0129] In certain embodiments, R⁵ is phenyl substituted with m instances of R¹⁰. In certain embodiments, R⁵ is naphthyl substituted with m instances of R¹⁰. In certain embodiments, R⁵ is

. [0130] In certain embodiments, R⁵ is phenyl. In certain embodiments, R⁵ is naphthyl. In certain embodiments, R⁵ is 1-naphthyl. In certain embodiments, R⁵ is 2-naphthyl. In certain embodiments, R⁵ is selected from the groups depicted in the compounds in Table 1, below. [0131] As defined generally above, R⁶ is hydrogen or C_1-4 alkyl. In certain embodiments, R⁶ is hydrogen or methyl. [0132] In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is C1-4 alkyl. In certain embodiments, R⁶ is C2-4 alkyl. In certain embodiments, R⁶ is methyl. In certain embodiments, R⁶ is selected from the groups depicted in the compounds in Table 1, below. [0133] As defined generally above, R⁷ is -C(R⁸)2-CO2R⁹. In certain embodiments, R⁷ is - C(H)(R⁸)-CO2R⁹.

. In certain embodiments,

. In certain embodiments,

certain embodiments,

[0137] In certain embodiments, R⁷ is

. In certain embodiments, R⁷ is

. , . certain embodiments, R⁷ n embodiments, R⁷ is

. In certain embodiments, R⁷ is certain embodiments, R⁷ is

. In certain embodiments, R⁷ is

. ce a embodiments,

. [0138] In certain embodiments, R⁷ is selected from the groups depicted in the compounds in Table 1, below. [0139] As defined generally above, R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. [0140] In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl. In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl; wherein said C_1-6 alkyl is optionally substituted with phenyl. [0141] In certain embodiments, R⁸ represents independently for each occurrence methyl, benzyl, or hydrogen. In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl optionally substituted with phenyl. In certain embodiments, R⁸ represents independently for each occurrence methyl or benzyl. In certain embodiments, R⁸ represents independently for each occurrence benzyl or hydrogen. [0142] In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. [0143] In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen. In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C_1-4 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C_1-3 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C_2-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C3-6 alkyl. [0144] In certain embodiments, one occurrence of R⁸ is C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is C1-6 alkyl optionally substituted with phenyl, and the other occurrence of R⁸ is hydrogen. [0145] In certain embodiments, one occurrence of R⁸ is C_1-6 alkyl or hydrogen, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is C_1-4 alkyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is methyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, R⁸ is methyl. In certain embodiments, R⁸ is hydrogen. [0146] In certain embodiments, two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. In certain embodiments, two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-membered saturated carbocyclic ring. [0147] In certain embodiments, R⁸ is selected from the groups depicted in the compounds in Table 1, below. [0148] As defined generally above, R⁹ is C_1-6 alkyl or C_2-6 alkenyl; wherein said C_1-6 alkyl is optionally substituted with phenyl. [0149] In certain embodiments, R⁹ is C_1-6 alkyl, allyl, or -CH₂-phenyl. In certain embodiments, R⁹ is allyl or -CH₂-phenyl. In certain embodiments, R⁹ is allyl. In certain embodiments, R⁹ is -CH2-phenyl. [0150] In certain embodiments, R⁹ is C1-6 alkyl or C2-6 alkenyl. [0151] In certain embodiments, R⁹ is C1-6 alkyl optionally substituted with phenyl. In certain embodiments, R⁹ is C1-6 alkyl substituted with phenyl. [0152] In certain embodiments, R⁹ is C1-6 alkyl. In certain embodiments, R⁹ is C1-4 alkyl. In certain embodiments, R⁹ is C1-2 alkyl or C4-6 alkyl. In certain embodiments, R⁹ is methyl, ethyl, or C₄ alkyl. In certain embodiments, R⁹ is methyl, ethyl, or isopropyl. In certain embodiments, R⁹ is methyl or ethyl. In certain embodiments, R⁹ is ethyl or isopropyl. [0153] In certain embodiments, R⁹ is C_2-6 alkenyl. [0154] In certain embodiments, R⁹ is selected from the groups depicted in the compounds in Table 1, below. [0155] As defined generally above, R¹⁰ represents independently for each occurrence halo, C_1-4 alkyl, C_1-4 haloalkyl, or C_1-4 alkoxyl. In certain embodiments, R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, or C1-4 haloalkyl. [0156] In certain embodiments, R¹⁰ represents independently for each occurrence halo. In certain embodiments, R¹⁰ represents independently for each occurrence fluoro, chloro, or bromo. In certain embodiments, R¹⁰ is bromo. In certain embodiments, R¹⁰ represents independently for each occurrence C_1-4 alkyl. In certain embodiments, R¹⁰ represents independently for each occurrence C_1-4 haloalkyl. In certain embodiments, R¹⁰ represents independently for each occurrence C_1-4 alkoxyl. In certain embodiments, R¹⁰ is selected from the groups depicted in the compounds in Table 1, below. [0157] As defined generally above, R¹¹ is hydrogen, halo, -CH₃, or -CF_3. [0158] In some embodiments, R¹¹ is hydrogen, fluoro, -CH₃, or -CF₃. In some embodiments, R¹¹ is halo, -CH3, or -CF3. In some embodiments, R¹¹ is hydrogen, -CH3, or -CF3. In some embodiments, R¹¹ is hydrogen, halo, or -CF3. In some embodiments, R¹¹ is hydrogen, halo, or - CH3. In some embodiments, R¹¹ is -CH3 or -CF3. In some embodiments, R¹¹ is hydrogen or halo. In some embodiments, R¹¹ is hydrogen or fluoro. In some embodiments, R¹¹ is hydrogen or - CH₃. In some embodiments, R¹¹ is hydrogen or -CF₃. In some embodiments, R¹¹ is halo or -CF₃. In some embodiments, R¹¹ is halo or -CH₃. [0159] In some embodiments, R¹¹ is hydrogen. In some embodiments, R¹¹ is halo. In some embodiments, R¹¹ is chloro, bromo, or fluoro. In some embodiments, R¹¹ is bromo or fluoro.. In some embodiments, R¹¹ is chloro or fluoro. In some embodiments, R¹¹ is chloro or bromo. In some embodiments, R¹¹ is chloro. In some embodiments, R¹¹ is bromo. In some embodiments, R¹¹ is fluoro. In some embodiments, R¹¹ is -CH₃. In some embodiments, R¹¹ is -CF₃. In certain embodiments, R¹¹ is selected from the groups depicted in the compounds in Table 1, below. [0160] As defined generally above,

. some embodiments, B¹ is

. In some embodiments,

. [0161] In some embodiments, B¹ is

and R¹¹ is hydrogen or halo. In some

[0162] 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 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Table 1, below. [0163] The description above describes multiple embodiments relating to compounds of Formula I-A. The patent application specifically contemplates all combinations of the embodiments. [0164] Another aspect of the disclosure provides a compound represented by Formula I-B:

or a pharmaceutically acceptable salt thereof; wherein: R² is fluoro, hydrogen, or -OH; R³ is -CH₂Cl or -CH₂F; R⁴ represents independently for each occurrence C_1-6 alkyl, -(C_1-4 alkylene)-OC(O)O-(C_1- 10 alkyl), or hydrogen; R¹¹ is hydrogen, halo, -CH3, or -CF3; and

. [0165] The definitions of variables in Formula I-B above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0166] In certain embodiments, the compound is a compound of Formula I-B. [0167] As defined generally above, R² is fluoro, hydrogen, or -OH. In some embodiments, R² is fluoro or hydrogen. In some embodiments R² is hydrogen or -OH. In some embodiments, R² is fluoro or -OH. In some embodiments, R² is fluoro. In some embodiments. R² is hydrogen. In some embodiments, R² is -OH. In certain embodiments, R² is selected from the groups depicted in the compounds in Table 2, below. [0168] As defined generally above, R³ is -CH2Cl or -CH2F. In some embodiments, R³ is - CH2Cl. In some embodiments, R³ is -CH2F. In certain embodiments, R³ is selected from the groups depicted in the compounds in Table 2, below. [0169] As defined generally above, R⁴ represents independently for each occurrence C1-6 alkyl, -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl), or hydrogen. In some embodiments, R⁴ represents independently for each occurrence C_1-6 alkyl or -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl. In some embodiments, R⁴ represents independently for each occurrence C_1-6 alkyl or hydrogen. In some embodiments, R⁴ represents independently for each occurrence -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl) or hydrogen. [0170] In some embodiments, R⁴ represents independently for each occurrence C1-6 alkyl. In some embodiments, R⁴ represents independently for each occurrence C1-4 alkyl. In some embodiments, R⁴ represents independently for each occurrence C3-6 alkyl. [0171] In some embodiments, R⁴ represents independently for each occurrence -(C1-4 alkylene)-OC(O)O-(C_1-10 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C_1-4 alkylene)-OC(O)O-(C_1-6 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C_1-4 alkylene)-OC(O)O-(C_6-10 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C1-2 alkylene)-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ represents independently for each occurrence -CH2-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C1-2 alkylene)-OC(O)O- (C6-10 alkyl). In some embodiments, R⁴ represents independently for each occurrence -(C2-4 alkylene)-OC(O)O-(C_1-10 alkyl). [0172] In some embodiments, R⁴ is C1-6 alkyl. In some embodiments, R⁴ is C1-4 alkyl. In some embodiments, R⁴ is C_3-6 alkyl. [0173] In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl). In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C_1-6 alkyl). In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C6-10 alkyl). In some embodiments, R⁴ is -(C1-2 alkylene)-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ is -CH2-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ is -(C1- 2 alkylene)-OC(O)O-(C6-10 alkyl). In some embodiments, R⁴ is -(C2-4 alkylene)-OC(O)O-(C1-10 alkyl). In certain embodiments, R⁴ is selected from the groups depicted in the compounds in Table 2, below. [0174] As defined generally above, R¹¹ is hydrogen, halo, -CH3, or -CF3. [0175] In some embodiments, R¹¹ is hydrogen, fluoro, -CH3, or -CF3. In some embodiments, R¹¹ is halo, -CH3, or -CF3. In some embodiments, R¹¹ is hydrogen, -CH3, or -CF3. In some embodiments, R¹¹ is hydrogen, halo, or -CF3. In some embodiments, R¹¹ is hydrogen, halo, or - CH₃. In some embodiments, R¹¹ is -CH₃ or -CF₃. In some embodiments, R¹¹ is hydrogen or halo. In some embodiments, R¹¹ is hydrogen or fluoro. In some embodiments, R¹¹ is hydrogen or - CH₃. In some embodiments, R¹¹ is hydrogen or -CF₃. In some embodiments, R¹¹ is halo or -CF₃. In some embodiments, R¹¹ is halo or -CH₃. [0176] In some embodiments, R¹¹ is hydrogen. In some embodiments, R¹¹ is halo. In some embodiments, R¹¹ is chloro, bromo, or fluoro. In some embodiments, R¹¹ is bromo or fluoro. In some embodiments, R¹¹ is chloro or fluoro. In some embodiments, R¹¹ is chloro or bromo. In some embodiments, R¹¹ is chloro. In some embodiments, R¹¹ is bromo. In some embodiments, R¹¹ is fluoro. In some embodiments, R¹¹ is -CH₃. In some embodiments, R¹¹ is -CF₃. In certain embodiments, R¹¹ is selected from the groups depicted in the compounds in Table 2, below. [0177] As defined generally above,

. some embodiments, B¹ is

. In some embodiments,

. In some embodiments, B¹ is

, and R¹¹ is hydrogen or halo_. In some embodiments,

certain embodiments, B¹ is selected from the groups depicted in the compounds in Table 2, below. [0178] The description above describes multiple embodiments relating to compounds of Formula I-B. The patent application specifically contemplates all combinations of the embodiments. [0179] In certain embodiments, the present disclosure provides a compound of Formula I-C:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², and B¹ is as defined in embodiments of Formula I herein, both singly and in combination. [0180] In certain embodiments, the present disclosure provides a compound of Formula I-D or I-E:

(I-D) (I-E) or a pharmaceutically acceptable salt thereof, wherein each of R¹, R³, and B¹ is as defined in embodiments of Formula I herein, both singly and in combination. [0181] In certain embodiments, the present disclosure provides a compound of Formula I-F or I-G:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, and R¹¹ is as defined in embodiments of Formula I herein, both singly and in combination. [0182] In certain embodiments, the present disclosure provides a compound of Formula I-J, I-K, I-L, or I-M:

(I-L) (I-M) or a pharmaceutically acceptable salt thereof, wherein each of R¹ and R¹¹ is as defined in embodiments of Formula I herein, both singly and in combination. [0183] In certain embodiments, the present disclosure provides a compound of Formula I-A- 1, I-A-2, I-A-3, I-A-4, I-A-5, I-A-6, I-A-7, I-A-8, or I-A-9:

(I-A-2) (I-A-3)

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁵, R⁶, R⁷, R¹¹, and B¹ is as defined in embodiments of Formula I-A herein, both singly and in combination. [0184] In certain embodiments, the present disclosure provides a compound of Formula I-B- 1, I-B-2, I-B-3, I-B-4, I-B-5, I-B-6, I-B-7, I-B-8, or I-B-9:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R¹¹, and B¹ is as defined in embodiments of Formula I-B herein, both singly and in combination. [0185] Another aspect of the disclosure provides a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -OR⁴ or -N(R⁶)(R⁷); R² is halo, hydrogen, or -OH; R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, -CF3, or C1-3 aliphatic; R⁴ is C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl), or hydrogen; R⁵ is hydrogen, halo, -CH3, or -CF3; R⁶ is hydrogen or C1-4 alkyl; R⁷ is -C(R⁸)2-CO2R⁹; R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C_1-6 alkyl or C_2-6 alkenyl; wherein said C_1-6 alkyl is optionally substituted with phenyl; and

. [0186] The definitions of variables in Formula II above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0187] In certain embodiments, the compound is a compound of Formula II. [0188] As defined generally above, R¹ is -OR⁴ or -N(R⁶)(R⁷). In certain embodiments, R¹ is -OR⁴. In certain embodiments, R¹ is -N(R⁶)(R⁷). In certain embodiments, R¹ is selected from the groups depicted in the compounds in Table 4, below. [0189] As defined generally above, R² is halo, hydrogen, or -OH. In some embodiments, R² is halo or hydrogen. In some embodiments, R² is hydrogen or -OH. In some embodiments, R² is halo or -OH. In some embodiments, R² is -OH. In some embodiments, R² is fluoro, hydrogen, or -OH. In some embodiments, R² is fluoro or hydrogen. [0190] In some embodiments, R² is halo. In some embodiments, R² is chloro, fluoro, or bromo. In some embodiments R² is chloro. In some embodiments, R² is fluoro. In some embodiments, R² is bromo. In some embodiments, R² is hydrogen. In some embodiments, R² is - OH. In certain embodiments, R² is selected from the groups depicted in the compounds in Table 4, below. [0191] As defined generally above, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, -CF₃, or C_1-3 aliphatic. In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, or -CF₃. In some embodiments, R³ is -CH₂F or -CF₃. In some embodiments, R³ is -CH₂Cl or -CH₂F. [0192] In some embodiments, R³ is C_1-3 aliphatic. In some embodiments, R³ is C_2-3 aliphatic. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, -C≡CH, or cyclopropyl. In some embodiments, R³ is -CH3, -CH2CH3, -C(H)=CH2, -CH2C(H)=CH2, or - C≡CH. In some embodiments, R³ is -CH3 or -CH2CH3. In some embodiments, R³ is -C(H)=CH2, -CH2C(H)=CH2, or -C≡CH. In some embodiments, R³ is -CH3. In some embodiments, R³ is - CH₂CH₃. In some embodiments, R³ is -C(H)=CH₂. In some embodiments, R³ is -CH₂C(H)=CH₂. In some embodiments, R³ is -C≡CH. In some embodiments, R³ is cyclopropyl. [0193] In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, or -CH₂I. In some embodiments, R³ is -CH₂Cl. In some embodiments, R³ is-CH₂F. In some embodiments, R³ is- CH₂Br. In some embodiments, R³ is-CH₂I. In some embodiments, R³ is -CF₃. In certain embodiments, R³ is selected from the groups depicted in the compounds in Table 4, below. [0194] As defined generally above, R⁴ is C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl), or hydrogen. In some embodiments, R⁴ is C1-6 alkyl or -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl. In some embodiments, R⁴ is C1-6 alkyl or hydrogen. In some embodiments, R⁴ is -(C1-4 alkylene)- OC(O)O-(C_1-10 alkyl) or hydrogen. [0195] In some embodiments, R⁴ is C_1-6 alkyl. In some embodiments, R⁴ is C_1-4 alkyl. In some embodiments, R⁴ is C_3-6 alkyl. [0196] In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl). In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C_1-6 alkyl). In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C6-10 alkyl). In some embodiments, R⁴ is -(C1-2 alkylene)-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ is -CH2-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ is -(C1- 2 alkylene)-OC(O)O-(C6-10 alkyl). In some embodiments, R⁴ is -(C2-4 alkylene)-OC(O)O-(C1-10 alkyl). In certain embodiments, R⁴ is selected from the groups depicted in the compounds in Table 4, below. [0197] As defined generally above, R⁵ is hydrogen, halo, -CH₃, or -CF₃. [0198] In some embodiments, R⁵ is hydrogen, fluoro, -CH₃, or -CF₃. In some embodiments, R⁵ is halo, -CH₃, or -CF₃. In some embodiments, R⁵ is hydrogen, -CH₃, or -CF₃. In some embodiments, R⁵ is hydrogen, halo, or -CF₃. In some embodiments, R⁵ is hydrogen, halo, or - CH₃. In some embodiments, R⁵ is -CH₃ or -CF₃. In some embodiments, R⁵ is hydrogen or halo. In some embodiments, R⁵ is hydrogen or fluoro. In some embodiments, R⁵ is hydrogen or -CH3. In some embodiments, R⁵ is hydrogen or -CF3. In some embodiments, R⁵ is halo or -CF3. In some embodiments, R⁵ is halo or -CH3. [0199] In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is halo. In some embodiments, R⁵ is chloro, bromo, or fluoro. In some embodiments, R⁵ is bromo or fluoro. In some embodiments, R⁵ is chloro or fluoro. In some embodiments, R⁵ is chloro or bromo. In some embodiments, R⁵ is chloro. In some embodiments, R⁵ is bromo. In some embodiments, R⁵ is fluoro. In some embodiments, R⁵ is -CH3. In some embodiments, R⁵ is -CF3. In certain embodiments, R⁵ is selected from the groups depicted in the compounds in Table 4, below. [0200] As defined generally above, R⁶ is hydrogen or C1-4 alkyl. In certain embodiments, R⁶ is hydrogen or methyl. In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is C1-4 alkyl. In certain embodiments, R⁶ is methyl. In certain embodiments, R⁶ is selected from the groups depicted in the compounds in Table 4, below. [0201] As defined generally above, R⁷ is -C(R⁸)2-CO2R⁹. In certain embodiments, R⁷ is - C(H)(R⁸)-CO2R⁹.

embodiments,

[0204] In certain embodiments,

,

certain embodiments,

. [0205] In certain embodiments, R⁷ is . In certain embodiments, R⁷ is . In certain embodiments, R⁷ is . In certain embodiments, R⁷

is

. In certain embodiments, R⁷ is

. In certain embodiments, R⁷ is

. , . [0206] In certain embodiments, R⁷ is selected from the groups depicted in the compounds in Table 4, below. [0207] As defined generally above, R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. [0208] In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl. In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl; wherein said C1-6 alkyl is optionally substituted with phenyl. [0209] In certain embodiments, R⁸ represents independently for each occurrence methyl, benzyl, or hydrogen. In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl optionally substituted with phenyl. In certain embodiments, R⁸ represents independently for each occurrence methyl or benzyl. In certain embodiments, R⁸ represents independently for each occurrence benzyl or hydrogen. [0210] In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. [0211] In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen. In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C1-4 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C1-3 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C_2-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C_3-6 alkyl. [0212] In certain embodiments, one occurrence of R⁸ is C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is C1-6 alkyl optionally substituted with phenyl, and the other occurrence of R⁸ is hydrogen. [0213] In certain embodiments, one occurrence of R⁸ is C1-6 alkyl or hydrogen, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is C1-4 alkyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is methyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, R⁸ is methyl. In certain embodiments, R⁸ is hydrogen. [0214] In certain embodiments, two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. In certain embodiments, two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-membered saturated carbocyclic ring. [0215] In certain embodiments, R⁸ is selected from the groups depicted in the compounds in Table 4, below. [0216] As defined generally above, R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl. [0217] In certain embodiments, R⁹ is C_1-6 alkyl, allyl, or -CH₂-phenyl. In certain embodiments, R⁹ is allyl or -CH₂-phenyl. In certain embodiments, R⁹ is allyl. In certain embodiments, R⁹ is -CH₂-phenyl. [0218] In certain embodiments, R⁹ is C_1-6 alkyl or C_2-6 alkenyl. [0219] In certain embodiments, R⁹ is C_1-6 alkyl optionally substituted with phenyl. In certain embodiments, R⁹ is C_1-6 alkyl substituted with phenyl. [0220] In certain embodiments, R⁹ is C_1-6 alkyl. In certain embodiments, R⁹ is C_1-4 alkyl. In certain embodiments, R⁹ is C1-2 alkyl or C4-6 alkyl. In certain embodiments, R⁹ is methyl, ethyl, or C4 alkyl. In certain embodiments, R⁹ is methyl, ethyl, or isopropyl. In certain embodiments, R⁹ is methyl or ethyl. In certain embodiments, R⁹ is ethyl or isopropyl. [0221] In certain embodiments, R⁹ is C2-6 alkenyl. [0222] In certain embodiments, R⁹ is selected from the groups depicted in the compounds in Table 4, below. [0223] As defined generally above,

. embodiments, B¹ is

. In some embodiments,

. [0224] In some embodiments, B¹ is

, and R⁵ is hydrogen or halo. In some embodiments, B¹ is , and R⁵ is -CH3 or -CF3. In certain embodiments, B¹ is selected from the groups depicted in the compounds in Table 4, below. [0225] 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 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Table 4, below. [0226] The description above describes multiple embodiments relating to compounds of Formula II. The patent application specifically contemplates all combinations of the embodiments. [0227] In certain embodiments, the present disclosure provides a compound of Formula II-A or II-B:

or a pharmaceutically acceptable salt thereof, wherein each of R², R³, R⁴, R⁶, R⁷, and B¹ is as defined in embodiments of Formula II herein, both singly and in combination. [0228] In certain embodiments, the present disclosure provides a compound of Formula II-C:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², and B¹ is as defined in embodiments of Formula II herein, both singly and in combination. [0229] In certain embodiments, the present disclosure provides a compound of Formula II-D or II-E:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R³, and B¹ is as defined in embodiments of Formula II herein, both singly and in combination. [0230] In certain embodiments, the present disclosure provides a compound of Formula II-F or II-G:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, and R⁵ is as defined in embodiments of Formula II herein, both singly and in combination. [0231] In certain embodiments, the present disclosure provides a compound of Formula II-J, II-K, II-L, or II-M:

(II-L) (II-M) or a pharmaceutically acceptable salt thereof, wherein each of R⁴ and R⁵ is as defined in embodiments of Formula II herein, both singly and in combination. [0232] In certain embodiments, the present disclosure provides a compound of Formula II-N, II-O, II-P, or II-Q:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and R¹¹ is as defined in embodiments of Formula II herein, both singly and in combination. [0233] Another aspect of the disclosure provides a compound represented by Formula V:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)) or -P(O)(OR⁴)₂; R² is halo, hydrogen, or -OH; R³ is halomethyl or C_1-3 aliphatic; R⁴ represents independently for each occurrence C_1-6 alkyl, -(C_1-4 alkylene)-OC(O)O-(C_1- 10 alkyl), or hydrogen; R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰; R⁶ is hydrogen or C1-4 alkyl; R⁷ is -C(R⁸)₂-CO₂R⁹; R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl; R¹¹ is hydrogen, halo, -CH3, or -CF3;

m is 0, 1, 2, or 3; provided that if R⁶ is hydrogen and R⁷ is

, then m is 1, 2, or 3. [0234] The definitions of variables in Formula V above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0235] In certain embodiments, the compound is a compound of Formula V. [0236] As defined generally above, R³ is halomethyl or C_1-3 aliphatic. In certain embodiments, R³ is halomethyl. In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, - CHF₂, -CF₃, or C_1-3 aliphatic. In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, - CHF₂, or -CF₃. In some embodiments, R³ is -CH₂F, -CHF₂, or -CF₃. In some embodiments, R³ is -CH2Cl or -CH2F. In some embodiments, R³ is -CHF2 or -CH2F. [0237] In some embodiments, R³ is C1-3 aliphatic. In some embodiments, R³ is C2-3 aliphatic. In some embodiments, R³ is -CH3, -CH2CH3, -C(H)=CH2, -CH2C(H)=CH2, -C≡CH, or cyclopropyl. In some embodiments, R³ is -CH3, -CH2CH3, -C(H)=CH2, -CH2C(H)=CH2, or - C≡CH. In some embodiments, R³ is -CH₃ or -CH₂CH₃. In some embodiments, R³ is -C(H)=CH₂, -CH₂C(H)=CH₂, or -C≡CH. In some embodiments, R³ is -CH₃. In some embodiments, R³ is - CH2CH3. In some embodiments, R³ is -C(H)=CH2. In some embodiments, R³ is -CH2C(H)=CH2. In some embodiments, R³ is -C≡CH. In some embodiments, R³ is cyclopropyl. [0238] In some embodiments, R³ is -CH2Cl, -CH2F, -CH2Br, or -CH2I. In some embodiments, R³ is -CH2Cl. In some embodiments, R³ is-CH2F. In some embodiments, R³ is- CH₂Br. In some embodiments, R³ is-CH₂I. In certain embodiments, R³ is -CHF₂. In some embodiments, R³ is -CF₃. In certain embodiments, R³ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0239] As defined generally above, m is 0, 1, 2, or 3; provided that if R⁶ is hydrogen and R⁷ is

