Prodrugs of phosphonamide nucleotide analogs and pharmaceutical uses thereof

Abstract

Disclosed are compounds, compositions, and methods useful for treating viral infections, such as human immunodeficiency virus (HIV) and / or hepatitis B virus (HBV) infection. In particular, prodrugs of phosphonamide nucleotide analogs, and methods for their preparation and use as therapeutic or prophylactic agents, are disclosed. The disclosure relates to novel prodrugs of the nucleotide analog reverse transcriptase inhibitor tenofovir and pharmaceutically acceptable salts thereof. In some embodiments, the compounds can be used to treat HIV infection, inhibit the activity of HIV reverse transcriptase, and / or reduce HIV replication.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 062,899, filed August 7, 2020, which is incorporated herein by reference in its entirety for all purposes.

[0002] FIELD OF THE INVENTION Disclosed are compounds, compositions, and methods useful for treating viral infections, such as human immunodeficiency virus (HIV) infection. [Background technology]

[0003] Human immunodeficiency virus infections and related diseases are major public health problems worldwide. Human immunodeficiency virus encodes three enzymes necessary for viral replication: reverse transcriptase, protease, and integrase. Drugs targeting reverse transcriptase are widely used and have shown efficacy, especially when used in combination with, for example, protease inhibitors and integrase inhibitors. There is no known cure for HIV, and therefore, individuals infected with HIV may require lifelong treatment. Improved treatments for HIV and other viral infections are desirable. Summary of the Invention [Means for solving the problem]

[0004] The present disclosure relates to novel prodrugs of the nucleotide analog reverse transcriptase inhibitor tenofovir and pharmaceutically acceptable salts thereof. In some embodiments, the compounds can be used to treat HIV infection, inhibit the activity of HIV reverse transcriptase, and / or reduce HIV replication. In some embodiments, the compounds disclosed herein can be effective against a range of known drug-resistant HIV variants. In some embodiments, the compounds disclosed herein have properties that allow them to be administered less frequently than daily, for example, weekly, monthly, or at longer intervals.

[0005] In one embodiment, there is provided a compound having the following formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 independently, C 1-12 Alkyl, aryl-C 1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, C 7-12 Spirocycloalkyl-C 1-4 Alkylene, Bridged C 5-10 Bicycloalkyl, Bridged C 5-10 Bicycloalkyl-C 1-4 Alkylene, fused C 5-10 Bicycloalkyl, C 10-16 Dispirocycloalkyl, C 10-16 Dispirocycloalkyl-C 1-4 Alkylene, Bridged C 9-12 Tricycloalkyl, Bridged C 9-12 Tricycloalkyl-C 1-4 Alkylene, C 3-7 Cycloalkyl-C 3-7cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; 1-12 Alkyl, aryl-C 1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a optionally substituted with R 3 , R 4 , R 5 and R 6 independently, C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b or optionally substituted with R 3 and R 4 together with the carbon atoms to which they are attached, form 1 to 3 R b forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R 5 and R 6 But independently, C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b optionally substituted with R 3 and R 4 But independently, C 1-4 Alkyl, C 3-6Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R 3 and R 4 together with the carbon atoms to which they are attached, form 1 to 3 R b forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with B is [ka] and R 7 is hydrogen or R 8 and R 8 -L 1 -(L 2 ) m -(L 3 ) n -R 8a and L 1 is selected from a bond, —C(O)—, and —C(O)O—; L 2 is C 1-6 is alkylene, L 3 is -C(O)O- or [ka] and R 8a is C1-12 Alkyl, aryl, -C(O)-aryl, -C(O)-C 1-4 Alkyl, -SC(O)-C 1-4 Alkyl, [ka] aryl and —C(O)-aryl are selected from one or two R c optionally substituted with Each R a independently, C 1-4 Alkyl, Halo, C 1-4 Haloalkyl and -OC 1-4 alkyl, Each R b independently, C 1-4 is alkyl, Each R c independently, C 1-4 Alkyl or -OC(O)-C 1-4 is alkyl, m and n are independently 0 or 1; p is 0, 1, or 2.

[0006] In another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In another embodiment, there is provided a pharmaceutical composition comprising a means for maintaining a therapeutically effective concentration of TFV-DP in PBMCs over an extended period of time and a pharmaceutically acceptable excipient, wherein the means for maintaining a therapeutically effective concentration of TFV-DP in PBMCs over an extended period of time is a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0008] In another embodiment, there is provided a pharmaceutical composition comprising a means for maintaining a therapeutically effective concentration of TFV-DP in a PHH over an extended period of time and a pharmaceutically acceptable excipient, wherein the means for maintaining a therapeutically effective concentration of TFV-DP in a PHH over an extended period of time is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0009] In another embodiment, there is provided a kit or article of manufacture comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and instructions for use.

[0010] In another embodiment, a kit or article of manufacture is provided that includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and instructions for use.

[0011] In another embodiment, there is provided a method of treating an HIV infection by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0012] In another embodiment, there is provided a method of treating an HIV infection by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] In another embodiment, there is provided a method of preventing HIV infection by administering to a subject at risk of HIV infection a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0014] In another embodiment, there is provided a method of preventing HIV infection by administering to a subject at risk of HIV infection a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] In another embodiment, there is provided a method of treating an HIV infection by administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0016] In another embodiment, there is provided a method of treating HIV infection by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] In another embodiment, there is provided a method of preventing HIV infection by administering to a subject at risk for HBV infection a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0018] In another embodiment, there is provided a method of preventing HIV infection by administering to a subject at risk of HBV infection a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0019] In another embodiment, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating HIV infection.

[0020] In another embodiment, there is provided the use of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for treating HIV infection.

[0021] In another embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of HIV infection.

[0022] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0023] In another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in the treatment of HIV infection.

[0024] In another embodiment, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating HBV infection.

[0025] In another embodiment, there is provided a use of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for treating HBV infection.

[0026] In another embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating HBV infection.

[0027] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of HBV infection.

[0028] In another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in treating HBV infection.

[0029] In another embodiment, there is provided a compound of Formula I or a pharmaceutically acceptable salt thereof for use in medical therapy.

[0030] In another embodiment, there is provided a pharmaceutical composition for use in medical therapy comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0031] In another embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as a research tool.

[0032] In another embodiment, there is provided a method of using a compound of Formula I in therapy, particularly a method of treating HIV viral growth, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering to the mammal a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0033] In another embodiment, there is provided a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in a method for treating the growth of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

[0034] In another embodiment, a kit or article of manufacture is provided that includes a composition effective for treating or preventing HIV infection, and packaging material that includes a label indicating that the composition can be used to treat or prevent infection by HIV. An exemplary composition includes a compound of Formula I, or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0035] In another embodiment, there is provided a method of inhibiting the replication of HIV, the method comprising exposing the virus to an effective amount of a compound of Formula I or a salt thereof under conditions such that the replication of HIV is inhibited.

[0036] In another embodiment, there is provided the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for inhibiting the activity of HIV reverse transcriptase.

[0037] In another embodiment, there is provided a use of a compound of Formula I or a salt thereof for inhibiting the replication of HIV. Other embodiments may be described in the detailed description of the embodiments that follows, and in part will be obvious from the description of the claimed embodiments or may be learned by practice thereof. They may be realized and attained by means of the processes and compositions particularly pointed out in the detailed description and claims. The foregoing summary is intended as a brief and general overview of some of the embodiments disclosed herein, with the understanding that it is not intended to limit in any way the scope of the appended claims to which they are legally entitled or to equivalents. DETAILED DESCRIPTION OF THE INVENTION

[0038] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The following description of several embodiments is made with the understanding that the disclosure should be considered as an illustration of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. definition

[0039] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" or "comprising," are to be interpreted in an open and inclusive sense, i.e., "including but not limited to."

[0040] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment disclosed herein. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0041] The terms "about" or "approximately" used in connection with a quantity are inclusive of the stated value and have the meaning dictated by the context (e.g., include the degree of error associated with measurement of the particular quantity).

[0042] As used herein, the term "administering" or "administration" typically refers to administration of a composition to a subject to achieve delivery of the composition or an agent contained in the composition to a target site or site to be treated. Those of skill in the art will recognize various routes that may be utilized for administration to a subject, e.g., a human, in appropriate circumstances. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be by injection (e.g., intramuscular, intravenous, or subcutaneous injection). In some embodiments, administration may comprise only a single dose. In some embodiments, administration may comprise the application of a fixed number of doses. In some embodiments, administration may comprise administration that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., individual administrations separated by a common time). In some embodiments, administration may comprise continuous administration (e.g., perfusion application) for at least a selected period of time.

[0043] "Alkyl" is saturated and has 1 to 12 carbon atoms (C 1-12 alkyl), and in certain embodiments, have 1 to 8 carbon atoms (C 1-8 alkyl), or having 1 to 6 carbon atoms (C 1-6 alkyl), having 1 to 4 carbon atoms (C1-4 alkyl), or having 5 to 8 carbon atoms (C 5-8 Alkyl) refers to a straight or branched chain hydrocarbon radical attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (t-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

[0044] "Alkylene" is a saturated alkyl group containing 1 to 12 carbon atoms (C 1-12 alkylene), in certain embodiments, 1 to 8 carbon atoms (C 1-8 alkylene), or 1 to 6 carbon atoms (C 1-6 alkylene), or 1 to 4 carbon atoms (C 1-4 "(C)" refers to a divalent, straight- or branched-chain hydrocarbon radical having an alkylene group. Examples include methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCHCH), 1-methylethylene (-CH(CH)CH), butylene (-CHCHCHCHCH-), 1-methylpropylene (-CH(CH)CHCHCH), 1,1-dimethylethylene (-C(CH)CH), and 1,2-dimethylethylene (-CH(CH)CH(CH). Unless otherwise specified, the definitions propylene and butylene include all possible isomeric forms of the groups in question having the same number of carbons. Thus, for example, propylene also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0045] "Amino" refers to the -NH2 radical.

[0046] As used herein, the term "antiviral agent" is intended to mean an agent (compound or biological) that is effective to inhibit the formation and / or replication of a virus in a subject, e.g., a human, including, but not limited to, an agent that interferes with either the host or viral mechanisms necessary for the formation and / or replication of a virus in a subject, e.g., a human.

[0047] The term "aryl" refers to a single aromatic ring, or a bicyclic or polycyclic ring. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical or an ortho, spiro, or bridged bicyclic or polycyclic radical having about 9 to 14 atoms, in which at least one ring is aromatic (e.g., an aryl ring fused to one or more aryl or carbocyclic rings). Such bicyclic or polycyclic rings may be optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the bicyclic or polycyclic ring. It is understood that the point of attachment of the bicyclic or polycyclic radical defined above can be at any position on the ring, including the aryl or carbocyclic portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0048] "Arylalkylene" refers to an alkylene radical, as defined herein, attached to an aryl radical, as defined herein. Thus, the point of attachment of the arylalkylene radical is the alkylene group. The alkylene group of an "arylalkylene" is typically 1 to 6 carbon atoms (i.e., aryl (C 1-6Aryl alkylene groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. The aryl alkylene can contain 6 to 20 carbon atoms, e.g., the alkylene portion of the aryl alkylene group is 1 to 6 carbon atoms and the aryl portion is 5 to 14 carbon atoms.

[0049] "Arylcycloalkylene" refers to a cycloalkylene radical, as defined herein, attached to an aryl radical, as defined herein. Thus, the point of attachment of the arylcycloalkylene radical is the cycloalkylene group. The cycloalkylene group of an "arylcycloalkylene" is typically 3 to 7 carbon atoms (i.e., aryl (C 3-7 cycloalkylene).

[0050] As used herein, "bicycloalkyl" refers to a hydrocarbon radical having a specified number of carbon atoms and two rings, which may be bridged, fused, or spirocyclic. In certain embodiments, bicycloalkyls have 7 to 12 carbon atoms, 6 to 12 carbon atoms, 6 to 10 carbon atoms, or 5 to 10 carbon atoms, are saturated, and are attached to the rest of the molecule by a single bond. A bridged bicycloalkyl has two rings connected through two non-adjacent shared atoms. A fused bicycloalkyl has two rings connected through a covalent bond. A spirocyclic bicycloalkyl (denoted "spirocycloalkyl") has two rings connected through a single shared atom. For example, bicycloheptyl may be a bridged bicycloheptyl, a fused bicycloheptyl, or a spirocycloheptyl, as exemplified below: [ka]

[0051] "Bridged" refers to a carbocyclic or heterocyclic ring structure, as described herein, that contains two non-adjacent atoms in the ring that are connected through a single atom or a divalent group. Exemplary bridged bicyclic compounds are bicyclo[2.2.1]heptane and 1,4-diazabicyclo[2.2.2]octane, shown below. [ka] The bridged ring structure may be polycyclic (ie, bicyclic, tricyclic, etc.).

[0052] As used herein, "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any dose of a second regimen); and in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administration of one or more agents or modalities to a subject receiving other agents or modalities in combination. For clarity, combination therapy does not require that the individual agents be administered together (or necessarily simultaneously) in a single composition, although in some embodiments, two or more agents or active portions thereof may be administered together in a combination composition or even as a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0053] "C u-v " or "(C u -C v A prefix such as "C" indicates that the following group has u to v carbon atoms. 1-6 "Alkyl group" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0054] "Carbocycle" refers to a non-aromatic hydrocarbon ring having 3 to 15 carbon atoms, and in certain embodiments 3 to 10 carbon atoms, or 3 to 7 carbon atoms, or 3 to 6 carbon atoms, that is saturated or partially unsaturated and is attached to the rest of the molecule by a single bond. Examples of carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0055] "Cycloalkyl" refers to a saturated alkyl group having 3 to 15 carbon atoms (C 3-15 cycloalkyl), and in certain embodiments, has 3 to 10 carbon atoms (C 3-10 cycloalkyl), 3 to 7 carbon atoms (C 3-7 cycloalkyl), 3 to 6 carbon atoms (C 3-6 cycloalkyl), or 5 to 7 carbon atoms (C 5-7 Cycloalkyl refers to a non-aromatic cyclic hydrocarbon radical having a substituent (cycloalkyl) attached to the rest of the molecule by a single bond. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0056] As used herein, "cycloalkylene" refers to a non-aromatic cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent cycloalkane (i.e., it is divalent). Thus, cyclobutylene radicals include: [ka] A cycloalkylene group can have 3 to 15 carbon atoms, 3 to 10 carbon atoms, 3 to 7 carbon atoms, or 3 to 6 carbon atoms. As used herein, cycloalkylene can be saturated or partially unsaturated. Examples of cycloalkylene groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, 1,3-cyclohexadienylene, 1,4-cyclohexadienylene, cycloheptylene, cycloheptenylene, and cyclooctylene.

[0057] As used herein, the term "dosage form" refers to a physically discrete unit of an active agent (e.g., a therapeutic, prophylactic, or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount is a unit dose (whole fraction thereof) appropriate for administration according to a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a prophylactic or therapeutic dosing regimen). One of skill in the art will understand that the total amount of a composition or agent to be administered to a particular subject is determined by one or more attending physicians and may include administration of multiple dosage forms.

[0058] "Fused" refers to ring structures described herein that contain carbocyclic, heterocyclic, aromatic, and / or heteroaromatic rings joined through two adjacent atoms. For example, the bicyclic compounds shown below incorporate a cyclopropane fused to a cyclohexane, a pyrrolidine fused to a benzene, and a thien fused to a furan, respectively. [ka] The fused ring structure may be polycyclic (ie, bicyclic, tricyclic, etc.).

[0059] "Halo" or "halogen" refers to bromo, chloro, fluoro, and iodo.

[0060] "Haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms are replaced by a halo substituent. For example, C 1-6 Haloalkyl is C 1-6 The alkyl group is an alkyl group, and one or more of the hydrogen atoms are replaced with a halo substituent. This range includes one halo substituent on the alkyl group to complete the halogenation of the alkyl group. Exemplary haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0061] "Heterocyclyl" or "heterocycle" refers to a non-aromatic radical or ring having 3 to 15 atoms, of which 1 to 6 atoms are heteroatoms selected from nitrogen, oxygen, and sulfur and are attached to the remainder of the molecule by single bonds. In certain embodiments, a "heterocyclyl" has 3 to 10 atoms, of which 1 to 4 atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, or 3 to 7 atoms, of which 1 to 2 atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atom in a heterocyclyl may be optionally oxidized, and the nitrogen atom may be optionally quaternized. As used herein, "heterocyclyl" or "heterocycle" refers to a saturated ring unless otherwise indicated; for example, in some embodiments, "heterocyclyl" or "heterocycle" refers to a saturated ring, or, where specified, a partially saturated ring. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuran, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0062] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0063] As used herein, the term "HIV replication inhibitor" is intended to mean an agent that is capable of reducing or eliminating the ability of HIV to replicate in host cells, whether in vitro, ex vivo, or in vivo.

[0064] As used herein, the term "HBV replication inhibitor" is intended to mean an agent that can reduce or eliminate the ability of HBV to replicate in host cells, whether in vitro, ex vivo, or in vivo.

[0065] "Mammal" includes both humans and non-domestic animals such as domestic animals, eg, laboratory animals and household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and wildlife.

[0066] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may be substituted or unsubstituted, and that the description includes both substituted and unsubstituted heterocyclyl radicals.

[0067] "Oxo" refers to the =O substituent.

[0068] A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein with a vehicle generally accepted in the art for delivering biologically active compounds to mammals, e.g., humans. Such vehicles include all pharmaceutically acceptable excipients.

[0069] "Pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, emulsifier, or other pharmacologically inactive substance that can be formulated in combination with a pharmacologically active ingredient of a pharmaceutical composition, is compatible with the other ingredients of the formulation, and is suitable for use in humans or veterinary animals without undue toxicity, irritation, allergic response, etc.

[0070] The term "pharmaceutically acceptable salt," as used herein, refers to a salt of such a compound that is suitable for use in a pharmaceutical context, i.e., a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and / or animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., Journal of Pharmaceutical Sciences, S. M. Berge et al., J. Pharma. Sci., 66:119 (1977), describe several pharmaceutically acceptable salts in detail.

[0071] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. + (Wherein, X is C 1-4Pharmaceutically acceptable salts of a nitrogen atom or amino group include, for example, salts derived from appropriate bases such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphoric acid, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, nicotinic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, ... Pharmaceutically acceptable salts of hydroxy compounds include salts of organic carboxylic acids such as propionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. + and NX4 + (Wherein, X is H or C 1-4 The anions of the compounds include the anions of the compounds in combination with suitable cations such as alkyl groups.

[0072] For therapeutic use, salts of the active ingredients of the compounds disclosed herein are typically pharmaceutically acceptable, i.e., salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of Formula I or another compound of an embodiment disclosed herein. All salts, whether derived from a physiologically acceptable acid or base, are within the scope of the embodiments disclosed herein.

[0073] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to an embodiment disclosed herein. Examples of metal salts prepared in this manner include Li + , Na + , and K +A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

[0074] Additionally, salts may be formed from the acid addition of certain organic and inorganic acids, such as HCl, HBr, HSO, HPO, or organic sulfonic acids, to a basic center, typically an amine. Finally, it should be understood that the compositions herein include the non-ionized and zwitterionic forms of the compounds disclosed herein.

[0075] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, a compound may be administered to a subject (including a human) at risk for a disease or condition. As used herein, the terms "preventing" and "prevention" encompass administering a compound, composition, or pharmaceutically acceptable salt according to embodiments disclosed herein before or after an individual is exposed to HIV or HBV, but before symptoms of HIV or HBV infection appear and / or before the virus is detected in the blood. The terms also refer to preventing disease symptoms from appearing and / or preventing the virus from reaching detectable levels in the blood. The terms include both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) and event-driven or "on-demand" prophylaxis. These terms also refer to preventing perinatal transmission of HIV from mother to infant by administration to the mother before birth and to the child within the first few days of life. The term also refers to preventing the transmission of HIV through blood transfusions.

[0076] "Spiro" or "spirocyclo" refers to a ring structure, as described herein, having two ring structures, each of which may be carbocyclic or heterocyclic, connected through a single shared atom (this atom represents the spiro atom). Thus, "spirocyclo" refers to a spirocycloalkyl radical or a spiroheterocycloalkyl radical. "Dispiro" or "dispirocyclo" refers to a ring structure, as described herein, having three ring structures, each of which may be carbocyclic or heterocyclic, connected through two spiro atoms.

[0077] "Stereoisomer" refers to a compound composed of the same atoms connected by the same bonds but with different, non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. In any of the embodiments disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

[0078] As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human). In some embodiments, a human subject is an adult, adolescent, or pediatric subject. In some embodiments, the subject is suffering from the relevant disease or condition. In some embodiments, the subject is susceptible to the disease or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease or condition. In some embodiments, the subject does not exhibit symptoms or characteristics of the disease or condition. In some embodiments, the subject possesses one or more characteristics characteristic of susceptibility to or risk for the disease or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom and / or has been administered a diagnostic and / or therapeutic and / or prophylactic agent.

[0079] As used herein, the term "therapeutically effective amount" refers to an amount that produces a desired effect for which it is administered. In some embodiments, the term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount sufficient when administered to a population suffering from or susceptible to a disease or condition in accordance with a therapeutic administration regimen to treat the disease or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity of, stabilizes one or more characteristics of, and / or delays the onset of, one or more symptoms of a disease or condition. Those skilled in the art will understand that the term "therapeutically effective amount" does not actually require successful treatment to be achieved in specific individuals. Rather, a therapeutically effective amount may be an amount that, when administered to patients in need of such treatment, provides a specific, desired pharmacological response in a significant number of subjects. In some embodiments, reference to a therapeutically effective amount may be a reference to the amount measured in one or more specific tissues (e.g., tissues affected by a disease or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount may be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated and / or administered in multiple doses, for example as part of a dosing regimen.

[0080] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: b) slowing or arresting the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival). As used herein, the terms "treatment" and "treating" encompass administering a compound, composition, or pharmaceutically acceptable salt according to embodiments disclosed herein to alleviate or eliminate symptoms of HIV infection or HBV infection and / or reduce viral load in a subject in need of treatment. In some embodiments, the subject is a patient.

[0081] As used herein, "tricycloalkyl" refers to a hydrocarbon radical having a specified number of carbon atoms and three rings, which may be bridged, fused, spirocyclic, or combinations thereof. In certain embodiments, the tricycloalkyl has 10 to 16 carbon atoms, or 9 to 12 carbon atoms, is saturated, and is attached to the rest of the molecule by a single bond. For example, tricyclodecyl may be a bridged tricyclodecyl, a fused tricyclodecyl, a dispirocyclodecyl, or a mixed (e.g., bridged-fused) tricyclodecyl, as shown below: [ka]

[0082] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 In certain embodiments, these radiolabeled compounds are useful for determining or measuring the efficacy of compounds, for example, by characterizing the site or mode of action or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug research and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose because of their ease of incorporation and facile means of detection.

[0083] In certain embodiments, deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced required dosage. Thus, in some situations, heavier isotopes may be preferred.

[0084] Substitution with positron-emitting isotopes, e.g. 11 C. 18 F, 15O, and 13 N may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula I can be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples below, using the appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0085] The methods, compositions, kits, and articles of manufacture provided herein employ or include a compound (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds have increased resistance to metabolism and are therefore useful for increasing the half-life of a compound or its pharmaceutically acceptable salt when administered to a mammal. See, for example, Allen B. Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, 5 Trends Pharmacol. Sci. 524, 524-27 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0086] The embodiments disclosed herein are also meant to encompass in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to embodiments disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound according to embodiments disclosed herein to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0087] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms. compound

[0088] Provided herein are compounds that function as anti-HIV or anti-HBV agents, pharmaceutical compositions containing such compounds, optionally in combination with one or more (e.g., two, three, or four) additional therapeutic agents, and methods of using such compounds and compositions. All compound embodiments described herein include any pharmaceutically acceptable salt thereof, its stereoisomer, or mixture of its stereoisomers.

[0089] In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 and R 2 independently, cycloC 1-12 Alkyl, aryl-C 1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, C 7-12 Spirocycloalkyl-C 1-4 Alkylene, Bridged C 5-10 Bicycloalkyl, Bridged C 5-10 Bicycloalkyl-C 1-4 Alkylene, fused C 5-10 Bicycloalkyl, C 10-16 Dispirocycloalkyl, C 10-16 Dispirocycloalkyl-C 1-4 Alkylene, Bridged C 9-12 Tricycloalkyl, Bridged C 9-12 Tricycloalkyl-C 1-4 Alkylene, C 3-7 Cycloalkyl-C 3-7 cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; 1-12 Alkyl, aryl-C1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a optionally substituted with R 3 , R 4 , R 5 and R 6 independently, C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b or optionally substituted with R 3 and R 4 together with the carbon atoms to which they are attached, form 1 to 3 R b forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R 5 and R 6 But independently, C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b optionally substituted with R 3 and R 4 But independently, C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4Alkylene is a group consisting of 1 to 3 R b optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form 1 to 3 R b forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R 3 and R 4 together with the carbon atoms to which they are attached, form 1 to 3 R b forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with B is [ka] and R 7 is hydrogen or R 8 and R 8 -L 1 -(L 2 ) m -(L 3 ) n -R 8a and L 1 is selected from a bond, —C(O)—, and —C(O)O—; L 2 is C 1-6 is alkylene, L 3 is -C(O)O- or [ka] and R 8a is C 1-12 Alkyl, aryl, -C(O)-aryl, -C(O)-C 1-4 Alkyl, -SC(O)-C 1-4 Alkyl, [ka] aryl and —C(O)-aryl are selected from one or two R c optionally substituted with Each R a independently, C 1-4 Alkyl, Halo, C 1-4 Haloalkyl and -OC 1-4 alkyl, Each R b independently, C 1-4 is alkyl, Each R c independently, C 1-4 Alkyl or -OC(O)-C 1-4 is alkyl, m and n are independently 0 or 1; p is 0, 1, or 2.

[0090] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, B is [ka] In some embodiments, B is [ka] is.

[0091] In some embodiments, the compound of formula I is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined in Formula I.

[0092] In some embodiments, the compound of formula I is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is as defined in Formula I.

[0093] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 1 and R 2 independently, C 1-8 Alkyl, aryl-C 1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, C 7-12 Spirocycloalkyl-C 1-4 Alkylene, Bridged C 5-10 Bicycloalkyl, Bridged C 5-10 Bicycloalkyl-C 1-4 Alkylene, fused C 5-10 Bicycloalkyl, C 10-16 Spirocycloalkyl, C 10-16 Spirocycloalkyl-C 1-4 Alkylene, Bridged C 9-12 Tricycloalkyl, Bridged C 9-12 Tricycloalkyl-C 1-4 Alkylene, C 3-7 Cycloalkyl-C 3-7 cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; 1-8 Alkyl, aryl-C 1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a optionally substituted with R a is as defined above. In some embodiments, R 1 and R 2 independently, C 1-8 Alkyl, aryl-C 1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, C 7-12 Spirocycloalkyl-C 1-4 Alkylene, Bridged C 5-10 Bicycloalkyl-C 1-4 Alkylene, fused C 5-10 Bicycloalkyl, C 10-16 Dispirocycloalkyl-C 1-4 Alkylene, Bridged C 9-12 Tricycloalkyl-C 1-4 Alkylene, C 3-7 Cycloalkyl-C 3-7 cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; 1-8 Alkyl, aryl-C 1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a optionally substituted with R a is as defined above. In some embodiments, R 1and R 2 independently, C 1-8 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, C 7-12 Spirocycloalkyl, C 7-12 Spirocycloalkyl-C 1-4 Alkylene and bridge C 5-10 Bicycloalkyl-C 1-4 alkylene, and each C 1-8 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, C 7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a optionally substituted with R a is as defined above. In some embodiments, R 1 and R 2 independently, C 5-8 Alkyl, C 5-7 Cycloalkyl, C 5-7 Cycloalkyl-C 1-4 Alkylene, C 7-9 Spirocycloalkyl, C 7-9 Spirocycloalkyl-C 1-4 Alkylene and bridge C 5-7 Bicycloalkyl-C 1-4 alkylene, and each C 5-8 Alkyl, C 5-7 Cycloalkyl, C 5-7 Cycloalkyl-C 1-4 Alkylene, C 7-9 Spirocycloalkyl, C 7-9 Spirocycloalkyl-C 1-4 Alkylene and bridge C 5-7 Bicycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a optionally substituted with R a is as defined above.

[0094] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 1 and R 2 are different. In some embodiments, R 1 and R 2 are the same. In some embodiments, R 1 and R 2 are the same, and C 1-8 Alkyl, aryl-C 1-4 Alkylene, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, aryl-C 3-7 Cycloalkylene, C 7-12 Spirocycloalkyl, C 7-12 Spirocycloalkyl-C 1-4 Alkylene, Bridged C 5-10 Bicycloalkyl-C 1-4 Alkylene, fused C 5-10 Bicycloalkyl, C 10-16 Spirocycloalkyl-C 1-4 Alkylene, Bridged C 9-12 Tricycloalkyl-C 1-4 Alkylene, C 3-7 Cycloalkyl-C 3-7 cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; 1-8 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, C 7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a optionally substituted with R a is as defined above. In some embodiments, R 1 and R 2 are the same, and C 1-8 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, C7-12 Spirocycloalkyl, C 7-12 Spirocycloalkyl-C 1-4 Alkylene and bridge C 5-10 Bicycloalkyl-C 1-4 alkylene, and each C 1-8 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkylene, C 7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a optionally substituted with R a is as defined above. In some embodiments, R 1 and R 2 are the same, and C 3-7 Cycloalkyl-C 1-4 Alkylene, C 7-12 Spirocycloalkyl, C 7-12 Spirocycloalkyl-C 1-4 Alkylene and bridge C 5-10 Bicycloalkyl-C 1-4 alkylene, and each C 3-7 Cycloalkyl-C 1-4 Alkylene, C 7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is a group consisting of 1 to 3 R a is selectively substituted with R a is as defined above. In some embodiments, R 1 and R 2 are the same, and C 1-8 Alkyl and C 3-7 cycloalkyl, and each C 1-8 Alkyl and C 3-7 Cycloalkyl is one to three R a optionally substituted with R a is as defined above.

[0095] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 1 and R 2 is, independently, [ka] is selected from.

[0096] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] is selected from.

[0097] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 2 teeth, [ka] is selected from.

[0098] In some embodiments, R 1 and R 2 are the same, and [ka] In some embodiments, R 1 and R 2 are the same, and [ka] In some embodiments, R 1 and R 2 are the same, and [ka] In some embodiments, R 1 and R 2 are the same, and [ka] is selected from. In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 3 , R 4 , R 5 , and R 6 independently, C 1-3 Alkyl, C 3-5 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-3 Alkyl, C 3-5 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b optionally substituted with R b is as defined above. In some embodiments, R 3 , R 4 , R 5 , and R 6 is independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is selected from 1 to 3 R b optionally substituted with R b is as defined above.

[0099] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 3 and R 5 are the same. In some embodiments, R 3 and R 5 and are both methyl. In some embodiments, R 3 and R 5 and are both ethyl. In some embodiments, R 3 and R 5 and R are both cyclopropyl. 3 and R 5 Both are benzyl.

[0100] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 4 and R 6 are the same. In some embodiments, R 4 and R 6 are both ethyl or both benzyl. In some embodiments, R 4 and R 6 and are both methyl. In some embodiments, R 4 and R 6 and are both ethyl. In some embodiments, R 4 and R 6 and R are both cyclopropyl. 4 and R 6 Both are benzyl.

[0101] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 3 and R 4 are the same. In some embodiments, R 3 and R 4 and are both methyl. In some embodiments, R 3 and R 4 and are both ethyl. In some embodiments, R 3 and R 4 and R are both cyclopropyl. 3 and R 4 Both are benzyl.

[0102] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 5 and R 6 are the same. In some embodiments, R 5 and R 6 and are both methyl. In some embodiments, R 5 and R 6 and are both ethyl. In some embodiments, R 5 and R6 and R are both cyclopropyl. 5 and R 6 Both are benzyl.

[0103] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b forming a 3- to 5-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R 5 and R 6 independently, C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b and each R b is as defined above. In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a cyclopropane ring or a cyclobutane ring, and the cyclopropane ring or the cyclobutane ring is b optionally substituted with R b is as defined above. In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b In some embodiments, the cyclopropane or cyclobutane ring is unsubstituted. In some embodiments, the cyclopropane or cyclobutane ring is optionally substituted with one R bIn some embodiments, the cyclopropane or cyclobutane ring is substituted with two R b In some embodiments, the cyclopropane or cyclobutane ring is substituted with three R b In some embodiments, R 5 and R 6 independently, C 1-3 Alkyl, C 3-5 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b In some embodiments, R 5 and R 6 is independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is selected from 1 to 3 R b In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a cyclopropane ring or a cyclobutane ring, and the cyclopropane ring or the cyclobutane ring is b optionally substituted with R 5 and R 6 is independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is selected from 1 to 3 R b is optionally substituted with

[0104] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 3 and R 4 independently, C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C1-4 Alkylene is a group consisting of 1 to 3 R b optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b forming a 3- to 5-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R b is as defined above. In some embodiments, R 5 and R 6 together with the carbon atoms to which they are attached form a cyclopropane ring or a cyclobutane ring, and the cyclopropane ring or the cyclobutane ring is b optionally substituted with R b is as defined above. In some embodiments, R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b In some embodiments, R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b In some embodiments, the cyclopropane or cyclobutane ring is unsubstituted. In some embodiments, the cyclopropane or cyclobutane ring is optionally substituted with one R b In some embodiments, the cyclopropane or cyclobutane ring is substituted with two R b In some embodiments, the cyclopropane or cyclobutane ring is substituted with three R b In some embodiments, R 3 and R 4 independently, C 1-3 Alkyl, C 3-5 Cycloalkyl and aryl-C 1-4 alkylene, and each C 1-4 Alkyl, C 3-6 Cycloalkyl and aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R bIn some embodiments, R 3 and R 4 is independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is selected from 1 to 3 R b In some embodiments, R 3 and R 4 is independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is selected from 1 to 3 R b optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached form a cyclopropane ring or a cyclobutane ring, and the cyclopropane ring or the cyclobutane ring is b is optionally substituted with

[0105] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b forming a 3- to 5-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a cyclopropane ring or a cyclobutane ring, and the cyclopropane ring or the cyclobutane ring is b optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached form a cyclopropane ring or a cyclobutane ring, and the cyclopropane ring or the cyclobutane ring is b optionally substituted with R bis as defined above. In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b In some embodiments, R 5 and R 6 together with the carbon atoms to which they are attached form a cyclopropane ring. 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b In some embodiments, R 5 and R 6 taken together with the carbon atoms to which they are attached form a cyclobutane ring. 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b forming a cyclopropane ring optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b Some embodiments form a cyclopropane ring optionally substituted with R 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b forming a cyclopropane ring optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b Some embodiments form a cyclopropane ring optionally substituted with R 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b forming a cyclobutane ring optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R bSome embodiments form a cyclobutane ring optionally substituted with R 3 and R 4 together with the carbon atoms to which they are attached, form one to three R b forming a cyclobutane ring optionally substituted with R 5 and R 6 together with the carbon atoms to which they are attached, form one to three R b to form a cyclobutane ring optionally substituted with

[0106] In some embodiments of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, each R b is independently methyl, ethyl, propyl, or butyl. In some embodiments, each R b is independently methyl, ethyl, or propyl. In some embodiments, each R b is independently methyl or ethyl. In some embodiments, each R b is methyl. In some embodiments, each R b is ethyl.

[0107] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 3 , R 4 , R 5 , and R 6 are the same. In some embodiments, R 3 , R 4 , R 5 , and R 6 are respectively, C 1-3 Alkyl, C 3-5 Cycloalkyl or aryl-C 1-4 alkylene, and each C 1-3 Alkyl, C 3-5 Cycloalkyl or aryl-C 1-4 Alkylene is a group consisting of 1 to 3 R b optionally substituted with R b is as defined above. In some embodiments, R 3 , R4 , R 5 , and R 6 are each methyl, ethyl, cyclopropyl, or benzyl, and each methyl, ethyl, cyclopropyl, or benzyl is selected from 1 to 3 R b optionally substituted with R b is as defined above. In some embodiments, R 3 , R 4 , R 5 , and R 6 are each methyl or cyclopropyl. In some embodiments, R 3 , R 4 , R 5 , and R 6 are each methyl. In some embodiments, R 3 , R 4 , R 5 , and R 6 are each ethyl. In some embodiments, R 3 , R 4 , R 5 , and R 6 and R are each cyclopropyl. 3 , R 4 , R 5 , and R 6 are benzyl, respectively.

[0108] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 7 is hydrogen. In some embodiments, R 7 is R 8 is.

[0109] In some embodiments, in compounds of Formula I, II, or III, R 8 -L 1 -L 2 -L 3 -R 8a In some embodiments, R 8 -L 1 -(L 3 ) n -R8a In some embodiments, R 8 -L 1 -(L 2 ) m -R 8a In some embodiments, R 8 -L 1 -L 3 -R 8a In some embodiments, R 8 -L 1 -L 2 -R 8a In some embodiments, R 8 -L 1 -R 8a In some embodiments, R 8 is R 8a In some embodiments, R 8 teeth, [ka] [ka] In some embodiments, R 8 teeth, [ka] [ka] In some embodiments, R 8 teeth, [ka] is selected from.

[0110] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, L 1 is a bond. In some embodiments, L 1 is —C(O)—. In some embodiments, L 1 is -C(O)O-.

[0111] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, L 2 is selected from -CH-, -CH-CH-, -CH-CH-CH-, -CH-CH-CH-, -CH-C(CH)-, -CH-CH-CH-CH-CH-, -CH-C(CH)-CH-, -CH-CH-C(CH)-, -CH-C(CH)-CH-, -CH-C(CH)-CH-CH-, and -CH-CH-CH-C(CH)-. 2 is selected from -CH-, -CH-CH-, -CH-CH-CH-, -CH-C(CH)-, -CH-C(CH)-CH-, -CH-CH-C(CH)-, and -CH-C(CH)-CH-CH-. 2 is -CH-. In some embodiments, L 2 is -CH-CH-. In some embodiments, L 2 is -CH-CH-CH-. In some embodiments, L 2 is —CH—C(CH)—. In some embodiments, L 2 is —CH—C(CH)—CH—. In some embodiments, L 2 is —CH—CH—C(CH)—. In some embodiments, L 2 is -CH2-C(CH3)2-CH2-CH2-.

[0112] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, L 3 is —C(O)O—. In some embodiments, L 3 teeth, [ka] is.