, then m is 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 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments m is 1, 2, or 3. [0240] In certain embodiments, m is 0, 1, 2, or 3; and R⁶ is C1-4 alkyl. In certain embodiments, m is 0, 1, 2, or 3; and R⁷ is not

. In certain embodiments, m is 0, 1, 2, or 3; and R⁸ represents independently for each occurrence C_2-6 alkyl or hydrogen. In certain embodiments, m is 0, 1, 2, or 3; and R⁹ is -CH3, -CH2CH3, C4-6 alkyl, or C2-6 alkenyl. [0241] In certain embodiments, m is 0; and R⁶ is C_1-4 alkyl. In certain embodiments, m is 0; and R⁷ is not

. In certain embodiments, m is 0; and R⁸ represents independently for each occurrence C2-6 alkyl or hydrogen. In certain embodiments, m is 0; and R⁹ is -CH3, - CH2CH3, -CH2CH2CH3, C4-6 alkyl, or C2-6 alkenyl. [0242] Additionally, embodiments described above for variables R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ of Formula I also apply to compounds of Formula V, both singly and in combination. For example, in certain embodiments, R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)). As another example, in certain embodiments, R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)), R² is fluoro or hydrogen, and R³ is -CHF2. [0243] The description above describes multiple embodiments relating to compounds of Formula V. The patent application specifically contemplates all combinations of the embodiments. [0244] Another aspect of the disclosure provides a compound represented by Formula VI:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -OR⁴ or -N(R⁶)(R⁷); R² is halo, hydrogen, or -OH; R³ is halomethyl or C_1-3 aliphatic; R⁴ is -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, C_4-6 alkyl, -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl), or hydrogen; R⁵ is hydrogen, halo, -CH₃, or -CF₃; R⁶ is hydrogen or C_1-4 alkyl; R⁷ is -C(R⁸)₂-CO₂R⁹; R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; and

. [0245] The definitions of variables in Formula VI above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0246] In certain embodiments, the compound is a compound of Formula VI. [0247] As defined generally above, R³ is halomethyl or C1-3 aliphatic. In certain embodiments, R³ is halomethyl. In some embodiments, R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, - CHF2, -CF3, or C1-3 aliphatic. In some embodiments, R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, - CHF₂, or -CF₃. In some embodiments, R³ is -CH₂F, -CHF₂, or -CF₃. In some embodiments, R³ is -CH₂Cl or -CH₂F. In some embodiments, R³ is -CHF₂ or -CH₂F. [0248] In some embodiments, R³ is C_1-3 aliphatic. In some embodiments, R³ is C_2-3 aliphatic. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, -C≡CH, or cyclopropyl. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, or - C≡CH. In some embodiments, R³ is -CH3 or -CH2CH3. In some embodiments, R³ is -C(H)=CH2, -CH2C(H)=CH2, or -C≡CH. In some embodiments, R³ is -CH3. In some embodiments, R³ is - CH2CH3. In some embodiments, R³ is -C(H)=CH2. In some embodiments, R³ is -CH2C(H)=CH2. In some embodiments, R³ is -C≡CH. In some embodiments, R³ is cyclopropyl. [0249] In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, or -CH₂I. In some embodiments, R³ is -CH₂Cl. In some embodiments, R³ is-CH₂F. In some embodiments, R³ is- CH₂Br. In some embodiments, R³ is-CH₂I. In certain embodiments, R³ is -CHF₂. In some embodiments, R³ is -CF3. In certain embodiments, R³ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0250] As defined generally above, R⁴ is -CH3, -CH2CH3, -CH2CH2CH3, C4-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl), or hydrogen. In some embodiments, R⁴ is -CH3, -CH2CH3, - CH2CH2CH3, C4-6 alkyl, or -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl. In some embodiments, R⁴ is - CH3, -CH2CH3, -CH2CH2CH3, C4-6 alkyl, or hydrogen. In some embodiments, R⁴ is -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl) or hydrogen. [0251] In some embodiments, R⁴ is -CH3, -CH2CH3, -CH2CH2CH3, or C4-6 alkyl. In some embodiments, R⁴ is -CH₃, -CH₂CH₃, or -CH₂CH₂CH₃. In some embodiments, R⁴ is -CH₃. In some embodiments, R⁴ is -CH₂CH₃. In some embodiments, R⁴ is -CH₂CH₂CH₃. In some embodiments, R⁴ is C_4-6 alkyl. [0252] In some embodiments, R⁴ is -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl). In some embodiments, R⁴ is -(C1-4 alkylene)-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ is -(C1-4 alkylene)-OC(O)O-(C6-10 alkyl). In some embodiments, R⁴ is -(C1-2 alkylene)-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ is -CH2-OC(O)O-(C1-6 alkyl). In some embodiments, R⁴ is -(C1- 2 alkylene)-OC(O)O-(C6-10 alkyl). In some embodiments, R⁴ is -(C2-4 alkylene)-OC(O)O-(C1-10 alkyl). [0253] Additionally, embodiments described above for variables R¹, R², R⁵, R⁶, R⁷, R⁸, R⁹, and B¹ of Formula II also apply to compounds of Formula VI, both singly and in combination. For example, in certain embodiments, R¹ is -OR⁴. As another example, in certain embodiments, R² is -N(R⁶)(R⁷), R² is fluoro or hydrogen, and R³ is -CHF2. [0254] The description above describes multiple embodiments relating to compounds of Formula VI. The patent application specifically contemplates all combinations of the embodiments. [0255] Another aspect of the disclosure provides a compound represented by Formula VII:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)), -P(O)(OR⁵)(pyrrolidinyl substituted by -CO2-(C1-6 aliphatic)), or -P(O)(OR⁴)2; R² is halo, hydrogen, or -OH; R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, -CF3, C1-3 aliphatic, -N3, or hydrogen; R⁴ represents independently for each occurrence C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1- 10 alkyl), or hydrogen; R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰; R⁶ is hydrogen, C1-4 alkyl, or -C(R⁸)2-CO2R⁹; R⁷ is -C(R⁸)2-CO2R⁹; R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C_1-6 alkyl or C_2-6 alkenyl; wherein said C_1-6 alkyl is optionally substituted with phenyl; R¹⁰ represents independently for each occurrence halo, C_1-4 alkyl, C_1-4 haloalkyl, or C_1-4 alkoxyl; R¹¹ is hydrogen, halo, -CH₃, or -CF₃;

m is 0, 1, 2, or 3. [0256] The definitions of variables in Formula VII above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0257] In certain embodiments, the compound is a compound of Formula VII. [0258] As defined generally above, R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)), -P(O)(OR⁵)(pyrrolidinyl substituted by -CO2-(C1-6 aliphatic)), or -P(O)(OR⁴)2. In certain embodiments, R¹ is - P(O)(OR⁵)(N(R⁶)(R⁷)). In certain embodiments, R¹ is -P(O)(OR⁵)(pyrrolidinyl substituted by - CO₂-(C_1-6 aliphatic)). In certain embodiments, R¹ is -P(O)(OR⁴)₂. In certain embodiments, R¹ is selected from the groups depicted in the compounds in Table 7, below. [0259] As defined generally above, R² is halo, hydrogen, or -OH. In certain embodiments, R² is halo. In certain embodiments, R² is hydrogen. In certain embodiments, R² is -OH. In certain embodiments, R² is fluoro, hydrogen, or -OH. In certain embodiments, R² is selected from the groups depicted in the compounds in Table 7, below. [0260] As defined generally above, R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, -CF3, C1-3 aliphatic, -N3, or hydrogen. In certain embodiments, R³ is -CH2Cl. In certain embodiments, R³ is -CH2F. In certain embodiments, R³ is -CH2Br. In certain embodiments, R³ is -CH2I. In certain embodiments, R³ is -CF₃. In certain embodiments, R³ is C_1-3 aliphatic. In certain embodiments, R³ is -N₃. In certain embodiments, R³ is hydrogen. In certain embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, or -CF₃. In certain embodiments, R³ is -CH₂Cl or -CH₂F. In certain embodiments, R³ is C1-3 aliphatic. In certain embodiments, R³ is -CH3, -CH2CH3, - C(H)=CH2, -CH2C(H)=CH2, -C≡CH, or cyclopropyl. In certain embodiments, R³ is selected from the groups depicted in the compounds in Table 7, below. [0261] As defined generally above, R⁴ represents independently for each occurrence C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl), or hydrogen. In certain embodiments, R⁴ is C1-6 alkyl. In certain embodiments, R⁴ is -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl). In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is selected from the groups depicted in the compounds in Table 7, below. [0262] As defined generally above, R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰. In certain embodiments, R⁵ is phenyl is substituted with m instances of R¹⁰. In certain embodiments, R⁵ is naphthyl is substituted with m instances of R¹⁰. In certain embodiments, R⁵ is selected from the groups depicted in the compounds in Table 7, below. [0263] As defined generally above, R⁶ is hydrogen, C1-4 alkyl, or -C(R⁸)2-CO2R⁹. In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is C1-4 alkyl. In certain embodiments, R⁶ is C2-4 alkyl. In certain embodiments, R⁶ is methyl. In certain embodiments, R⁶ is -C(R⁸)2- CO₂R⁹. In certain embodiments, R⁶ is selected from the groups depicted in the compounds in Table 7, below. [0264] As defined generally above, R⁷ is -C(R⁸)₂-CO₂R⁹. In certain embodiments, R⁷ is -

embodiments,

[0266] In certain embodiments,

,

certain embodiments,

. [0267] In certain embodiments, R⁷ is . In certain embodiments, R⁷ is . In certain embodiments, R⁷ is . In certain embodiments, R⁷

is

. In certain embodiments, R⁷ is

. In certain embodiments, R⁷ is

. , . [0268] In certain embodiments, R⁷ is selected from the groups depicted in the compounds in Table 7, below. [0269] As defined generally above, R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. [0270] In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl. In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl; wherein said C1-6 alkyl is optionally substituted with phenyl. [0271] In certain embodiments, R⁸ represents independently for each occurrence methyl, benzyl, or hydrogen. In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl optionally substituted with phenyl. In certain embodiments, R⁸ represents independently for each occurrence methyl or benzyl. In certain embodiments, R⁸ represents independently for each occurrence benzyl or hydrogen. [0272] In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. [0273] In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen. In certain embodiments, R⁸ represents independently for each occurrence C1-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C1-4 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C1-3 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C_2-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence C_3-6 alkyl. [0274] In certain embodiments, one occurrence of R⁸ is C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is C1-6 alkyl optionally substituted with phenyl, and the other occurrence of R⁸ is hydrogen. [0275] In certain embodiments, one occurrence of R⁸ is C1-6 alkyl or hydrogen, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is C1-4 alkyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, one occurrence of R⁸ is methyl, and the other occurrence of R⁸ is hydrogen. In certain embodiments, R⁸ is methyl. In certain embodiments, R⁸ is hydrogen. [0276] In certain embodiments, two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. In certain embodiments, two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-membered saturated carbocyclic ring. [0277] In certain embodiments, R⁸ is selected from the groups depicted in the compounds in Table 7, below. [0278] As defined generally above, R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl. [0279] In certain embodiments, R⁹ is C_1-6 alkyl, allyl, or -CH₂-phenyl. In certain embodiments, R⁹ is allyl or -CH₂-phenyl. In certain embodiments, R⁹ is allyl. In certain embodiments, R⁹ is -CH₂-phenyl. [0280] In certain embodiments, R⁹ is C_1-6 alkyl or C_2-6 alkenyl. [0281] In certain embodiments, R⁹ is C_1-6 alkyl optionally substituted with phenyl. In certain embodiments, R⁹ is C_1-6 alkyl substituted with phenyl. [0282] In certain embodiments, R⁹ is C_1-6 alkyl. In certain embodiments, R⁹ is C_1-4 alkyl. In certain embodiments, R⁹ is C1-2 alkyl or C4-6 alkyl. In certain embodiments, R⁹ is methyl, ethyl, or C4 alkyl. In certain embodiments, R⁹ is methyl, ethyl, or isopropyl. In certain embodiments, R⁹ is methyl or ethyl. In certain embodiments, R⁹ is ethyl or isopropyl. [0283] In certain embodiments, R⁹ is C2-6 alkenyl. [0284] In certain embodiments, R⁹ is selected from the groups depicted in the compounds in Table 7, below. [0285] As defined generally above, R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl. In certain embodiments, R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, or C1-4 haloalkyl. [0286] In certain embodiments, R¹⁰ represents independently for each occurrence halo. In certain embodiments, R¹⁰ represents independently for each occurrence fluoro, chloro, or bromo. In certain embodiments, R¹⁰ is bromo. In certain embodiments, R¹⁰ represents independently for each occurrence C_1-4 alkyl. In certain embodiments, R¹⁰ represents independently for each occurrence C_1-4 haloalkyl. In certain embodiments, R¹⁰ represents independently for each occurrence C1-4 alkoxyl. In certain embodiments, R¹⁰ is selected from the groups depicted in the compounds in Table 7, below. [0287] As defined generally above, R¹¹ is hydrogen, halo, -CH3, or -CF3. [0288] In some embodiments, R¹¹ is hydrogen, fluoro, -CH3, or -CF3. In some embodiments, R¹¹ is halo, -CH3, or -CF3. In some embodiments, R¹¹ is hydrogen, -CH3, or -CF3. In some embodiments, R¹¹ is hydrogen, halo, or -CF₃. In some embodiments, R¹¹ is hydrogen, halo, or - CH₃. In some embodiments, R¹¹ is -CH₃ or -CF₃. In some embodiments, R¹¹ is hydrogen or halo. In some embodiments, R¹¹ is hydrogen or fluoro. In some embodiments, R¹¹ is hydrogen or - CH3. In some embodiments, R¹¹ is hydrogen or -CF3. In some embodiments, R¹¹ is halo or -CF3. In some embodiments, R¹¹ is halo or -CH3. [0289] In some embodiments, R¹¹ is hydrogen. In some embodiments, R¹¹ is halo. In some embodiments, R¹¹ is chloro, bromo, or fluoro. In some embodiments, R¹¹ is bromo or fluoro.. In some embodiments, R¹¹ is chloro or fluoro. In some embodiments, R¹¹ is chloro or bromo. In some embodiments, R¹¹ is chloro. In some embodiments, R¹¹ is bromo. In some embodiments, R¹¹ is fluoro. In some embodiments, R¹¹ is -CH₃. In some embodiments, R¹¹ is -CF₃. In certain embodiments, R¹¹ is selected from the groups depicted in the compounds in Table 7, below. [0290] As defined generally above,

. some embodiments, B¹ is

. In some embodiments,

. [0291] In some embodiments, B¹ is

and R¹¹ is hydrogen or halo. In some embodiments,

certain embodiments, B1 is selected from the groups depicted in the compounds in Table 7, below. [0292] 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 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Table 7, below. [0293] The description above describes multiple embodiments relating to compounds of Formula VII. The patent application specifically contemplates all combinations of the embodiments. [0294] Another aspect of the disclosure provides a compound in Table 1, 2, 3, 4, 5, 6 or 7 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, 5, 6 or 7 below. Another aspect of the disclosure provides a compound in Table 1, 2, 3, 4, or 5, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, or 5, below. In certain embodiments, the compound is a compound in Table 1, 2, or 3, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, or 3, below. In certain other embodiments, the compound is a compound in Table 1 or 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 or 2 below. In certain embodiments, the compound is a compound in Table 4 or 5, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4 or 5, below. [0295] In certain embodiments, the compound is a compound in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 below. In certain embodiments, the compound is a compound in Table 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 2 below. In certain embodiments, the compound is a compound in Table 3 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 3 below. In certain embodiments, the compound is a compound in Table 4 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4 below. In certain embodiments, the compound is a compound in Table 5 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 5 below.. In certain embodiments, the compound is a compound in Table 6 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 6 below.. In certain embodiments, the compound is a compound in Table 7 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 7 below. TABLE 1.

TABLE 2.

TABLE 3.

TABLE 4.

TABLE 5.

TABLE 6.

TABLE 7.

[0296] Methods for preparing compounds described herein are illustrated in the Examples below, and the following synthetic Schemes. The Schemes are given for the purpose of illustrating the disclosure and are not intended to limit the scope or spirit of the disclosure. Starting materials shown in the Schemes can be obtained from commercial sources or can be prepared based on procedures described in the literature. [0297] Strategies and procedures for preparing 4'-halomethyl-cytidines and related compounds (intermediates in the preparation of 4'-halomethyl-cytidine phosphoramidates and related compounds described herein), are described in, for example, WO 2016/100569, Sugimoto, I. et al. in Bioorganic & Medicinal Chemistry Letters, 1999, Vol.9, No.3, p. 385- 388, and Wang, Q. et al. in Bioorganic & Medicinal Chemistry Letters, 2010, Vol. 20, No.14, p. 4053-4056. Strategies and procedures for preparing phosphoramidate, and other phosphorous- containing, compounds described herein 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. Compounds in Table 6, above, can be prepared based on procedures described in, for example, WO 2015/120237. Each of the foregoing is hereby incorporated by reference in its entirety. [0298] The synthetic route illustrated in Scheme 1 is a general method for preparing 4'- halomethyl-cytidine cyclic phosphoramidates and related compounds C. Coupling phosphoramidite reagent R¹-P(LG)₂ (wherein each LG is a suitable leaving group, such as diisopropylamino) with diol A (using, for example, a base, such as 1H-tetrazole, in a solvent, such as pyridine) affords cyclic phosphite B. Oxidation of phosphite B (using, for example, an oxidant, such as tBuOOH, in a polar aprotic solvent, such as MeCN) affords 4'-halomethyl- cytidine cyclic phosphoramidates and related compounds C. SCHEME 1.

[0299] The synthetic route illustrated in Scheme 2 is a general method for preparing 4'- halomethyl-cytidine cyclic phosphates and related compounds E. Treating diol A with POCl₃ and a trialkyl phosphate, such as trimethyl or triethyl phosphate, followed by partial hydrolysis (using, for example, an inorganic base, such as KOH) affords cyclic hydrogen phosphate D. Condensation of electrophilic reagent R⁴-LG (wherein LG is a leaving group, such as a halide or sulfonate) with compound D (using, for example, a base, such as Et3N, and a catalyst, such as NaI, in a polar aprotic solvent, such as DMF) affords 4'-halomethyl-cytidine cyclic phosphates and related compounds E. SCHEME 2.

[0300] The synthetic route illustrated in Scheme 3 is a general method for preparing 4'- halomethyl-cytidine cyclic phosphoramidates and related compounds G. Phosphoramidite reagent F (wherein LG is a suitable leaving group, such as 4-nitrophenoxy) is prepared from POCl3, H-LG, and H-NR⁶R⁷ (using, for example, a base, such as TEA, in a polar aprotic solvent, such as Et₂O). Coupling diol A with phosphoramidite reagent F (using, for example, a base, such as DBU, in a polar aprotic solvent, such as THF) affords 4'-halomethyl-cytidine cyclic phosphoramidates and related compounds H. SCHEME 3. 6⁷ O HNR R POCl_{3 H LG} ^LG P L_G ^NR6R7 F

[0301] In the Schemes, 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, as described in certain Examples, below. [0302] 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 4'-halomethyl-cytidine phosphoramidates 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). II. Methods of Treating Medical Disorders [0303] Another aspect of the disclosure provides methods for treating medical disorders. This is described in more detail below. [0304] 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). [0305] 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. [0306] 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). [0307] 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)). [0308] 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)). [0309] 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. [0310] 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). [0311] 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. [0312] 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 [0313] 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 or II, to a subject in need thereof to treat the disorder. In certain embodiments, the particular compound of Formula I or II is a compound defined by embodiments described in Section I, above, either singly or in combination. [0314] In certain embodiments, the disorder is an immune disorder that is a viral infection. [0315] 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 [0316] 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 an influenza viral infection. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula III or Formula IV to treat the disorder; wherein Formula III is represented by:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)) or -P(O)(OR⁴)2; R² is halo, hydrogen, or -OH; R³ is C1-3 haloalkyl or C1-3 aliphatic; R⁴ represents independently for each occurrence C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1- 6 alkyl), or hydrogen; R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰; R⁶ is hydrogen or C1-4 alkyl; R⁷ is -C(R⁸)2-CO2R⁹; R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; R¹⁰ represents independently for each occurrence halo, C_1-4 alkyl, C_1-4 haloalkyl, or C_1-4 alkoxyl; R¹¹ is hydrogen, halo, -CH₃, or -CF₃;

m is 0, 1, 2, or 3; and wherein Formula IV is represented by:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -OR⁴ or -N(R⁶)(R⁷); R² is halo, hydrogen, or -OH; R³ is C1-3 haloalkyl or C1-3 aliphatic; R⁴ is C_1-6 alkyl, -(C_1-4 alkylene)-OC(O)O-(C_1-6 alkyl), or hydrogen; R⁵ is hydrogen, halo, -CH3, or -CF3; R⁶ is hydrogen or C_1-4 alkyl; R⁷ is -C(R⁸)₂-CO₂R⁹; R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen, wherein said C_1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ represents independently for each occurrence C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; and

. [0317] In certain embodiments, the disorder is an immune disorder other than an influenza viral infection. [0318] The definitions of variables in Formula III and Formula IV above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0319] In certain embodiments, the compound is a compound of Formula III, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula III. [0320] As defined generally above, R³ is C1-3 haloalkyl or C1-3 aliphatic. In certain embodiments, R³ is halomethyl or C1-3 aliphatic. In some embodiments, R³ is -CH2Cl, -CH2F, - CH₂Br, -CH₂I, -CHF₂, -CF₃, or C_1-3 aliphatic. [0321] In some embodiments, R³ is C_1-3 aliphatic. In some embodiments, R³ is C_2-3 aliphatic. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, -C≡CH, or cyclopropyl. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, or - C≡CH. In some embodiments, R³ is -CH₃ or -CH₂CH₃. In some embodiments, R³ is -C(H)=CH₂, -CH2C(H)=CH2, or -C≡CH. In some embodiments, R³ is -CH3. In some embodiments, R³ is - CH2CH3. In some embodiments, R³ is -C(H)=CH2. In some embodiments, R³ is -CH2C(H)=CH2. In some embodiments, R³ is -C≡CH. In some embodiments, R³ is cyclopropyl. [0322] In certain embodiments, R³ is C1-3 haloalkyl. In certain embodiments, R³ is halomethyl. In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, -CHF₂, -CF₃, or C_1-3 aliphatic. In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, -CHF₂, or -CF₃. In some embodiments, R³ is -CH₂F, -CHF₂, or -CF₃. In some embodiments, R³ is -CH₂Cl or -CH₂F. In some embodiments, R³ is -CHF2 or -CH2F. [0323] In some embodiments, R³ is -CH2Cl, -CH2F, -CH2Br, or -CH2I. In some embodiments, R³ is -CH2Cl. In some embodiments, R³ is-CH2F. In some embodiments, R³ is- CH2Br. In some embodiments, R³ is-CH2I. In certain embodiments, R³ is -CHF2. In some embodiments, R³ is -CF3. In certain embodiments, R³ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0324] Additionally, embodiments described in Section I above for variables R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, B¹, and m of Formula I also apply to compounds of Formula III, both singly and in combination. For example, in certain embodiments, the compound is a compound of Formula III wherein R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)). As another example, in certain embodiments, the compound is a compound of Formula III wherein R¹ is - P(O)(OR⁵)(N(R⁶)(R⁷)), R² is fluoro or hydrogen, and R³ is -CHF₂. [0325] In certain embodiments, the compound is a compound of Formula IV, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula IV. [0326] As defined generally above, R³ is C1-3 haloalkyl or C1-3 aliphatic. In certain embodiments, R³ is halomethyl or C1-3 aliphatic. In some embodiments, R³ is -CH2Cl, -CH2F, - CH₂Br, -CH₂I, -CHF₂, -CF₃, or C_1-3 aliphatic. [0327] In some embodiments, R³ is C_1-3 aliphatic. In some embodiments, R³ is C_2-3 aliphatic. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, -C≡CH, or cyclopropyl. In some embodiments, R³ is -CH₃, -CH₂CH₃, -C(H)=CH₂, -CH₂C(H)=CH₂, or - C≡CH. In some embodiments, R³ is -CH₃ or -CH₂CH₃. In some embodiments, R³ is -C(H)=CH₂, -CH2C(H)=CH2, or -C≡CH. In some embodiments, R³ is -CH3. In some embodiments, R³ is - CH2CH3. In some embodiments, R³ is -C(H)=CH2. In some embodiments, R³ is -CH2C(H)=CH2. In some embodiments, R³ is -C≡CH. In some embodiments, R³ is cyclopropyl. [0328] In certain embodiments, R³ is C1-3 haloalkyl. In certain embodiments, R³ is halomethyl. In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, -CHF₂, -CF₃, or C_1-3 aliphatic. In some embodiments, R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, -CHF₂, or -CF₃. In some embodiments, R³ is -CH₂F, -CHF₂, or -CF₃. In some embodiments, R³ is -CH₂Cl or -CH₂F. In some embodiments, R³ is -CHF2 or -CH2F. [0329] In some embodiments, R³ is -CH2Cl, -CH2F, -CH2Br, or -CH2I. In some embodiments, R³ is -CH2Cl. In some embodiments, R³ is-CH2F. In some embodiments, R³ is- CH2Br. In some embodiments, R³ is-CH2I. In certain embodiments, R³ is -CHF2. In some embodiments, R³ is -CF3. In certain embodiments, R³ is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. [0330] Additionally, embodiments described in Section I above for variables R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and B¹ of Formula II also apply to compounds of Formula IV, both singly and in combination. For example, in certain embodiments, the compound is a compound of Formula III wherein R¹ is -OR⁴. As another example, in certain embodiments, the compound is a compound of Formula III wherein R² is -N(R⁶)(R⁷), R² is fluoro or hydrogen, and R³ is -CHF₂. [0331] In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, 5, 6, or 7 above, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, 5, 6 or 7, above. In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, 5, or 6, above, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, 5, or 6, above. In certain embodiments, the compound is a compound in Table 5 or 6, above, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 5 or 6, above. In certain embodiments, the compound is a compound in Table 6, above, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 6, above. [0332] 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 [0333] 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 [0334] In certain embodiments, the compound of Formula I, II, III, or IV, 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. [0335] 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 [0336] 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. [0337] 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. [0338] 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. [0339] 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). [0340] 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. [0341] 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 [0342] 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. [0343] 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. [0344] 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. [0345] 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. [0346] 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. [0347] 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. [0348] 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. [0349] 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. [0350] 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. [0351] 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. [0352] 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. [0353] 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. [0354] 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. [0355] 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. [0356] 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. [0357] 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. [0358] 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. [0359] 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. [0360] 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. [0361] 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. [0362] 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. [0363] 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. [0364] 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). [0365] 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. [0366] 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. [0367] 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 [0368] 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. [0369] 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. [0370] 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 [0371] In certain embodiments, the disorder is an immune disorder other than a viral infection. [0372] 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. [0373] 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. [0374] 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. [0375] 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. [0376] 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. [0377] 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. [0378] 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. [0379] 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. [0380] 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). [0381] 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. [0382] 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. [0383] 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 [0384] 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. [0385] 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. [0386] 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. [0387] 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 [0388] 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. [0389] 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. [0390] 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. [0391] 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. [0392] 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. [0393] 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. [0394] 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 [0395] Another aspect of the disclosure provides for the use of a compound described herein (such as a compound of Formula I, II, III, or IV, or other compounds described above) for treating a medical disorder, such as a medical disorder described herein (for example, cancer). [0396] Another aspect of the disclosure provides for the use of a compound described herein (such as a compound of Formula I, II, III, or IV, 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 [0397] Another aspect of the disclosure provides methods for inhibiting reverse transcriptase activity. This is described in more detail below. [0398] 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 or II, in order to inhibit the activity of said LINE1 reverse transcriptase. In certain embodiments, the particular compound of Formula I or II 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. [0399] 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 an influenza viral infection. The method comprises contacting a LINE1 reverse transcriptase with an effective amount of a compound described in Section I or II above, such as a compound of Formula I, II, III, or IV, in order to inhibit the activity of said LINE1 reverse transcriptase. In certain embodiments, the particular compound of Formula I, II, III, or IV, 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. [0400] 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 or II, in order to inhibit the activity of said HERV-K reverse transcriptase. In certain embodiments, the particular compound of Formula I or II 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. [0401] 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 an influenza viral infection. The method comprises contacting a HERV-K reverse transcriptase with an effective amount of a compound described in Section I or II above, such as a compound of Formula I, II, III, or IV, in order to inhibit the activity of said HERV-K reverse transcriptase. In certain embodiments, the particular compound of Formula I, II, III, or IV, 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. [0402] 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 [0403] Another aspect of the disclosure provides for combination therapy. Substituted 4'- halomethyl-cytidine phosphoramidates or related compounds described herein (e.g., a compound of Formula I, II, III, or IV, 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. [0404] 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. [0405] 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. [0406] 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. [0407] One or more other therapeutic agent 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. [0408] 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 4'- halomethyl-cytidine phosphoramidate or related compound described herein (e.g., a compound of Formula I, II, III, or IV, 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 4'-halomethyl-cytidine phosphoramidate or related compound described herein (e.g., a compound of Formula I, II, III, or IV, 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 4'-halomethyl-cytidine phosphoramidate or related compound described herein (e.g., a compound of Formula I, II, III, or IV, 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. [0409] In certain embodiments, the substituted 4'-halomethyl-cytidine phosphoramidate or related compound described herein (e.g., a compound of Formula I, II, III, or IV, 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. [0410] Another aspect of this disclosure is a kit comprising a therapeutically effective amount of the substituted 4'-halomethyl-cytidine phosphoramidate or related compound described herein (e.g., a compound of Formula I, II, III, or IV, or other compounds described above), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above. Cancer [0411] 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 4'-halomethyl-cytidine phosphoramidate or related compound described herein and (ii) a second anti-cancer agent, in order to treat the cancer. [0412] In certain embodiments, the second anti-cancer agent is radiation therapy. [0413] 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. [0414] 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. [0415] 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. [0416] 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. [0417] 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. [0418] 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. [0419] 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. [0420] 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). [0421] 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. [0422] 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. [0423] 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. [0424] 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. [0425] 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. [0426] 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. [0427] 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. [0428] 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. [0429] 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). [0430] 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. [0431] 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. [0432] 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. [0433] 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. [0434] 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. [0435] 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. [0436] 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 [0437] 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 4'-halomethyl-cytidine phosphoramidate or related compound described herein and (ii) a second therapeutic agent, in order to treat the inflammatory disorder. [0438] 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. [0439] 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. [0440] 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. [0441] 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. [0442] 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 [0443] 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 4'-halomethyl-cytidine phosphoramidate or related compound described herein and (ii) a second therapeutic agent, in order to treat the immune disorder other than a viral infection. [0444] 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. [0445] 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. [0446] 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. [0447] 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. [0448] 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 [0449] 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 4'-halomethyl-cytidine phosphoramidate 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. [0450] 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. [0451] 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. [0452] 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. [0453] 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. [0454] 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. [0455] 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 [0456] 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 4'-halomethyl-cytidine phosphoramidate or related compound described herein and (ii) a second therapeutic agent, in order to treat the neurodegenerative disorder. [0457] 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. [0458] 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. [0459] 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. [0460] 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. [0461] 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 [0462] 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. [0463] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I or II) 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, II, III, or IV), an additional therapeutic agent (e.g., a compound described in Section IV), and a pharmaceutically acceptable carrier. [0464] 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. [0465] 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. [0466] 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. [0467] 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. [0468] 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. [0469] 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. [0470] 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. [0471] 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. [0472] 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. [0473] 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. [0474] 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. [0475] 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. [0476] 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. 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. [0477] 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. [0478] 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. [0479] 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. [0480] 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. [0481] 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. [0482] 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. [0483] 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. [0484] 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. [0485] 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. [0486] 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. [0487] 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. [0488] 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. [0489] 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. [0490] 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. [0491] 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. [0492] The disclosure further provides a unit dosage form (such as a tablet or capsule) comprising a substituted 4'-halomethyl-cytidine phosphoramidate or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. EXAMPLES [0493] 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 III-19: 4-Amino-1-[(2R,4S,5R)-5-[({di[(isopropoxy- carbonyl)oxy] methoxyphosphoryl} oxy) methyl]-5-ethenyl-4-hydroxyoxolan-2-yl] pyrimidin-2-one ^

[0494] Step 1: To a stirred solution of 2'-deoxyuridine (50 g, 219.1 mmol) and imidazole (149.1 g, 2191.0 mmol) in pyridine (500 mL) was added TBSCl (99.1 g, 657.3 mmol) in portions at room temperature under nitrogen atmosphere. The mixture was stirred for 15 h at 80°C. LCMS showed the reaction was completed. The mixture was cooled to room temperature and diluted with EA, washed with brine and dried over anhydrous Na₂SO₄. The solids were filtered out, and the filtrate was combined and concentrated to afford 1-[(2R,4S,5R)-4-[(tert- butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl} oxolan-2-yl]-3H-pyrimidine- 2,4-dione (98 g, 215 mmol, crude) as a light yellow oil. LC-MS (ES, m/z): 457 (M+H⁺). [0495] Step 2: To a stirred solution of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- {[(tert-butyldimethylsilyl) oxy] methyl} oxolan-2-yl]-3H-pyrimidine-2,4-dione (90 g, 197.1 mmol) in methanol (500 mL) was added PPTS (74.3 g, 295.5 mmol) in portions at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 h at 35°C. LC/MS indicated the reaction was completed. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with an aqueous solution of citric acid and brine and dried over anhydrous Na2SO4. The solids were filtered out, the filtrate was combined and concentrated under reduced pressure to afford 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- (hydroxymethyl) oxolan-2-yl]-3H-pyrimidine-2,4-dione (65 g, 190 mmol, crude) as white solid. LC/MS (ES, m/z): 343 (M+H⁺). [0496] Step 3: To a stirred solution of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- (hydroxymethyl) oxolan-2-yl]-3H-pyrimidine-2,4-dione (65 g, 189.7 mmol) in CH3CN (500 mL) was added IBX (159.4 g, 569.4 mmol). The mixture was stirred for 3 h at 60°C. LC/MS indicated the reaction had gone to completion. The reaction was cooled to room temperature. The solids were filtered out, and the filtrate was concentrated to afford (2S,3S,5R)-3-[(tert- butyldimethylsilyl)oxy]-5-(2,4-dioxo-3H-pyrimidin-1-yl) oxolane-2-carbaldehyde (60 g, 176 mmol, crude) as an off-white solid. LC/MS (ES, m/z): 341 (M+H⁺). [0497] Step 4: To a stirred solution of (2S,3S,5R)-3-[(tert-butyldimethylsilyl) oxy]-5-(2,4- dioxo-3H-pyrimidin-1-yl) oxolane-2-carbaldehyde (60 g, 176.2 mmol) and formaldehyde (26.4 g, 881.1 mmol) in dioxane (500 mL) was added a solution of NaOH (21.1 g, 528.7 mmol) in water (50 mL) dropwise at room temperature under nitrogen atmosphere. The mixture was stirred for 15 h at room temperature. LC/MS indicated the starting material was consumed which was then followed by the addition of NaBH₄ (20 g, 528.7 mmol) 0°C. The mixture was stirred for 30 min at 0°C, LC/MS showed the reaction was completed. The reaction was quenched with aqueous NH4Cl, and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous Na2SO4. The solids were filtered out and the filtrate was concentrated. The residue was purified by silica gel column chromatography and eluted with methanol / dichloromethane (7/93) to afford 1-[(2R,4S)-4-[(tert-butyldimethylsilyl) oxy]-5,5- bis(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (20 g, 53.7 mmol, 30.47%) as a white solid. LC/MS (ES, m/z): 372 (M+H⁺). [0498] Step 5: To a stirred solution of 1-[(2R,4S)-4-[(tert-butyldimethylsilyl) oxy]-5,5- bis(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (20 g, 53.6 mmol) in pyridine (200 mL) was added 4,4'-(chloro(phenyl)methylene) bis(methoxybenzene) (18 g, 53.6 mmol) portion- wise at room temperature under a nitrogen atmosphere. The mixture was stirred for 3 h at 30°C. LC/MS indicated the reaction had proceeded to completion. The mixture was used in the next step without further purification. LC/MS (ES, m/z): 675 (M+H⁺). [0499] Step 6: To the crude material prepared in Step 5 was added TBS-Cl (20 g, 133.3 mmol). The mixture was stirred for 15 h at 30°C. LC/MS indicated the reaction had proceeded to completion.. The mixture was diluted with EtOAc, washed with an aqueous solution of citric acid and brine. The organic layer was dried over anhydrous Na2SO4. The solids were filtered out, and the filtrate was combined and concentrated under reduced pressure to afford 1-[(2R,4S,5R)- 5-{[bis(4-methoxyphenyl) (phenyl)methoxy] methyl}-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert- butyldimethylsilyl) oxy] methyl} oxolan-2-yl]-3H-pyrimidine-2,4-dione (40 g, 50.7 mmol, crude) as a yellow solid. LC/MS (ES, m/z): 787 (M-H⁺)-. [0500] Step 7: To a stirred solution of 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl) methoxy] methyl}-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl} oxolan-2-yl]-3H-pyrimidine-2,4-dione (40 g, 50.6 mmol) in CH3CN (50 mL) was added 80% aqueous CH₃COOH (200 mL) dropwise at room temperature under nitrogen atmosphere. The mixture was stirred for 15 h at room temperature. LC/MS indicated the reaction had proceeded to completion. The pH of the reaction was adjusted to 8 with an aqueous solution of sodium bicarbonate, and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous Na2SO4. The solids were filtered off, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography, eluted with methanol/dichloromethane (3/97) to afford 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- {[(tert-butyldimethylsilyl) oxy] methyl}-5-(hydroxymethyl) oxolan-2-yl]-3H-pyrimidine-2,4- dione (18 g, 37.0 mmol, 72.95%) as a light yellow solid. LC/MS (ES, m/z): 487 (M+H⁺). [0501] Step 8: A solution of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert- butyldimethylsilyl)oxy]methyl}-5-(hydroxymethyl) oxolan-2-yl]-3H-pyrimidine-2,4-dione (18 g, 37.0 mmol) and IBX (31 g, 111.1 mmol) in acetonitrile (200 mL) was stirred for 2 h at 60°C. LC/MS analysis indicated the reaction was complete. The reaction was cooled to room temperature, and the solids were filtered off. The filtrate was combined and concentrated under reduced pressure to afford (2R,3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-2-{[(tert-butyl- dimethylsilyl)oxy]methyl}-5-(2,4-dioxo-3H-pyrimidin-1-yl) oxolane-2-carbaldehyde (17 g, 35.1 mmol, crude) as a white solid. LC/MS (ES, m/z): 485 (M+H⁺). [0502] Step 9: To a stirred solution of methyltriphenylphosphonium bromide (37.5 g, 105.2 mmol) in THF (200 mL) was added n-BuLi (42 mL, 105.2 mmol) dropwise at -78°C under a nitrogen atmosphere. The mixture was stirred for 30 min at 0°C, then (2R,3S,5R)-3-[(tert- butyldimethylsilyl) oxy]-2-{[(tert-butyldimethylsilyl) oxy] methyl}-5-(2,4-dioxo-3H-pyrimidin- 1-yl) oxolane-2-carbaldehyde (17 g, 35.1 mmol) in THF (20 mL) was added. The mixture was stirred for 1.5 h at room temperature. LC/MS indicated the reaction had proceeded to completion. The reaction was quenched with a solution of NH₄Cl, and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous Na₂SO₄. The solids were filtered off, and the filtrate was combined and concentrated to dryness. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1/10) to afford 1- [(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-5- ethenyloxolan-2-yl]-3H-pyrimidine-2,4-dione (15 g, 31.1 mmol, 88.60%) as an off-white solid. LC/MS (ES, m/z): 483 (M+H⁺). [0503] Step 10: To a stirred solution of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- {[(tert-butyldimethylsilyl) oxy] methyl}-5-ethenyloxolan-2-yl]-3H-pyrimidine-2,4-dione (15 g, 31.1 mmol) and DMAP (7.6 g, 62.1 mmol) in acetonitrile (200 mL) was added TEA (9.4 g, 93.2 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (18.7 g, 62.1 mmol). The mixture was stirred for 1 h at room temperature. LC/MS analysis indicated the reaction had proceeded to completion. The reaction was quenched with NH₃ ^.H₂O. The mixture was then diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solids were filtered off, and the filtrate was combined and concentrated. The residue was purified by silica gel column chromatography, eluted with methanol/dichloromethane (7/93) to afford 4-amino-1-[(2R,4S,5R)- 4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-5-ethenyloxolan-2- yl] pyrimidin-2-one (14 g, 29.1 mmol, 93.52%) as a light yellow solid. LC/MS (ES, m/z): 482 (M+H⁺). [0504] Step 11: To a solution of 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- {[(tert-butyldimethylsilyl) oxy] methyl}-5-ethenyloxolan-2-yl] pyrimidin-2-one (400 mg, 0.83 mmol) in pyridine (5 mL) was added 4,4'-dimethoxytrityl chloride (509 mg, 1.66 mmol) under a nitrogen atmosphere. The mixture was stirred overnight at room temperature. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with citric acid and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40% ethyl acetate in petroleum ether) to afford 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-5-ethenyloxolan-2-yl] pyrimidin-2-one (400 mg, 0.51 mmol, 61%) as an orange solid. LC/MS (ES, m/z): 784 (M+H⁺). [0505] Step 12: To a solution of 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1- [(2R,4S,5R)-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-5- ethenyloxolan-2-yl] pyrimidin-2-one (500 mg, 0.64 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (945 mg, 25.52 mmol) under nitrogen atmosphere. The mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel chromatography (10% methanol in dichloromethane) to afford 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1-[(2R,4S,5R)-5-ethenyl-4- hydroxy-5-(hydroxymethyl) oxolan-2-yl] pyrimidin-2-one (300 mg, 0.54 mmol, 85%) as a light yellow solid. LC/MS (ES, m/z): 556 (M+H⁺). [0506] Step 13: To a solution of SM1 (178 mg, 0.54 mmol) and 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1-[(2R,4S,5R)-5-ethenyl-4-hydroxy-5-(hydroxymethyl) oxolan-2-yl] pyrimidin-2-one (150 mg, 0.27 mmol) in tetrahydrofuran (5 mL) was added bis(2-oxo-1,3- oxazolidin-3-yl) phosphinoyl chloride (137 mg, 0.54 mmol), N, N-diisopropylethylamine (140 mg, 1.08 mmol) and 3-nitro-1H-1,2,4-triazole (62 mg, 0.54 mmol) under nitrogen atmosphere. The reaction was stirred for 3 h and quenched with ice water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (50% EtOAc in petroleum ether) to afford 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1-[(2R,4S,5R)-5-[({di[(isopropoxy- carbonyl)oxy] methoxyphosphoryl} oxy) methyl]-5-ethenyl-4-hydroxyoxolan-2-yl] pyrimidin-2- one (120 mg, 0.14 mmol, 51.2%) as a light yellow solid. LC/MS (ES, m/z): 868 (M+H⁺). [0507] Step 14: A solution of 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1- [(2R,4S,5R)-5-[({di[(isopropoxycarbonyl)oxy] methoxyphosphoryl} oxy) methyl]-5-ethenyl-4- hydroxyoxolan-2-yl] pyrimidin-2-one (120 mg, 0.14 mmol) in water (0.5 mL) and formic acid (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford an oil. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 45% B in 8 min; Wavelength: 254/220 nm). The product-containing fractions were combined and lyophilized overnight to afford 4-amino-1- [(2R,4S,5R)-5-[({di[(isopropoxycarbonyl)oxy]methoxyphosphoryl}oxy)methyl]-5-ethenyl-4- hydroxyoxolan-2-yl]pyrimidin-2-one (18.5 mg, 0.03 mmol, 23.1%) as an off-white solid. [0508] LC/MS (ES, m/z): 566 (M+H⁺). 97.5% purity. Conditions for the LC/MS: (Column: Kinetex EVO C18 Column, 100*4.6 mm, 2.6μm; Mobile Phase A: Water/5 mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.5000 mL/min; Gradient: 10% B to 95% B in 2.30 min, 95% B to 95% B in 2.80 min, 95% B to 10% B in 2.83 min; wavelength: 254/220 nm; RT1(min): 1.356). ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1H), 8.61 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 6.13 – 6.02 (m, 2H), 5.90 (m, J = 17.3, 10.9 Hz, 1H), 5.65 (s, 1H), 5.61 (s, 2H), 5.57 (s, 2H), 5.41 (m, J = 17.3, 1.8 Hz, 1H), 5.34 (m, J = 10.9, 1.8 Hz, 1H), 4.83 (m, J = 6.2, 2.5 Hz, 2H), 4.33 (m, J = 7.4 Hz, 1H), 4.23 (m, J = 11.1, 5.5 Hz, 1H), 4.11 (m, J = 11.1, 6.7 Hz, 1H), 2.30 (m, J = 13.6, 7.3, 4.0 Hz, 1H), 2.17 (m, J = 13.9, 7.4 Hz, 1H), 1.25 (m, J = 6.3, 2.1 Hz, 12H). EXAMPLE 2 – Synthesis of Compound III-18: 4-Amino-1-[(2R,4S,5R)-5-[({di[(isopropoxy- carbonyl)oxy]methoxyphosphoryl}oxy)methyl]-5-ethyl-4-hydroxyoxolan-2-yl]pyrimidin-2- one

[0509] Step 1: To a solution of 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1- [(2R,4S,5R)-5-ethenyl-4-hydroxy-5-(hydroxymethyl) oxolan-2-yl] pyrimidin-2-one (450 mg, 0.81 mmol) in EtOH (10 mL) was added Pd/C (45 mg, 10% Pd on carbon) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 h. The mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by Prep-TLC (40% EtOAc in petroleum ether) to afford 4-{[bis(4-methoxyphenyl)(phenyl) methyl]amino}-1-[(2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl) oxolan-2-yl] pyrimidin-2- one (370 mg, 1.11 mmol, 82%) as a light yellow solid. LC/MS (ES, m/z): 558 (M+H⁺). [0510] Step 2: To a solution of 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1- [(2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl) oxolan-2-yl] pyrimidin-2-one (150 mg, 0.27 mmol) in tetrahydrofuran (5 mL) was added SM1 (178 mg, 0.54 mmol) at 0 °C under a nitrogen atmosphere. Then N, N-diisopropylethylamine (139 mg, 1.07 mmol) and 3-nitro-1H-1,2,4- triazole (61 mg, 0.54 mmol) were added under a nitrogen atmosphere. The mixture was stirred for 3 h at 0 °C and quenched by addition of ice-water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford an oil. The residue was purified by Prep-TLC (50% EtOAc in petroleum ether) to afford 4-{[bis(4-methoxyphenyl)(phenyl)methyl]amino}-1-[(2R,4S,5R)-5-[({di[(isopropoxycarbonyl) oxy]methoxyphosphoryl}oxy)methyl]-5-ethyl-4-hydroxyoxolan-2-yl] pyrimidin-2-one (120 mg, 0.21 mmol, 51 %) as a light yellow solid. LC/MS (ES, m/z): 870 (M+H⁺). [0511] Step 3: A solution of 4-{[bis(4-methoxyphenyl)(phenyl)methyl]amino}-1- [(2R,4S,5R)-5-[({di[(isopropoxycarbonyl)oxy]methoxyphosphoryl}oxy) methyl]-5-ethyl-4- hydroxyoxolan-2-yl] pyrimidin-2-one (90 mg, 0.10 mmol) in water (0.5 mL) and formic acid (2 mL) was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated and purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 60% B in 10 min; wavelength: 254 nm). The product-containing fractions were combined and lyophilized overnight to afford 4-amino-1- [(2R,4S,5R)-5-[({di[(isopropoxycarbonyl)oxy]methoxyphosphoryl}oxy)methyl]-5-ethyl-4- hydroxyoxolan-2-yl] pyrimidin-2-one (5.7 mg, 0.06 mmol, 9.64%) as an off-white oil. [0512] LC/MS (ES, m/z): 568 (M+H⁺). 99.3% purity. Conditions for the LC/MS: (Column: XSelect HSS T3 Column, 30*2.1 mm, 2.5 μm; Mobile Phase A: Water/0.05%TFA, Mobile Phase B: Acetonitrile/0.05%TFA; Flow rate: 1.2000 mL/min; Gradient: 5% B to 100% B in 2.40 min, 100% B to 100% B in 2.80 min, 100% B to 5% B in 2.85 min; wavelength: 254/220 nm; RT1(min): 1.571). ¹H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 7.4 Hz, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 6.15 (m, J = 6.9 Hz, 1H), 5.71 (d, J = 7.4 Hz, 1H), 5.61 (d, J = 13.8 Hz, 4H), 4.89-4.77 (m, 2H), 4.21 (m, J = 6.2, 3.3 Hz, 1H), 4.04 (m, J = 10.7, 5.0 Hz, 2H), 2.22 - 2.13 (m, 1H), 2.13- 2.05 (m, 1H), 1.62 (m, J = 37.5, 7.4 Hz, 2H), 1.25 (d, J = 5.9 Hz, 12H), 0.87 (m, J = 7.5 Hz, 3H). EXAMPLE 3 – Synthesis of Compound II-5: 4-Amino-1-[(2R,3S,4R,5R)-5-(chloromethyl)- 5-[({di[(isopropoxycarbonyl)oxy] methoxyphosphoryl} oxy) methyl]-3-fluoro-4- hydroxyoxolan-2-yl] pyrimidin-2-one ^