[0113] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R8a is C 1-12 Alkyl, aryl, -C(O)-C 1-4 Alkyl, -SC(O)-C 1-4 Alkyl, [ka] and the aryl is selected from one or two R c In some embodiments, R 8a is C 1-8 Alkyl, aryl, -C(O)-C 1-4 Alkyl, -SC(O)-C 1-4 Alkyl, [ka] and the aryl is selected from one or two R c is optionally substituted with

[0114] In some embodiments of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, each R a independently, C 1-4 Alkyl, halo, and C 1-4 In some embodiments, each R a independently, C 1-4 In some embodiments, each R a is independently halo. In some embodiments, each R a independently, C 1-4 In some embodiments, each R a independently, -OC 1-4 In some embodiments, each R a is independently selected from methyl, ethyl, n-propyl, isopropyl, fluoro, methoxy, and trifluoromethyl.

[0115] In some embodiments of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, each R b is independently methyl or ethyl.

[0116] In some embodiments of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, each R c independently, C 1-4 In some embodiments, each R c are independently -OC(O)-C 1-4 In some embodiments, each R c is independently methyl or —OC(O)-methyl.

[0117] In some embodiments of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, m and n are both 0. In some embodiments, m is 0 and n is 1. In some embodiments, m is 1 and n is 0. In some embodiments, m and n are both 1.

[0118] In some embodiments of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, p is 0 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0119] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 1 and R 2 is the same as R 3 , R 4 , R 5 , and R 6 are the same. In some embodiments, R 1 and R 2 is the same as R 3 , R 4 , R 5 , and R 6 are each methyl or cyclopropyl. In some embodiments, R 1 and R 2 is the same as R 3 , R 4 , R 5 , and R6 and each is cyclopropyl. In some embodiments, R 1 and R 2 is the same as R 3 , R 4 , R 5 , and R 6 are each methyl.

[0120] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 7 is hydrogen and R 1 and R 2 are the same.

[0121] In some embodiments, R 7 is hydrogen and R 3 , R 4 , R 5 , and R 6 and are the same. In some embodiments, R 7 is hydrogen and R 3 , R 4 , R 5 and R 6 are each methyl or cyclopropyl. In some embodiments, R 7 is hydrogen and R 3 , R 4 , R 5 , and R 6 and R are each cyclopropyl. 7 is hydrogen and R 3 , R 4 , R 5 , and R 6 are each methyl.

[0122] In some embodiments of the compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 7 is hydrogen and R 1 and R 2 is the same as R 3 , R 4 , R 5 , and R 6 are the same. In some embodiments, R 7is hydrogen and R 1 and R 2 is the same as R 3 , R 4 , R 5 , and R 6 are each methyl or cyclopropyl. In some embodiments, R 7 is hydrogen and R 1 and R 2 is the same as R 3 , R 4 , R 5 , and R 6 Each is cyclopropyl. In some embodiments, R 7 is hydrogen and R 1 and R 2 is the same as R 3 , R 4 , R 5 , and R 6 are each methyl.

[0123] In some embodiments, the compound of Formula I or II is a compound of Formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 is as defined in formula I.

[0124] In some embodiments of the compound of Formula IV, R 1 and R 2 are different. In some embodiments, R 1 and R 2 are the same.

[0125] In some embodiments, the compound of Formula I or III is a compound of Formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 7 , and R 8is as defined above.

[0126] In some embodiments of the compound of Formula V, R 1 and R 2 are different. In some embodiments, R 1 and R 2 are the same. In some embodiments, R 7 is H. In some embodiments, R 7 is R 8 is.

[0127] In some embodiments, the compound has the following formula: [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0128] In some embodiments, the compound has the following formula: [ka] It has.

[0129] If any variable is an asymmetric divalent group, both orientations of the group are intended to be encompassed unless otherwise specified. For example, L 3 is -C(O)O-, both orientations of -C(O)O- are included (i.e., R 8 Ga-L 1 -L 3 -R 8aIf both -L 1 -C(O)OR 8a and -L 1 -OC(O)-R 8a (includes) or L 2 is -CH2-CH2-C(CH3)2-, both orientations of -CH2-CH2-C(CH3)2- are included (i.e., R 8 Ga-L 1 -L 2 -R 8a If both R 8 -L 1 -CH2-CH2-C(CH3)2-R 8a and -L 1 -C(CH3)2-CH2-CH2-R 8a (included).

[0130] Compounds of any one of formulas I, II, III, IV, and V as shown above, and any particular group or substituent (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and substituents thereof) may be combined independently with other embodiments and / or substituents of compounds of any one of Formulas I, II, III, IV, and V to form embodiments not specifically set forth above. In addition, the list of substituents may be combined with any particular R in a particular embodiment and / or claim. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 If no substituent is recited for a group, it is understood that each individual substituent may be deleted from a particular embodiment and / or claim, and the remaining list of substituents is considered to be within the scope of the embodiments disclosed herein.

[0131] The compounds of Formula I, II, III, IV, and V, or pharmaceutically acceptable salts thereof, are prodrugs in which the promoiety is rapidly cleaved in the intracellular environment to yield tenofovir (TFV). In some embodiments, the compounds of Formula I, II, III, IV, and V, or pharmaceutically acceptable salts thereof, are suitable for use in long-acting formulations. Adherence to a daily oral therapeutic or prophylactic regimen for treating or preventing a viral infection (e.g., HIV infection) can be difficult for certain patients, for example, those with poor or limited access to medical care. Drugs that offer favorable pharmaceutical or physicochemical properties for sustained release (e.g., improved efficacy, long-acting pharmacokinetics, low solubility, reduced solubility, enhanced plasma stability, and / or other properties) can be suitable for less frequent administration and provide better patient compliance. Such improvements, in turn, can optimize drug exposure and limit the emergence of drug resistance.

[0132] Without being bound by theory, it is believed that the low solubility of the compounds of Formulas I, II, III, IV, and V, or pharmaceutically acceptable salts thereof, can result in sustained release of the compounds after intramuscular or subcutaneous administration and sustained intracellular levels of the pharmacologically active agent, tenofovir diphosphate (TFV-DP), thereby enabling the maintenance of therapeutically effective concentrations of TFV-DP in relevant cell types for extended periods, making them useful as sustained- or long-acting agents for treating or preventing viral infections. The development of poorly soluble prodrugs for safe and effective long-acting injectable formulations is discussed in Remenar, Mol. Pharmaceutics 2014, 11, 1739-1749. Pharmaceutical Compositions

[0133] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0134] In some embodiments, the pharmaceutical composition comprises one, two, three, or four additional therapeutic agents, as described more fully below.

[0135] In some embodiments, compositions comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof in one variation do not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, in one aspect, it is understood that a composition comprising a compound of the present disclosure does not contain an agent that affects (e.g., slows, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of the present disclosure. In one aspect, it is also understood that none of the methods, kits, articles of manufacture, etc. detailed herein contain an agent that affects (e.g., slows, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of the present disclosure.

[0136] In some embodiments, the pharmaceutical compositions are for human or animal use.

[0137] The present disclosure further includes compounds of the present disclosure for administration as the sole active ingredient of a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art, for example, by combining or mixing the active ingredient with pharmaceutically acceptable, therapeutically inert organic and / or inorganic carriers or excipients.

[0138] In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient in a known drug that has a synergistic effect with that other active ingredient, or the co-administration of a compound of the present disclosure with such a drug. Treatment method HIV infection

[0139] The present disclosure provides methods of treating and / or preventing human immunodeficiency virus (HIV) infection in a subject. In some embodiments, the method of treating and / or preventing HIV infection in a subject comprises administering a composition provided herein to the subject. In some embodiments, the method is for treating and / or preventing HIV-1 infection. In some embodiments, the method is for treating and / or preventing HIV-2 infection.

[0140] In some embodiments, a method of treating an HIV infection in a subject in need thereof comprises administering a composition provided herein to the subject. In some embodiments, the subject is HIV-positive. In some such embodiments, the subject has an unknown HIV status. In some such embodiments, the subject is not HIV-negative.

[0141] In some embodiments, a method for preventing HIV infection in a subject at risk of HIV infection comprises administering a composition provided herein to the subject. In some embodiments, the subject is HIV-negative. In some embodiments, the subject is at risk of HIV infection.

[0142] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reactivators, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0143] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reactivators, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0144] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof. HBV infection

[0145] The present disclosure provides methods of treating and / or preventing hepatitis B virus (HBV) infection in a subject. In some embodiments, the methods of treating and / or preventing HBV infection in a subject comprise administering to the subject a composition provided herein.

[0146] In some embodiments, a method of treating an HBV infection in a subject in need thereof comprises administering to the subject a composition provided herein.

[0147] In some embodiments, a method for preventing HBV infection in a subject at risk for HBV infection comprises administering a composition provided herein to the subject. In some embodiments, the subject is at risk for HBV infection.

[0148] In some embodiments, the compositions provided include HBV combination drugs, HBV vaccines, HBV polymerase inhibitors, HBV capsid modulators, TLR7, TLR8, and TLR9 agonists, cytokines, immune checkpoint inhibitors, FLT3 ligands, interferon alpha receptor ligands, interferon alpha, interferon lambda, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, HBV X protein (HBV X protein, HBx) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides, short interfering RNA (siRNA) and DNA directed RNA interference (ddRNAi), endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen (HBeAg) inhibitors, covalently closed circular DNA, and / or cyclophilin inhibitors. DNA, cccDNA inhibitors, farnesoid X receptor agonists, HBV antibodies, bispecific antibodies that mobilize T cells and NK cells, chimeric T cell receptors targeting HBV antigens or peptides, CAR-T cell therapy, thymosin agonists, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO1) pathway inhibitors, anti-OX40, anti-CD40, anti-CD160, HBV gene editors, PAPD5 / PAPD7 inhibitors, ZCCHC14 inhibitors, Bruton's tyrosine kinase (BKT) inhibitors, and one, two, three, or four additional therapeutic agents selected from: inhibitors of HBV (BTK) kinase, epigenetic regulators, inducers of tertiary lymphoid aggregates, antagonists of IAP / XIAP, nucleic acid polymers (e.g., nucleic acid polymers (NAPs) and STOPS), modulators of lipid metabolism or transport, arginase inhibitors, and other drugs for treating HBV, and combinations thereof.

[0149] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from adefovir, entecavir, telbivudine, lamivudine, and lenacapavir, and combinations thereof.

[0150] In some embodiments, provided compositions are combined with one, two, three, or four additional therapeutic agents selected from adefovir, entecavir, telbivudine, lamivudine, and lenacapavir. HIV combination therapy

[0151] In certain embodiments, methods are provided for treating HIV infection, comprising administering to a human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents. In one embodiment, methods are provided for treating HIV infection, comprising administering to a human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents.

[0152] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0153] In certain embodiments, the present disclosure provides a method for treating an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents suitable for treating an HIV infection.

[0154] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four additional therapeutic agents. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents. Administration of HIV combination therapy

[0155] In certain embodiments, a compound disclosed herein is administered with one, two, three, or four additional therapeutic agents. Co-administration of a compound disclosed herein with one, two, three, or four additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein with one, two, three, or four additional therapeutic agents such that therapeutically effective amounts of both the compound disclosed herein and the one, two, three, or four additional therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in two or more administrations.

[0156] Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of unit doses of one, two, three, or four additional therapeutic agents. For example, a compound disclosed herein may be administered within seconds, minutes, or hours of administration of one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by unit doses of one, two, three, or four additional therapeutic agents. Alternatively, unit doses of one, two, three, or four additional therapeutic agents are administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by unit doses of one, two, three, or four additional therapeutic agents. In still other embodiments, unit doses of one, two, three, or four additional therapeutic agents are administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein.

[0157] In certain embodiments, kits are provided that include a compound disclosed herein (e.g., a compound of Formula I, II, III, IV, or V) or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, or four) additional therapeutic agents.

[0158] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. HIV combination therapy

[0159] In the above embodiments, the additional therapeutic agent or agents may be anti-HIV agents. In some cases, the additional therapeutic agent or agents are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulatory agents, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapies (chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, etc.), latent infection reactivators, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF alpha ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (mixed lineage kinase-3, MLK-3 inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIVThe inhibitor may be a POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, an mTOR complex 1 inhibitor, an mTOR complex 2 inhibitor, a P-glycoprotein modulator, a TAT protein inhibitor, a prolyl endopeptidase inhibitor, a phospholipase A2 inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, an HIV vaccine, and combinations thereof.

[0160] In some embodiments, the additional therapeutic agent or agents are selected from HIV combination drugs, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0161] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutics, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0162] In some embodiments, the additional therapeutic agent or agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latent infection reactivators, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0163] In some embodiments, the additional therapeutic agent or additional therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0164] In some embodiments, the additional therapeutic agent or agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir. HIV combination drugs

[0165] Examples of combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOV® (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); Y® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; tenofovir analogs; COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); KALETRA (registered trademark Trademarks) (ALUVIA®, lopinavir and ritonavir), TRIUMEQ® (dolutegravir, abacavir, and lamivudine); BIKTARVY (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO, TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine;Dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir These include, but are not limited to, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, and lamivudine; cabotegravir + rilpivirine; 3-BNC117 + albuvirtide, Elpida (elsulfavirine; VM-1500; VM-1500A; Other HIV drugs

[0166] Examples of other drugs for treating HIV include aspernigrin C, acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkephalin, naltrexone, prolastin, REP9, RPI-MN, VSSP, H1 viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, Bevirimat derivatives, ABX-464, AG-1105, APH-0812, bryostatin analogs, BIT-225, CYT-107, CS-TATI-1, fluoro-beta-D-arabinose nucleic acid, and the like. acid, FANA)-modified antisense oligonucleotides, FX-101, griffithsin, HGTV-43, HPH-116, HS-10234, hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, MK-8591 (islatravir), NOV-205, OB-002H, ODE-Bn-TFV, PA-1050040 (PA-040), PC-707, PGN-007, QF-036, S-648414, SCY-635, SB -9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-4467, thrombospondin analogs, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, and IML-106, antiviral fc conjugates (AVC), and VIR-576. HIV protease inhibitors

[0167] Examples of HIV protease inhibitors include, but are not limited to, amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC-09 plus ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911. HIV ribonuclease H inhibitors

[0168] An example of an HIV RNase H inhibitor is NSC-727447. HIV Nef inhibitors

[0169] An example of an HIV Nef inhibitor is FP-1. HIV reverse transcriptase inhibitors

[0170] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include, but are not limited to, dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, elsulfavirine (extended-release oral, HIV infection), doravirine plus islatravir (fixed-dose combination / oral tablet formulation, HIV-1 infection), elsulfavirine (long-acting injectable nanosuspension, HIV infection), and elsulfarabine (VM-1500).

[0171] Examples of HIV nucleoside or nucleotide inhibitors that are reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir disoproxil hemifumarate, VIDEX® and VIDEXEC® (didanosine, ddl), abaca. These include, but are not limited to, abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, ethidovudine lavirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, fofazide, stavudine, zalcitabine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, islatravir, MK-8583, VM-2500, and KP-1461. HIV integrase inhibitors

[0172] Examples of HIV integrase inhibitors include elvitegravir, elvitegravir (sustained-release microcapsules), curcumin, curcumin derivatives, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, pegylated raltegravir, dolutegravir, JTK-351, and Bicteg. These include, but are not limited to, ravir, AVX-15567, cabotegravir (long-acting injectable solution), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, STP-0404, VM-3500, and cabotegravir.

[0173] Examples of HIV non-catalytic site, or allosteric, integrase inhibitos (NCINI) include, but are not limited to, CX-05045, CX-05168, and CX-14442. HIV viral infectivity factor inhibitors

[0174] Examples of HIV viral infectivity factor inhibitors include 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives. HIV entry inhibitors

[0175] Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0176] Examples of CCR5 inhibitors include, but are not limited to, aplaviroc, vicriviroc, maraviroc, maraviroc (long-acting injectable nanoemulsion), cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc, and vMIP (Haimipu).

[0177] Examples of gp41 inhibitors include, but are not limited to, albuvirtide, enfuvirtide, griffithsin (gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biobetter, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifuvirtide.

[0178] Examples of CD4 binding inhibitors include, but are not limited to, ibalizumab and CDA analogs.

[0179] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicides, Radha-108 (receptor) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemasavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0180] An example of a gp160 inhibitor is fangchinoline.

[0181] Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). HIV maturation inhibitors

[0182] Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232. Latent infection reactivator

[0183] Examples of latent infection reactivators include toll-like receptor (TLR) agonists (including TLR7 agonists, e.g., GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors, e.g., Velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BET-bromodomain 4) inhibitors, and the like. 4, BRD4 inhibitors (e.g., ZL-0580, apabetalone), ionomycin, IAP antagonists (inhibitors of apoptotic proteins such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (IL-15, IL-15 fusion proteins, and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, and GSK-343. Examples of PKC activators include indolactams, prostratin, ingenol B, and DAG-lactone. Histone deacetylase (HDAC) inhibitors

[0184] In some embodiments, the agents described herein are combined with inhibitors of histone deacetylase, e.g., histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat. Capsid inhibitors

[0185] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, lenacavir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, PF-3450074, Capsid Inhibitor (HIV-1 Infection, Shandong University), and compounds described in (GSK WO 2019 / 087016). Immune Checkpoint Modulators

[0186] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can effectively regulate T cell or NK cell activation and prevent immune leakage of infected cells. Activating or stimulating stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in infection treatments. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (reviewed, e.g., in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0187] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane domain and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T-cell activation inhibitory factor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BT) LA); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing (PVRIG, CD112R);T-cell immunoreceptor with Ig and ITIM domains (TIGIT); T-cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family members SLAM family member 7 (SLAMF7, CD319); UL16-binding protein 1 (ULBP1); UL16-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, Killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0188] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, agents as described herein are combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0189] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and a long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0190] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0191] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, and PBI -5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0192] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, and BI-75409. 1, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (budidalimab), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostallimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).Not limited to these.

[0193] In various embodiments, the agents described herein are combined with an anti-TIGIT antibody, such as BMS-986207, RG-6058, AGEN-1307. Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF)

[0194] In various embodiments, the agents described herein are agonists of one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene No. 7132), TNFRSF1B (NCBI Gene No. 7133), TNFRSF4 (OX40, CD134; NCBI Gene No. 7293), TNFRSF5 (CD40; NCBI Gene No. 958), TNFRSF6 (FAS, NCBI Gene No. 355), TNFRSF7 (OX40, CD134; NCBI Gene No. 355), TNFRSF8 (OX40, CD134; NCBI Gene No. 355), TNFRSF9 (OX40, CD134; NCBI Gene No. 355), TNFRSF10 (OX40, CD134; NCBI Gene No. 355), TNFRSF11 (OX40, CD134; NCBI Gene No. 355), TNFRSF12 (OX40, CD134; NCBI Gene No. 355), TNFRSF13 (OX40, CD134; NCBI Gene No. 355), TNFRSF14 (OX40, CD134; NCBI Gene No. 355), TNFRSF15 (OX40, CD134; NCBI Gene No. 355), TNFRSF16 (OX40, CD134; NCBI Gene No. 355), TNFRSF17 (OX40, CD134; NCBI Gene No. 355), TNFRSF18 (OX40, CD134; NCBI Gene No. 355), TNFRSF19 (OX40, CD134; NCBI Gene No. 355), TNFRSF19 (OX40, CD134; NCBI Gene No. 355), TN 7 (CD27, NCBI gene number 939), TNFRSF8 (CD30, NCBI gene number 943), TNFRSF9 (4-1BB, CD137, NCBI gene number 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene number 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene number 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene number 8794) , TNFRSF10D (CD264, TRAILR4, NCBI gene number 8793), TNFRSF11A (CD265, RANK, NCBI gene number 8792), TNFRSF11B (NCBI gene number 4982), TNFRSF12A (CD266, NCBI gene number 51330), TNFRSF13B (CD267, NCBI gene number 23495), TNFRSF13C (CD268, NCBI gene number 115650), TNFRSF16( in combination with one or more agonists of NGFR, CD271, NCBI Gene No. 4804), TNFRSF17 (BCMA, CD269, NCBI Gene No. 608), TNFRSF18 (GITR, CD357, NCBI Gene No. 8784), TNFRSF19 (NCBI Gene No. 55504), TNFRSF21 (CD358, DR6, NCBI Gene No. 27242), and TNFRSF25 (DR3, NCBI Gene No. 8718).