[0513] Step 1: To a stirred solution of 1-[(2R,3S,4R,5R)-3-fluoro-4-hydroxy-5- (hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (60 g, 243.7 mmol) and imidazole (166 g, 2437.1 mmol) in DMF (500 mL) was added TBS-Cl (110 g, 731.1 mmol) portion-wise at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 h at 80°C. LC/MS indicated the reaction had proceeded to completion. The mixture was cooled to room temperature, diluted with EtOAc, washed with brine and dried over anhydrous Na₂SO₄. The solids were filtered out, and the filtrate was concentrated to afford 1-[(2R,3S,4R,5R)-4-[(tert- butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-3-fluorooxolan-2-yl]-3H- pyrimidine-2,4-dione (110 g, 231.7 mmol, crude) as a white solid. LC/MS (ES, m/z): 475 (M+H⁺). [0514] Step 2: To a stirred solution of 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- {[(tert-butyldimethylsilyl) oxy] methyl}-3-fluorooxolan-2-yl]-3H-pyrimidine-2,4-dione (110 g, 231.7 mmol, 1 equiv) in MeOH (500 mL) was added PPTS (175 g, 695.1 mmol) portion-wise at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 h at 50°C. LC/MS indicated the reaction has proceeded to completion. The mixture was cooled to room temperature and concentrated giving rise to an oil. The residue was diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solids were filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluted with methanol/dichloromethane = 3/97 to afford 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl) oxy]-3- fluoro-5-(hydroxymethyl) oxolan-2-yl]-3H-pyrimidine-2,4-dione (66 g, 183.3 mmol, 79.02%) as an off-white solid. LC/MS (ES, m/z): 361 (M+H⁺). [0515] Step 3: To a stirred solution of 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-3- fluoro-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (66 g, 183.3 mmol) in CH3CN (500 mL) was added IBX (47 g, 166.4 mmol) portion-wise at room temperature under a nitrogen atmosphere. The mixture was stirred for 5 h at 60°C. LC/MS analysis indicated the completion of the reaction. The mixture was cooled to room temperature. The solids were filtered off, and the filtrate was concentrated to afford (2S,3R,4S,5R)-3-[(tert-butyldimethylsilyl)oxy] -5-(2,4- dioxo-3H-pyrimidin-1-yl)-4-fluorooxolane-2-carbaldehyde (60 g, 167.5 mmol, crude) as a white solid. LC/MS (ES, m/z): 359 (M+H⁺). [0516] Step 4: To a stirred solution of (2S,3R,4S,5R)-3-[(tert-butyldimethylsilyl) oxy]-5-(2,4- dioxo-3H-pyrimidin-1-yl)-4-fluorooxolane-2-carbaldehyde (60 g, 167.5 mmol) and HCHO (33 g, 1089.3 mmol, 6.5 equiv) in dioxane (1000 mL) was added a solution of NaOH (20 g, 502.7 mmol, 3 equiv) in water (50 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added NaBH₄ (29 g, 754.1 mmol) portion-wise at 0 °C. The resulting mixture was stirred for an additional 30 min. The mixture was quenched with aqueous NH4Cl. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated brine, 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 (4.9% MeOH) to afford 1-[(2R,3S,4R)-4-[(tert- butyldimethylsilyl)oxy]-3-fluoro-5,5-bis(hydroxymethyl)oxolan-2-yl] -3H-pyrimidine-2,4-dione (35 g, 89.7 mmol, 53.55%) as a white solid. LC/MS (ES, m/z): 391 (M+H⁺). [0517] Step 5: To a stirred solution of 1-[(2R,3S,4R)-4-[(tert-butyldimethylsilyl) oxy]-3- fluoro-5,5-bis(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (31 g, 79.4 mmol) in DCM (500 mL) was added pyridine (31 g, 396.9 mmol) and triflic anhydride (49 g, 174.6 mmol) dropwise at -35°C under a nitrogen atmosphere. The mixture was stirred for 30 min at 0°C, LC/MS indicated complete conversion. The mixture was quenched with water and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous Na2SO4. The solids were filtered out, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (1/1) to afford [(3R,4S,5R)-3-[(tert- butyldimethylsilyl) oxy]-5-(2,4-dioxo-3H-pyrimidin-1-yl)-4-fluoro-2-[(trifluoromethane- sulfonyloxy)methyl]oxolan-2-yl]methyl trifluoromethanesulfonate (30 g, 45.8 mmol, 57.05%) as an off-white solid. LC/MS (ES, m/z): 655 (M+H⁺). [0518] Step 6: To a stirred solution of [(3R,4S,5R)-3-[(tert-butyldimethylsilyl) oxy]-5-(2,4- dioxo-3H-pyrimidin-1-yl)-4-fluoro-2-[(trifluoromethanesulfonyloxy)methyl] oxolan-2-yl] methyl trifluoromethanesulfonate (30 g, 45.8 mmol) in THF (500 mL) was added TEA (46 g, 458.3 mmol) dropwise at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 h at 60°C. Upon complete conversion as judged by LC/MS lithium chloride (19 g, 458.3mmol) was added in one portion to the crude reaction mixture. The resulting mixture was stirred for 2 h at 60 °C, LC/MS showed the reaction was completed. The mixture was used in the next reaction without further purification. LC/MS (ES, m/z): 391 (M+H⁺). [0519] Step 7: To the crude reaction above was slowly added a solution of NaOH (5.5 g, 136.6 mmol) in water (50 mL). The mixture was stirred for 48h at room temperature. LC/MS analysis indicated complete conversion. The solids were filtered off, and the filtrate was combined and concentrated. The residue was diluted with EtOAc, washed with brine and dried over anhydrous Na₂SO₄. The solids were filtered out, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography, eluting with methanol / dichloromethane (7/93) to afford 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5- (chloromethyl)-3-fluoro-5-(hydroxymethyl) oxolan-2-yl]-3H-pyrimidine-2,4-dione (11 g, 26.9 mmol, 59.07%) as light yellow solid. LC-MS (ES, m/z): 409 (M+H⁺). [0520] Step 8: To a stirred solution of 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- (chloromethyl)-3-fluoro-5-(hydroxymethyl) oxolan-2-yl]-3H-pyrimidine-2,4-dione (10 g, 24.4 mmol) and imidazole (17 g, 244.5 mmol) in dimethylformamide (200 mL) was added tert- butyldimethylchlorosilane (11 g, 73.3 mmol) portionwise at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 h at 80°C. LC/MS indicated complete conversion. The mixture was then cooled to room temperature, diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solids were filtered off, and the filtrate was combined and concentrated to dryness. The residue was purified by silica gel column chromatography, eluting with methanol/dichloromethane (7/93) to afford 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-5- (chloromethyl) -3-fluorooxolan-2-yl] -3H- pyrimidine-2,4-dione (12 g, 23.0 mmol, 93.79%) as light yellow solid. LC/MS (ES, m/z): 523 (M+H⁺). [0521] Step 9: To a stirred solution of 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl) oxy]-5- {[(tert-butyldimethylsilyl) oxy] methyl}-5-(chloromethyl)-3-fluorooxolan-2-yl]-3H-pyrimidine- 2,4-dione (12 g, 22.9 mmol) and DMAP (5.6 g, 45.8 mmol) in CH3CN (200 mL) was added TEA (7 g, 68.8 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (14 g, 45.8 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 h at 40°C. Upon completion of the reaction,NH₃.H₂O (50 mL) was added slowly to the reaction. The resulting mixture was stirred for 1h at room temperature. LC/MS analysis indicated complete conversion. The mixture was diluted with EtOAc, washed with brine, and dried over anhydrous Na₂SO₄. The solids were filtered off, and the filtrate was combined and concentrated to dryness. The residue was purified by silica gel column chromatography, elutingwith methanol/dichloromethane (7/93) to afford 4-amino-1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyl- dimethylsilyl)oxy]methyl}-5-(chloromethyl)-3-fluorooxolan-2-yl] pyrimidin-2-one (11 g, 21.1 mmol, 91.84%) as a light yellow solid. LC/MS (ES, m/z): 522 (M+H⁺). [0522] Step 10: To a stirred solution of 4-amino-1-[(2R,3S,4R,5R)-4-[(tert-buty-dimethyl- silyl)oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-5-(chloromethyl)-3-fluorooxolan-2-yl] pyrimidin-2-one (200 mg, 0.4 mmol) in pyridine (10 mL) was added DMTr-Cl (176 mg, 0.6 mmol) portionwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions (Column, C18; mobile phase, Water (10 M NH4HCO3) and ACN (45% ACN up to 50% in 10 min); Detector, UV 254/220 nm) to afford 4-{[bis(4-methoxy-phenyl)(phenyl) methyl]amino}-1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-5-(chloromethyl)-3-fluorooxolan-2-yl]pyrimidin-2-one (250 mg, 0.3 mmol, 79.1%) as a white solid. LC/MS (ES, m/z): 824 (M+H⁺). [0523] Step 11: To a stirred solution of 4-{[bis(4-methoxyphenyl)(phenyl)methyl] amino}-1- [(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl) oxy]-5-{[(tert-butyldimethylsilyl) oxy] methyl}-5- (chloromethyl)-3-fluorooxolan-2-yl] pyrimidin-2-one (250 mg, 0.3 mmol) in methanol (5 mL) was added NH₄F (449 mg, 12.1 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60°C. After which point, the mixture was cooled to room temperature and concentrated to dryness. The residue was purified by reverse flash chromatography with the following conditions (Column, C18; mobile phase, Water (10 M NH4HCO3) and ACN (20% ACN up to 30% in 10 min); Detector, UV 254/220 nm) to afford 4- {[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1-[(2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4- hydroxy-5-(hydroxymethyl) oxolan-2-yl] pyrimidin-2-one (170 mg, 0.28 mmol, 94.4%) as a white solid. LC/MS (ES, m/z): 596 (M+H⁺). [0524] Step 12: Into a vial containing SM1 (166.2 mg, 0.5 mmol) and 4-{[bis(4- methoxyphenyl) (phenyl)methyl] amino}-1-[(2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4- hydroxy-5-(hydroxymethyl) oxolan-2-yl] pyrimidin-2-one (100 mg, 0.2 mmol) were suspended in pyridine (0.5 mL). After which point, 1-methyl-1H-imidazole (207 mg, 2.5 mmol) was added, and the mixture was sonicated for 30 seconds. The mixture was evaporated to a residue by rotary evaporation for 20 minutes. The residue was then resuspended in acetonitrile (6 mL) and sonicated for 30 seconds. Bis(2-oxo-1,3-oxazolidin-3-yl) phosphinoyl chloride (239mg, 0.9 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. The residue was purified by reverse flash chromatography using the following conditions (Column, C18; mobile phase, Water (10 M NH4HCO3) and ACN (50% ACN up to 55% in 10 min); Detector, UV 254/220 nm) to afford 4-{[bis(4-methoxy- phenyl) (phenyl)methyl] amino}-1-[(2R,3S,4R,5R)-5-(chloromethyl)-5-[({di[(isopropoxy- carbonyl)oxy]methoxyphosphoryl} oxy) methyl]-3-fluoro-4-hydroxyoxolan-2-yl] pyrimidin-2- one (80 mg, 0.08mmol, 52.50%) as a white solid. LC/MS (ES, m/z): 908 (M+H⁺). [0525] Step 13: A solution of 4-{[bis(4-methoxyphenyl) (phenyl)methyl] amino}-1- [(2R,3S,4R,5R)-5-(chloromethyl)-5-[({di[(isopropoxycarbonyl)oxy] methoxyphosphoryl} oxy) methyl]-3-fluoro-4-hydroxyoxolan-2-yl] pyrimidin-2-one (80 mg, 0.8 mmol) in H₂O (2.0 mL) and HCOOH (8 mL) was stirred overnight at 40 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC using the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 45% B in 8 min; wavelength: 254/220 nm). The product-containing fractions were combined and lyophilized overnight to afford 4-amino-1- [(2R,3S,4R,5R)-5-(chloromethyl)-5-[({di[(isopropoxycarbonyl)oxy] methoxyphosphoryl} oxy) methyl]-3-fluoro-4-hydroxyoxolan-2-yl] pyrimidin-2-one (17.3 mg, 0.02 mmol, 32.4%) as an off-white solid. [0526] LC/MS (ES, m/z): 606 (M+H⁺).97.9% purity. Conditions for the LC/MS: Column: Shim‐pack Scepter C18, 33*3.0 mm; Mobile Phase A: Water/5mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.5000 mL/min; Gradient: 0% B to 95% B in 2.8 min, 95% B to 95% B in 1.5 min, 95% B to 10% B in 0.03 min; wavelength: 254/220 nm; RT1 (min): 1.468.

NMR (400 MHz, DMSO-d6) δ 7.54 (dd, J = 7.5, 1.7 Hz, 1H), 7.29 (d, J = 30.1 Hz, 2H), 6.42 (d, J = 5.2 Hz, 1H), 6.30 (dd, J = 20.8, 3.3 Hz, 1H), 5.73 (d, J = 7.5 Hz, 1H), 5.62 (dd, J = 13.9, 4.6 Hz, 4H), 5.23-4.93 (m, 1H), 4.90-4.75 (m, 2H), 4.39 (dd, J = 15.4, 5.6 Hz, 1H), 4.26 (qd, J = 10.8, 5.8 Hz, 2H), 3.90 (d, J = 11.7 Hz, 1H), 3.78 (d, J = 11.8 Hz, 1H), 1.25 (dd, J = 6.3, 3.1 Hz, 12H). EXAMPLE 4 – Synthesis of Compound I-1: Methyl ((((2R,3S,5R)-5-(4-amino-5-fluoro-2- oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-3-hydroxytetrahydrofuran-2-yl) methoxy) (4- bromophenoxy) phosphoryl)-L-alaninate ^

[0527] Step 1: To a stirred mixture of floxuridine (4 g, 16.247 mmol) in pyridine (40 mL) was added 1-[chloro(4-methoxyphenyl)phenylmethyl]-4-methoxybenzene (6.06 g, 17.872 mmol) in portionwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere and concentrated under vacuum. The crude product was re-crystallized from petroleum ether/EtOAc (10:1) to afford 1-[(2R,4S,5R)-5- {[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-hydroxyoxolan-2-yl]-5-fluoro-3H- pyrimidine-2,4-dione (8 g, 89.8%) as a yellow solid. Product (ES, m/z): 549 (M+H⁺). [0528] Step 2: To a stirred mixture of 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl) methoxy]methyl}-4-hydroxyoxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (11 g, 20.052 mmol) and imidazole (16.38 g, 240.624 mmol) in DMF (200 mL) was added TBS-Cl (12.09 g, 80.208 mmol) portionwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere and then quenched by the addition of saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4- [(tert-butyldimethylsilyl)oxy]oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (11 g, 82.76%) as a yellow solid. Product (ES, m/z): 663 (M+H⁺). [0529] Step 3: A mixture of 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy] methyl}-4-[(tert-butyldimethylsilyl)oxy]oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (8 g, 12.069 mmol) in AcOH (80 mL) was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]- 5-(hydroxymethyl) oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (4 g, 91.94%) as a white solid. Product (ES, m/z): 361 (M+H⁺). [0530] Step 4: To a mixture of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5- (hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (5 g, 13.871 mmol) in ACN (100 mL), was added IBX (7.77 g, 27.742 mmol). The reaction mixture was stirred for 2 h at 60°C. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated to dryness under vacuum. This gave rise to (2S,3S,5R)-3-[(tert- butyldimethylsilyl)oxy]-5-(5-fluoro-2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (4.5 g, 90.51%) as a yellow solid. Product (ES, m/z): 359 (M+H⁺). [0531] Step 5: To a stirred mixture of (2S,3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(5- fluoro-2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (5.0 g, 0.330 mmol) and NaOH aqueous (5 mL, 2M) in 1,4-dioxane (50 mL) was added formaldehyde (2.5 mL, 37%) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature, then adjusted to pH 7 with AcOH. This was followed by the addition of EtOH (7.5 mL) and NaBH4 (2.22 g, 58.586 mmol) at 0°C. The resulting mixture was stirred for 30 min at room temperature and quenched by the addition of saturated aqueous NH₄Cl. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 1-[(2R,4S)-4-[(tert-butyldimethylsilyl)oxy]-5,5- bis(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (4 g, 73.44%) as a white solid. Product (ES, m/z): 391 (M+H⁺). [0532] Step 6: To a mixture of 1-[(2R,4S)-4-[(tert-butyldimethylsilyl)oxy]-5,5- bis(hydroxymethyl) oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (800 mg, 2.049 mmol) in pyridine (8 mL) was added Tf₂O (1213.83 mg, 4.303 mmol) at -30°C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at -30°C under nitrogen atmosphere and then quenched by the addition of saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (2:1) to afford [(3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(5-fluoro-2,4- dioxo-3H-pyrimidin-1-yl)-2-[(trifluoromethanesulfonyloxy)methyl]oxolan-2-yl]methyl trifluoromethanesulfonate (1.1 g, 82.02%) as a yellow solid. Product (ES, m/z): 655 (M+H⁺). [0533] Step 7: A mixture of [(3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(5-fluoro-2,4-dioxo- 3H-pyrimidin-1-yl)-2-[(trifluoromethanesulfonyloxy)methyl]oxolan-2-yl]methyl trifluoro- methanesulfonate (800 mg, 1.222 mmol) and TEA (247.34 mg, 2.444 mmol) in THF (8 mL) was stirred overnight at room temperature under a nitrogen atmosphere. To the described mixture was added lithium chloride (155.42 mg, 3.666 mmol). The resulting mixture was stirred for additional 2 h at 60°C and judged to be complete by LC/MS. The crude resulting mixture was used in the next step directly without further purification. Product (ES, m/z): 391 (M+H⁺). [0534] Step 8: The solution from the previous step was diluted with H₂O (8 mL), followed by addition of NaOH (245.56 mg, 6.141 mmol). The reaction mixture was stirred overnight at room temperature and then quenched by the addition of saturated aqueous NH₄Cl. The resulting mixture was then extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to afford 1-[(2R,4S,5R)-4- [(tert-butyldimethylsilyl)oxy]-5-(chloromethyl)-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H- pyrimidine-2,4-dione (600 mg, 71.70%) as a white solid. Product (ES, m/z): 409 (M+H⁺). [0535] Step 9: To a stirred mixture of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5- (chloromethyl)-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (500 mg, 1.223 mmol) and imidazole (166.48 mg, 2.446 mmol) in DMF (10 mL) was added TBS-Cl (276.43 mg, 1.835 mmol) portionwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere and then quenched by the addition of saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. This resulted in 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert- butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (600 mg, 93.79%) as a yellow solid. Product (ES, m/z): 523 (M+H⁺). [0536] Step 10: To a stirred mixture of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5- {[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine- 2,4-dione (500 mg, 0.956 mmol), DMAP (350.27 mg, 2.868 mmol), and TEA (290.12 mg, 2.868 mmol) in ACN (20 mL), was added 2,4,6-tris(propan-2-yl)benzene-1-sulfonyl chloride (868.31 mg, 2.868 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. After which point, to the above mixture was added dropwise NH₃.H₂O (10.00 mL). The resulting mixture was stirred for an additional 1 h at room temperature and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 15 min; detector, UV 254 nm. This resulted in 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyl- dimethylsilyl)oxy]methyl}-5-(chloromethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (400 mg, 80.15%) as a white solid. Product (ES, m/z): 522 (M+H⁺). [0537] Step 11: To a mixture of 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5- {[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (400 mg, 0.766 mmol) in MeOH (4 mL) was added NH4F (851.08 mg, 22.980 mmol). The reaction mixture was stirred overnight at 60°C. The resulting mixture was filtered, and the filter cake was washed with EtOH. The combined filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5µm; mobile phase, Water (10 mmol/L NH₄HCO₃) and ACN (2% ACN up to 15% in 7 min); Detector, UV 254 nm. This resulted in 4-amino-1- [(2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-fluoropyrimidin-2- one (71.4 mg, 31.58%) as a white solid. LC-MS (ES, m/z): 294 (M+H⁺). ¹H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 7.2 Hz, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 6.22–6.18 (m, 1H), 5.45 (d, J = 4.4 Hz, 1H), 5.30 (t, J = 5.2 Hz, 1H), 4.38–4.36 (m, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.71 (d, J = 11.6 Hz, 1H), 3.66–3.56 (m, 2H), 2.24–2.17 (m, 2H). [0538] Step 12: To a stirred solution of 4-bromophenyl chlorophosphonochloridate (184 mg, 0.6 mmol) in DCM (3 mL) was added 4A molecular sieves and the reaction was cooled to -78 °C under a nitrogen atmosphere. After which point, methyl L-alaninate hydrochloride (76 mg, 0.5 mmol) and triethylamine (0.12 mL, 0.8 mmol) were added, and the resulting mixture was stirred for 2 h at -50°C under a nitrogen atmosphere. LC/MS analysis indicated complete conversion. The reaction mixture was directly used in the next step. LC/MS (ES, m/z): 356/358/360 [M+H⁺]. [0539] Step 13: To the above mixture was added a solution of 4-amino-1-[(2R,4S,5R)-5- (chloromethyl)-4-hydroxy-5-(hydroxymethyl) oxolan-2-yl]-5-fluoropyrimidin-2-one (40 mg, 0.13 mmol) and triethylamine (0.2 mL, 1.6 mmol) in DCM (3 mL). The resulting mixture was stirred for 15 h at 0 °C. After which point, the resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*250 mm, 10 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 20% B to 39% B in 2 min, 39% B to 39% B in 7 min; wavelength: 254 nm). The product-containing fractions were combined and lyophilized overnight to afford methyl (2S)-2-({[(2R,3S,5R)-5-(4-amino-5-fluoro-2- oxopyrimidin-1-yl)-2-(chloromethyl)-3-hydroxyoxolan-2-yl] methoxy(4-bromophenoxy) phosphoryl} amino) propanoate (13.9 mg, 4.2%) as an off-white solid. LC/MS (ES, m/z): 613/615 [M+H] ⁺. 99.0% purity. Conditions for the LCMS: (Column: Luna Omega PS C18, 30*2.1 mm; Mobile Phase A: Water/0.1%FA; Mobile Phase B: Acetonitrile; Flow rate: 1.2000 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): 0.673). ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (dd, J = 17.9, 7.0 Hz, 2H), 7.61-7.53 (m, 3H), 7.24-7.13 (m, 2H), 6.31-6.16 (m, 2H), 5.65 (dd, J = 11.0, 4.8 Hz, 1H), 4.47-4.33 (m, 1H), 4.28-4.13 (m, 2H), 3.95-3.72 (m, 3H), 3.59 (d, J = 2.1 Hz, 3H), 2.24 (s, 2H), 1.28-1.20 (m, 3H). Example 5 – Synthesis of Compound III-16: 1-[(2R,4S,5R)-5-[({di[(isopropoxy-carbonyl) oxy]methoxyphosphoryl}oxy)methyl]-5-ethynyl-4-hydroxyoxolan-2-yl]-5-methyl-3H- pyrimidine-2,4-dione

[0540] The starting material 1-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl) oxolan- 2-yl]-5-methyl-3H-pyrimidine-2,4-dione can be prepared, for example, as described by Sugimoto, I. et al. in Bioorganic & Medicinal Chemistry Letters, 1999, Vol.9, No.3, p. 385- 388. [0541] Step 1: To a stirred solution of 1-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxy- methyl)oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (30 mg, 0.1 mmol), 1-methyl-1H- imidazole (185 mg, 2.3 mmol) and SM1 (149 mg, 0.5 mmol) in ACN (3 mL, 57 mmol) were added 4A molecular sieves and bis(2-oxo-1,3-oxazolidin-3-yl) phosphinoyl chloride (229 mg, 0.9 mmol) at 0°C. The resulting mixture was stirred for 3 h at room temperature under a nitrogen atmosphere. The reaction was concentrated to dryness. After which point,the crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 40% B in 10 min, 40% B; wavelength: 254/220 nm; RT1(min): 10.22) to afford 1-[(2R,4S,5R)-5-[({di[(isopropoxycarbonyl)oxy]methoxy phosphoryl}oxy)methyl]-5-ethynyl-4-hydroxyoxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (1.7 mg, 0.003 mmol, 2.53%) as a yellow oil. LC/MS (ES, m/z): 579 (M+H⁺).97.0% purity. Conditions for the LC/MS: (Column: Shim-pack Scepter C18, 33*3.0 mm, 3μm; Mobile Phase A: Water + 5 mM NH₄HCO₃, Mobile Phase B: Acetonitrile; Flow rate: 1.5000 mL/min; Gradient: 10% B to 95% B in 1.20 min, 95% B to 95% B in 0.58 min, 95% B to 10% B in 0.05 min; wavelength: 254 nm; RT1(min): 0.846). ¹H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 7.40 (s, 1H), 6.19 (dd, J = 7.3, 5.6 Hz, 1H), 5.78 (d, J = 5.4 Hz, 1H), 5.60 (dd, J = 13.7, 1.5 Hz, 4H), 4.87 – 4.74 (m, 2H), 4.35 (td, J = 7.2, 5.1 Hz, 1H), 4.29 – 4.16 (m, 2H), 3.68 (s, 1H), 2.25 (hept, J = 7.5 Hz, 2H), 1.77 (s, 3H), 1.24 (ddd, J = 6.5, 4.1, 2.4 Hz, 12H). Example 6 – Synthesis of Compound III-17: 1-[(2R,3S,4R,5R)-5-[({di[(isopropoxy- carbonyl)oxy]methoxyphosphoryl} oxy) methyl]-5-ethynyl-3-fluoro-4-hydroxyoxolan-2-yl]- 5-methyl-3H-pyrimidine-2,4-dione

[0542] The starting material 1-[(2R,3S,4R,5R)-5-ethynyl-3-fluoro-4-hydroxy-5- (hydroxymethyl) oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione can be prepared, for example, as described by Wang, Q. et al. in Bioorganic & Medicinal Chemistry Letters, 2010, Vol. 20, No. 14, p.4053-4056. [0543] Step 1: In a vial, SM1 (22 mg, 0.1 mmol) and 1-[(2R,3S,4R,5R)-5-ethynyl-3-fluoro-4- hydroxy-5-(hydroxymethyl) oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (6 mg, 0.02 mmol) were suspended in pyridine (0.5 mL).1-methyl-1H-imidazole (27 mg, 0.3 mmol) was added, and the mixture was sonicated for 30 seconds. After which point, the mixture was evaporated to a residue by rotary evaporation for 20 minutes. The residue was resuspended in ACN (1 mL) and sonicated for 30 seconds. After which point, bis(2-oxo-1,3-oxazolidin-3-yl) phosphinoyl chloride (31 mg, 0.1 mmol) was added, and the reaction was stirred at room temperature for 3 h. When the reaction was completed, water (1 mL) was added to quench it. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 33% B in 10 min, 33% B; wavelength: 254 nm; RT1(min): 18.5;) to afford 1-[(2R,3S,4R,5R)-5-[({di[(isopropoxy carbonyl)oxy]methoxyphosphoryl}oxy)methyl]-5-ethynyl-3-fluoro-4-hydroxyoxolan-2-yl]-5- methyl-3H-pyrimidine-2,4-dione (0.2 mg, 0.0003 mmol, 1.50%) as a light yellow solid. LC/MS (ES, m/z): 597(M+H⁺), 97.4% purity. Conditions for the LC/MS: (Column: HALO C18 Column, 30*3.0 mm, 3μm; Mobile Phase A: Water/0.05%TFA, Mobile Phase B: Acetonitrile/0.05%TFA; Flow rate: 1.5000 mL/min; Gradient: 5% B to 95% B in 2.00 min, 95% B to 95% B in 2.60 min, 95% B to 5% B in 2.70 min; wavelength: 254/220 nm; RT1(min): 1.391).