[0195] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tabolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0196] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0197] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0198] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0199] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in International Publication Nos. WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. WO 2017096179 and WO 2018089628. Bispecific and trispecific natural killer (NK) cell engagers

[0200] In various embodiments, the agents described herein are bi-specific NK-cell engagers (BiKE) or tri-specific NK-cell engagers (TKIs) directed against NK cell activating receptors, e.g., CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). The anti-CD16 binding bispecific molecule may be combined with an Fc-free antibody (e.g., Fc-free antibody, TriKE) or a bispecific antibody (e.g., Fc-free antibody). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell inducers that can be co-administered target CD16 and one or more HIV-associated antigens, as described herein. BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell inducers (TRiKE) include OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKE. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0201] In various embodiments, the agents described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene No. 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Toll-like receptor (TLR) agonists

[0202] In various embodiments, the agents described herein are combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene No. 7096), TLR2 (NCBI Gene No. 7097), TLR3 (NCBI Gene No. 7098), TLR4 (NCBI Gene No. 7099), TLR5 (NCBI Gene No. 7100), TLR6 (NCBI Gene No. 10333), TLR7 (NCBI Gene No. 51284), TLR8 (NCBI Gene No. 51311), TLR9 (NCBI Gene No. 54106), and / or TLR10 (NCBI Gene No. 81793). Exemplary TLR7 agonists that may be co-administered include AL-034, DSP-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and those disclosed in U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20110098248 (Gilead Sciences). Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (VentirxNo. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include NKTR-262, tellurolimod, and BDB-001. Examples of TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in U.S. Patent Application Publication No. 20140045849 (Janssen) and U.S. Patent Application Publication No. 20140073642 (J Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (VentirxNo. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091. CDK inhibitors or antagonists

[0203] In some embodiments, an agent described herein is combined with an inhibitor or antagonist of a CDK, hi some embodiments, the inhibitor or antagonist of a CDK is selected from the group consisting of VS2-370. STING agonists, RIG-I and NOD2 modulators

[0204] In some embodiments, an agent described herein is combined with a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic di-AMP. In some embodiments, an agent described herein is combined with a RIG-I modulator such as RGT-100, or a NOD2 modulator such as SB-9200 and IR-103. LAG-3 and TIM-3 inhibitors

[0205] In certain embodiments, the agents described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, or INCAGN-2390.

[0206] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with an anti-LAG-3 (lymphocyte activating) antibody, such as leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, or INCAGN2385. Interleukin agonists

[0207] In certain embodiments, the agents described herein are interleukin agonists, such as IL-2, IL-7, IL-15, IL-10, and IL-12 agonists; examples of IL-2 agonists include Proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214), modified variants of IL-2 (e.g., THOR-707), bempegaldsulkin, AIC-284, and ALKS-4. Examples of IL-15 agonists include IL-15 agonists such as IL-15 agonist 230, CUI-101, Neo-2 / 15; ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 symbolin (PEGylated IL-15), P-22339, and IL-15-PD-1 fusion protein N-809; and examples of IL-7 agonists include CYT-107.

[0208] Examples of additional immune-based therapies that can be combined with the agents of the present disclosure include interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; FLT3 agonists such as CDX-301 and GS-3583; gepon; nucleoferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, RPI-MN. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0209] Examples of PI3K inhibitors include idelalisib, alpelisib, bupallisib, CAI orotate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonoliside, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and DS-742. 3, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474. Alpha-4 / beta-7 antagonists

[0210] Examples of integrin alpha-4 / beta-7 antagonists include, but are not limited to, PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab. HIV targeting antibody

[0211] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies), TMB-360, and HIV These include, but are not limited to, antibodies targeting gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, KLIC-targeting clone 3 human monoclonal antibody (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0212] Various bNAbs can be used, including, but not limited to, those described in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, WO 2014 / 063059, WO 2012 / 158948, WO 2015 / 117008, and International Application Nos. US2015 / 41272 and WO 2017 / 096221. Examples of antibodies include antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include Klein et al., Nature, 492(7427):118-22 (2012), Horwitz et al., Proc Natl Acad Sci USA, 110(41):16538-43 (2013), Scheid et al., Science, 333:1633-1637 (2011), Scheid et al., Nature, 458:636-640 (2009), Eroshkin et al., Nucleic Acids Res., 42(Database Issue):Dl 133-9 (2014), Mascola et al., Immunol Rev., 254(l):225-44(2013), for example, 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to the V1V2-glycan), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site).

[0213] Additional broadly neutralizing antibodies that can be used as second therapeutic agents in combination therapy are described in, for example, U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, and WO 2012 / 154312, WO 2012 / 158948, WO 2013 / 086533, WO 2013 / 142324, WO 2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, Nos. WO 2015 / 103549, WO 2015 / 117008, WO 2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO 2017 / 096221, WO 2017 / 133639, WO 2017 / 133640, which are incorporated herein by reference in their entireties for all purposes. Additional examples include Sajadi, et al., Cell. (2018) 173(7):1783-1795, Sajadi, et al., J Infect Dis. (2016) 213(1): 156-64, Klein et al., Nature, 492(7427): 118-22 (2012), Horwitz et al., Proc. Natl Acad Sci USA,110(41):16538-43(2013),Scheid,et al.,Science,333:1633-1637(2011),Scheid,et al.,Nature,458:636-640(2009),Eroshkin et al,Nucleic Acids Res.,42(Database issue):Dl 133-9(2014), Mascola et. et al., Immunol Rev., 254(1):225-44(2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074, and LN01 (all of which bind to the MPER of gp41).

[0214] Examples of additional antibodies include bavituximab, UB-421, BF520.1, BiIA-SG, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, Cl3hmAb, GS-9722 (elipovimab), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PGT-121.66, and PGT12. 2, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (I Pilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH45-46, PGC14, PGG14 , PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, VRC- HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.0 3, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E, and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34, and VRC34.Examples of suitable fluoropolymers include, but are not limited to, 01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

[0215] Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, BiIA-SG, TMB bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121-VRC01.

[0216] Examples of bNAbs delivered in vivo include AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and genetically engineered B cells encoding 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301). Pharmacokinetic enhancers

[0217] Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir. Additional medications

[0218] Examples of additional therapeutic agents include those described in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0165489 (University of No. 2014 / 0221378 (Japan Tobacco), U.S. Patent Application Publication No. 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), U.S. Patent Application Publication No. 20140221356 (Gilead Sciences), U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim). HIV vaccine

[0219] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus macaque, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan8, Pan9, Pan10, Pan11, Pan12, Pan13, Pan14, Pan15, Pan16, Pan17, Pan18, Pan19, Pan20, Pan21, Pan22, Pan23, Pan24, Pan25, Pan26, Pan27, Pan28, Pan29, Pan30, Pan31, Pan32, Pan33, Pan34, Pan35, Pan36, Pan37, Pan38, Pan39, Pan39, Pan40, Pan41, Pan42, Pan43, Pan44, Pan45, Pan46, Pan47, Pan48, Pan49 ... an7, Pan9), coxsackievirus-based vaccines, enteric virus-based vaccines, gorilla adenovirus vaccines, lentivirus-vectored vaccines, arenavirus vaccines (e.g., LCMV, Pichinde), two-segmented or three-segmented arenavirus-based vaccines, trimerized HIV-1 vaccines, measles virus-based vaccines, flavivirus-vectored vaccines, tobacco mosaic virus-vectored vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines, rhabdovirus-based vaccines such as VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines such as Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128 / CVI.00298-16); LNP-formulated mRNA-based therapeutic vaccines; and LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0220] Examples of vaccines include AAVLP-HIV vaccine, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvant vaccine, BG505 SOSIP.GT1.1 gp140 adjuvant vaccine, ChAdOx1.tHIV consv1 vaccine, CMV-MVA triplex vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, MPER-656 liposomal subunit vaccine, Remune, ITV-1, and Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclad DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4(Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vector vaccines expressing SCaVII, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.Virus-like particle vaccines such as HIV+MVA mosaic vaccine+gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001, and pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine (e.g., DermaVir), gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclad Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 These include the 60-mer vaccine, PD-201401, env (A, B, C, A / E) / gag (C) DNA vaccine, gp120 (A, B, C, A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag prime-boost plasmid DNA vaccine, HIV-1 iglb12-neutralizing VRC-01 antibody-priming anti-CD4 vaccine, MVA-BN HIV-1 vaccine regimen, UBI HIV gp120, mRNA-based prophylactic vaccine, VPI-211, and TBL-1203HI. Combined birth control (contraceptive) therapy

[0221] In certain embodiments, the agents described herein are combined with a birth control or contraceptive regimen. Therapeutic agents used for birth control (contraception) that can be combined with the agents of the present disclosure include cyproterone acetate, desostril, ethinyl estradiol, ethynodiol, etonogestrill, levomycin, levonorgestrel, linepolistin, misoprostrol, nomedistrol acetate, norelgestromin, norethindrone, noregestrol, norelgestromin, norethoxyfene, sedisterone acetate, and any combination thereof.

[0222] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate, and emtricitabine); adefovir and emtricitabine; TDF+FTC; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir alafenamide Fenamide and elvitegravir; Tenofovir alafenamide + elvitegravir (rectal formulation, HIV infection), Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); Dolutegravir, abacavir sulfate, and lamivudine; Raltegral; Pegylated raltegravir; Raltegravir and lamivudine; Maraviroc; Tenofovir + emtricitabine + maraviroc, Enfuvirtide; ALUVI A® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir;Atazanavir sulfate; Dolutegravir; Elvitegravir; Ritonavir; Atazanavir sulfate and ritonavir; Darunavir; Lamivudine; Prolastine; Fosamprenavir; Fosamprenavir calcium; Efavirenz; Etravirine; Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; A In combination with one, two, three, or four additional therapeutic agents selected from ludesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir and abacavir sulfate;

[0223] In some embodiments, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In an additional embodiment, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0224] In another embodiment, a drug disclosed herein or a pharmaceutical composition thereof is combined with a first additional therapeutic agent selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0225] In some embodiments, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with a first additional therapeutic agent (a contraceptive) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, norethynodrel, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof. Gene Therapy and Cell Therapy

[0226] In certain embodiments, the agents described herein are combined with gene or cell therapy regimens. Gene therapy and cell therapy include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches to modify cell activity to further alter endogenous immune responsiveness to infection. Examples of cell therapy include LB-1903, ENOB-HV-01, GOVX-B01, HSPC-overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapy. Examples of dendritic cell therapy include AGS-004. CCR5 gene editing agents include SB-728T. CCR5 gene inhibitors include Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells (HIV infection / HIV-associated lymphoma). In some embodiments, C34-CCR5 / C34-CXCR4-expressing CD4-positive T cells are co-administered with one or more multispecific antigen binding molecules. In some embodiments, agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy. Gene Editor

[0227] In certain embodiments, the agents described herein are combined with a gene editor, such as an HIV-targeting gene editor. In various embodiments, the genome editing system can be selected from the group consisting of a CRISPR / Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonuclease complex, and a meganuclease complex. Exemplary HIV targets for the CRISPR / Cas9 system include, but are not limited to, EBT-101. CAR-T cell therapy

[0228] In some embodiments, the agents described herein can be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen comprises an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4-binding site on gp120, a CD4-inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, or a membrane-proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic. Examples of HIV CAR-T include convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-CD4 CAR-cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, anti-CD4 MicAbody antibody+anti-MicAbody CAR T-cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express CD4 CAR, and C46 peptide. TCR-T cell therapy

[0229] In certain embodiments, the agents described herein are combined with a population of TCR-T cells that are genetically engineered to target an HIV-derived peptide, e.g., ImmTAV, present on the surface of virally infected cells. B cell therapy

[0230] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells engineered to express broadly neutralizing antibodies, such as 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019).

[0231] A compound disclosed herein (e.g., any compound of Formula I, II, III, IV, or V) may be combined with one, two, three, or four additional therapeutic agents in any dosage of the compound of Formula I, II, III, IV, or V (e.g., 1 mg to 500 mg of the compound).

[0232] In one embodiment, a kit is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents.

[0233] In one embodiment, the additional therapeutic agent or agents of the kit are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulatory agents, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (such as chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, etc.), compounds targeting the HIV capsid, latency reactivators, capsid polymerization inhibitors, HIV bNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIVThe anti-HIV agent is selected from a POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, an HIV vaccine, and a combination thereof.

[0234] In some embodiments, the additional therapeutic agent or agents of the kit are selected from HIV combination drugs, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0235] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitor compound. In an additional embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside inhibitor of reverse transcriptase and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and one, two, three, or four HIV bNAbs. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor.In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, and an HIV nucleoside inhibitor of reverse transcriptase. HIV long-acting therapy

[0236] Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, islatravir implant, doravirine, raltegravir, and long-acting dolutegravir. HBV combination therapy

[0237] In certain embodiments, methods are provided for treating or preventing HBV infection, comprising administering to a human a therapeutically effective amount of a composition described herein in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. In one embodiment, methods are provided for treating HBV infection, comprising administering to a human a therapeutically effective amount of a composition described herein in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0238] In certain embodiments, the present specification provides a method for treating HBV infection, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a composition described herein in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents suitable for treating HBV infection.

[0239] The compounds described herein can be used or combined with one or more of chemotherapeutic agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (DART®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates (ADCs), genetic modifying agents or gene editors (CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs, etc.), cell therapies such as CAR-T (chimeric antigen receptor T cells), and TCR-T (genetically engineered T cell receptor) agents, or any combination thereof.

[0240] In some embodiments, the additional therapeutic agent or agents are selected from the group consisting of HBV combination drugs, HBV vaccines, HBV polymerase inhibitors, HBV capsid modulators, agonists of TLR7, TLR8, and TLR9, cytokines, immune checkpoint inhibitors, FLT3 ligands, interferon alpha receptor ligands, interferon alpha, interferon lambda, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, HBV X protein (HBx) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides, short interfering RNA (siRNA) and DNA-directed RNA interference (ddRNAi), endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen (HBeAg) inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors targeting HBV antigens or peptides, CAR-T cell therapy, thymosin agonists, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, and indoleamine 2,3-dioxygenase (IDO1) pathway inhibitors agents, anti-OX40, anti-CD40, anti-CD160, HBV gene editors, PAPD5 / PAPD7 inhibitors, ZCCHC14 inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, epigenetic regulators, inducers of tertiary lymphoid aggregates, antagonists of IAP / XIAP, nucleic acid polymers (e.g., NAPs and STOPS), modulators of lipid metabolism or transport, arginase inhibitors, and other drugs for treating HBV, and combinations thereof.

[0241] In some embodiments, the additional therapeutic agent or additional therapeutic agents are selected from adefovir, entecavir, telbivudine, lamivudine, and lenacapavir, and combinations thereof.

[0242] In some embodiments, the additional therapeutic agent or agents are selected from adefovir, entecavir, telbivudine, lamivudine, and lenacapavir. HBV combination drugs

[0243] Examples of combination drugs for the treatment of HBV include, but are not limited to, TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN-α; ABX-203 adefovir, and PEG-IFN-α; and INO-1800 (INO-9112 and RG7944). Other HBV medications

[0244] Examples of other drugs for the treatment of HBV include α-hydroxytropolone, amdoxovir, β-hydroxycytosine nucleoside, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, Feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551, and ZH-2N, as well as U.S. Patent Application Publication No. 20150210682 (Roche), U.S. Patent Application Publication No. 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), WO 16128335(A)

[0033] Examples of compounds that can be used in the present invention include, but are not limited to, compounds described in WO 16120186(A1) (Roche), U.S. Patent Application Publication No. 2016237090(A) (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), U.S. Patent Application Publication No. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), U.S. Patent Application Publication No. 2016220586(A) (Roche), and U.S. Patent Application Publication No. 2015031687(A) (Roche). HBV vaccine

[0245] HBV vaccines include both prophylactic and therapeutic vaccines. Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-HepB-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Products), and recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Products). Engineering), Recombinant Hepatitis B Surface Antigen Vaccine, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV Vaccine, DTP-HBV Vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib Vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac B, Hebsulin, Recombivax HB, Revac B mcf, Revac These include, but are not limited to, B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hib vaccine.

[0246] Examples of HBV therapeutic vaccines include HBsAG-HBIG conjugate, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202, ChronVac-B, TG-1050, and Lm HBV. HBV DNA polymerase inhibitors

[0247] Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, bicifovir, entecavir (BARAC), LUDE®), entecavir maleate, telbivudine (TYZEKA®), filocillovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusorin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil asparagine orotate, and HS-10234. immunomodulators

[0248] Examples of immunomodulators include lintatolimod, imidole hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, and the polymer polyethyleneimine (polymer polyethyleneimine, PEI), Gepon, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, GS-9688, RO-7011785, RG-7854, AB-506, RO-6871765, AIC-649, and IR-103. Toll-like receptor (TLR) modulators

[0249] In various embodiments, the agents described herein are combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene No. 7096), TLR2 (NCBI Gene No. 7097), TLR3 (NCBI Gene No. 7098), TLR4 (NCBI Gene No. 7099), TLR5 (NCBI Gene No. 7100), TLR6 (NCBI Gene No. 10333), TLR7 (NCBI Gene No. 51284), TLR8 (NCBI Gene No. 51311), TLR9 (NCBI Gene No. 54106), and / or TLR10 (NCBI Gene No. 81793). Exemplary TLR7 agonists that may be co-administered include AL-034, DSP-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and those disclosed in U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20110098248 (Gilead Sciences). Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (VentirxNo. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists that may be co-administered include, but are not limited to, compounds disclosed in U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists that may be co-administered include NKTR-262, tellurolimod, and BDB-001. Examples of TLR8 agonists that may be co-administered include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and those described in U.S. Patent Application Publication No. 20140045849 (Janssen), ... 40073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (VentirxPharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). Exemplary TLR9 agonists that may be co-administered include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091 interferon alpha receptor ligands.

[0250] Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®), pegylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPEG-interferon alpha-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), YPEG-interferon alpha-2b ( PEG-rhIFNalpha-2b, MOR-22, pegylated interferon alpha-2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alpha-n1 (HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferon alpha-2b (Axxo), Alfaferone, interferon alpha-2b (BioGeneric Pharma), interferon-α2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PD-feron-B, interferon α-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon α 2b (Zydus-Cadila), interferon α 2a, Optipeg AA), Realfa 2B, Reliferon, interferon α-2b (Amega), interferon α-2b (Virchow), ropeg interferon α-2b, rHSA-IFN α-2a (recombinant human serum albumin interferon α-2a fusion protein), rHSA-IFN α 2b, recombinant human interferon α-(1b, 2a, 2b), pegylated interferon α-2b (Amega), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α-2b (Changchun Institute of Biological Products, Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216, and Interapo. hyaluronidase inhibitors

[0251] Examples of hyaluronidases include, but are not limited to, astodrimers. Hepatitis B surface antigen (HBsAg) inhibitors

[0252] Examples of HBsAg inhibitors include, but are not limited to, HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2165, REP-2163, REP-2053, REP-2031, and REP-006, and REP-9AC'.