EXAMPLE 7 – Synthesis of Compound VII-1: 2-Ethylbutyl (2S)-2-({[(2R,5R)-5-(4-amino- 2-oxopyrimidin-1-yl)-2-ethyl-3-hydroxyoxolan-2-yl]methoxy(phenoxy)phosphoryl} amino)propanoate

[0544] To a stirred solution of 4-amino-1-[(2R,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl) oxolan-2-yl]pyrimidin-2-one (153.05 mg, 0.60 mmol) in THF (2 mL) was added tert- butyl(chloro)magnesium (3.00 ml, 1 mol/L in THF) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 ℃ under nitrogen atmosphere. This was followed by the addition of a solution of 4-amino-1-[(2R,5R)-5-ethyl-4- hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one (153.05 mg, 0.60 mmol) in THF (2 mL) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The crude product was purified by Prep-HPLC under 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; RT1(min): 6.56) to afford 2-ethylbutyl (2S)-2- ({[(2R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-2-ethyl-3-hydroxyoxolan-2-yl]methoxy(phenoxy) phosphoryl}amino)propanoate (23.4 mg, 0.04 mmol, 7.58%) as a brown yellow solid. LC/MS (ES, m/z): 567 [M+H]⁺, 96.0% purity. [0545] LC/MS 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: 1.5000 mL/min; Gradient: 10% B to 95% B in 1.19min, 95% B to 95% B in 0.6 min, 95% B to 10% B in 0.02 min; wavelength: 254nm; RT1(min): 0.911).¹H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.61 (m, 1H), 7.40 - 7.35 (m, 2H), 7.23 - 7.17 (m, 4H), 7.15 - 7.11 (m, 1H), 6.15 - 6.08 (m, 2H), 5.69 - 5.66 (m, 1H), 5.25 (brs, 1H), 4.23 - 4.21 (m, 1H), 4.04 - 3.90 (m, 5H), 2.20 - 2.14 (m, 1H), 2.09 – 2.01 (m, 1H), 1.70 -1.67 (m, 1H), 1.58 - 1.55 (m, 1H), 1.46-1.44 (m, 1H), 1.33 - 1.23 (m, 7H), 0.91 - 0.81 (m, 9H). EXAMPLE 8 – Synthesis of Compound VII-2: tert-Butyl (2S)-1-{[(2R,3R,4S,5R)-5-(4- amino-5-fluoro-2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl] methoxy(phenoxy)phosphoryl} pyrrolidine-2-carboxylate

[0546] Step 1: To a solution of phenyl dichlorophosphate (616.0 mg, 2.92 mmol) in DCM (10 mL) was added 2,3,4,5,6-pentafluorophenol (591.2 mg, 3.21 mmol) and TEA (590.9 mg, 5.84 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To this mixture was added a solution of tert-butyl (2S)-pyrrolidine-2-carboxylate (500 mg, 2.92 mmol) and TEA (590.9 mg, 5.84 mmol) in DCM (5 mL) dropwise at -20 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase flash chromatography under the following conditions: Column: C18; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 0% B to 50% B in 15 min, detector: UV 254 nm. This resulted in tert-butyl (2S)-1-[2,3,4,5,6- pentafluorophenoxy(phenoxy)phosphoryl] pyrrolidine-2-carboxylate (570 mg, 1.15 mmol, 39.57%) as a colorless oil. LCMS (ES, m/z): 494 [M+H]⁺. [0547] Step 2: To a solution of 4-amino-1-[(2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4- hydroxy-5-(hydroxymethyl) oxolan-2-yl]-5-fluoropyrimidin-2-one (356.29 mg, 1.14 mmol) in THF (5 mL) was added tert-butyl(chloro)magnesium (5.70 ml, 1 mol/L in THF) at 0 °C under nitrogen atmosphere. The resulting solution was stirred for 1 h at 0 °C under nitrogen atmosphere, followed by the addition of a solution of tert-butyl (2S)-1-[2,3,4,5,6- pentafluorophenoxy(phenoxy)phosphoryl] pyrrolidine-2-carboxylate (470 mg, 0.95 mmol) in THF (5 mL) dropwise at 0 °C. This mixture was stirred overnight at room temperature under nitrogen atmosphere, then concentrated under vacuum. The crude product was purified by Prep- HPLC under the following conditions (Column: xBridge Prep Phenyl 5μm OBD 19*250 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient: isocratic 35% B - 65% B in 20 min; wavelength: 220/254 nm; RT1(min): 13). The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford to afford tert-butyl (2S)-1-{[(2R,3R,4S,5R)-5-(4-amino-5- fluoro-2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl]methoxy (phenoxy)phosphoryl} pyrrolidine-2-carboxylate (5 mg, 0.01 mmol, 0.82%) as a white solid. LC/MS (ES, m/z): 621 [M+H]⁺.97.1% purity. LC/MS Conditions: (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: 1.5000 mL/min; Gradient: 10% B to 95% B in 6.00 min, 95% B to 95% B in 2.00 min; wavelength: 254/220 nm; RT1(min): 3.683; RT2(min): 3.750.¹H NMR (400 MHz, DMSO- d6) δ 7.93 - 7.91 (m, 1H), 7.85-7.80 (m, 1H), 7.68 - 7.66 (m, 1H), 7.40 - 7.37 (m, 2H), 7.26 - 7.20 (m, 3H), 6.43 (brs, 1H), 6.28 - 6.23 (m, 1H), 5.16 - 5.03 (m, 1H), 4.45 - 4.21 (m, 3H), 4.11 - 4.05 (m, 1H), 3.89 - 3.84 (m, 1H), 3.77 – 3.72 (m, 1H), 3.28 - 3.21 (m, 2H), 2.10 - 2.08 (m, 1H), 1.91 - 1.71 (m, 3H), 1.37 (s, 9H). EXAMPLE 9 – Synthesis of Compound VII-3: Methyl (2S)-1-{[(2R,3R,4S,5R)-5-(4-amino- 5-fluoro-2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl] methoxy(phenoxy)phosphoryl} pyrrolidine-2-carboxylate

[0548] Step 1: To a stirred solution of phenyl dichlorophosphate (637 mg, 3.02 mmol) in DCM (10 mL) was added 2,3,4,5,6-pentafluorophenol (556 mg, 3.02 mmol) and Et3N (611 mg, 6.04 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -78 °C under nitrogen atmosphere. To this mixture was added a solution of methyl (2S)- pyrrolidine-2-carboxylate hydrochloride (500 mg, 3.02 mmol) and Et₃N (611 mg, 6.04 mmol) in DCM (5 mL) dropwise at -78 °C. The resulting mixture was stirred overnight at room temperature, then concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 10% to 60% gradient in 20 min; detector, UV 254 nm, resulting in methyl (2S)-1-[2,3,4,5,6- pentafluorophenoxy(phenoxy)phosphoryl] pyrrolidine-2-carboxylate (500 mg, 1.1 mmol, 36.70%) as a light yellow oil. LCMS (ES, m/z): 452 [M+H]⁺. [0549] Step 2: To a solution of 4-amino-1-[(2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4- hydroxy-5-(hydroxymethyl) oxolan-2-yl]-5-fluoropyrimidin-2-one (380 mg, 1.22 mmol) in THF (10 mL) was added tert-butyl(chloro)magnesium (6.1 ml, 1 mol/L in THF) dropwise at -10 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -10 °C under nitrogen atmosphere. This was followed by the addition of a solution of methyl (2S)-1- [2,3,4,5,6-pentafluorophenoxy(phenoxy)phosphoryl] pyrrolidine-2-carboxylate (500 mg, 1.11 mmol) in THF (5mL) dropwise at -10 °C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere and then concentrated under vacuum. The residue was purified by reverse-phase flash chromatography 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; RT1(min): 6.56. The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford methyl (2S)-1-{[(2R,3R,4S,5R)-5-(4- amino-5-fluoro-2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl] methoxy(phenoxy)phosphoryl} pyrrolidine-2-carboxylate (6.9 mg, 0.01mmol, 1.08%) as a white solid. LC/MS (ES, m/z): 579 [M+H]⁺. 96.8% purity. LC/MS Conditions: (HALO C18, 100*4.6 mm, 2.7 μm; Mobile Phase A: H2O+0.05%TFA, Mobile Phase B: ACN+0.05%TFA; Flow rate: 1.5000 mL/min; Gradient: 10% B to 95% B in 6.00 min, 95% B to 95% B in 2 min; wavelength: 254/220 nm; RT1(min): 3.02.¹H NMR (400 MHz, DMSO-d₆) 7.92 - 7.84 (m, 1H), 7.78 - 7.76 (m, 1H), 7.68 - 7.58 (m, 1H), 7.39 - 7.36 (m, 2H), 7.26 - 7.19 (m, 3H), 6.48 (brs, 1H), 6.29 - 6.24 (m, 1H), 5.21 - 5.03 (m, 1H), 4.44 - 4.22 (m, 4H), 3.89 - 3.86 (m, 1H), 3.78 - 3.74 (m, 1H), 3.62 - 3.56 (m, 3H), 3.26 - 3.22 (m, 2H), 2.12 - 2.07 (m, 1H), 1.90-1.82 (m, 3H). EXAMPLE 10 – Synthesis of Compound VII-4: 2-Ethyl-butyl (2S)-2-({[(2R,3R,4S,5R)-5-(4- amino-5-fluoro-2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2- yl]methoxy(phenoxy) phosphoryl} amino)propanoate

[0550] Step 1: To a solution of phenyl dichlorophosphate (503.03 mg, 2.38 mmol) in DCM (5 mL) was added 2,3,4,5,6-pentafluorophenol (482.74 mg, 2.62 mmol) and Et₃N (482.54 mg, 4.77 mmol) dropwise at -78 °C under a nitrogen atmosphere. After stirring for 30 min at -78 °C under nitrogen atmosphere, a solution of 2-ethylbutyl (2S)-2-aminopropanoate hydrochloride (100 mg, 0.48 mmol) and Et3N (482.54 mg, 4.78 mmol) in DCM (5 mL) was added dropwise at - 20 °C. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere, then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: C18; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 10%B to 50%B in 10 min; detector, UV 254 nm, resulting in 2-ethylbutyl (2S)-2-{[2,3,4,5,6-pentafluoro- phenoxy(phenoxy)phosphoryl] amino} propanoate (350 mg, 0.40 mmol, 29.63%) as a white solid. LCMS (ES, m/z): 496 [M+H]⁺. [0551] Step 2: To a solution of 4-amino-1-[(2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4- hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (138.41 mg, 0.44 mmol) in THF (4 mL) was added tert-butyl(chloro)magnesium (2.2 mL, 1 mol/L in THF) at 0 °C under nitrogen atmosphere, followed by stirring for 30 min at 0 °C under nitrogen atmosphere. Thereafter, a solution of 2-ethylbutyl (2S)-2-{[2,3,4,5,6-pentafluorophenoxy (phenoxy)phosphoryl]amino}propanoate (200 mg, 0.40 mmol) in THF (4 mL) was added dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere, then concentrated under reduced pressure. The crude product was purified by Prep-HPLC under 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: isocratic 35%B - 65%B in 20 min; wavelength: 220/254 nm; RT1(min): 13) to afford 2-ethylbutyl (2S)-2-({[(2R,3R,4S,5R)-5-(4-amino-5-fluoro- 2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl] methoxy (phenoxy) phosphoryl} amino) propanoate (33.8 mg, 0.05 mmol, 13.37%) as a white solid. LC/MS (ES, m/z): 623 [M+H]⁺, 99.5% purity. LC/MS Conditions: (Column: Luna Omega PS C18, 33*2.1 mm, 3.0 μm; Mobile Phase A: water/0.1%FA, Mobile Phase B: ACN/0.07%FA; Flow rate: 1.2000 mL/min; Gradient: 5% B to 60% B in 1.19min, 60% 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: 254nm; RT1(min): 1.478.¹

NMR (400 MHz, DMSO-d6) δ 8.01 - 7.86 (brs, 1H), 7.87 - 7.77 (m, 2H), 7.40 - 7.33 (m, 2H), 7.23-7.16 (m, 3H), 6.38 (brs, 1H), 6.27 - 6.16 (m, 2H), 5.18 - 5.02 (m, 1H), 4.44 - 4.40 (m, 1H), 4.25 (t, J = 7.6 Hz, 2H), 3.98 - 3.85 (m, 4H), 3.77 - 3.73 (m, 1H), 1.47 - 1.44 (m, 1H), 1.30 - 1.24 (m, 7H), 0.84 - 0.80 (m, 6H). EXAMPLE 11 – Synthesis of Compound VII-5: Methyl ((((2R,3S,5R)-5-(4-amino-5-fluoro- 2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-3-hydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)-L-alaninate

[0552] To a stirred solution of 4-amino-1-((2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl)-5-fluoropyrimidin-2(1H)-one (115 mg, 392 μmol) in THF (5 mL) was added t-BuMgCl (588 μL, 588 μmol, 1.0 M in THF) at 0 °C under N₂ atmosphere. The resulting mixture was stirred for 30 min at 0 °C under N₂ atmosphere, then methyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (249 mg, 588 μmol) in THF (1.5 mL) was added. The resulting mixture was stirred overnight at room temperature, then concentrated under reduced pressure and 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 fraction was collected and concentrated under reduced pressure. After which point, the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford methyl ((((2R,3S,5R)-5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)- yl)-2-(chloromethyl)-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy)phosphoryl)-L- alaninate (40.5 mg, 75 μmol, 19.1%) as an off-white solid. (ES,m/z): 535/537 [M+H]⁺, 98.7% purity. LC/MS Conditions: (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 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): 0.695).¹H NMR (400 MHz, DMSO-d6) δ 7.83 – 7.75 (dd, J = 20.2, 6.9 Hz, 2H), 7.61 – 7.56 (m, 1H), 7.38 (dt, J = 8.3, 6.6 Hz, 2H), 7.25 – 7.13 (m, 3H), 6.35 – 6.22 (m, 1H), 6.21 – 6.10 (m, 1H), 5.65 (s, 1H), 4.43 – 4.33 (m, 1H), 4.25 – 4.11 (m, 2H), 3.96 – 3.72 (m, 3H), 3.60 (d, J = 2.6 Hz, 3H), 2.28 – 2.13 (m, 2H), 1.27 – 1.20 (m, 3H). EXAMPLE 12 – Synthesis of Compound VII-6: Ethyl (2S)-2-({[(2R,3R,4S,5R)-5-(4-amino- 5-fluoro-2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl]methoxy ([(2S)-1-ethoxy-1-oxopropan-2-yl]amino)phosphoryl} amino) propanoate

[0553] Step 1: To a solution of POCl₃ (199 mg, 1.30 mmol) in DCM (12 mL) was added TEA (527 mg, 5.21 mmol) and 2,3,4,5,6-pentafluorophenol (240 mg, 1.30 mmol) dropwise at - 78 °C under a nitrogen atmosphere. The resulting solution was stirred for 20 min at -78°C under a nitrogen atmosphere, followed by the addition of a solution of ethyl (2S)-2-aminopropanoate hydrochloride (400 mg, 2.60 mmol) and TEA (527 mg, 5.21 mmol) in DCM (5 mL) dropwise at -78 °C. The resulting mixture was stirred for an additional 4 h at room temperature and then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography under the following conditions: Column: C18; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 0% B to 100% in 20min, detector: UV254 nm, resulting in ethyl (2S)-2-({[(2S)-1-ethoxy-1-oxopropan-2-yl] amino(2,3,4,5,6-pentafluorophenoxy) phosphoryl} amino) propanoate (200 mg, 0.43 mmol, 33.23%) as a white solid. LCMS (ES, m/z): 463 [M+H]⁺. [0554] Step 2: To a solution of 4-amino-1-[(2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4- hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (111 mg, 0.36 mmol) in THF (2 mL) was added tert-butyl(chloro)magnesium (0.81 mL, 1 mol/L in THF) at 0 °C under nitrogen atmosphere. The resulting solution was stirred for 30 min at 0 °C under nitrogen atmosphere, followed by the addition of a solution of ethyl (2S)-2-({[(2S)-1-ethoxy-1- oxopropan-2-yl] amino(2,3,4,5,6-pentafluorophenoxy) phosphoryl} amino) propanoate (150 mg, 0.32 mmol) in THF (5 mL) dropwise at 0 °C. The mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The crude product was purified by Prep- HPLC under 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; RT1(min): 6.56). The product- containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford ethyl (2S)-2-({[(2R,3R,4S,5R)-5-(4-amino-5-fluoro-2- oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl]methoxy([(2S)-1-ethoxy-1- oxopropan-2-yl]amino)phosphoryl}amino)propanoate (49.2 mg, 0.08 mmol, 25.68%) as a white solid. LCMS (ES, m/z): 590 [M+H]⁺.99.9% purity. 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: 1.2000 mL/min; Gradient: 5% 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; wavelength: 254 nm; RT1(min): 0.967. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.98 (m, 2H), 7.66 (brs, 1H), 6.31 - 6.23 (m, 2H), 5.16 – 5.15 (m, 0.5H), 5.03 – 5.02 (m, 0.5H), 4.98 - 4.90 (m, 2H), 4.45 - 4.40 (m, 1H), 4.12 - 4.03 (m, 6H), 3.90 - 3.76 (m, 1H), 3.79 - 3.76 (m, 3H), 1.28 - 1.26 (m, 6H), 1.19 - 1.11 (m, 6H). EXAMPLE 13 – Synthesis of Compound VII-7: Methyl ((((2R,3S,5R)-5-(4-amino-2- oxopyrimidin-1(2H)-yl)-2-ethyl-3-hydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)-L-alaninate

Compound VII-7 [0555] Step 1: To a stirred solution of phenyl phosphorodichloridate (4.1 g, 19.4 mmol) in DCM (40 mL) was added C₆F₅OH (3.6 g, 19.4 mmol) and DIEA (5 g, 38.8 mmol) in DCM (20 mL) at -78 C under N₂ atmosphere, then stirred for 30 min at -78 °C. To the mixture was added methyl L-alaninate hydrochloride (2 g, 19.4 mmol) and DIEA (5 g, 38.8 mmol) in DCM (20 mL) at -45 C, stirred overnight at room temperature, 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 Water (10 mmol/L NH4HCO3), 45% to 50% gradient in 10 min; detector, UV 254 nm to afford methyl((perfluorophenoxy)(phenoxy) phosphoryl)-L-alaninate (2.5 g, 5.87 mmol, 30.3%) as a white solid. LC/MS (ES, m/z): 426 [M+H]⁺. [0556] Step 2: To a stirred solution of 4-amino-1-((2R,4S,5R)-5-ethyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (180 mg, 705 μmol) in THF (6 mL) was added t-BuMgCl (811 μL, 811 μmol, 1.0 M in THF) at 0 °C under N2 atmosphere,stirred for 30 min at 0 °C, then methyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (345 mg, 811 μmol) was added at 0 °C, then stirred overnight at room temperature, followed by filtration; the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue 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 fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford methyl ((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-ethyl-3-hydroxytetrahydrofuran- 2-yl) methoxy) (phenoxy)phosphoryl)-L-alaninate (30.7 mg, 62 μmol, 18.7%) as a white solid. LC/MS (ES, m/z): 497 [M+H]⁺, 99.9% purity. [0557] LC/MS conditions: (Column: Shim‐pack Scepter C18, 33*3.0 mm, 3.0 μm; Mobile Phase A: water/5 mM NH₄HCO₃, Mobile Phase B: ACN; Flow rate: 1.50 mL/min; Gradient: 10% B to 50% B in 1.70 min, 50% B to 95% B in 0.60 min, 95% B to 95% B in 0.50 min, 95% B to 10% B in 0.03 min; wavelength: 254/220 nm; RT1(min): 1.119), RT2(min): 1.156).

NMR (400 MHz, DMSO-d6) δ7.66 – 7.60 (m, 1H), 7.43 – 7.34 (m, 2H), 7.27 – 7.03 (m, 5H), 6.21 – 6.01 (m, 2H), 5.69 (dd, J = 7.4, 5.5 Hz, 1H), 5.29 (s, 1H), 4.22 (dd, J = 6.1, 3.1 Hz, 1H), 4.08 – 3.81 (m, 3H), 3.60 (s, 3H), 2.19 – 2.16 (m, 1H), 2.08 – 2.04 (m, 1H), 1.65 – 1.62 (m, 2H), 1.24 (d, J = 7.0 Hz, 3H), 0.91 – 0.88 (m, 3H). EXAMPLE 14 – Synthesis of Compound VII-9: 1-((2R,3S,4R,5R)-5-(({di ((isopropoxy- carbonyl)oxy)methoxyphosphoryl}oxy)methyl)-3-fluoro-4-hydroxy-2,5-dihydrofuran-2-yl)- 5-methyl-3H-pyrimidine-2,4-dione

[0558] To a solution of ((hydroxyphosphoryl)bis(oxy))bis(methylene) diisopropyl bis(carbonate) (230 mg, 700 μmol) and 1-((2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (60 mg, 200 μmol) in pyridine (2 mL) was added NMI (286 mg, 3.5 mmol) at room temperature. The mixture was evaporated to a residue by rotary evaporation for 20 minutes. The residue was then resuspended in ACN (3 mL) and BOP-Cl (325 mg, 1.3 mmol) was added at room temperature under N₂ atmosphere. The reaction was stirred for 3 h at room temperature. When the reaction was complete, water (5 mL) was added to quench the reaction. The resulting mixture was extracted with EtOAc (3 x 5 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 with PE/EA (1/3) to afford the crude product which was re-purified by Prep-HPLC under the following conditions (Column: Sunfire prep C₁₈ column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 48% B in 10 min, 48% B; wavelength: 254/220 nm; RT1(min): 7.92). The fraction was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford 1-((2R,3S,4R,5R)-5-(({di ((isopropoxycarbonyl) oxy) methoxyphosphoryl} oxy) methyl)-3-fluoro-4-hydroxy-2,5-dihydrofuran-2-yl)-5-methyl-3H- pyrimidine-2,4-dione (Compound VII-9) (31.5 mg, 60 μmol, 22.8%) as a light yellow oil. LC- MS (ES, m/z): 573 [M+H]⁺; 96.0% purity. [0559] Conditions for the LCMS: (Column: HALOWA C18 Column, 30*3.0 mm, 3 μm; Mobile Phase A: Water+0.05% TFA, Mobile Phase B: Acetonitrile+0.05% TFA; Flow rate: 1.20 mL/min; Gradient: 5% B to 100% B in 2.40 min, 100% B to 100% B in 2.80 min, 100% B to 5% B in 2.85 min; wavelength: 254/220 nm; RT1(min): 1.640).