[0253] Examples of HBsAg secretion inhibitors include, but are not limited to, BM601. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor

[0254] Examples of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors include, but are not limited to, AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, probody mAbs, tremelimumab, and JHL-1155. Cyclophilin inhibitors

[0255] Examples of cyclophilin inhibitors include, but are not limited to, CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds described in U.S. Pat. No. 8,513,184 (Gilead Sciences), U.S. Pat. Appl. Pub. No. 20140030221 (Gilead Sciences), U.S. Pat. Appl. Pub. No. 20130344030 (Gilead Sciences), and U.S. Pat. Appl. Pub. No. 20130344029 (Gilead Sciences). HBV virus entry inhibitor

[0256] Examples of HBV virus entry inhibitors include, but are not limited to, Myrcludex B. antisense oligonucleotides

[0257] Examples of viral mRNA-targeting antisense oligonucleotides include, but are not limited to, ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004. Antisense oligonucleotides that target host factors such as PD-L1 are also known. Short interfering RNA (siRNA) and ddRNAi

[0258] Examples of siRNA include, but are not limited to, TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, and ARB-1467.

[0259] Examples of DNA-guided RNA interference include, but are not limited to, BB-HB-331. Endonuclease Modulators

[0260] An example of an endonuclease modulator includes, but is not limited to, PGN-514. Ribonucleotide reductase inhibitors

[0261] An example of a ribonucleotide reductase inhibitor includes, but is not limited to, Trimidox. HBV E antigen inhibitors

[0262] Examples of HBV E antigen (HBeAg) inhibitors include, but are not limited to, wogonin. Covalently closed circular DNA (cccDNA) inhibitors

[0263] Examples of cccDNA inhibitors include, but are not limited to, BSBI-25 and CHR-101. Farnesoid X receptor agonists

[0264] Examples of farnesoid x receptor agonists include, but are not limited to, EYP-001, cilofexor, EDP-305, MET-409, tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670. HBV antibody

[0265] Examples of HBV antibodies targeting the surface antigen of hepatitis B virus include, but are not limited to, GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy (Hepatitis B Virus Infection, Humabs BioMed), and anti-HBsAg (small, medium, large).

[0266] Examples of HBV antibodies, including monoclonal and polyclonal antibodies, include, but are not limited to, Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, Igantibe, Niuliva, CT-P24, Hepatitis B Immune Globulin (Intravenous, pH4, HBV Infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

[0267] An example of a fully human monoclonal antibody includes, but is not limited to, HBC-34. CCR2 chemokine antagonists

[0268] An example of a CCR2 chemokine antagonist includes, but is not limited to, propagermanium. Thymosin agonists

[0269] Examples of thymosin agonists include, but are not limited to, thymalfasin, recombinant thymosin alpha 1 (GeneScience). cytokines

[0270] Examples of cytokines include, but are not limited to, interferon alpha, interferon lambda, recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, celmoleukin, and CD4, CD8, or B cell targeting cytokines, including, but not limited to, IL-2, IL-7, IL-12, IL-15, and IL-21. Nucleoprotein Modulators

[0271] The nucleoprotein modulator may be either an HBV core or capsid protein inhibitor. Examples of nucleoprotein modulators include, but are not limited to, GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY41-4109, morphotiazine mesylate, ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158, and DVR-23.

[0272] Examples of capsid inhibitors include those disclosed in U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics), U.S. Patent Application Publication No. 20140343032 (Roche), WO 2014037480 (Roche), U.S. Patent Application Publication No. 20130267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Janssen), WO 2014033167 (Janssen), WO 2015 / 059212 (Janssen), and WO 2015 / 059212 (Janssen). en), WO 2015118057 (Janssen), WO 2015011281 (Janssen), WO 2014184365 (Janssen), WO 2014184350 (Janssen), WO 2014161888 (Janssen), WO 2013096744 (Novira), U.S. Patent Application Publication No. 20150225355 (Novira), U.S. Patent Application Publication No. 20140178337 (Novira), U.S. Patent Application No. Patent Application Publication No. 20150315159 (Novira), U.S. Patent Application Publication No. 20150197533 (Novira), U.S. Patent Application Publication No. 20150274652 (Novira), U.S. Patent Application Publication No. 20150259324 (Novira), U.S. Patent Application Publication No. 20150132258 (Novira), U.S. Patent No. 9,181,288 (Novira), WO 2014184350 (Janssen), WO 2013144129 (Roche), WO 2014184350 (Janssen), WO 2014184350 (Roche ... 017198744 (Roche), U.S. Patent Application Publication No. 20170334882 (Novira), U.S. Patent Application Publication No. 20170334898 (Roche), WO 2017202798 (Roche), WO 2017214395 (Enanta), WO 2018001944 (Roche), WO 2018001952 (Roche), WO 2018005881 (Novira), WO 2018005883 (Novira),WO 2018011100 (Roche), WO 2018011160 (Roche), WO 2018011162 (Roche), WO 2018011163 (Roche), WO 2018036941 (Roche), WO 2018043747 (Kyoto Univ), U.S. Patent Application Publication No. 20180065929 (Janssen), WO 2016168619 (Indiana University), WO 2016195982 (The Penn State Foundation), WO 2017001655 (Janssen), WO 2017048950 (Assembly Biosciences), WO 2017048954 (Assembly Examples of compounds that can be used include, but are not limited to, compounds described in International Publication No. 2017048962 (Assembly Biosciences), U.S. Patent Application Publication No. 20170121328 (Novira), and U.S. Patent Application Publication No. 20170121329 (Novira).

[0273] Examples of transcription inhibitors include, but are not limited to, the compounds described in WO 2017013046 (Roche), WO 2017016960 (Roche), WO 2017017042 (Roche), WO 2017017043 (Roche), WO 2017061466 (Toyoma chemicals), WO 2016177655 (Roche), and WO 2016161268 (Enanta). International Publication No. 2017001853 (Redex Pharma), International Publication No. 2017211791 (Roche), International Publication No. 2017216685 (Novartis), International Publication No. 2017216686 (Novartis), International Publication No. 2018019297 (Ginkgo Pharma), International Publication No. 2018022282 (Newave Pharma), U.S. Patent Application Publication No. 20180030053 (Novartis), and International Publication No. 2018045911 (Zhejiang Pharma). Retinoic acid-inducible gene 1 stimulator

[0274] Examples of stimulators of retinoic acid-inducible gene 1 include, but are not limited to, SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100. NOD2 stimulator

[0275] Examples of NOD2 stimulators include, but are not limited to, SB-9200. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0276] Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, bupalisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765, jedatolisib, ME-401, VS-5584, copanlisib, CAI otrose salt, perifosine, RG-7666, GSK-2636771, DS-7423, These include, but are not limited to, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, pukitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401. Indoleamine-2,3-dioxygenase (IDO1) pathway inhibitors

[0277] In various embodiments, the agents described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene No. 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Recombinant Thymosin α-1

[0278] Examples of recombinant thymosin alpha-1 include, but are not limited to, NL-004 and PEGylated thymosin alpha-1. Bruton's tyrosine kinase (BTK) inhibitors

[0279] Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and the compounds described in U.S. Patent Application Publication No. 20140330015 (Ono). No. 20130079327 (Ono Pharmaceutical), and U.S. Patent Application Publication No. 20130217880 (Ono Pharmaceutical). KDM inhibitors

[0280] Examples of KDM5 inhibitors include those described in WO 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140275092 (Genentech / Constellation Pharmaceuticals), Pharmaceuticals), U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), and compounds described in U.S. Patent Application Publication No. 20140371214 (Epitherapeutics), U.S. Patent Application Publication No. 20160102096 (Epitherapeutics), U.S. Patent Application Publication No. 20140194469 (Quanticel), U.S. Patent Application Publication No. 20140171432, U.S. Patent Application Publication No. 20140213591 (Quanticel), U.S. Patent Application Publication No. 20160039808 (Quanticel), U.S. Patent Application Publication No. 20140275084 (Quanticel), and WO 2014164708 (Quanticel).

[0281] Examples of KDM1 inhibitors include, but are not limited to, the compounds disclosed in US Pat. No. 9,186,337(B2) (Oryzon Genomics), GSK-2879552, and RG-6016. STING agonists

[0282] Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX, and the antibodies disclosed in WO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), U.S. Patent Application Publication No. 20170158724 (GlaxoSmithkline), WO 2017075477 (Aduro Biotech). Biotech), U.S. Patent Application Publication No. 20170044206 (Merck), WO 2014179760 (University of California), WO 2018098203 (Janssen), WO 2018118665 (Merck), WO 2018118664 (Merck), WO 2018100558 (Takeda), WO 2018067423 (Merck), WO 2018060323 (Boehringer). Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[0283] Examples of NNRTIs include, but are not limited to, compounds described in WO 2018118826 (Merck), WO 2018080903 (Merck), WO 2018119013 (Merck), WO 2017100108 (Idenix), WO 2017027434 (Merck), WO 2017007701 (Merck), and WO 2008005555 (Gilead). HBV replication inhibitors

[0284] Examples of hepatitis B virus replication inhibitors include, but are not limited to, isothiafluridine, IQP-HBV, RM-5038, and Xingantie. Arginase inhibitors

[0285] Examples of arginase inhibitors include, but are not limited to, CB-1158, C-201, and resminostat. Gene Therapy and Cell Therapy

[0286] Gene and cell therapy include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace large parts of a patient's own immune system to enhance the immune response against infected cells or to kill infected cells or activate the patient's own immune system to find and kill infected cells; and genetic approaches to alter cellular activity to further alter the endogenous immune response to infection. Gene Editor

[0287] Examples of genome editing systems include, but are not limited to, CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems; for example, cccDNA elimination by targeted cleavage, and modifying one or more of the hepatitis B virus (HBV) viral genes. Modifying (e.g., knocking out and / or knocking down) the PreC, C, X, PreSI, PreS2, S, P, or SP genes refers to (1) reducing or eliminating PreC, C, X, PreSI, PreS2, S, P, or SP gene expression; (2) interfering with precore, core, X protein, long surface protein, middle surface protein, S protein (also known as HBsAg and HBsAg), polymerase protein, and / or hepatitis B splice protein function (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and / or HBSP); or (3) reducing or eliminating intracellular, serum, and / or parenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHB, Pol, and / or HBSP proteins. Knocking down one or more of the PreC, C, X, PreSI, PreS2, S, P, and / or SP genes may reduce or eliminate expression of the genes within the HBV cccDNA and / or HBV This is done by targeting the gene into which the DNA is integrated. CAR-T cell therapy

[0288] CAR T cell therapy involves a population of immune effector cells genetically engineered to express a chimeric antigen receptor (CAR), which contains an HBV antigen-binding domain. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic. TCR-T cell therapy

[0289] TCR T cell therapy involves T cells expressing an HBV-specific T cell receptor. The TCR-T cells are genetically engineered to target HBV-derived peptides (e.g., HLA / pMHC-presented peptides) present on the surface of virus-infected cells. In some embodiments, the T cells express an HBV surface antigen (HBsAg)-specific TCR. Examples of TCR-T therapies for the treatment of HBV include, but are not limited to, LTCR-H2-1.

[0290] In another specific embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in combination with HBV DNA polymerase inhibitors and immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies and bispecific antibodies, including HBV antibodies targeting the surface antigen of the hepatitis B virus, including anti-HBsAg (small, medium, large), and "antibody-like" therapeutic proteins (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, One or two additional therapeutic agents selected from RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators are combined with one or two additional therapeutic agents selected from HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigens, siRNAs, miRNA gene therapy drugs, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).

[0291] In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBV therapeutic vaccine, an HBV antibody and bispecific antibody, including an HBV antibody targeting the surface antigen of the hepatitis B virus, including anti-HBsAg (small, medium, large), and an "antibody-like" therapeutic protein (e.g., DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), a cyclophilin inhibitor, a stimulator of retinoic acid-inducible gene 1, a stimulator of RIG-I-like receptors, a PD-1 inhibitor, a PD-L1 inhibitor, an arginase inhibitor, a PI3K inhibitor, an IDO1 inhibitor, and a stimulator of NOD2.

[0292] In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from an HBV viral entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody targeting a hepatitis B virus surface antigen, including anti-HBsAg (small, medium, large), an siRNA, an miRNA gene therapy, an sshRNA, a KDM5 inhibitor, and a nucleoprotein modulator (an HBV core or capsid protein inhibitor).

[0293] In certain embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are disclosed in U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Patent Application Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent No. 8,722,054 ... Sciences), U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent No. 8,513,184 (Gilead Sciences), U.S. Patent Application Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344029 (GileadSciences), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics), U.S. Patent Application Publication No. 2014 / 0343032 (Roche), WO 2014037480 (Roche), U.S. Patent Application Publication No. 2013 / 0267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Janssen), WO 2014033167 (Janssen), WO 2015 / 059212 (Janssen), WO 2015118057 (Janssen), WO 2015011281 (Janssen), WO 2014184365 (Janssen), WO 2014184350 (Janssen), WO 2014161888 (Janssen), WO No. 2013096744 (Novira), U.S. Patent Application Publication No. 20150225355 (Novira), U.S. Patent Application Publication No. 20140178337 (Novira), U.S. Patent Application Publication No. 20150315159 (Novira), U.S. Patent Application Publication No. 20150197533 (Novira), U.S. Patent Application Publication No. 20150274652 (Novira), U.S. Patent Application Publication No. No. 150259324 (Novira), U.S. Patent Application Publication No. 20150132258 (Novira), U.S. Patent Application Publication No. 9181288 (Novira), WO 2014184350 (Janssen), WO 2013144129 (Roche), U.S. Patent Application Publication No. 20100015178 (Incyte), U.S. Patent Application Publication No. 2016137652 (Flexus Biosciences, Inc.), WO 2014073738 (Flexus Biosciences, Inc.), WO 2015188085 (Flexus Biosciences, Inc.), U.S. Patent Application Publication No. 2014 / 0330015 (Ono Pharmaceutical), U.S. Patent Application Publication No. 2013 / 0079327 (OnoPharmaceutical), U.S. Patent Application Publication No. 2013 / 0217880 (Ono Pharmaceutical), WO 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140275092 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), and U.S. Patent Application Publication No. 20140371214 (Epitherapeutics), U.S. Patent Application Publication No. 20160102096 (Epitherapeutics), U.S. Patent Application Publication No. 20140194469 (Quanticel), U.S. Patent Application Publication No. 20140171432, U.S. Patent Application Publication No. 20140213591 (Quanticel), U.S. Patent Application Publication No. 20160039808 (Quanticel), U.S. Patent Application Publication No. 20140275084 (Quanticel), WO 2014164708 (Quanticel), U.S. Patent Application Publication No. 9186337(B2) (Oryzon These compounds are combined with compounds such as those described in J. Med. Genomics, as well as other drugs to treat HBV, and combinations thereof. Administration Administration route

[0294] A compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof (also referred to herein as the active ingredient) can be administered by any route appropriate to the condition to be treated. Suitable routes include, but are not limited to, oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that suitable routes may vary depending, for example, on the condition of the recipient. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the compounds disclosed herein can be and are orally administered.

[0295] In some embodiments, a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, can be administered using a syringe suitable for administering the compound. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, can be administered with an auto-injector equipped with a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof. Dosing regimen

[0297] In some embodiments, a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, can be administered to a subject according to an effective dosing regimen for a desired period or duration, such as, for example, at least about once daily, at least about once weekly, at least about once monthly, at least about once every two months, at least about once every three months, at least about once every four months, at least about once every six months, or at least about once every twelve months or more. In some embodiments, the compound is administered on a daily or intermittent schedule. In some embodiments, the compound is administered on a weekly schedule. In some embodiments, the compound is administered on a monthly schedule. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every five months. In some embodiments, the compound is administered every six months.

[0298] In some embodiments, a compound, such as a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered subcutaneously or intramuscularly to a subject at least about once per month. In some embodiments, a compound (e.g., a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof) is administered subcutaneously or intramuscularly to a subject at least about once per two months, or at least about once per three months, or at least about once per four months, or at least about once per six months. In some embodiments, a compound (e.g., a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof) or a pharmaceutically acceptable salt thereof is administered subcutaneously to a subject at least about once per month. In some embodiments, a compound (e.g., a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof) or a pharmaceutically acceptable salt thereof is administered subcutaneously to a subject at least about once per two months. In some embodiments, the compound (e.g., a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof), or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the subject at least about once every three months.

[0299] In some embodiments, for example, the dosage or frequency of administration of a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, will be adjusted over the course of treatment based on the judgment of the administering physician.

[0300] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I, II, III, IV, or V) or a pharmaceutically acceptable salt thereof can be administered in an effective dosage. For example, the dosage can be from 1 mg to 1000 mg of the compound.

[0301] In some embodiments, the methods disclosed herein include event-driven administration to a subject of, for example, a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof.

[0302] As used herein, the terms "event-driven" and "event-driven administration" refer to administering, e.g., a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, (1) before an event (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event) that exposes an individual to HIV (or otherwise increases the individual's risk of contracting HIV); and / or (2) during an event (or two or more recurring events) that exposes an individual to HIV (or otherwise increases the individual's risk of contracting HIV); and / or (3) after an event (or after the last event in a series of recurring events) that exposes an individual to HIV (or otherwise increases the individual's risk of contracting HIV). In some embodiments, event-driven administration occurs before the subject's exposure to HIV. In some embodiments, event-driven administration occurs after the subject's exposure to HIV. In some embodiments, event-driven administration occurs before the subject's exposure to HIV and after the subject's exposure to HIV.

[0303] In some embodiments, for example, a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered prior to the subject's exposure to HIV.

[0304] An example of an event-driven dosing regimen includes administering, e.g., a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, within 24 hours prior to HIV exposure (e.g., sexual intercourse, including the first sexual intercourse, with a sex partner known to be HIV-positive), followed by administering a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, every 24 hours during the exposure period (e.g., sexual intercourse with a sex partner known to be HIV-positive), followed by an additional dose of, e.g., a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, after final exposure (e.g., sexual intercourse with a sex partner known to be HIV-positive), followed by a final dose of, e.g., a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 24 hours thereafter.

[0305] A further example of an event-driven dosing regimen includes administering, for example, a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, within 24 hours before HIV exposure (e.g., sexual intercourse with a sex partner known to be HIV-positive), daily dosing during the exposure period (e.g., sexual intercourse with a sex partner known to be HIV-positive, including the last sexual intercourse), followed by a final dose (which may be an increased dose, such as a double dose) about 24 hours after the last exposure.

[0306] In certain embodiments, e.g., when administered as PrEP, a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered daily. In certain embodiments, e.g., when administered as event-driven PrEP, a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered 1 hour to 10 days, 1 hour to 7 days, 1 hour to 5 days, 1 to 72 hours, 1 to 48 hours, 1 to 24 hours, or 12 to 12 hours before an event that will increase the individual's risk of contracting HIV (e.g., before sex or other exposure to the HIV virus). In some embodiments, the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered 10 days, 7 days, 5 days, 72 hours, 60 hours, 48 ​​hours, 24 hours, 12 hours, 9 hours, 6 hours, 4 hours, 3 hours, 2 hours, or 1 hour before an event that would increase the individual's risk of contracting HIV (e.g., before sexual or other exposure to the HIV virus). In certain embodiments, when the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered before an event that would increase the individual's risk of contracting HIV (e.g., administered before the event), it is administered daily before the event (e.g., sexual activity). In certain embodiments, when the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered before an event that would increase the individual's risk of contracting HIV (e.g., administered before the event), it is administered 1 to 3 times before the event.

[0307] In some embodiments, for example, when administered as part of an event-driven PrEP regimen, the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered daily during HIV exposure. In certain embodiments in which the compound of Formula I, II, III, IV, or V is administered pre-exposure, the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., as a single dose) during HIV exposure (e.g., during sexual activity with a sex partner known to be HIV-positive). In some embodiments, the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., for 1 to 7 days) after the last exposure to HIV (e.g., after the last sexual activity with a sex partner known to be HIV-positive). In some embodiments, administration continues for 1 or 2 days after the last exposure to HIV.

[0308] Further examples of PrEP and / or PEP can be found, for example, in the summary of the clinical trial entitled "On Demand Antiretroviral Pre-exposure Prophylaxis for HIV Infection in Men Who Have Sex With Men" (Clinical Trial #NCT01473472), the summary of the clinical trial entitled "Prevention of HIV in Ile-de-France" (Clinical Trial #NCT03113123), and Molina et al. N. Engl. J. Med. 2015, 353:2237-2246, the disclosures of each of which are incorporated herein by reference in their entirety.

[0309] In some embodiments, a method for reducing the risk of contracting HIV (e.g., HIV-1 and / or HIV-2) comprises administering a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, in combination with safer sex practices. In certain embodiments, a method for reducing the risk of contracting HIV (e.g., HIV-1 and / or HIV-2) comprises administering to an individual at risk of contracting HIV. Examples of individuals at high risk of contracting HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

[0310] In some embodiments, the reduction in risk of contracting HIV is at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In some embodiments, the reduction in risk of contracting HIV is at least about 75%. In some embodiments, the reduction in risk of contracting HIV is about 80%, about 85%, or about 90%. formulation

[0311] Formulations suitable for parenteral administration include, but are not limited to, aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. In certain embodiments, the suspension is a microsuspension. In certain embodiments, the suspension is a nanosuspension.

[0312] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) comprise one or more excipients. The excipient must be compatible with the other ingredients of the formulation and physiologically harmless to the recipient thereof. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[0313] In certain embodiments, the active ingredient (eg, a compound of Formula I, II, III, IV, or V) is present as the free acid.

[0314] In certain embodiments, the pharmaceutical compositions disclosed herein are parenteral formulations. In certain embodiments, the formulations are administered to a subject subcutaneously. In certain embodiments, the formulations are administered to a subject intramuscularly.

[0315] The amount of active ingredient that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended therapeutic subject and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain from about 1 mg to 1000 mg of active agent, formulated with an appropriate and convenient amount of pharmaceutically acceptable carrier material (e.g., inactive ingredient or excipient). In certain embodiments, the carrier material varies from about 5 to about 95% (weight:weight or wt:wt) of the total composition.

[0316] It will be understood that in addition to the ingredients specifically mentioned above, the compositions of these embodiments may include other agents conventional in the art having regard to the type of composition in question; for example, those suitable for oral administration may include flavoring agents. Kits and manufactured products

[0317] Also included in the present disclosure are kits comprising a compound of the present disclosure, or an enantiomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compound in treating an indication, such as a disease or ill health condition described herein. In one embodiment, a kit is provided that comprises a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents.

[0318] Also provided herein is an article of manufacture comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, in a suitable container, which may be a vial, jar, ampoule, pre-filled syringe, implant, or infusion bag.

[0319] In some embodiments, the present disclosure relates to a kit comprising a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit may include one, two, three, or four additional therapeutic agents described hereinabove. The kit may further include instructions for use, e.g., for use in inhibiting HIV integrase, such as for use in treating HIV infection or AIDS, or for use as a research tool. The instructions will generally be written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing the instructions are also acceptable.

[0320] In some embodiments, the present disclosure also relates to pharmaceutical kits comprising one or more containers containing a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof. Such containers may optionally be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting approval by the agency for manufacture, use, or sale for human administration. Each component (if two or more components are present) may be packaged in a separate container, or several components may be combined in a single container, if cross-reactivity and shelf life permit. The kit may be in unit dosage form, bulk package (e.g., multi-dose package), or subunit dose. The kit may also include multiple unit doses of the compound and instructions for use, and may be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0321] In some embodiments, disclosed herein are articles of manufacture comprising a unit dose of a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The articles of manufacture may further be sterilized and / or sealed. [Table 1-1] [Table 1-2]

[0322] The following examples are offered by way of illustration and not by way of limitation. [Example]

[0323] General Scheme A [ka] Compounds of formula A can be prepared in a two- or three-step sequence from geminal disubstituted amino acids according to general scheme A. The amino acid can be converted to an amino ester intermediate of formula a by reaction with an alcohol in the presence of thionyl chloride or 4N HCl in dioxane. Alternatively, a protected amino acid can be esterified with an alcohol in the presence of EDCI, DMAP, and ACN. The resulting N-protected amino ester can be deprotected by treatment with 4N HCl in dioxane and DCM to give the amino ester intermediate of formula a. The intermediate of formula a can be coupled with (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid (PMPA) using triphenylphosphine, 2,2'-dipyridyl disulfide, triethylamine, and pyridine to give compounds of formula A. General Scheme B [ka]

[0324] R 1 and R 2 Compounds of formula A, where R is different, can be prepared by reacting PMPA, an intermediate of formula b, and an intermediate of formula b (R 1 ≠R 2 It can be prepared in one step from a different alcohol than that used to make R. This can be done by mixing PMPA, the intermediate of formula b, and the alcohol with triphenylphosphine, 2,2'-dipyridyl disulfide, triethylamine, and pyridine to give R. 1 and R 2 This can be done by obtaining a compound of formula A where General Scheme C [ka]

[0325] Compounds of formula C can be prepared in one step from compounds of formula A according to general scheme C. Compounds of formula A can be mixed with an anhydride and pyridine to give compounds of formula C. Alternatively, compounds of formula A can be mixed with an acid chloride and pyridine to give compounds of formula C. Alternatively, compounds of formula A can be mixed with a carboxylic acid, EDCI, DMAP, and ACN to give compounds of formula C. R A L 1 is -C(O)-, then R 8 is defined by General Scheme D [ka]

[0326] Compounds of formula D can be prepared in three steps from compounds of formula A according to general scheme D (which involves the addition of the appropriate R A (This is in addition to the one-step preparation according to General Scheme C using R). Compounds of Formula A can be mixed with the monobenzyl ester of a dicarboxylic acid, EDCI, DMAP, and ACN. The benzyl protecting group of the resulting product can be removed by mixing with 10% Pd / C and EtOAc under an atmosphere of H2. The carboxylic acid of the resulting product can be converted to R 8a The compound of formula D can be alkylated by mixing with an alkyl halide defined by: General Scheme E [ka]

[0327] Compounds of formula E can be prepared in one step from compounds of formula A according to general scheme E. Compounds of formula A can be mixed with chloroformate and pyridine to give compounds of formula E. Alternatively, compounds of formula A can be mixed with an alcohol, triphosgene, DMAP and DCM to give compounds of formula E. 1 is -C(O)O-, then R B is R8 is defined by General Scheme F [ka]

[0328] Compounds of formula F-1, F-2 and F-3 can be prepared in one step from compounds of formula A according to general scheme F. Compounds of formula A can be prepared by reacting R 8a and DMF to give compounds of formula F-1, F-2 and F-3. Alternatively, compounds of formula A can be prepared by mixing the compound of formula A with an alkyl halide defined by R 8a with an alkyl halide defined by: potassium bicarbonate and NMP to give compounds of formula F-1, F-2 and F-3. Example 1: Dihexyl 2,2'-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (1) [ka] Synthesis of hexyl 2-amino-2-methylpropanoate hydrochloride (1a)

[0329] To a suspension of 2-amino-2-methyl-propanoic acid (5 g, 48.5 mmol) in 1-hexanol (49.5 g, 485 mmol) in a sealed tube under an argon atmosphere at 5° C. was added thionyl chloride (7.07 mL, 97 mmol) over 10 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and quenched with water (100 mL). The aqueous layer was washed with 1:1 EtOAc:Hex (50 mL×2) and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 1a. 1H NMR (400 MHz, methanol-d4) δ 4.27 (t, J = 6.6 Hz, 2H), 1.77-1.67 (m, 2H), 1.59 (s, 6H), 1.46-1.33 (m, 6H), 0.99-0.89 (m, 3H). [ka]

[0330] (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid (PMPA) (100 mg, 0.35 mmol), Intermediate 1a (234 mg, 1.04 mmol), triphenylphosphine (344 mg, 1.39 mmol), 2,2′-dipyridyl disulfide (307 mg, 1.39 mmol), and triethylamine (0.38 mL, 2.79 mmol) were combined in pyridine (2 mL) under argon. The reaction was heated to 70° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. After removing the drying agent, the resulting solution was concentrated and loaded onto silica gel (12 g). EtOAc (100 mL) was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The product-containing solution was concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (1). 1 H NMR(400MHz,DMSO-d6)δ 8.17(s,1H),8.13(s,1H),7.19(s,2H),4.33-4.14(m,4H),4.11-3.91(m,5H),3.63-3.48(m,2H),1.61-1.51(m,4H),1.40 1.46-1.35(m,12H),1.33-1.19(m,12H),1.06(d,J=6.2Hz,3H),0.84(td,J=6.9,2.1Hz,6H). 31P NMR(162MHz,DMSO-d6)δ 18.41(t,J=10.2Hz).LCMS:MS m / z=626.36[M+1],t R = 1.78 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2-100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 3.35 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2 to 98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 2: Bis(2-ethylbutyl) 2,2′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (2) [ka] Synthesis of 2-ethylbutyl 2-amino-2-methylpropanoate hydrochloride (2a)

[0331] To a suspension of 2-amino-2-methyl-propanoic acid (20 g, 194 mmol) in 2-ethylbutan-1-ol (85.3 g, 835 mmol) in a sealed tube under an argon atmosphere at 5° C. was added thionyl chloride (28.3 mL, 388 mmol) over 10 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and quenched with water (100 mL). The aqueous layer was washed with 1:1 EtOAc:Hex (50 mL×2) and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 2a. 1 H NMR(400MHz,DMSO-d6)δ 8.77(s,3H),4.08(d,J=5.5Hz,2H),1.49(s,7H),1.33(p,J=7.3Hz,4H),0.86(t,J=7.5Hz,6H). [ka]

[0332] PMPA (100 mg, 0.35 mmol), Intermediate 2a (195 mg, 0.87 mmol), and triethylamine (0.38 mL, 2.79 mmol) were combined in pyridine (1 mL) and heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (344 mg, 1.39 mmol) and 2,2'-dipyridyl disulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100 mL) was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100×30 mm column, 25% to 100% acetonitrile gradient in water over 30 minutes) to give the title compound (2). 1H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.12(s,1H),7.17(s,2H),4.31-4.12(m,4H),4.05-3.89(m,5H),3.66-3 .47(m,2H)),1.54-1.22(m,22H),1.06(d,J=6.2Hz,3H),0.83(td,J=7.4,3.3Hz,12H). 31 P NMR(162MHz,DMSO-d6)δ 18.43(t,J=10.2Hz).LCMS:MS m / z=626.38[M+1],t R = 1.74 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2-100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 3.31 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min, 2-98% ACN, 5.0 min to 6.0 min, 98% ACN at 2 mL / min. Example 3: Dibenzyl 2,2'-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (3) [ka] Synthesis of benzyl 2-amino-2-methylpropanoate hydrochloride (3a)

[0333] To a suspension of 2-amino-2-methyl-propanoic acid (2 g, 19.4 mmol) in benzyl alcohol (10.4 g, 97.0 mmol) in a sealed tube under an argon atmosphere at 5° C. was added thionyl chloride (28.3 mL, 38.8 mmol) over 10 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and quenched with water (100 mL). The aqueous layer was washed with 1:1 EtOAc:Hex (50 mL×2) and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 3a. 1 H NMR(400MHz,DMSO-d6)δ 8.46(s,3H),7.46-7.33(m,5H),5.26(s,2H),1.49(s,6H). [ka]

[0334] PMPA (100 mg, 0.35 mmol), Intermediate 3a (239 mg, 1.04 mmol), and triethylamine (0.38 mL, 2.79 mmol) were combined in pyridine (1 mL) and heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (344 mg, 1.39 mmol) and 2,2'-dipyridyl disulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100 mL) was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100×30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (3). 1H NMR(400MHz,DMSO-d6)δ 8.13(s,1H),8.12(s,1H),7.39-7.28(m,10H),7.22(s,2H),5.17-5.03 (m,4H),4.28-4.06(m,4H),3.91-3.83(m,1H),3.63-3.45(m,2H),1.39 1.44-1.34(m,12H),1.00(d,J=6.2Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ 18.71(t,J=9.2Hz).LCMS:MS m / z=638.13[M+1],t R = 1.46 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2 - 100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 2.91 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2-98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 4: Dipentyl 2,2'-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (4) [ka] Synthesis of pentyl 2-amino-2-methylpropanoate hydrochloride (4a)

[0335] To a suspension of 2-amino-2-methyl-propanoic acid (2 g, 19.4 mmol) in 1-pentanol (8.55 g, 97.0 mmol) in a sealed tube under an argon atmosphere at 5° C. was added thionyl chloride (28.3 mL, 38.8 mmol) over 10 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and quenched with water (100 mL). The aqueous layer was washed with 1:1 EtOAc:Hex (50 mL×2) and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give intermediate 4a. 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,3H),4.17(t,J=6.5Hz,2H),1.68-1.57(m,2H),1.48(s,6H),1.36-1.28(m,4H),0.92-0.86(m,3H). [ka]

[0336] PMPA (100 mg, 0.35 mmol), Intermediate 4a (219 mg, 1.04 mmol), and triethylamine (0.38 mL, 2.79 mmol) were combined in pyridine (1 mL) and heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (344 mg, 1.39 mmol) and 2,2'-dipyridyl disulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100 mL) was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100×30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (4). 1H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.12(s,1H),7.19(s,2H),4.32-4.11(m,4H),4.09-3.90(m,5H),3.63-3.47(m,2H),1.56 (q,J=6.7Hz,4H),1.45-1.35(m,12H),1.27(p,J=3.6Hz,8H),1.06(d,J=6.2Hz,3H),0.90-0.79(m,6H). 31 P NMR(162MHz,DMSO-d6)δ 18.43(t,J=10.1Hz).LCMS:MS m / z=598.25[M+1],t R = 1.61 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2 - 100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 3.11 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2 to 98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 5: Dipentyl 2,2'-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (5) [ka] Synthesis of neopentyl 2-amino-2-methylpropanoate hydrochloride (5a)

[0337] To a suspension of 2-amino-2-methyl-propanoic acid (2 g, 19.4 mmol) in 2,2-dimethylpropan-1-ol (8.55 g, 97.0 mmol) in a sealed tube under an argon atmosphere at 5° C. was added thionyl chloride (2.83 mL, 38.8 mmol) over 10 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and quenched with water (100 mL). The aqueous layer was washed with 1:1 EtOAc:Hex (50 mL×2) and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give intermediate 5a. 1 H NMR(400MHz,DMSO-d6)δ 8.67(s,3H),3.88(s,2H),1.51(s,6H),0.94(s,9H). [ka]

[0338] PMPA (100 mg, 0.35 mmol), Intermediate 5a (219 mg, 1.04 mmol), and triethylamine (0.38 mL, 2.79 mmol) were combined in pyridine (1 mL) and heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (344 mg, 1.39 mmol) and 2,2'-dipyridyl disulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100 mL) was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100×30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (5). 1H NMR(400MHz,DMSO-d6)δ 8.15(s,1H),8.12(s,1H),7.17(s,2H),4.30-3.67(m,9H),3.63-3.50(m ,2H),1.48-1.39(m,12H),1.05(d,J=6.2Hz,3H),0.89(d,J=5.1Hz,18H). 31 P NMR(162MHz,DMSO-d6)δ 18.52-18.37(m).LCMS:MS m / z=589.12[M+1],t R = 1.57 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2 - 100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 3.06 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2 to 98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 6: Diisopentyl 2,2'-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (6) [ka] Synthesis of isopentyl 2-amino-2-methylpropanoate hydrochloride (6a)

[0339] To a suspension of 2-amino-2-methyl-propanoic acid (2 g, 19.4 mmol) in 3-methylbutan-1-ol (8.55 g, 97.0 mmol) in a sealed tube under an argon atmosphere at 5° C. was added thionyl chloride (2.83 mL, 38.8 mmol) over 10 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and quenched with water (100 mL). The aqueous layer was washed with 1:1 EtOAc:Hex (50 mL×2) and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give intermediate 6a. 1 H NMR(400MHz,DMSO-d6)δ 8.71-8.54(m,3H),4.20(t,J=6.7Hz,2H),1.75-1.62(m,1H),1.52(q,J=6.7Hz,2H),1.48(s,6H),0.90(d,J=6.6Hz,6H). [ka]

[0340] PMPA (100 mg, 0.35 mmol) and Intermediate 6a (219 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (6). 1 H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.13(s,1H),7.17(s,2H),4.32-3.91(m,9H),3.63-3.50(m,2H),1. 70-1.58(m,2H),1.51-1.34(m,16H),1.07(d,J=6.3Hz,3H),0.89-0.84(m,12H). 31 P NMR(162MHz,DMSO-d6)δ 18.60-18.39(m).LCMS:MS m / z=598.10[M+1],t R = 1.60 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2-100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R= 3.14 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2–98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 7: Bis(3-ethylpentyl) 2,2′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (7) [ka] Synthesis of 3-ethylpentyl 2-amino-2-methylpropanoate hydrochloride (7b)

[0341] To a solution of 2-amino-2-methyl-propanoic acid (2 g, 9.84 mmol), 3-ethylpentan-1-ol (1.37 g, 11.8 mmol), and HATU (2.34 g, 9.84 mmol) in DCM (50 mL) was added TEA (5.37 mL, 39.4 mmol), followed by DMAP (60 mg, 0.49 mmol). After 3 h, the reaction was diluted with DCM (50 mL) and washed with saturated sodium bicarbonate solution (50 mL), water (50 mL), and brine (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. Intermediate 7a was purified by silica gel chromatography (0–50% EtOAc in Hex). Intermediate 7a was dissolved in 4 N HCl in dioxane (48.5 mL, 194 mmol). After 2 h, the reaction was concentrated. The residue was dissolved in water (20 mL) and concentrated (this process was repeated twice). The residue was dissolved in toluene and concentrated to give intermediate 7b. 1 H NMR(400MHz,DMSO-d6)δ 8.57(s,3H),4.20(t,J=6.8Hz,2H),1.61-1.54(m,2H),1.48(s,5H),1.35-1.26(m,6H),0.87-0.81(m,6H). [ka]

[0342] PMPA (100 mg, 0.35 mmol) and Intermediate 7b (335 mg, 1.41 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (7). 1 H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.12(s,1H),7.17(s,2H),4.32-3.90(m,9H),3.63-3.48(m,2H),1.55-1.48( m,4H),1.46-1.35(m,12H),1.29-1.22(m,10H),1.06(d,J=6.2Hz,3H),0.83-0.77(m,12H). 31 P NMR(162MHz,DMSO-d6)δ 18.44(t,J=9.6Hz).LCMS:MS m / z=654.17[M+1],t R= 1.92 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2-100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 3.50 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2-98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 8: Bis(3,3-dimethylbutyl) 2,2′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (8) [ka] Synthesis of 3,3-dimethylbutyl 2-amino-2-methyl-propanoate hydrochloride (8a)