(400 MHz, Methanol-d4) δ 7.63 – 7.52 (m, 1H), 6.43 – 6.21 (m, 1H), 5.73 – 5.62 (m, 4H), 5.06 – 4.85 (m, 1H), 4.96 – 4.86 (m, 2H), 4.47 – 4.29 (m, 3H), 4.18 – 4.05 (m, 1H), 1.89 (d, J = 1.2 Hz, 3H), 1.33 – 1.26 (m, 12H). ¹⁹F NMR (376 MHz, Methanol-d4) δ -200.90. EXAMPLE 15 – Synthesis of Compound VII-10

[0560] A suspension of 1-((2R,4S,5R)-5-azido-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (0.100 g, 0.353 mmol), ((hydroxyphosphoryl)bis(oxy))bis(methylene) diisopropyl bis(carbonate) (0.583 g, 1.765 mmol) and 1-methyl-imidazole (0.667g, 8.120 mmol) was co-distilled with pyridine (3 x 5 mL) and dissolved in ACN (3 x 5 mL). To this BOP-Cl (0.809 g, 3.178 mmol) was added at 0^oC and stirred for 1 h at 0°C to 10°C. The reaction progress was monitored by TLC and LC/MS analysis. Upon completion of the reaction as judged by LC/MS analysis, the reaction mixture was filtered via syringe filter, and the filtrate was subjected to Prep HPLC purification under these conditions: Mobile Phase: A: 0.1% formic acid in water; B: MeCN; Column: : WATERS X BRIDGE (150mmx20.0mm), 5.0µ; Flow rate: 15mL/min; Gradient program: Time/% B: 0/20,2/30,8/60 to afford desired product (38 mg, 18 %) as Sticky colorless liquid. LC-MS (ES, m/z): 594.10 (M-1).¹H NMR (400 MHz, DMSO-d₆) δ = 11.42 - 11.38 (m, 1H), 7.43 (s, 1H), 6.37 (t, J = 6.6 Hz, 1H), 6.01 (d, J = 5.4 Hz, 1H), 5.61 (d, J = 13.8 Hz, 4H), 4.82 (dtd, J = 3.2, 6.1, 12.4 Hz, 2H), 4.51 (q, J = 6.4 Hz, 1H), 4.30 - 4.19 (m, 2H), 2.34 - 2.26 (m, 2H), 1.79 (s, 3H), 1.27 - 1.23 (m, 12H)

EXAMPLE 16 – Synthesis of Compound VII-11: Methyl (2S)-2-({[(2R,3R, 4S,5R)-5-(4- amino-5-fluoro-2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl] methoxy(4-bromophenoxy)phosphoryl}amino)propanoate

[0561] Step 1: To a stirred solution of 4-bromophenyl chlorophosphonochloridate (350 mg, 1.21 mmol) in DCM (10 mL) was added pentafluorophenol (222.2 mg, 1.21 mmol) and TEA (244.4 mg, 2.41 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added a solution of methyl L-alaninate hydrochloride (186.8 mg, 1.81 mmol) and TEA (244.4 mg, 2.41 mmol) in DCM (10 mL) dropwise at -20 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C₁₈ silica gel; mobile phase A: 10mmol/L NH₄HCO₃, mobile phase B: MeCN, 10% B to 50% B gradient in 10 min; detector, UV 254 nm. This resulted in methyl (2S)-2-{[4-bromophenoxy (2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino}propanoate (200 mg, 0.40 mmol, 32.86%) as a white solid. LC-MS (ES, m/z): 504/506 [M+H]⁺. [0562] Step 2: To a solution of 4-amino-1-[(2R,3S,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy- 5-(hydroxymethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (123.0 mg, 0.40 mmol) in THF (2 mL) was added tert-butyl(chloro)magnesium (0.99 ml, 1 mol/L in THF) for 1 h at 0 °C under a nitrogen atmosphere. The resulting solution was stirred for 2 h at 0 °C under an inert atmosphere. This was followed by the addition of a solution of methyl (2S)-2-{[4- bromophenoxy(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino}propanoate (200 mg, 0.40 mmol) in THF (2 mL) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under under reduced pressure. The crude product was purified by Prep-HPLC under 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; RT1 (min): 6.56 and RT2 (min): 6.68). The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford a mixture of Compound VII-11 (5.9 mg, 0.01 mmol, 4.54%, first peak) as a white solid and the second eluting compound (9.4 mg, 0.015 mmol, 7.50%, second peak) as a white solid. LC/MS Compound VII- 11 (ES, m/z): 631/633 [M+H]⁺. [0563] Conditions for the LC/MS: (Column: Shim‐pack Scepter C₁₈30*3.0mm,2.0um; Mobile phase A: water/0.05%TFA; Mobile phase B: ACN/0.05%TFA; Flow rate: 1.5000 mL/min; Gradient: ACN‐Water‐0.05%TFA‐5%B‐60‐100%B‐1.5‐3.0min (90‐900). lcm; wavelength: 254/220 nm; RT1(min): 1.263. [0564] ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (brs, 1H), 7.86 - 7.81 (m, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 6.45 (brs, 1H), 6.30 - 6.24 (m, 2H), 5.19 - 5.06 (m, 1H), 4.46 - 4.42 (m, 1H), 4.29 - 4.27 (m, 2H), 3.89 - 3.86 (m, 2H), 3.79 - 3.76 (m, 1H), 3.60 (s, 3H), 1.25 (d, J = 7.2 Hz, 3H).

EXAMPLE 17 – Synthesis of Compound VII-12: Methyl (2S)-2-({[(2R,3R,4S,5R)-5-(4- amino-5-fluoro-2-oxopyrimidin-1-yl)-2-(chloromethyl)-4-fluoro-3-hydroxyoxolan-2-yl] methoxy(4-bromophenoxy)phosphoryl}amino)propanoate

[0565] To a solution of 4-amino-1-[(2R,3S,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy-5- (hydroxymethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (123.0 mg, 0.40 mmol) in THF (2 mL) was added tert-butyl(chloro)magnesium (0.99 ml, 1 mol/L in THF) for 1 h at 0 °C under nitrogen atmosphere. The resulting solution was stirred for 2 h at 0 °C under a nitrogen atmosphere. This was followed by the addition of a solution of methyl (2S)-2-{[4- bromophenoxy(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino}propanoate (200 mg, 0.40 mmol) in THF (2 mL) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under 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; RT1(min): 6.56 and RT2 (min): 6.68). The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford the first eluting diastereomer (5.9 mg, 0.01 mmol, 4.54%, first peak) as a white solid and the second eluting diastereomer, Compound VII-12, (9.4 mg, 0.015 mmol, 7.50%, second peak) as a white solid. Compound VII-12 LC-MS (ES, m/z): 631/633 [M+H]⁺. [0566] Conditions for the LCMS: (Column: Shim‐pack Scepter C1830*3.0mm,2.0um; Mobile phase A: water/0.05%TFA; Mobile phase B: ACN/0.05%TFA; Flow rate: 1.5000 mL/min; Gradient: ACN‐Water‐0.05%TFA‐5%B‐60‐100%B‐1.5‐3.0MIN (90‐900). lcm; wavelength: 254/220 nm; RT1(min): 1.286. [0567] ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (brs, 1H), 7.86 - 7.84 (m, 1H), 7.69 (brs, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 6.40 (d, J = 4.8 Hz, 1H), 6.31 - 6.23 (m, 2H), 5.16 - 5.03 (m, 1H), 4.44-4.40 (m, 1H), 4.26 (d, J = 6.0 Hz, 2H), 3.92 - 3.85 (m, 2H), 3.78 – 3.75 (m, 1H), 3.60 (s, 3H), 1.26 (s, 3H). EXAMPLE 18 – Synthesis of Compounds VII-13 and VII-14: 4-Amino-1- ((2S,4aR,6R,7S,7aR)-4-(chloromethyl)-7-fluoro-2-isopropoxy-2-oxidotetrahydro-4H- furo[3,2-d][1,3,2]dioxaphosphinin-6-yl)-5-fluoropyrimidin-2(1H)-one and 4-amino-1- ((2R,4aR,6R,7S,7aR)-4-(chloromethyl)-7-fluoro-2-isopropoxy-2-oxidotetrahydro-4H- furo[3,2-d][1,3,2]dioxaphosphinin-6-yl)-5-fluoropyrimidin-2(1H)-one, respectively

[0568] Step 1: To a stirred mixture of isopropyl alcohol (392 mg, 6.52 mmol) and POCl3 (1 g, 6.52 mmol) in DCM (10 mL) was added TEA (660 mg, 6.52 mmol) at -78 °C under N2 atmosphere. The mixture was stirred for 10 minutes at -78 °C and an additional 30 minutes at 0 °C. To this mixture was added a solution of 4-nitrophenol (1.8 g, 13 mmol) and TEA (1.3 g, 13 mmol) in DCM (10 mL) dropwise at 0 °C under N2 atmosphere. The mixture was stirred for an additional 30 minutes at room temperature. The resulting mixture was diluted with n-hexane (60 mL), then filtered, and the filter cake was washed with hexane (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford isopropyl bis(4-nitrophenyl) phosphate (1.29 g, 3.38 mmol, 51.7%) as a light yellow solid. LC-MS (ES, m/z): 383 [M+H]⁺. [0569] Step 2: To a stirred mixture of 4-amino-1-((2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro- 4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-5-fluoropyrimidin-2(1H)-one (100 mg, 322 μmol) in THF (2.5 mL) were added DBU (117 mg, 770 μmol) in ACN (5 mL) and isopropyl bis(4-nitrophenyl) phosphate (147 mg, 385 μmol) in DCM (2.5 mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 hours at room temperature and concentrated to dryness. The residue was purified by Prep-TLC (DCM / MeOH 10:1) to afford 4-amino-1- ((4R,6R,7S,7aR)-4α-(chloromethyl)-7-fluoro-2-isopropoxy-2-oxidotetrahydro-4H-furo[3,2-d] [1,3,2] dioxaphosphinin-6-yl)-5-fluoropyrimidin-2(1H)-one (89 mg, 214 μmol, 66.7%) as a light yellow solid. LC/MS (ES, m/z): 416/418 [M+H]⁺. [0570] Step 3: The 4-Amino-1-((4aR,6R,7S,7aR)-4a-(chloromethyl)-7-fluoro-2-isopropoxy- 2-oxidotetrahydro-4H-furo[3,2-d] [1,3,2] dioxaphosphinin-6-yl)-5-fluoropyrimidin-2(1H)-one (110 mg, 265 μmol) was purified by Prep-HPLC under the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 5% B in 9 min; wavelength: 254 nm/220 nm; RT1(min): 8.9). The first 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 4-amino-1-((2S,4aR,6R,7S,7aR)-4a-(chloromethyl)-7-fluoro-2- isopropoxy-2-oxidotetrahydro-4H-furo[3,2-d] [1,3,2] dioxaphosphinin-6-yl)-5-fluoropyrimidin- 2(1H)-one (Compound VII-13) (20.4 mg, 49 μmol, 18.5%) as an off-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 afford 4-amino-1-((2R,4aR,6R,7S,7aR)- 4a-(chloromethyl)-7-fluoro-2-isopropoxy-2-oxidotetrahydro-4H-furo[3,2-d] [1,3,2] dioxaphosphinin-6-yl)-5-fluoropyrimidin-2(1H)-one (Compound VII-14) (17.2 mg, 41 μmol, 17.1%) as an off-white solid. [0571] LC-MS (Compound VII-13) (ES, m/z): 416/418 [M+H]⁺; 99.5% purity. Conditions for the LCMS: (Column: Shim‐pack Scepter C18, 33*3.0 mm; 3.0 μm; Mobile Phase A: Water/5 mM NH₄HCO₃; Mobile Phase B: ACN; Flow rate: 1.50 mL/min; Gradient: 10% B to 60% B in 1.70 min, 60% B to 95% B in 0.50 min, 95% B to 95% B in 0.50 min, 95% B to 10% B in 0.03 min; wavelength: 254 nm; RT1(min): 0.995). Conditions for the Chiral SFC: (Column: (R, R) Whelk-O14.60*50 mm; 3 μm; Mobile Phase: MeOH (0.5% 2 M NH₃-MeOH); Flow rate: 4.0 mL/min; wavelength: 220 nm; RT1(min): 1.210). ¹H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.1 Hz, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 6.57 (s, 1H), 5.85 (m, J = 56.0, 6.9 Hz, 1H), 5.35 – 5.12 (m, 1H), 4.81 (d, J = 9.6 Hz, 1H), 4.71 (m, J = 6.2 Hz, 1H), 4.53 (dd, J = 22.1, 9.6 Hz, 1H), 4.35 (d, J = 13.1 Hz, 1H), 3.85 (d, J = 13.0 Hz, 1H), 1.38 (dd, J = 10.4, 6.1 Hz, 6H). [0572] LC-MS (Compound VII-14) (ES, m/z): 416/418 [M+H]⁺; 99.3% purity. Conditions for the LCMS: (Column: Shim‐pack Scepter C₁₈, 33*3.0 mm; 3.0 μm; Mobile Phase A: Water/5 mM NH₄HCO₃; Mobile Phase B: ACN; Flow rate: 1.50 mL/min; Gradient: 10% B to 60% B in 1.70 min, 60% B to 95% B in 0.50 min, 95% B to 95% B in 0.50 min, 95% B to 10% B in 0.03 min; wavelength: 254 nm; RT1(min): 1.083). Conditions for the Chiral SFC: (Column: (R, R) Whelk-O14.60*50 mm; 3 μm; Mobile Phase: MeOH (0.5% 2 M NH3-MeOH); Flow rate: 4.0 mL/min; wavelength: 220 nm; RT1(min): 1.005).¹H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 6.60 (s, 1H), 5.74 (dd, J = 76.9, 40.7 Hz, 2H), 4.83 (d, J = 49.6 Hz, 2H), 4.43 (dd, J = 82.3, 15.4 Hz, 2H), 3.80 (d, J = 13.2 Hz, 1H), 1.60 – 1.07 (m, 6H).

EXAMPLE 19 – Synthesis of Compound VII-15: Methyl ((((2R,3S,5R)-5-(4-amino-2- oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-3-hydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)-L-alaninate

[0573] To a stirred solution of 4-amino-1-((2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl) pyrimidin-2(1H)-one (120 mg, 435 μmol) in THF (6 mL) was added t-BuMgCl (500 μL, 500 μmol, 1.0 M in THF) at 0 °C under N₂ atmosphere. The resulting mixture was stirred for 30 min at 0°C. To this solution was added methyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (213 mg, 500 μmol) at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue 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 fraction was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford methyl ((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-3- hydroxytetrahydrofuran-2-yl) methoxy)(phenoxy)phosphoryl)-L-alaninate (28.8 mg, 56 μmol, 12.8%) as a white solid. LC/MS (ES, m/z): 517/519 [M+H]⁺, 98.4% purity. [0574] 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: ACN; Flow rate: 1.50 mL/min; Gradient: 0% B to 10% B in 0.01 min, 10% B to 50% B in 1.70 min, 50% B to 95% B in 0.60 min, 95% B to 95% B in 0.50 min, 95% B to 10% B in 0.03 min; wavelength: 254/220 nm; RT1(min): 1.181, RT2(min): 1.213).¹H NMR (400 MHz, DMSO-d6) δ 7.61 (dd, J = 7.4, 3.4 Hz, 1H), 7.41 – 7.38 (m, 2H), 7.27 – 7.13 (m, 5H), 6.32 – 6.29 (m, 1H), 6.16 (dd, J = 13.1, 10.1 Hz, 1H), 5.71 (t, J = 7.0 Hz, 1H), 5.63 (s, 1H), 4.37 (s, 1H), 4.17 (dd, J = 11.8, 5.2 Hz, 2H), 3.99 – 3.72 (m, 3H), 3.61 (s, 3H), 2.23 – 2.09 (m, 2H), 1.24 (dd, J = 7.2, 4.1 Hz, 3H). EXAMPLE 20 – Synthesis of Compound VII-16: Isopropyl ((((2R,3S,4S,5R)-5-(4-amino-5- fluoro-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy)phosphoryl)-L-alaninate

[0575] To a stirred solution of 4-amino-1-((2R,3S,4S,5R)-5-(chloromethyl)-3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl)-5-fluoropyrimidin-2(1H)-one (23 mg, 74 μmol) in THF (5 mL) was added t-BuMgCl (87 μL, 85 μmol, 1M in THF) at 0°C under N₂ atmosphere. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added a solution of isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (39 mg, 85 μmol) in THF (1 mL) via syringe at 0 °C and the resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by Prep-TLC(DCM/MeOH=12/1) to give the crude product. The crude product was re-purified by Prep-HPLC with the following conditions (Column: xBridge Prep Phenyl 5 μm OBD 19 * 250 mm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient: isocratic 35% B - 65% B in 20 min; wavelength: 220/254 nm; RT1(min): 13). The fractions were collected and concentrated under reduced pressure, the residue was re- dissolved in ACN and H2O and was lyophilized overnight to afford isopropyl ((((2R,3S,4S,5R)- 5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-3,4-dihydroxytetrahydrofuran- 2-yl) methoxy) (phenoxy)phosphoryl)-L-alaninate (4.9 mg, 8 μmol, 11.4%) as an off-white solid. [0576] LC/MS (ES, m/z): 579/581 [M+H]⁺, 99.9% purity. Conditions for the LC/MS: (Column: HALO C18, 30 * 3.0 mm, 2.0 μm; Mobile Phase A: water/0.05 % TFA, Mobile Phase B: ACN/0.05% TFA; 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; wavelength: 254/220 nm; RT1(min): 1.385), RT2(min): 1.405).¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (dd, J = 20.3, 7.1 Hz, 2H), 7.50 (s, 1H), 7.43 – 7.31 (m, 2H), 7.27 – 7.13 (m, 3H), 6.17 – 6.03 (m, 2H), 6.05 – 5.80 (m, 2H), 4.93 – 4.81 (m, 1H), 4.49 – 4.39 (m, 1H), 4.27 (dd, J = 10.7, 5.6 Hz, 1H), 4.17 – 3.98 (m, 2H), 3.85 – 3.67 (m, 3H), 1.32 – 1.08 (m, 9H). EXAMPLE 21 – Synthesis of Compound VII-17: Isopropyl ((((2R,3S,5R)-2-azido-3- hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

[0577] Step 1: To a stirred solution of phenyl phosphorodichloridate (2.52 g, 11.9 mmol) in DCM (350 mL) was added C₆F₅OH (2.2 g, 11.9 mmol) and DIEA (3.08 g, 23.9 mmol) at -78 °C under N₂ atmosphere. The resulting mixture was stirred for 30 min at -78 °C. To the above mixture was added isopropyl L-alaninate hydrochloride (2 g, 11.9 mmol) and DIEA (3.08 g, 23.9 mmol) at -45 °C. The resulting mixture was stirred overnight at room temperature, then concentrated underreduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10 mmol/L NH4HCO3), 40% to 50% gradient in 10 min; detector, UV 254 nm to afford isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (2.5 g, 5.51 mmol, 46.2%) as a white solid. LC-MS (ES, m/z): 454 [M+H]⁺. [0578] Step 2: To a stirred solution of 1-((2R,4S,5R)-5-azido-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (45 mg, 159 μmol) in THF (4 mL) was added t-BuMgCl (183 μL, 183 μmol, 1.0 M in THF) at 0 °C under N2 atmosphere. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (83 mg, 183 μmol) at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue 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: 38% B to 54% B in 12 min; wavelength: 254 nm/220 nm; RT1(min): 8.24). The fraction was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H₂O, and then was lyophilized to afford isopropyl ((((2R,3S,5R)-2-azido-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (18.8 mg, 34 μmol, 21.4%) as a white solid. LC/MS (ES, m/z): 553 [M+H]⁺, 99.9% purity. [0579] Conditions for the LC/MS: (Column: HALO C18, 33*3.0 mm, 2.0 μm; Mobile Phase A: water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; 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; wavelength: 254/220 nm; RT1(min): 1.406), RT2(min): 1.425).¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H), 7.47 (dd, J = 9.9, 1.4 Hz, 1H), 7.39 – 7.36 (m, 2H), 7.26 – 7.15 (m, 3H), 6.43 – 6.32 (m, 1H), 6.10 (dd, J = 13.3, 10.1 Hz, 1H), 5.99 (dd, J = 12.8, 5.3 Hz, 1H), 4.91 – 4.78 (m, 1H), 4.54 – 4.52 (m, 1H), 4.31 – 4.19 (m, 1H), 4.13 (dd, J = 11.1, 5.1 Hz, 1H), 3.82 – 3.79 (m, 1H), 2.43 – 2.23 (m, 2H), 1.76 (dd, J = 4.9, 1.2 Hz, 3H), 1.21 (dd, J = 7.2, 2.3 Hz, 3H), 1.15 (d, J = 6.3 Hz, 6H). EXAMPLE 22 – Synthesis of Compound VII-18: Isopropyl ((((2R,3S,5R)-5-(4-amino-5- methyl-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy)phosphoryl)-L-alaninate, formic acid

[0580] To a stirred solution of 4-amino-1-((2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl)-5-methylpyrimidin-2(1H)-one (40 mg, 138 μmol) in THF (2 mL) was added t-BuMgCl (159 μL, 159 μmol, 1M in THF) dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (72 mg, 159 μmol) in THF (2 mL) dropwise at 0°C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 10:1) to afford the crude product. The crude product was re-purified by Prep-HPLC under the following conditions: (Column: Xselect CSH Prep Fluoro-Phenyl Column, 19 * 250 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 61% B to 91% B in 12 min; wavelength: 254 nm/220 nm; RT1(min): 9.2). The fraction was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H₂O, and then was lyophilized to afford isopropyl ((((2R,3S,5R)-5-(4-amino-5-methyl-2- oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy)phosphoryl)-L-alaninate, formic acid (12.4 mg, 22 μmol, 15.8%) as a white solid. LC/MS (ES, m/z): 559/561 [M+H]⁺; 98.4% purity. [0581] Conditions for the LCMS: (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 1.2 min, 100% B to 100% B in 0.60 min, 100% B to 5% B in 0.02 min; wavelength: 254/220 nm; RT1(min): 0.593).¹H NMR (400 MHz, DMSO-d6) δ, 7.45 (d, J = 15.0 Hz, 1H), 7.40 – 7.28 (m, 3H), 7.27 – 7.15 (m, 3H), 6.83 (s, 1H), 6.31 (dd, J = 8.4, 6.4 Hz, 1H), 6.17 – 6.04 (m, 1H), 5.63 (s, 1H), 4.92 – 4.80 (m, 1H), 4.43 – 4.33 (m, 1H), 4.26 – 4.10 (m, 2H), 3.87 – 3.71 (m, 3H), 2.19 – 2.11 (m, 2H), 1.81 (s, 3H), 1.26 – 1.12 (m, 9H). EXAMPLE 23 – Synthesis of Compound VII-19: Isopropyl 2-(((((2R,3R,4S,5R)-5-(4-amino- 5-fluoro-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl) methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate

[0582] Step 1: To a stirred solution of phenyl dichlorophosphate (1.16 g, 5.5 mmol) in DCM (25 mL) were added C6F5OH (1.11 g, 6.05 mmol) and TEA (1.11 g, 11 mmol) at -78 °C. The resulting mixture was stirred for 30 min at -78 °C under N₂ atmosphere. To the above solution, isopropyl 2-amino-2-methylpropanoate hydrochloride (1 g, 5.5 mmol) and TEA (1.11 g, 11 mmol) was added- at -20 °C under N2 atmosphere. The mixture was stirred for 16 h at room temperature under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; Mobile Phase A: Water (0.5% FA), Mobile Phase B: ACN, 10% to 90% gradient in 25 min; detector, UV 254 nm. The fraction was collected and concentrated under reduced pressure to afford isopropyl 2-methyl-2-(((perfluorophenoxy) (phenoxy)phosphoryl)amino)propanoate (420 mg, 897 μmol, 16.3%) as a white solid. LC/MS (ES, m/z): 468 [M+H]⁺. [0583] Step 2: To a stirred solution of 4-amino-1-((2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro- 4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-fluoropyrimidin-2(1H)-one (80 mg, 257 μmol) in THF (4 mL) was added t-BuMgCl (295 μL, 295 μmol, 1.0 M in THF) at 0 °C under N₂ atmosphere. The mixture was stirred for 20 min at 0 °C. To the above solution was added a solution of isopropyl 2-methyl-2-(((perfluorophenoxy)(phenoxy)phosphoryl) amino) propanoate (138 mg, 296 μmol) in THF (2 mL) via syringe at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by Prep-TLC(DCM/MeOH=12/1) to give the crude product. Then the crude product was re-purified by Prep-HPLC with following conditions (Column: X-Select prep OBD C18 Column, 30*150 mm, 5.0 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL/min; Gradient: 30% B – 50% B in 11 min; wavelength: 254/220 nm; RT1(min): 6.56). The product-containing fractions were collected and concentrated under vacuum, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford isopropyl 2- (((((2R,3R,4S,5R)-5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate, formic acid (14.3 mg, 24 μmol, 8.6%) as a white solid. LCMS: (ES, m/z): 595/597 [M+H]⁺; 99.7% purity. [0584] Conditions for the LC/MS: (Column: HALO CS C₁₈, 30*2.1 mm, 2.7 μm; Mobile Phase A: water/0.1% FA, Mobile Phase B: ACN/0.07% FA; Flow rate: 1.50 mL/min; Gradient: 5% B to 60%B in 1.70 min, 60% B to 100% B in 0.60 min, 100% B to 5% B in 0.03 min; wavelength: 254/220 nm; RT1(min): 1.278).¹H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.81 (d, J = 6.9 Hz, 1H), 7.66 (s, 1H), 7.42 – 4.32 (m, 2H), 7.28 – 7.12 (m, 3H), 6.39 (s, 1H), 6.24 (dd, J = 19.9, 4.1 Hz, 1H), 5.97 (t, J = 8.8 Hz, 1H), 5.03 (t, J = 2.7 Hz, 1H), 4.91 – 4.79 (m, 1H), 4.43 (dd, J = 15.7, 11.8 Hz, 1H), 4.27 (d, J = 5.8 Hz, 2H), 3.85 (dd, J = 16.7, 11.5 Hz, 1H), 3.75 (d, J = 11.5 Hz, 1H), 1.38 (d, J = 16.3 Hz, 6H), 1.19 – 1.11 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ -167.26, -196.91. EXAMPLE 24 – Synthesis of Compound VII-20: Isopropyl 2-(((((2R,3S,5R)-5-(4-amino-2- oxopyrimidin-1(2H)-yl)-2-ethyl-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)-2-methylpropanoate

[0585] To a stirred solution of 4-amino-1-((2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (80 mg, 313 μmol) in THF (3 mL) was added t- BuMgCl (360 μL, 360 μmol, 1.0 M in THF) at 0 °C under N2 atmosphere. The resulting mixture was stirred for 30 min at 0 °C under N2 atmosphere. To the above mixture was added a solution of isopropyl 2-methyl-2-(((perfluorophenoxy)(phenoxy)phosphoryl) amino) propanoate (168 mg, 360 μmol) in THF (2 mL) via syringe. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by Prep- TLC(DCM/MeOH=12/1) to give the crude product which was re-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; Wave Length: 254 nm/220 nm; RT1(min): 6.56). The fraction was collected and concentrated under vacuum, the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford isopropyl 2-(((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-ethyl-3- hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy)phosphoryl) amino)-2-methylpropanoate, formic acid (23.1 mg, 42 μmol, 13.5%) as an off-white solid. LC/MS: (ES, m/z): 539 [M+H]⁺; 98.7% purity. [0586] Conditions for the HPLC: (Column: HALO C₁₈, 100*4.6 mm, 2.7 μm; Mobile Phase A: H2O+0.05% TFA, Mobile Phase B: ACN+0.05% TFA; Flow rate: 1.20 mL/min; Gradient: 10% B to 60%B in 10.00 min, 60% B to 95% B in 12.00 min, 95% B to 95% B in 1.70 min, 95% B to 10% B in 0.30 min; Wave Length: 254/220 nm; RT1(min): 6.318).¹H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J = 7.9 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.26 – 7.05 (m, 5H), 6.14 (t, J = 6.9 Hz, 1H), 5.86 (t, J = 10.1 Hz, 1H), 5.66 (dd, J = 7.5, 2.9 Hz, 1H), 5.27 (t, J = 4.8 Hz, 1H), 4.91 – 4.80 (m, 1H), 4.26 -4.19 (m, 1H), 4.08 – 3.94 (m, 2H), 2.20 -2.10 (m, 1H), 2.09 -1.92 (m, 1H), 1.74 – 1.51 (m, 2H), 1.37 (d, J = 13.7 Hz, 6H), 1.16 (t, J = 6.3 Hz, 6H), 0.88 (t, J = 7.4 Hz, 3H). EXAMPLE 25 – Synthesis of Compound VII-21: Isopropyl ((((2R,3S,5R)-2-(chloromethyl)- 3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl) methoxy)(phenoxy)phosphoryl)-L-alaninate

[0587] Step 1: To a stirred solution of phenyl dichlorophosphate (1.26 g, 5.96 mmol) in DCM (15 mL) was added C₆F₅OH (1.21 g, 6.56 mmol) and TEA (1.11 g, 11 mmol) at -78 °C. The resulting mixture was stirred for 30 min at -78 °C under N2 atmosphere. To the above solution, isopropyl 2-amino-2-methylpropanoate hydrochloride (1 g, 5.50 mmol) and TEA (1.11 g, 11 mmol) was added at -20 °C. The reaction mixture was stirred for 16 h at room temperature under N₂ atmosphere, then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: (column, C₁₈ silica gel; Mobile Phase A: Water (0.5% FA), Mobile Phase B: ACN, 10% to 90% gradient in 25 min; UV detection at 254 nm). The fractions were collected and concentrated under reduced pressure to afford isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (1.5 g, 3.3 mmol, 55.4%) as a white solid. LC/MS (ES, m/z): 454 [M+H]⁺. [0588] Step 2: To a stirred solution of 1-((2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (65 mg, 224 μmol) in THF (4 mL) was added t-BuMgCl (257 μL, 257 μmol, 1.0 M in THF) at 0 °C under N₂ atmosphere. The mixture was stirred for 20 min at 0 °C. To the above solution was added a solution of isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (116 mg, 258 μmol) in THF (2 mL) at 0 °C. The resulting mixture was stirred for 16 h at room temperature, then concentrated under reduced pressure purified by Prep-TLC (DCM/MeOH = 12/1) to give the crude product which was re-purified by Prep-HPLC under following conditions (Column: X- Select prep OBD C18 Column, 30*150 mm, 5.0 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B - 50% B in 11min; Wave Length: 254/220 nm; RT1(min): 6.56). The fractions were collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H₂O, and then was lyophilized overnight to afford isopropyl ((((2R,3S,5R)-2-(chloromethyl)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (25.7 mg, 45 μmol, 20.2%) as a white solid. LC/MS: (ES, m/z): 560/562 [M+H]⁺; 98.7% purity. [0589] Conditions for the LC/MS: (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: 1.50 L/min; Gradient: 5% B to 60% B in 1.70 min, 60% B to 100% B in 0.60 min, 100% B to 5% B in 0.03 min; Wave Length: 254/220 nm; RT1(min): 1.217).¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 7.53 (d, J = 1.4 Hz, 1H), 7.42 – 7.32 (m, 2H), 7.21 (dd, J = 18.8, 3H), 6.28 (dd, J = 8.7, 1H), 6.09 (dd, J = 13.2, 1H), 5.67 (dd, J = 14.1, 5.0 Hz, 1H), 4.92 – 4.82 (m, 1H), 4.39 (s, 1H), 4.26 – 4.11 (m, 2H), 3.88 – 3.71 (m, 2H), 2.34 – 2.26 (m, 1H), 2.19 – 2.10 (m, 2H), 1.76 (d, J = 1.1 Hz, 3H), 1.23 (d, J = 7.1 Hz, 3H), 1.19 – 1.13 (m, 6H). EXAMPLE 26 – Synthesis of Compound VII-22: 1-((2R,4S,5R)-5-(chloromethyl)-5- (({di((isopropoxycarbonyl)oxy)methoxyphosphoryl}oxy)methyl)-4-hydroxyoxolan-2-yl)-5- methyl-3H-pyrimidine-2,4-dione

[0590] Pre-dry process: A solution of ((hydroxyphosphoryl)bis(oxy))bis(methylene) diisopropyl-bis(carbonate) (306 mg, 930 umol) and 1-((2R,4S,5R)-5-(chloromethyl)-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (90 mg, 310 μmol) was suspended in pyridine (1 mL). NMI (381 mg, 4.65 mmol) was added and the mixture was evaporated to dryness on rotary evaporator for 20 minutes. [0591] The residue was then dissolved in ACN (2 mL) and BOP-Cl (433 mg, 1.71 mmol) was added under N2 atmosphere. The resulting mixture was stirred for 2 h at room temperature under N₂ atmosphere, then concentrated under reduced pressure and the crude product was purified by Prep-HPLC under the following conditions (Column: Xselect CSH Prep 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 60% B in 11 min; Wave Length: 254nm/220 nm; RT1(min): 6.86). The fraction was collected and concentrated under vacuum, the residue was re-dissolved in CH3CN and H2O, and then lyophilized to afford 1-((2R,4S,5R)-5-(chloromethyl)-5- (({di((isopropoxycarbonyl)oxy)methoxyphosphoryl}oxy)methyl)-4-hydroxyoxolan-2-yl)-5- methyl-3H-pyrimidine-2,4-dione (16.8 mg, 27 umol, 8.9%) as a white solid. LC/MS (ES, m/z): 603/605 [M+H]⁺; 99.9% purity. [0592] Conditions for the LC/MS: (Column: Shim‐pack Scepter C18, 33*3.0 mm; Mobile Phase A: Water/5mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.50 mL/min; Gradient: 20% B to 60% B in 1.70 min, 60% B to 95% B in 2.30 min, 95% B to 95% B in 2.80 min, 95% B to 10% B in 2.83 min; Wave Length: 254/220 nm; RT1(min): 1.333).¹H NMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H), 7.46 (s, 1H), 6.29 (dd, J = 8.5, 5.9 Hz, 1H), 5.73 (s, 1H), 5.63 (dd, J = 13.9, 2.5 Hz, 4H), 4.83 (dq, J = 12.2, 6.1 Hz, 2H), 4.39 (d, J = 5.8 Hz, 1H), 4.26 (h, J = 5.4 Hz, 2H), 3.89 – 3.71 (m, 2H), 2.35 (td, J = 8.1, 4.1 Hz, 1H), 2.25 – 2.12 (m, 1H), 1.79 (s, 3H), 1.35 – 1.16 (m, 12H). EXAMPLE 27 – Synthesis of Compound VII-23: 4-amino-1-((2R,4S,5R)-5-(({di[(iso- propoxycarbonyl)oxy)methoxyphosphoryl}oxy)methyl)-5-ethyl-4-hydroxyoxolan-2-yl) pyrimidin-2-one

[0593] Step 1: To a solution of (S)-3-((2S,3R,4R,5R)-5-(chloromethyl)-3-fluoro-5- (hydroxymethyl)-4-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)-5- fluoropyridine-2,6(1H,3H)-dione (200 mg, 342 μmol) in DMF (3 mL) was added imidazole (70 mg, 1.03 mmol) under N2 atmosphere, then TBSCl (103 mg, 684 μmol) at 0 °C. After stirring for 16 h at 80 °C under N2 atmosphere the resulting mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure and purified by Prep-TLC (PE: EA = 2:1) to afford 1-((2R,3S,4R,5R)-5-(((tert-butyldimethylsilyl) oxy) methyl)-5-(chloromethyl)-3-fluoro-4- ((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)- dione (200 mg, 287 μmol, 83.7%) as a light yellow solid. LC/MS (ES, m/z): 697/699 [M-H]-. [0594] Step 2: A solution of 1-((2R,3S,4R,5R)-5-(((tert-butyldimethylsilyl) oxy) methyl)-5- (chloromethyl)-3-fluoro-4-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)-5- fluoropyrimidine-2,4(1H,3H)-dione (200 mg, 287 μmol) in ACN (4 mL) was added DMAP (143 mg, 1.18 mmol) and TEA (119 mg, 1.18 mmol) under N2 atmosphere. The reaction was stirred for 10 mins. and TPSCl (178 mg, 588 μmol) was added at 0 °C. The mixture was stirred for 16 h at room temperature under N2 atmosphere. When the starting material was consumed, concentrated aqueous ammonia (2 mL) was added and the reaction was stirred for 30 mins. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep- TLC (DCM: MeOH=10:1) to afford 4-amino-1-((2R,3S,4R,5R)-5-(((triisopropylsilyl) oxy) methyl)-5-(chloromethyl)-3-fluoro-4-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2- yl)-5-fluoropyrimidin-2(1H)-one (190 mg, 272 μmol, 95.1%) as a light yellow oil. LC/MS (ES, m/z): 696/698 [M-H]-. [0595] Step 3: To a solution of 4-amino-1-((2R,3S,4R,5R)-5-(((trisisopropylsilyl)oxy) methyl)-5-(chloromethyl)-3-fluoro-4-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2- yl)-5-fluoropyrimidin-2(1H)-one (190 mg, 272 μmol) in DCM (5 mL) was added collidine (208 mg, 1.72 mmol) and MMTrCl (354 mg, 1.14 mmol) at 0 °C. After stirring for 16 h at room temperature under N2 atmosphere, the resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers were washed with saturated NaCl solution and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE: EA = 3:1) to afford 1-((2R,3S,4R,5R)-5-(((tert- butyldimethylsilyl)oxy)methyl)-5-(chloromethyl)-3-fluoro-4-((4-methoxyphenyl) diphenylmethoxy)tetrahydrofuran-2-yl)-5-fluoro-4-(((4-methoxyphenyl)diphenylmethyl) amino) pyrimidin-2(1H)-one (250 mg, 258 μmol, 89.9%) as a light yellow solid. LC/MS (ES, m/z): 968/970 [M-H]-. [0596] Step 4: To a solution of 1-((2R,3S,4R,5R)-5-(((triisopropylsilyl) oxy) methyl)-5- (chloromethyl)-3-fluoro-4-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)-5-fluoro- 4-(((4-methoxyphenyl) diphenylmethyl) amino) pyrimidin-2(1H)-one (120 mg, 124 μmol) in MeOH (5 mL) was added NH4F (137 mg, 3.72 mmol) under N2 atmosphere. After stirring for 16 h at 60 °C under N2 atmosphere the resulting mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TLC (PE: EA=2:1) to afford 1-((2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-5-(hydroxymethyl)-4-((4-methoxyphenyl) diphenylmethoxy) tetrahydrofuran-2-yl)-5-fluoro-4-(((4-methoxyphenyl)diphenylmethyl) amino) pyrimidin-2(1H)-one (100 mg, 117 μmol, 94.4%) as a light yellow solid. LC/MS (ES, m/z): 854/856 [M-H]-. [0597] Step 5: Pre-dry process: A solution of ((hydroxyphosphoryl)bis(oxy)) bis(methylene) diisopropyl bis(carbonate) (308 mg, 936 μmol) and 1-((2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro- 5-(hydroxymethyl)-4-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)-5-fluoro-4- (((4-methoxyphenyl) diphenylmethyl) amino) pyrimidin-2(1H)-one (200 mg, 234 μmol) was suspended in pyridine (2 mL). The mixture was evaporated to dryness on rotary evaporator for 20 minutes. The residue was then dissolved in THF (10 mL). To the solution was added DIEA (302 mg, 2.34 mmol), BOP-Cl (297 mg, 1.17 mmol), and 3-nitro-1H-1,2,4-triazole (133 mg, 1.17 mmol) at 0 °C under N2 atmosphere. The mixture was stirred for 16 h at room temperature, filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure and purified by Prep-TLC (PE: EA=2:1) to afford 1-((2R,3S,4R,5R)-5-(chloromethyl)-5- [({di[(isopropoxycarbonyl)oxy)methoxyphosphoryl}oxy)methyl)-3-fluoro-4-((4-methoxy- phenyl)diphenylmethoxy) oxolan-2-yl)-5-fluoro-4-{((4-methoxyphenyl)diphenyl methyl) amino}pyrimidin-2-one (200 mg, 171 μmol, 73.2%) as a light yellow oil. LC/MS (ES, m/z): 1166/1168 [M-H]-. [0598] Step 6: A solution of 1-((2R,3S,4R,5R)-5-(chloromethyl)-5-[({di[(isopropoxy- carbonyl)oxy)methoxyphosphoryl}oxy)methyl)-3-fluoro-4-((4-methoxyphenyl) diphenylmethoxy)oxolan-2-yl)-5-fluoro-4-{((4-methoxyphenyl) diphenyl methyl) amino} pyrimidin-2-one (200 mg, 171 μmol) in AcOH (80% in water) (10 mL) was stirred for 16 h at room temperature. The resulting mixture was concentrated and purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm 5μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 45% B in 10 min; Wave Length: 254/210 nm; RT1(min): 8.15). The fraction was collected and concentrated under vacuum, the residue was re-dissolved in CH₃CN and H₂O, and then was lyophilized to afford 4-amino-1-((2R,4S,5R)-5-(({di[(isopropoxycarbonyl)oxy)methoxy- phosphoryl}oxy)methyl)-5-ethyl-4-hydroxyoxolan-2-yl)pyrimidin-2-one (43 mg, 69 μmol, 40.2%) as an off-white solid. LC/MS (ES, m/z): 624/626 [M+H]⁺; 99.9% purity. [0599] Conditions for the LC/MS: (Column: Shim‐pack Scepter C₁₈ Column, 30*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 95% B in 1.20 min, 95% B to 95% B in 0.60 min, 95% B to 10% B in 0.02 min; Wave Length: 254/220 nm; RT1(min): 0.854).¹H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.78 (dd, J = 7.0, 1.6 Hz, 1H), 7.69 (s, 1H), 6.45 (d, J = 5.2 Hz, 1H), 6.30 – 6.22 (m, 1H), 5.63 (dd, J = 13.9, 6.0 Hz, 4H), 5.09 (dt, J = 52.1, 2.6 Hz, 1H), 4.91 – 4.75 (m, 2H), 4.40 (ddd, J = 16.1, 5.2, 2.1 Hz, 1H), 4.36 – 4.26 (m, 2H), 3.92 – 3.76 (m, 2H), 1.25 (t, J = 5.8 Hz, 12H). EXAMPLE 28 – Synthesis of Compound VII-24: isopropyl ((((2R,3R,4S,5R)-5-(4-amino-5- fluoro-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl) methoxy)(phenoxy)phosphoryl)-L-alaninate

[0600] Step 1: To a stirred solution of phenyl phosphorodichloridate (2 g, 9.48 mmol) and C6F5OH (2.3 g, 10.4 mmol) in DCM (22 mL) was added TEA (1.9 g, 18.9 mmol) at -78°C under N2 atmosphere. The resulting mixture was stirred for 10 min at -78°C, then isopropyl L- alaninate (1.37 g, 10.5 mmol) and TEA (1.9 g, 18.9 mmol) in DCM (10 mL) was added. The resulting mixture was stirred for 2 h at -40 °C, then was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C₁₈ silica gel; mobile phase, ACN in water (10 mmol/L NH₄HCO₃), 35% to 50% gradient in 20 min; UV detection at 254 nm to afford isopropyl((perfluorophenoxy)(phenoxy) phosphoryl)-L-alaninate (1 g, 2.2 mmol, 23.3%) as an off-white solid. LC/MS (ES, m/z): 454 [M+H]⁺. [0601] Step 2: A solution of 4-amino-1-((2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4- hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-fluoropyrimidin-2(1H)-one (36 mg, 100 μmol) and t-BuMgCl (16 mg, 115 μmol) in THF (5 mL) was stirred for 30 min at 0 °C under N2 atmosphere. To the above mixture was added isopropyl((perfluorophenoxy)(phenoxy) phosphoryl)-L-alaninate (50 mg, 100 μmol) at 0°C, then stirred overnight at room temperature. The resulting mixture was diluted with water at 0 ^oC and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum, then the residue was purified by reversed- phase flash chromatography under the following conditions: (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 75% B in 8 min, 75% B; Wave Length: 210 nm). The fraction was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H₂O, and then was lyophilized to afford isopropyl ((((2R,3R,4S,5R)-5-(4-amino-5- fluoro-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (7.7 mg, 10 μmol, 11.5%) as a white solid. LC/MS (ES, m/z): 581 and 583 [M+H]⁺; 99.2% purity. [0602] Conditions for the LC/MS: (Column: Shim‐pack Scepter C18, 33*3.0 mm, 2.5 μm; Mobile Phase A: water/5mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.20 mL/min; Gradient: 0% B to 10% B in 0.01 min, 10% B to 95% B in 1.20 min, 95% B to 95% B in 0.60 min, 95% B to 10% B in 0.02 min; Wave Length: 254/220 nm; RT(min):

NMR (400 MHz, DMSO-d₆) δ 7.91 (s, 1H), 7.82 (dd, J = 19.4, 6.8 Hz, 1H), 7.67 (s, 1H), 7.43 – 7.32 (m, 2H), 7.28 – 7.11 (m, 3H), 6.38 (dd, J = 17.1, 4.8 Hz, 1H), 6.25 (d, J = 19.5 Hz, 1H), 6.17 – 6.10 (m, 1H), 5.27 – 4.99 (m, 1H), 4.91 – 4.84 (m, 1H), 4.43 (d, J = 16.7 Hz, 1H), 4.26 (t, J = 7.1 Hz, 2H), 3.90 – 3.71 (m, 3H), 1.31 – 1.21 (m, 3H), 1.19 – 1.15 (m, 6H).

EXAMPLE 29 – Synthesis of Compound VII-25 and Compound VII-26: isopropyl ((R)- (((2R,3R,4S,5R)-5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro- 3-hydroxytetrahydrofuran-2-yl) methoxy)(phenoxy)phosphoryl)-L-alaninate and isopropyl ((S)-(((2R,3R,4S,5R)-5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4- fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy)(phenoxy)phosphoryl)-L-alaninate, respectively

[0603] The isopropyl ((((2R,3R,4S,5R)-5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-2- (chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy)(phenoxy)phosphoryl)-L- alaninate (65 mg, 112 μmol) was purified by Prep-Chiral-HPLC with the following conditions (Column: JW-CHIRALPAK-ID 2*25 cm; 5um; Mobile Phase A: IPA--HPLC, Mobile Phase B: Hex (0.5% 2 M NH₃-MeOH) --HPLC; Flow rate: 16 mL/min; Gradient: 50% B to 50% B in 20 min; Wave Length: 220/254 nm; RT1(min): 10.51; RT2(min): 18.21). Diastereomer 1 was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H₂O, and then was lyophilized to afford isopropyl ((R or S)-(((2R,3R,4S,5R)-5-(4-amino-5-fluoro-2- oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl)-L-alaninate (11.3 mg, 20 μmol, 22.6%) as a white solid. Diastereomer 2 was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H2O, and then was lyophilized to give isopropyl ((S or R)-(((2R,3R,4S,5R)-5-(4-amino-5-fluoro-2- oxopyrimidin-1(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (6.5 mg, 10 μmol, 13%) as a white solid. [0604] LC/MS (Compound VII-25) (ES, m/z): 581 and 583 [M+H]⁺; 97.2% purity. Conditions for the LC/MS: (Column: Shim‐pack Scepter C18, 33*3.0 mm, 2.5 μm; Mobile Phase A: water/5mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.20 mL/min; Gradient: 0% B to 10% B in 0.01 min, 10% B to 95% B in 1.20 min, 95% B to 95% B in 0.60 min, 95% B to 10% B in 0.02 min; Wave Length: 254/220 nm; RT(min): 1.247). [0605] Conditions for the Chiral-HPLC: (Column: JW-CHIRALPAK ID-3, 4.6*50 mm, 3 μm; Mobile Phase A: Hex (0.1%DEA): IPA = 50: 50; Flow rate: 1 mL/min; Wave Length: 254 nm; RT(min): 1.680).¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (s, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.67 (s, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.21 (dd, J = 17.7, 7.8 Hz, 3H), 6.35 (d, J = 5.2 Hz, 1H), 6.25 (dt, J = 19.8, 2.9 Hz, 1H), 6.14 (dd, J = 13.2, 10.1 Hz, 1H), 5.09 (dt, J = 52.3, 2.6 Hz, 1H), 4.91 – 4.85 (m, 1H), 4.49 – 4.38 (m, 1H), 4.25 (d, J = 6.4 Hz, 2H), 3.91 – 3.72 (m, 3H), 1.23 (d, J = 7.1 Hz, 3H), 1.17 (dd, J = 6.3, 3.0 Hz, 6H). [0606] LC/MS (Compound VII-26) (ES, m/z): 581 and 583 [M+H]⁺; 99.4% purity. Conditions for the LC/MS: (Column: Shim‐pack Scepter C18, 33*3.0 mm, 2.5 μm; Mobile Phase A: water/5mM NH₄HCO₃, Mobile Phase B: Acetonitrile; Flow rate: 1.20 mL/min; Gradient: 0% B to 10% B in 0.01 min, 10% B to 95% B in 1.20 min, 95% B to 95% B in 0.60 min, 95% B to 10% B in 0.02 min; Wave Length: 254/220 nm; RT1(min): 0.832). Conditions for the Chiral-HPLC: (Column: JW-CHIRALPAK ID-3, 4.6*50 mm, 3 μm; Mobile Phase A: Hex (0.1% DEA): IPA = 50: 50; Flow rate: 1 mL/min; Wave Length: 254 nm; RT1(min): 3.379). ¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (s, 1H), 7.80 (dd, J = 6.9, 1.5 Hz, 1H), 7.67 (s, 1H), 7.41 – 7.32 (m, 2H), 7.23 – 7.14 (m, 3H), 6.39 (d, J = 5.2 Hz, 1H), 6.29 – 6.23 (m, 1H), 6.13 (dd, J = 12.9, 9.9 Hz, 1H), 5.12 (dt, J = 52.3, 2.8 Hz, 1H), 4.87 (p, J = 6.2 Hz, 1H), 4.46 – 4.40 (m, 1H), 4.27 (d, J = 5.5 Hz, 2H), 3.92 – 3.71 (m, 3H), 1.23 (d, J = 7.1 Hz, 3H), 1.16 (dd, J = 6.2, 1.9 Hz, 6H).