[0343] 2-Amino-2-methyl-propanoic acid (2 g, 19.4 mmol) and 3,3-dimethylbutan-1-ol (9.91 g, 97.0 mmol) were dissolved in 4 N HCl in dioxane (19.4 mL, 77.6 mmol) in a sealed tube under an argon atmosphere. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give intermediate 8a. 1 H NMR(400MHz,DMSO-d6)δ 8.47(s,3H),4.23(t,J=7.1Hz,2H),1.56(t,J=7.1Hz,2H),1.46(s,6H),0.93(s,9H). [ka]

[0344] PMPA (100 mg, 0.35 mmol) and Intermediate 8a (315 mg, 1.41 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (8). 1 H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.12(s,1H),7.17(s,2H),4.32-3.90(m,9H),3.65-3.48(m,2H),1.49( q,J=7.2Hz,4H),1.45-1.34(m,12H),1.06(d,J=6.2Hz,3H),0.89(d,J=3.7Hz,18H). 31 P NMR(162MHz,DMSO-d6)δ 18.47(t,J=9.6Hz).LCMS:MS m / z=626.21[M+1],t R= 1.73 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2-100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 3.25 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min, 2-98% ACN, 5.0 min to 6.0 min, 98% ACN at 2 mL / min. Example 9: Di-tert-butyl 2,2′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (9) [ka]

[0345] PMPA (100 mg, 0.35 mmol) and tert-butyl 2-amino-2-methylpropanoate hydrochloride (204 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (9). 1 H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.13(s,1H),7.17(s,2H),4.29(dd,J=14.3,3.8Hz,1H),4.18(dd,J=14.4,6.0Hz,1H),4.12 (d,J=10.6Hz,1H),4.02(d,J=10.6Hz,1H),3.98-3.92(m,1H),1.45-1.30(m,30H),1.07(d,J=6.3Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ 18.60-18.39(m).LCMS:MS m / z=570.27[M+1],t R= 1.46 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2 - 100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 2.86 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2-98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 10: Dihexyl 2,2'-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(2S,2'S)-bis(2-methylbutanonoate) (10) [ka] Synthesis of hexyl (2S)-2-amino-2-methyl-butanoate hydrochloride (10a)

[0346] (2S)-2-Amino-2-methyl-butanoic acid (1 g, 8.6 mmol) and 1-hexanol (4.36 g, 42.7 mmol) were dissolved in 4 N HCl in dioxane (5.58 mL, 22.3 mmol) in a sealed tube under an argon atmosphere. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 10a. 1 H NMR(400MHz,DMSO-d6)δ 4.02(t,J=6.5Hz,2H),1.64-1.43(m,4H),1.35-1.24(m,6H),1.17(s,3H),0.90-0.84(m,3H),0.78(t,J=7.5Hz,3H). [ka]

[0347] PMPA (100 mg, 0.35 mmol) and Intermediate 10a (248 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (10). 1 H NMR(400MHz,acetonitrile-d3)δ 8.24(s,1H),8.04(s,1H),6.14(s,2H),4.33(dd,J=14.5,3.3Hz,1H),4.23-4.06(m,5H),3.98-3.92(m,1H),3.73-3.43(m,4H),1.90-1.60(m ,8H),1.57(s,3H),1.42(s,3H),1.39-1.28(m,12H),1.19(d,J=6.3Hz,3H),0.95-0.87(m,6H),0.83(t,J=7.4Hz,30H),0.78(t,J=7.4Hz,3H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.48 (t, J = 9.8 Hz). LCMS: MS m / z = 654.4 [M+1], t R= 1.17 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm x 2.1mm; Solvent: Acetonitrile with 0.1% acetic acid, Water with 0.1% acetic acid; Gradient: 2 μL / min, 0-1.00 min: 10%-100% acetonitrile, 1.00-1.35 min: 100% acetonitrile, 1.35-1.36 min: 100-10% acetonitrile. HPLC: t R = 3.55 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2-98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 11: Dihexyl 2,2'-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(2S,2'S)-bis(2-methyl-3-phenylpropanoate) (11) [ka] Synthesis of hexyl (2S)-2-amino-2-methyl-3-phenyl-propanoate hydrochloride (11a)

[0348] (2S)-2-Amino-2-methyl-3-phenyl-propanoic acid (1 g, 5.6 mmol) and 1-hexanol (2.85 g, 27.9 mmol) were dissolved in 4 N HCl in dioxane (5.58 mL, 22.3 mmol) in a sealed tube under an argon atmosphere. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 11a. 1H NMR(400MHz,DMSO-d6)δ 7.29-7.19(m,3H),7.16-7.10(m,2H),4.04-3.93(m,2H),2.89(d,J=12.9Hz,1H),2.76( d,J=12.9Hz,1H),1.59-1.50(m,2H),1.31-1.24(m,6H),1.22(s,3H),0.90-0.83(m,3H). [ka]

[0349] PMPA (100 mg, 0.35 mmol) and Intermediate 11a (275 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (11). 1 H NMR(400MHz,DMSO-d6)δ 8.12(s,1H),8.04(s,1H),7.30-7.08(m,12H),4.27-3.82(m,9H),3.61(d,J=8.7Hz,2H),3.11- 2.87(m,4H),1.55-1.39(m,10H),1.27-1.14(m,12H),0.97(d,J=6.3Hz,3H),0.86-0.78(m,6H). 31P NMR(162MHz,DMSO-d6)δ 18.45-18.23(m).LCMS:MS m / z=778.4[M+1],t R = 1.27 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm x 2.1mm; Solvent: Acetonitrile with 0.1% acetic acid, Water with 0.1% acetic acid; Gradient: 2 μL / min, 0-1.00 min: 10%-100% acetonitrile, 1.00-1.35 min: 100% acetonitrile, 1.35-1.36 min: 100-10% acetonitrile. HPLC: t R = 3.86 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min 2-98% ACN, 5.0 min to 6.0 min 98% ACN at 2 mL / min. Example 12: Bis(trans-4-(tert-butyl)cyclohexyl) 2,2′-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))bis(2-methylpropanoate) (12). [ka] Synthesis of trans-4-(tert-butyl)cyclohexyl 2-amino-2-methylpropanoate hydrochloride (12b)

[0350] To a solution of 2-amino-2-methyl-propanoic acid (2 g, 9.84 mmol), trans-4-(tert-butyl)cyclohexan-1-ol (1.69 g, 10.8 mmol), and HATU (2.34 g, 9.84 mmol) in DCM (50 mL) was added TEA (5.37 mL, 39.4 mmol), followed by DMAP (60 mg, 0.49 mmol). After 3 h, the reaction was diluted with DCM (50 mL) and washed with saturated sodium bicarbonate solution (50 mL), water (50 mL), and brine (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. Intermediate 12a was purified by silica gel chromatography (0–50% EtOAc in Hex). Intermediate 12a was dissolved in 4 N HCl in dioxane (48.5 mL, 194 mmol). After 2 h, the reaction was concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 12b. 1 H NMR(400MHz,DMSO-d6)δ 8.50(s,3H),4.71-4.59(m,1H),2.02-1.93(m,2H),1.81-1.75(m,2H),1.41-1.27(m,2H),1.19-0.95(m,3H),0.85(s,9H). [ka]

[0351] PMPA (100 mg, 0.35 mmol) and Intermediate 12b (290 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (12). 1 H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.12(s,1H),7.16(s,2H),4.57-4.44(m,2H),4.28(dd,J=14.3,3.8Hz,1H),4.21-4.06(m,3H),3.98-3.91(m,1H),3 .63-3.48(m,2H),1.96-1.86(m,4H),1.79-1.68(m,4H),1.44-1.32(m,12H),1.29-1.17(m,4H),1.13-0.90(m,9H),0.82(s,18H). 31 P NMR(162MHz,DMSO-d6)δ 18.27(t,J=9.5Hz).LCMS:MS m / z=734.14[M+1],t R= 1.99 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 4.6 mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μL / min, 0 min - 2.0 min 2-100% acetonitrile, 2.0 min - 3.05 min 100% acetonitrile, 3.05 min - 3.2 min 100% - 2% acetonitrile, 3.2 min - 3.5 min 2% ACN. HPLC: t R = 4.13 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 2 mL / min, 0 min–5.0 min 2–98% ACN, 5.0 min–6.0 min 98% ACN. Example 13: Bis((4,4-dimethylcyclohexyl)methyl) 2,2′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (13) [ka] Synthesis of (4,4-dimethylcyclohexyl)methyl 2-amino-2-methylpropanoate hydrochloride (13a)

[0352] 2-Amino-2-methyl-propanoic acid (1 g, 9.7 mmol) and (4,4-dimethylcyclohexyl)methanol (2.76 g, 19.4 mmol) were dissolved in 4 N HCl in dioxane (9.7 mL, 38.8 mmol) in a sealed tube under an argon atmosphere. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 13a. 1H NMR(400MHz,DMSO-d6)δ 8.58(s,3H),4.04(d,J=6.0Hz,2H),1.61-1.41(m,10H),1.40-1.31(m,2H),1.25-1.08(m,3H),0.88(d,J=11.2Hz,6H). [ka]

[0353] PMPA (100 mg, 0.35 mmol) and Intermediate 13a (276 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (13). 1 H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),8.13(s,1H),7.17(s,2H),4.32-4.14(m,4H),3.98-3.82(m,5H),3.65-3.49(m,2H),1.55-1 .27(m,22H),1.12(t,J=7.1Hz,8H),1.06(d,J=6.2Hz,3H),0.87(d,J=2.2Hz,6H),0.84(d,J=2.4Hz,6H). 31P NMR(162MHz,DMSO-d6)δ 18.35(t,J=9.7Hz).LCMS:MS m / z=706.40[M+1],t R =1.30 min;Agilent.HPLC:t R = 3.78 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 0 min to 5.0 min, 2-98% ACN, 5.0 min to 6.0 min, 98% ACN at 2 mL / min. Example 14: Bis(2-cyclohexylethyl) 2,2′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (14) [ka] Synthesis of 2-cyclohexylethyl 2-amino-2-methylpropanoate hydrochloride (14a)

[0354] 2-Amino-2-methyl-propanoic acid (1 g, 9.7 mmol) and 2-cyclohexylethanol (3.73 g, 29.1 mmol) were dissolved in 4 N HCl in dioxane (9.7 mL, 38.8 mmol) in a sealed tube under an argon atmosphere. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 14a. 1 H NMR(400MHz,DMSO-d6)δ 8.64(s,3H),4.20(t,J=6.7Hz,2H),1.72-1.58(m,5H),1.56-1.42(m,7H),1.40-1.27(m,2H),1.27-1.09(m,3H),0.99-0.81(m,2H). [ka]

[0355] PMPA (100 mg, 0.35 mmol) and Intermediate 14a (223 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (14). 1 H NMR(400MHz,DMSO-d6)δ 8.17(s,1H),8.13(s,1H),7.17(s,2H),4.32-3.91(m,9H),3.64-3.48(m,2H),1.69-1.56( m,10H),1.51-1.27(m,18H),1.24-1.11(m,6H),1.07(d,J=6.3Hz,3H),0.96-0.82(m,4H). 31 P NMR(162MHz,DMSO-d6)δ 18.43(t,J=9.7Hz).LCMS:MS m / z=678.40[M+1],t R = 1.32 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm x 2.1mm; Solvent: Acetonitrile with 0.1% acetic acid, Water with 0.1% acetic acid; Gradient: 2 μL / min, 0-1.00 min: 10%-100% acetonitrile, 1.00-1.35 min: 100% acetonitrile, 1.35-1.36 min: 100-10% acetonitrile. HPLC: tR = 3.34 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 2 mL / min, 0 min–5.0 min 2–98% ACN, 5.0 min–6.0 min 98% ACN. Example 15: Bis(cyclohexylmethyl) 2,2′-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl)) (2S,2′S)-bis(2-methyl-3-phenylpropanoate) (15) [ka] Synthesis of cyclohexylmethyl (S)-2-amino-2-methyl-3-phenylpropanoate hydrochloride (15a)

[0356] (2S)-2-Amino-2-methyl-3-phenyl-propanoic acid (1 g, 5.6 mmol) and cyclohexylmethanol (1.91 g, 16.7 mmol) were dissolved in 4 N HCl in dioxane (5.58 mL, 22.3 mmol) in a sealed tube under an argon atmosphere. The reaction was heated to 90° C. for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was dissolved in water (20 mL) and concentrated (twice). The residue was dissolved in toluene and concentrated to give Intermediate 15a. 1 H NMR(400MHz,DMSO-d6)δ 8.65(s,3H),7.39-7.28(m,3H),7.21-7.16(m,2H),3.98(dd,J=10.6,6.2Hz,1H),3.87(dd, J=10.6,6.1Hz,1H),3.15(s,2H),1.72-1.46(m,9H),1.27-1.09(m,3H),1.03-0.85(m,2H). [ka]

[0357] PMPA (100 mg, 0.35 mmol) and Intermediate 15a (326 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated under reduced pressure twice. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyl disulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL × 2), water (5 mL), and dried over sodium sulfate. The product was loaded onto silica gel (12 g). 100 mL of EtOAc was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110 Å 100 × 30 mm column, 25% to 100% acetonitrile gradient in water over 30 min) to give the title compound (15). 1 H NMR(400MHz,acetonitrile-d3)δ 8.23(s,1H),7.85(s,1H),7.36-7.12(m,10H),5.90(s,2H),4.22(dd,J=14.5,3.4Hz,1H),4.06-3.75(m,6H),3.70-3.50( m,4H),3.11-2.93(m,4H),1.79-1.61(m,13H),1.49(s,3H),1.36-1.14(m,8H),1.08(d,J=6.2Hz,3H),1.04-0.87(m,4H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.81-17.56 (m). LCMS: MS m / z = 802.30 [M+1], t R= 1.35 min; LC System: Agilent 1260 Infinity II HPLC; MS System: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm x 2.1mm; Solvent: Acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2µL / min, 0-1.00 min: 10%-100% acetonitrile, 1.00-1.35 min: 100% acetonitrile, 1.35-1.36 min: 100-10% acetonitrile. HPLC: t R = 3.34 min; HPLC system: Agilent 1100 Series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; gradient: 2 mL / min, 0 min–5.0 min 2–98% ACN, 5.0 min–6.0 min 98% ACN. Example 16: Hexyl (1R,2R)-1-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)amino)phosphoryl)amino)-2-ethylcyclopropane-1-carboxylate (16) Example 17: Dihexyl 1,1′-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(1R,1′R,2R,2′R)-bis(2-ethylcyclopropane-1-carboxylate) (17) [ka] Synthesis of hexyl (1R,2R)-1-((tert-butoxycarbonyl)amino)-2-ethylcyclopropane-1-carboxylate (16a)

[0358] To a mixture of (1R,2R)-1-((tert-butoxycarbonyl)amino)-2-ethylcyclopropane-1-carboxylic acid (1.0 g, 4.36 mmol), n-hexanol (0.82 mL, 6.542 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (813 mg, 5.234 mmol) in acetonitrile (30 mL) was added DMAP (1.07 g, 8.723 mmol). The mixture was then stirred at room temperature for 15 h, quenched with water, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0 to 70% EtOAc in hexanes) to give intermediate 16a. 1 H NMR (400 MHz, acetonitrile-d3) δ 5.93 (broad singlet, 1H), 4.08 (t, J = 6.5 Hz, 2H), 1.68-1.51 (m, 3H), 1.50-1.28 (m, 18H), 1.13 (dd, J = 8.9, 4.8 Hz, 1H), 0.94-0.82 (m, 6H). [ka] Synthesis of hexyl (1R,2R)-1-amino-2-ethylcyclopropane-1-carboxylate hydrochloride (16b)

[0359] To a solution of intermediate 16a (600 mg, 1.914 mmol) in DCM (12 mL) was added 4 M HCl in dioxane (1.9 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 2 hours, concentrated in vacuo, coevaporated with DCM several times, and dried under high vacuum for 15 hours to give intermediate 16b. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.59 (bs, 3H), 4.21 (m, 2H), 1.97 (m, 1H), 1.87 (dd, J = 10.1, 5.8 Hz, 1H), 1.75-1.61 (m, 4H), 1.54 (m, 1H), 1.47-1.25 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H), 0.95-0.88 (m, 3H). [ka]

[0360] A mixture of PMPA (100 mg, 0.348 mmol), Intermediate 16b (174 mg, 0.696 mmol), and triethylamine (0.73 mL, 2.785 mmol) in pyridine (1 mL) was heated to 50 °C for 5 min, and a freshly prepared bright yellow solution of 2,2'-dipyridyl disulfide (460 mg, 2.089 mmol) and triphenylphosphine (548 mg, 2.089 mmol) in pyridine (1 mL) was added to the reaction mixture. The resulting mixture was stirred at 90 °C for 5 h. Intermediate 1a (234 mg, 1.045 mmol) was added. The reaction mixture was stirred at 90°C for 18 hours, concentrated in vacuo, and purified by silica gel column chromatography (0-15% MeOH in DCM) to give a mixture of products, which were separated by preparative HPLC (35-90% ACN with 0.1% TFA in water). Each compound was dissolved in ACN (3 mL) and triethylamine (3 drops) was added to generate the free form, which was repurified by neutral HPLC (10-100% ACN in water for 12 minutes, 100% ACN for 5 minutes) to give 16 and 17.

[0361] 16: 1 H NMR (400 MHz, acetonitrile-d3) δ 8.24-8.21 (m, 1H), 8.05-8.02 (m, 1H), 6.13 (m, 2H), 4.32 (m, 1H), 4.23-4.04 (m, 5H), 4.02-3.84 (m, 2H), 3.78-3.59 (m, 2H), 3.47 (m, 1H), 1.76 (m, 1H), 1.68-1.52 (m, 5H), 1.51-1.22 (m, 21H), 1.17 (d, J = 6.22 Hz, 3H), 0.98-0.83 (m, 9H). 31 P NMR (162 MHz, acetonitrile-d3) δ 19.44, 18.94. LCMS: MS m / z = 652.27 [M+1]; t R= 1.66 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 6.64 min (45%) and 6.68 min (55%); HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 2–98% ACN from 0 min to 8.5 min at 1.5 mL / min.

[0362] 17: 1 H NMR(400MHz,acetonitrile-d3)δ 8.23(s,1H),8.03(s,1H),6.07(s,2H),4.35(dd,J=14.5,3.2Hz,1H),4.21-4.07(m,4H),4.08-3.84(m,4 H),3.73(dd,J=12.7,8.4Hz,1H),3.51(dd,J=12.6,10.1Hz,1H),1.72-1.09(m,26H),0.98-0.84(m,12H). 31 P NMR (162 MHz, acetonitrile-d3) δ 20.76. LCMS: MS m / z = 678.30 [M+1]; t R = 1.69 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R= 6.81 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 18: Hexyl 1-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)amino)phosphoryl)amino)cyclobutane-1-carboxylate (18) Example 19: Dihexyl 1,1′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(cyclobutane-1-carboxylate) (19) [ka] Synthesis of hexyl 1-aminocyclobutane-1-carboxylate hydrochloride (18a)

[0363] To a mixture of 1-aminocyclobutane-1-carboxylic acid (1.5 g, 13.03 mmol) and n-hexanol (30 mL) was added 4 M HCl in dioxane (6.5 mL, 26.06 mmol) slowly at room temperature. The resulting mixture was heated at 80° C. for 15 hours and concentrated under high vacuum at 65° C. The solid residue was triturated with ether, and the filter cake was washed with ether and dried under high vacuum for 15 hours to give intermediate 18a. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.74 (bs, 3H), 4.25 (t, J = 6.5 Hz, 2H), 2.84-2.70 (m, 2H), 2.58 (m, 2H), 2.32-2.05 (m, 2H), 1.80-1.62 (m, 2H), 1.53-1.23 (m, 6H), 0.93 (m, 3H). [ka] [ka]

[0364] Compounds 18 and 19 were prepared from PMPA by procedures similar to those used for 16 and 17.