EXAMPLE 30 – Synthesis of Compound VII-27: 1-((2R,3S,4R,5R)-5-(chloromethyl)-5- (((di((isopropoxycarbonyl)oxy)methoxyphosphoryl)oxy)methyl)-3-fluoro-4-hydroxy- oxolan-2-yl)-5-fluoro-3H-pyrimidine-2,4-dione

[0607] Pre-dry process: A solution of 1-((2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4- hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (65 mg, 208 μmol) and ((hydroxyphosphoryl)bis(oxy)) bis(methylene) diisopropyl bis(carbonate) (206 mg, 593 μmol) was suspended in pyridine (2 mL). NMI (512 mg, 6.2 mmol) was added and the mixture was evaporated to dryness on the rotary evaporator for 20 minutes. [0608] The residue was then dissolved in ACN (5 mL) and BOP-Cl (582 mg, 2.3 mmol) was added under N₂ atmosphere, then stirred for 2 h at room temperature under N₂ atmosphere. After completion, the resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC under the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 45% B in 7 min; Wave Length: 254/210 nm; RT1(min): 6.25). The fraction was collected and concentrated under vacuum, the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford 1- ((2R,3S,4R,5R)-5-(chloromethyl)-5-(((di((isopropoxycarbonyl)oxy) methoxyphosphoryl) oxy) methyl)-3-fluoro-4-hydroxyoxolan-2-yl)-5-fluoro-3H-pyrimidine-2,4-dione (5.9 mg, 9 μmol, 4.1%) as an off-white solid. LC/MS (ES, m/z): 625/627 [M+H]⁺; 91.2% purity. [0609] 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/0.1% FA; Flow rate: 1.50 mL/min; Gradient: 5% 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; Wave Length: 254; RT1(min): 1.26).¹H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.93 – 7.84 (m, 1H), 6.47 (d, J = 5.3 Hz, 1H), 6.37 – 6.21 (m, 1H), 5.62 (dd, J = 13.8, 6.1 Hz, 4H), 5.29 – 5.05 (m, 1H), 4.83 (h, J = 6.2 Hz, 2H), 4.50 – 4.41 (m, 1H), 4.33 (d, J = 6.2 Hz, 2H), 3.95 – 3.71 (m, 2H), 1.25 (dd, J = 6.2, 5.0 Hz, 12H). EXAMPLE 31 – Synthesis of Compound VII-28: 4-amino-1-((2R,4S,5R)-5-(({di [(iso- propoxycarbonyl)oxy)methoxyphosphoryl}oxy)methyl)-5-ethynyl-4-hydroxyoxolan-2-yl) pyrimidin-2-one

[0610] Pre-dry process: A solution of ((hydroxyphosphoryl)bis(oxy))bis(methylene) diisopropyl bis(carbonate) (79 mg, 240 μmol) and 4-amino-1-((2R,4S,5R)-5-ethynyl-4-hydroxy- 5-(hydroxymethyl) tetrahydrofuran-2-yl) pyrimidin-2(1H)-one (20 mg, 80 μmol) was suspended in pyridine (1 mL). NMI (98 mg, 1.2 mmol) was added and the mixture was then evaporated to a residue by rotary evaporation for 20 minutes. [0611] The residue was then dissolved in acetonitrile (2 mL) and BOP-Cl (111 mg, 440 μmol) was added under N2 atmosphere. The reaction was stirred for 3 h at room temperature. After completion, the resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC under the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47% B in 10 min, 47% B; Wave Length: 254 nm; RT1(min): 9.18). The fraction was collected and concentrated under vacuum, the residue was re- dissolved in CH₃CN and H₂O, and then was lyophilized to afford 4-amino-1-((2R,4S,5R)-5- (({di[(isopropoxycarbonyl)oxy) methoxyphosphoryl}oxy)methyl)-5-ethynyl-4-hydroxyoxolan-2- yl) pyrimidin-2-one (5.3 mg, 9 μmol, 11.4%) as an off-white oil. LC/MS (ES, m/z): 564 [M+H] ⁺. 96.9% purity. [0612] Conditions for the LC/MS: (Column: HALO AQ‐C₁₈ Column, 30*3.0 mm, 2.0 μm; Mobile Phase A: Water+0.05% TFA, Mobile Phase B: Acetonitrile+0.05% TFA; Flow rate: 1.20 mL/min; Gradient: 5% B to 100% B in 1.30 min, 100% B to 100% B in 0.50 min, 100% B to 5% B in 0.03 min; Wave Length: 254/220 nm; RT(min): 0.998).¹H NMR (400 MHz, DMSO-d6 + D2O) δ 7.97 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 6.09 (dd, J = 6.9, 4.9 Hz, 1H), 5.53 (d, J = 13.5 Hz, 4H), 4.80 (pd, J = 6.2, 1.7 Hz, 2H), 4.34 (t, J = 7.2 Hz, 1H), 3.67 (d, J = 12.1 Hz, 1H), 3.61 (d, J = 12.1 Hz, 1H), 2.78 (s, 1H), 2.29 (dp, J = 25.4, 6.5 Hz, 2H), 1.27 – 1.15 (m, 12H). EXAMPLE 32 – Synthesis of Compound VII-29

[0613] A suspension of 1-((2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (0.125g, 0.405mmol), ((hydroxyphosphoryl)bis(oxy))bis(methylene)diisopropyl bis(carbonate) (0.669 g, 2.025 mmol) and 1-Methyl-imidazole (0.765g, 9.31 mmol) was co distilled with pyridine (3 x 5 mL) and ACN (3 x 5 mL). To this MeCN (3 mL) was added and cooled to 0°C. BOP-Cl (0.93 g, 3.64 mmol) added and stirring was continued for 1 h at 0°C to 10°C. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mass was filtered via syringe filter and the filtrate was subjected to Prep HPLC purification under these conditions: Mobile Phase: A: 0.1% formic acid in water; B: MeCN; Column: X SELECT (250mmx20.0mm), 5.0µ; Flow rate: 15mL/min; Gradient program: Time/% B: 0/20,2/30,8/60 to afford the desired product (40 mg, 15 %) as colorless sticky liquid. LC/MS (ES, m/z): 621.15 (M+1). ¹H NMR (400 MHz, DMSO-d6) δ = 11.54 - 11.42 (m, 1H), 7.44 (s, 1H), 6.45 (br d, J = 1.0 Hz, 1H), 6.30 (dd, J = 3.8, 18.5 Hz, 1H), 5.62 (dd, J = 7.3, 13.9 Hz, 4H), 5.25 - 5.07 (m, 1H), 4.88 - 4.76 (m, 2H), 4.43 (br d, J = 17.6 Hz, 1H), 4.35 - 4.29 (m, 2H), 3.93 - 3.75 (m, 2H), 1.78 (s, 3H), 1.24 (t, J = 6.2 Hz, 12H). EXAMPLE 33 – Synthesis of Compound VII-30

Compound VII-30 [0614] A suspension of 1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4 (1H,3H)-dione (0.070 g, 0.23 mmol) and ((hydroxyphosphoryl)bis(oxy))bis(methylene) diisopropyl bis(carbonate) (0.153 g, 0.47 mmol) and 3-Nitro-1H-1,2,4-triazole (0.053g,0.47 mmol) were co-distilled with pyridine (3 x 5 mL) and then with acetonitrile for 3 times each. The reaction mixture was diluted with THF (3 mL) and DIEA (0.120g, 0.93 mmol) was added at rt. The reaction was stirred for 15 min, then cooled to 0°C, BOP-Cl (0.118g, 0.465 mmol) was added and stirring was continued at rt for 2h. The reaction progress was monitored by TLC and LC/MS. After completion, the reaction was concentrated and resulting residue was triturated with n-Hexane, dried under vacuum to get crude product as pale-yellow liquid and purified by prep-HPLC purification under these conditions: Mobile Phase: A: 0.1% formic acid in water; B: MeCN; Column: WATERS X BRIDGE (150mmx20.0mm), 5.0µ; Flow rate: 15mL/min; Gradient program: Time/% B: 0/20,2/30,8/60 to afford the desired product (10 mg, 7.04 %) as a viscous, colorless liquid. LC/MS (ES, m/z): 613.75 (M+1).¹H NMR (400 MHz, DMSO-d6) δ = 11.59 - 11.52 (m, 1H), 7.43 (s, 1H), 6.70 (d, J = 5.6 Hz, 1H), 5.62 (dd, J = 2.9, 13.8 Hz, 4H), 5.38 - 5.19 (m, 1H), 4.88 - 4.78 (m, 2H), 4.61 - 4.52 (m, 1H), 4.47 - 4.29 (m, 2H), 1.79 (s, 3H), 1.24 (dd, J = 4.9, 6.1 Hz, 13H). EXAMPLE 34 – Synthesis of Additional Compounds ^ [0615] The compounds listed in Table 8 below were prepared using experimental procedures and strategies described in Examples 1-6, the Detailed Description, and related strategies and procedures known to those skilled in the art of organic synthesis. Table 8 also lists each

NMR characterization data and mass-to-charge ratio observed by LC/MS. Chemical structures are presented in Tables 1 and 2, above. TABLE 8.

EXAMPLE 35 – Stable Cellular Assay for Inhibiting LINE1 Reverse Transcriptase ^ [0616] 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 [0617] A stable HeLa 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. [0618] 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 [0619] Experimental results are provided in Table 9, below. The symbol “***” indicates an IC₅₀ less than or equal to 0.05 ^M. The symbol “**” indicates an IC₅₀ in the range of greater than 0.05 ^M to less than or equal to 0.5 ^M. The symbol “*” indicates an IC50 greater than 0.5 ^M. TABLE 9.

EXAMPLE 36 – Biochemical Assay for Inhibiting LINE1 Reverse Transcriptase ^ [0620] 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 [0621] 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) . [0622] 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 37 – Biochemical Assay for Inhibiting HERV-K Reverse Transcriptase ^ [0623] 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 [0624] 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). [0625] 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) . [0626] 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 38 – Cellular Assay for Altering IFN Production in THP1 TREX1 KO Cells [0627] Exemplary compounds were tested for their ability to alter the type 1 interferon response in THP1 Dual TREX1 KO cells treated with 5-aza-2ʹ-deoxycytidine. Assay procedures and results are described below. Part I – Procedure [0628] 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. [0629] 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. [0630] 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. [0631] For certain compounds, the assay was run in a 96-well format, with the following modifications: ^ 190 ^L, instead of 50 ^L, 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 ^L, instead of 20 ^L, of cell supernatant was added to the white-walled plate for QUANTI-LUC treatment; and ^ 25 ^L, instead of 30 ^L, of CellTiter-Glo was added to assess cell viability. [0632] 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. [0633] 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 (benzyl N-[(2S)-4-methyl-1-[[(2S)- 4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2- yl]carbamate). Part II - Results [0634] Results are shown in Table 10, below. In the table, “A” represents values ≤ 0.050 µM; “B” represents values from > 0.050 µM to ≤ 0.100 µM; “C” represents values from > 0.100 µM to ≤ 0.250µM; “D” represents values from > 0.250 µM to ≤ 1 µM; and “E” represents values >1 µM:

EXAMPLE 39 – Cancer Cell Viability Assay with 3D Cell Colonies [0635] 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 [0636] 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 – RPMI-1640 + 10% FBS ^ Esophageal cancer KYSE-410 cells – RPMI-1640 + 5~10% FBS ^ Esophageal cancer KYSE-70 cells – RPMI-1640 + 10% h.i.FBS. ^ Pharyngeal cancer FaDu cells – MEM + 0.01mM NEAA + 10% FBS [0637] 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 ^L 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 40 – In Vivo Decitabine Challenge Model [0638] 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. [0639] 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:

[0640] 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 41 – Decitabine-Stimulated Human PBMC Assay [0641] 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. [0642] 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). [0643] 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 42 – Producing THP1 TREX1 KO Xenografts with Decitabine-Induced IFN [0644] The ability to produce THP1-Dual^TM 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 [0645] 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 [0646] Experimental results are depicted in Figure 1. Data was normalized relative to vehicle. In Figure 1, “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 43 – Assay for Altering IFN Production in THP1 TREX1 KO Xenografts [0647] 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 [0648] 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. [0649] 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 [0650] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS [0651] 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:

m is 0, 1, 2, or 3. 2. The compound of claim 1, wherein the compound is a compound of Formula I. 3. The compound of claim 1 or 2, wherein R² is fluoro, hydrogen, or -OH. 4. The compound of any one of claims 1-3, wherein R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, or - CF3. 5. The compound of any one of claims 1-3, wherein R³ is -CH2Cl or -CH2F. 6. The compound of any one of claims 1-3, wherein R³ is C1-3 aliphatic. 7. The compound of any one of claims 1-3, wherein R³ is -CH3, -CH2CH3, -C(H)=CH2, - CH2C(H)=CH2, -C≡CH, or cyclopropyl. 8. The compound of claim 1, wherein the compound is represented by Formula I-A:

(I-A) or a pharmaceutically acceptable salt thereof; wherein: R² is fluoro, hydrogen, or -OH; R³ is -CH2Cl or -CH2F; R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰; R⁶ is hydrogen or C1-4 alkyl; R⁷ is -C(R⁸)2-CO2R⁹; R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; R¹⁰ represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl; R¹¹ is hydrogen, halo, -CH3, or -CF3;

m is 0, 1, 2, or 3. 9. The compound of claim 8, wherein the compound is a compound of Formula I-A. 10. The compound of any one of claims 1-9, wherein R⁶ is hydrogen. 11. The compound of any one of claims 1-10, wherein R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen. . The compound of any one of claims 1-11, wherein R⁷ is

. 13. The compound of any one of claims 1-10, wherein two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. 14. The compound of any one of claims 1-13, wherein R⁹ is C_1-6 alkyl. 15. The compound of any one of claims 1-14, wherein R⁵ is phenyl substituted with m instances of R¹⁰. 16. The compound of any one of claims 1-14, wherein R⁵ is naphthyl substituted with m instances of R¹⁰. 17. The compound of any one of claims 1-15, wherein R⁵ is

. 18. The compound of any one of claims 1-16, wherein m is 1. 19. The compound of any one of claims 1-16, wherein m is 0.

20. The compound of any one of claims 1-18, wherein R¹⁰ represents independently for each occurrence halo. 21. The compound of claim 1, wherein the compound is represented by Formula I-B:

or a pharmaceutically acceptable salt thereof; wherein: R² is fluoro, hydrogen, or -OH; R³ is -CH2Cl or -CH2F; R⁴ represents independently for each occurrence C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1- 10 alkyl), or hydrogen; R¹¹ is hydrogen, halo, -CH3, or -CF3; and

. 22. The compound of claim 21, wherein the compound is a compound of Formula I-B. 23. The compound of any one of claims 1-7, 21, or 22, wherein R⁴ represents independently for each occurrence C1-6 alkyl. 24. The compound of any one of claims 1-7, 21, or 22, wherein R⁴ represents independently for each occurrence -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl). 25. The compound of any one of claims 1-7, 21, or 22, wherein R⁴ is -CH2-OC(O)O-(C1-6 alkyl). 26. The compound of any one of claims 1-25, wherein R² is fluoro. 27. The compound of any one of claims 1-25, wherein R² is hydrogen.

28. The compound of any one of claims 1-25, wherein R² is -OH. 29. The compound of any one of claims 1-5 or 8-28, wherein R³ is -CH2Cl. 30. The compound of any one of claims 1-5 or 8-28, wherein R³ is -CH2F. 31. The compound of any one of claims 1-30, wherein B¹ is

. 32. The compound of any one of claims 1-30, wherein

. 33. The compound of any one of claims 1-32, wherein R¹¹ is hydrogen. 34. The compound of any one of claims 1-32, wherein R¹¹ is halo. 35. The compound of any one of claims 1-32, wherein R¹¹ is -CH3 or -CF3. 36. A compound represented by Formula II:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -OR⁴ or -N(R⁶)(R⁷); R² is halo, hydrogen, or -OH; R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, -CF3, or C1-3 aliphatic; R⁴ is C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl), or hydrogen; R⁵ is hydrogen, halo, -CH3, or -CF3; R⁶ is hydrogen or C1-4 alkyl; R⁷ is -C(R⁸)2-CO2R⁹; R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; and

. 37. The compound of claim 36, wherein the compound is a compound of Formula II. 38. The compound of claim 36 or 37, wherein R¹ is -OR⁴. 39. The compound of any one of claims 36-38, wherein R⁴ is C1-6 alkyl. 40. The compound of any one of claims 36-38, wherein R⁴ is -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl). 41. The compound of claim 36 or 37, wherein R¹ is -N(R⁶)(R⁷). 42. The compound of any one of claims 36, 37, or 41, wherein R⁶ is hydrogen. 43. The compound of any one of claims 36, 37, 41, or 42, wherein R⁸ represents independently for each occurrence C_1-6 alkyl or hydrogen. 44. The compound of any one of claims 36, 37, or 41-43, wherein R⁷ is or

. 45. The compound of any one of claims 36, 37, 41, or 42, wherein two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring. 46. The compound of any one of claims 36, 37, or 41-45, wherein R⁹ is C_1-6 alkyl.

47. The compound of any one of claims 36-46, wherein R² is fluoro. 48. The compound of any one of claims 36-46, wherein R² is hydrogen. 49. The compound of any one of claims 36-49, wherein R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, or -CF3. 50. The compound of any one of claims 36-49, wherein R³ is -CH2Cl. 51. The compound of any one of claims 36-49, wherein R³ is -CH2F. 52. The compound of any one of claims 36-49, wherein R³ is C1-3 aliphatic. 53. The compound of any one of claims 36-52, wherein B¹ is

. 54. The compound of any one of claims 36-52, wherein

. 55. The compound of any one of claims 36-54, wherein R⁵ is hydrogen. 56. The compound of any one of claims 36-54, wherein R⁵ is halo. 57. The compound of any one of claims 36-54, wherein R⁵ is -CH3 or -CF3. 58. A compound in Table 1, 2, or 3 herein, or a pharmaceutically acceptable salt thereof. 59. A compound represented by Formula VII:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)), -P(O)(OR⁵)(pyrrolidinyl substituted by -CO₂-(C_1-6 aliphatic)), or -P(O)(OR⁴)₂; R² is halo, hydrogen, or -OH; R³ is -CH2Cl, -CH2F, -CH2Br, -CH2I, -CF3, C1-3 aliphatic, -N3, or hydrogen; R⁴ represents independently for each occurrence C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1- 10 alkyl), or hydrogen; R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰; R⁶ is hydrogen, C1-4 alkyl, or -C(R⁸)2-CO2R⁹; R⁷ is -C(R⁸)2-CO2R⁹; R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; R¹⁰ represents independently for each occurrence halo, C_1-4 alkyl, C_1-4 haloalkyl, or C_1-4 alkoxyl; R¹¹ is hydrogen, halo, -CH₃, or -CF₃;

m is 0, 1, 2, or 3. 60. The compound of claim 59, wherein the compound is a compound of Formula VII. 61. The compound of claim 59 or 60, wherein R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)). 62. The compound of claim 59 or 60, wherein R¹ is -P(O)(OR⁵)(pyrrolidinyl substituted by - CO₂-(C_1-6 aliphatic)). 63. The compound of claim 59 or 60, wherein R¹ is -P(O)(OR⁴)₂. 64. The compound of any one of claims 59-63, wherein R² is fluoro, hydrogen, or -OH. 65. The compound of any one of claims 59-64, wherein R³ is -CH₂Cl, -CH₂F, -CH₂Br, -CH₂I, or -CF₃.

66. The compound of any one of claims 59-64, wherein R³ is -CH2Cl or -CH2F. 67. The compound of any one of claims 59-64, wherein R³ is C1-3 aliphatic. 68. The compound of any one of claims 59-64, wherein R³ is -CH3, -CH2CH3, -C(H)=CH2, - CH2C(H)=CH2, -C≡CH, or cyclopropyl. 69. The compound of any one of claims 59-68, wherein B¹ i

. 70. The compound of any one of claims 59-68, wherein

. 71. A compound in Table 5, 6, or 7 herein, or a pharmaceutically acceptable salt thereof. 72. A pharmaceutical composition comprising a compound of any one of claims 1-71 and a pharmaceutically acceptable carrier. 73. 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 1-71 to treat the disorder. 74. 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 an influenza viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula III or Formula IV to treat the disorder; wherein Formula III is represented by:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -P(O)(OR⁵)(N(R⁶)(R⁷)) or -P(O)(OR⁴)₂; R² is halo, hydrogen, or -OH; R³ is halomethyl or C1-3 aliphatic; R⁴ represents independently for each occurrence C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1- 10 alkyl), or hydrogen; R⁵ is phenyl or naphthyl, each of which is substituted with m instances of R¹⁰; R⁶ is hydrogen or C1-4 alkyl; R⁷ is -C(R⁸)2-CO2R⁹; R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; R¹⁰ represents independently for each occurrence halo, C_1-4 alkyl, C_1-4 haloalkyl, or C_1-4 alkoxyl; R¹¹ is hydrogen, halo, -CH₃, or -CF₃;

m is 0, 1, 2, or 3; and wherein Formula IV is represented by:

or a pharmaceutically acceptable salt thereof; wherein: R¹ is -OR⁴ or -N(R⁶)(R⁷); R² is halo, hydrogen, or -OH; R³ is halomethyl or C1-3 aliphatic; R⁴ is C1-6 alkyl, -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl), or hydrogen; R⁵ is hydrogen, halo, -CH3, or -CF3; R⁶ is hydrogen or C1-4 alkyl; R⁷ is -C(R⁸)2-CO2R⁹; R⁸ represents independently for each occurrence C1-6 alkyl or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl; or two instances of R⁸ are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring; R⁹ is C1-6 alkyl or C2-6 alkenyl; wherein said C1-6 alkyl is optionally substituted with phenyl; and

. 75. The method of claim 74, wherein the compound is a compound of Formula III, or a pharmaceutically acceptable salt thereof. 76. The method of claim 74, wherein the compound is a compound of Formula IV, or a pharmaceutically acceptable salt thereof. 77. The method of any one of claims 74-76, wherein the disorder is an immune disorder that is a viral infection other than an influenza viral infection. 78. The method of any one of claims 74-76, wherein the disorder is an immune disorder that is a viral infection. 79. The method of claim 77 or 78, 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. 80. The method of any one of claims 74-76, wherein the disorder is cancer. 81. The method of claim 80, 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. 82. The method of any one of claims 74-76, wherein the disorder is an inflammatory disorder. 83. The method of claim 82, 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. 84. The method of any one of claims 74-76, wherein the disorder is an immune disorder other than a viral infection. 85. The method of claim 84, 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. 86. The method of claim 84, 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. 87. The method of any one of claims 74-76, wherein the disorder is a neurodegenerative disorder. 88. The method of claim 87, 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. 89. The method of any one of claims 74-88, wherein the method further comprises administering an effective amount of an additional therapeutic agent. 90. The method of any one of claims 74-89, 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. 91. The method of any one of claims 74-90, wherein the subject has (i) expression of HERV-K RNA and/or (ii) activity of HERV-K reverse transcriptase. 92. The method of any one of claims 74-91, wherein the subject is a human. 93. 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 1-71, in order to inhibit the activity of said LINE1 reverse transcriptase. 94. 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 1-71, in order to inhibit the activity of said HERV-K reverse transcriptase.