[0365] 18: 1 H NMR (400 MHz, acetonitrile-d3) δ 8.22 (s, 1H), 8.06 (s, 1H), 6.31 (m, 2H), 4.34 (m, 1H), 4.23-4.02 (m, 5H), 4.01-3.85 (m, 2H), 3.82-3.60 (m, 2H), 3.47 (m, 1H), 2.68-2.23 (m, 4H), 2.03-1.82 (m, 2H), 1.73-1.56 (m, 4H), 1.53-1.25 (m, 18H), 1.17 (d, J = 6.2 Hz, 3H), 0.96-0.84 (m, 6H). 31 P NMR (162 MHz, acetonitrile-d3) δ 18.31, 18.29. LCMS: MS m / z = 638.38 [M+1]; t R = 1.77 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 6.50 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min.

[0366] 19: 1H NMR(400MHz,acetonitrile-d3)δ 8.22(s,1H),8.04(s,1H),6.23(s,2H),4.34(dd,J=14.5,3.2Hz,1H),4.22-4.01(m,5H),4.02-3.86(m,2H),3.82-3.66(m,2H),3.49(dd ,J=12.7,10.2Hz,1H),2.65-2.30(m,8H),2.01-1.80(m,4H),1.65(m,4H),1.49-1.24(m,12H),1.17(d,J=6.2Hz,3H),0.98-0.85(m,6H). 31 P NMR (162 MHz, acetonitrile-d3) δ 18.78. LCMS: MS m / z = 650.37 [M+1]; t R = 1.79 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 6.56 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 20: Hexyl 1-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)amino)phosphoryl)amino)cyclopropane-1-carboxylate (20) [ka] Synthesis of hexyl 1-aminocyclopropane-1-carboxylate hydrochloride (20a)

[0367] Intermediate 20a was obtained from 1-aminocyclopropane-1-carboxylic acid by a similar procedure as shown for intermediate 18a. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.52 (bs, 3H), 4.17 (t, J = 6.6 Hz, 2H), 1.75-1.58 (m, 4H), 1.52-1.42 (m, 2H), 1.43-1.28 (m, 6H), 1.03-0.82 (m, 3H). [ka]

[0368] A mixture of PMPA (170 mg, 0.59 mmol), Intermediate 1a (199 mg, 0.89 mmol), 2,2'-dipyridyl disulfide (782 mg, 3.55 mmol), triphenylphosphine (931 mg, 3.55 mmol), and triethylamine (0.66 mL, 4.74 mmol) in pyridine (3 mL) was heated to 70 °C for 1 h. Intermediate 20a (197 mg, 0.89 mmol) in pyridine (1 mL) was added, and the reaction mixture was stirred at 70 °C for 18 h. After concentration in vacuo, the residue was purified by silica gel column chromatography (0-15% MeOH in DCM) and preparative HPLC (10-100% ACN in water for 12 min, 100% ACN for 5 min) to give the title compound 20. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.25-8.20 (m, 1H), 8.10-8.06 (m, 1H), 6.48 (s, 2H), 4.42-4.26 (m, 2H), 4.24-3.82 (m, 7H), 3.71 (m, 1H), 3.57-3.42 (m, 1H), 1.73-1.21 (m, 26H), 1.16 (d, J = 6.2 Hz, 3H), 0.95-0.81 (m, 6H). 31 P NMR (162 MHz, acetonitrile-d3) δ 19.92, 19.85. LCMS: MS m / z = 624.30 [M+1]; t R= 1.76 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 6.21 min (43%), 6.28 min (54%); HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2–98% ACN at 1.5 mL / min. Example 21: Bis(trans-4-(trifluoromethyl)cyclohexyl) 2,2′-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))bis(2-methylpropanoate) (21) Example 22: Hexyl 2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-methyl-1-oxo-1-((trans-4-(trifluoromethyl)cyclohexyl)oxy)propan-2-yl)amino)phosphoryl)amino)-2-methylpropanoate (22) [ka] Synthesis of trans-4-(trifluoromethyl)cyclohexyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (21a)

[0369] To a mixture of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (650 mg, 3.20 mmol), trans-4-(trifluoromethyl)cyclohexan-1-ol (1076 mg, 6.40 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (993 mg, 6.40 mmol) in acetonitrile (30 mL) was added DMAP (781 mg, 6.40 mmol). The mixture was then stirred at room temperature for 15 h, quenched with water, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0 to 70% EtOAc in hexanes) to give intermediate 21a. 1 H NMR (400 MHz, acetonitrile-d3) δ 5.60 (bs, 1H), 4.66 (m, 1H), 2.27-2.09 (m, 1H), 2.07-1.91 (m, 4H), 1.59-1.30 (m, 19H). [ka] Synthesis of trans-4-(trifluoromethyl)cyclohexyl 2-amino-2-methylpropanoate hydrochloride (21b)

[0370] To a mixture of intermediate 21a (451 mg, 1.28 mmol) in DCM (10 mL) was slowly added 4 M HCl in dioxane (1.6 mL) at room temperature. The resulting mixture was stirred at room temperature for 15 hours, concentrated in vacuo, coevaporated with DCM several times, and dried under high vacuum for 15 hours to give intermediate 21b. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.62 (bs, 3H), 4.79 (m, 1H), 2.20 (s, 1H), 2.10 (d, J = 4.9 Hz, 2H), 2.07-1.99 (m, 2H), 1.65 (s, 6H), 1.54-1.44 (m, 4H). [ka]

[0371] A mixture of PMPA (100 mg, 0.348 mmol), Intermediate 21b (303 mg, 1.04 mmol), 2,2'-dipyridyl disulfide (460 mg, 2.089 mmol), triphenylphosphine (548 mg, 2.089 mmol), and triethylamine (0.4 mL, 2.785 mmol) in pyridine (2 mL) was heated at 80 °C for 3 h, and Intermediate 1a (117 mg, 0.522 mmol) in pyridine (0.5 mL) was added. The mixture was heated at 80 °C for 15 h, concentrated in vacuo, and purified by silica gel column chromatography (0-15% MeOH in DCM) to give a mixture of two products, which were separated by preparative HPLC (10-100% ACN in water for 12 min, 100% for 5 min) to give 21 and 22.

[0372] twenty one: 1 H NMR(400MHz,acetonitrile-d3)δ 8.24(s,1H),8.07(s,1H),6.35(s,2H),4.66(m,2H),4.34(dd,J=14.5,3.2Hz,1H),4.17(dd,J=14.5,7.1Hz,1H),3.94(m,1H),3.77-3.62 (m,2H),3.55(d,J=10.7Hz,1H),3.47(dd,J=12.6,9.8Hz,1H),2.18(m,2H),2.10-1.89(m,8H),1.57-1.27(m,20H),1.19(d,J=6.2Hz,3H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.89. LCMS: MS m / z = 758.27 [M+1]; t R = 1.70 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R= 6.12 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min.

[0373] twenty two: 1 H NMR (400 MHz, acetonitrile-d3) δ 8.23 ​​(s, 1H), 8.06 (s, 1H), 6.17 (s, 2H), 4.75-4.55 (m, 1H), 4.37-4.30 (m, 1H), 4.24-4.01 (m, 3H), 3.93 (m, 1H), 3.75 (m, 1H), 3.67 (m, 1H), 3.56 (m, 1H), 3.45 (m, 1H), 2.26-2.11 (m, 1H), 2.10-1.90 (m, 4H), 1.63 (m, 2H), 1.56-1.23 (m, 22H), 1.18 (m, 3H), 0.96-0.80 (m, 3H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.96, 17.90. LCMS: MS m / z = 692.25 [M+1]; R = 1.74 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 6.25 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 23: Hexyl (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl) ((2-methyl-1-oxo-1-((tetrahydro-2H-pyran-4-yl)oxy)propan-2-yl)amino)phosphoryl)-L-phenylalaninate (23) Example 24: Bis(tetrahydro-2H-pyran-4-yl)2,2′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (24) [ka] Synthesis of tetrahydro-2H-pyran-4-yl-2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (23a)

[0374] To a mixture of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (1.0 g, 4.92 mmol), tetrahydro-2H-pyran-4-ol (0.70 mL, 7.381 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.15 g, 7.381 mmol) in acetonitrile (20 mL) was added DMAP (1.20 g, 9.84 mmol). The mixture was then stirred at room temperature for 15 h, quenched with water, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0 to 50% EtOAc in hexanes) to give intermediate 23a. 1 H NMR (400 MHz, acetonitrile-d3) δ 5.62 (s, 1H), 4.92 (m, 1H), 3.83 (m, 2H), 3.53 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 1.77-1.59 (m, 15H). [ka] Synthesis of tetrahydro-2H-pyran-4-yl-2-amino-2-methylpropanoate hydrochloride (23b)

[0375] To a mixture of intermediate 23a (490 mg, 1.71 mmol) in DCM (10 mL) was slowly added 4 M HCl in dioxane (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 15 hours, concentrated in vacuo, coevaporated with DCM several times, and dried under high vacuum for 15 hours to give intermediate 23b. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.48 (bs, 3H), 5.06 (m, 1H), 3.89 (m, 2H), 3.55 (m, 2H), 1.92 (m, 2H), 1.76-1.59 (m, 8H). [ka] Synthesis of hexyl L-phenylalaninate hydrochloride (23c)

[0376] To a mixture of L-phenylalanine (2.5 g, 15.1 mmol) and n-hexanol (30 mL) was added SOCl (4.4 mL, 60.5 mmol) slowly at room temperature. The resulting mixture was heated at 80 °C for 15 hours and concentrated under high vacuum at 65 °C. After cooling, the product was precipitated and filtered. The filter cake was suspended in ether, stirred overnight, filtered, and dried under high vacuum for 24 hours to give intermediate 23c. 1 H NMR(400MHz, methanol-d4)δ 7.42-7.29(m,3H),7.28-7.22(m,2H),4.29(t,J=7.0Hz,1H),4.17(m,2H) ),3.21(m,2H),1.58(m,2H),1.35-1.25(m,6H),0.91(t,J=6.85Hz,3H). [ka] [ka]

[0377] A mixture of PMPA (100 mg, 0.348 mmol) and Intermediate 23b (156 mg, 0.696 mmol) was flushed with nitrogen several times and dissolved in pyridine (2 mL). Triphenylphosphine (548 mg, 2.09 mmol), 2,2'-dipyridyl disulfide (460 mg, 2.09 mmol), and triethylamine (0.39 mL, 2.79 mmol) were added. The resulting mixture was heated to 80 °C for 40 minutes. Intermediate 23c (299 mg, 1.04 mmol) in pyridine (0.5 mL) was added. The mixture was heated at 80° C. for 3 h, concentrated in vacuo, and purified by silica gel chromatography (0–25% MeOH in DCM) to two products, which were further purified by HPLC (10–100% ACN in water for 12 min, 100% ACN for 5 min for 23, and 10–100% ACN in water for 17 min for 24) to give 23 and 24.

[0378] twenty three: 1 H NMR(400MHz,acetonitrile-d3)δ 8.27(s,0.5H),8.25(s,0.5H),8.08(s,0.5H),8.03(s,0.5H),7.33-7.16(m,5H),6.87-6.55(m,2H),4.8 9(m,1H),4.39-3.95(m,4H),3.94-3.68(m,4H),3.61(dd,J=12.8,8.8Hz,0.5H),3.54-3.41(m,3.5H),3.2 4(dd,J=12.7,10.4Hz,0.5H),3.15(d,J=11.3Hz,0.5H),3.06-2.90(m,1.5H),2.82(dd,J=13.5,8.1Hz,0. 5H),1.92-1.77(m,2H),1.65-1.46(m,4H),1.43-1.19(m,12H),1.11(t,J=6.0Hz,3H),0.92-0.83(m,3H). 31 P NMR (162 MHz, acetonitrile-d3) δ 19.52, 19.39. LCMS: MS m / z = 688.31 [M+1]; t R= 1.57 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 5.57 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min.

[0379] twenty four: 1 H NMR (400 MHz, acetonitrile-d3) δ 8.23(s,1H),8.05(s,1H),5.99(s,2H),4.92(m,2H),4.34(dd,J=14.5,3.3Hz,1 H),4.17(dd,J=14.5,7.1Hz,1H),3.94(m,1H),3.82(dt,J=10.6,5.7Hz,4H),3. 75(d,J=10.7Hz,1H),3.67(dd,J=12.7,8.8Hz,1H),3.59-3.42(m,6H),1.89(m, 4H),1.62(m,4H),1.54(s,3H),1.47(s,6H),1.40(s,3H),1.19(d,J=6.2Hz,3H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.90. LCMS: MS m / z = 626.18 [M+1]; t R= 1.21 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 3.81 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 25: Bis(5,5,5-trifluoropentyl) 2,2′-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (25) [ka] Synthesis of 5,5,5-trifluoropentyl-2-amino-2-methylpropanoate hydrochloride (25a)

[0380] To a mixture of 2-amino-2-methylpropanoic acid (600 mg, 5.82 mmol) and 5,5,5-trifluoropentan-1-ol (5.0 g, 35.2 mmol), SOCl (0.72 mL, 9.89 mmol) was added slowly at room temperature. The resulting mixture was heated at 80 °C for 15 hours and concentrated under high vacuum at 70 °C. Hexane was added to the resulting residue, stirred for 30 minutes, and the precipitated solid was filtered. The filter cake was washed several times with ether and dried under high vacuum for 15 hours to give Intermediate 25a. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.69 (bs, 3H), 4.23 (t, J = 6.2 Hz, 2H), 2.25 (m, 2H), 1.86-1.73 (m, 2H), 1.72-1.59 (m, 8H).19 F NMR (376 MHz, acetonitrile-d3) δ -67.50. [ka]

[0381] A mixture of PMPA (500 mg, 1.74 mmol), Intermediate 25a (1.51 g, 5.74 mmol), 2,2'-dipyridyl disulfide (2.30 g, 10.4 mmol), and triphenylphosphine (2.74 g, 10.4 mmol) was flushed with nitrogen gas several times, dissolved in pyridine (10 mL), and triethylamine (0.4 mL, 2.785 mmol) was added. The resulting mixture was heated at 90 °C for 20 h, concentrated in vacuo, and purified by silica gel column chromatography (0-20% MeOH in DCM) and preparative HPLC (10-100% ACN in water for 12 min, 100% ACN for 5 min) to give the title compound 25. 1 H NMR(400MHz,acetonitrile-d3)δ 8.24(s,1H),8.06(s,1H),6.15(s,2H),4.34(dd,J=14.4,3.2Hz,1H),4.22-4.03(m,5H),3.94(m,1H),3.77-3.61(m,2H),3.56(d,J=10.6Hz,1 H),3.44(dd,J=12.7,9.8Hz,1H),2.22(m,4H),1.82-1.56(m,8H),1.53(s,3H),1.46(s,3H),1.45(s,3H),1.39(s,3H),1.19(d,J=6.3Hz,3H). 19 F NMR (376 MHz, acetonitrile-d3) δ -67.52 (d, J = 5.3 Hz). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.83. LCMS: MS m / z = 706.31 [M+1]; R= 1.57 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 5.53 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 26: Bis(trans-3-(trifluoromethyl)cyclobutyl) 2,2′-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))bis(2-methylpropanoate) (26) [ka] Synthesis of trans-3-(trifluoromethyl)cyclobutyl-2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (26a)

[0382] To a mixture of trans-3-(trifluoromethyl)cyclobutan-1-ol (1.0 g, 7.14 mmol), 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (2.9 g, 14.3 mmol), and DMAP (1.9 g, 15.7 mmol) in acetonitrile (30 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.44 g, 15.7 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with water, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0 to 70% EtOAc in hexanes) to give intermediate 26a. 1H NMR (400 MHz, acetonitrile-d3) δ 5.68 (s, 1H), 5.05 (m, 1H), 3.06 (m, 1H), 2.56 (m, 2H), 2.40 (m, 2H), 1.59-0.92 (m, 15H). 19 F NMR (376 MHz, acetonitrile-d3) δ -74.34. LCMS: MS m / z = 325.59 [M+1]; R = 1.84 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min to 1.8 min, 2 to 100% acetonitrile, 1.8 min to 1.85 min, 100% to 2% acetonitrile, 1.85 min to 2.00 min, 2% ACN at 1800 μL / min. [ka] Synthesis of trans-3-(trifluoromethyl)cyclobutyl 2-amino-2-methylpropanoate hydrochloride (26b)

[0383] To a mixture of intermediate 26a (1.96 g, 6.02 mmol) in DCM (10 mL) was slowly added 4 M HCl in dioxane (7.53 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, concentrated in vacuo, coevaporated with DCM several times, suspended in ether, stirred for 5 minutes, and filtered. The filter cake was washed several times with ether and dried under high vacuum for 15 hours to give intermediate 26b. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.70 (bs, 3H), 5.18 (t, J = 6.6 Hz, 1H), 3.20 (m, 1H), 2.66-2.49 (m, 2H), 2.40-2.25 (m, 2H), 1.74-1.57 (m, 6H). LCMS: MS m / z = 226.02 [M + 1-HCl]; t R= 0.96 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min to 1.8 min, 2 to 100% acetonitrile, 1.8 min to 1.85 min, 100% to 2% acetonitrile, 1.85 min to 2.00 min, 2% ACN at 1800 μL / min. [ka]

[0384] A mixture of PMPA (300 mg, 1.04 mmol), Intermediate 26b (600 mg, 2.29 mmol), 2,2'-dipyridyl disulfide (768 mg, 3.48 mmol), and triphenylphosphine (914 mg, 3.48 mmol) was flushed with nitrogen several times and dissolved in pyridine (5 mL). Triethylamine (0.8 mL, 5.77 mmol) was added. The resulting mixture was stirred at 90 °C for 20 h, concentrated in vacuo, coevaporated several times with toluene, and purified by silica gel chromatography (0-20% MeOH in DCM) and preparative HPLC (10-100% ACN in water for 12 min, 100% ACN for 5 min) to give the title compound (26). 1 H NMR(400MHz,acetonitrile-d3)δ 8.24(s,1H),8.03(s,1H),5.91(s,2H),5.06(m,2H),4.34(dd,J=14.5,3 .2Hz,1H),4.17(dd,J=14.5,7.3Hz,1H),3.94(m,1H),3.73-3.63(m,2H), 3.55-3.35(m,2H),3.11(m,2H),2.65-2.51(m,2H),2.51-2.36(m,2H),1. 53(s,3H),1.47(s,3H),1.43(s,3H),1.40(s,3H),1.20(d,J=6.2Hz,3H). 19 F NMR (376 MHz, acetonitrile-d3) δ -74.27. 31P NMR (162 MHz, acetonitrile-d3) δ 18.10. LCMS: MS m / z = 702.22 [M+1]; t R = 1.37 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 5.50 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 27: Bis((trans-4-propylcyclohexyl) 2,2′-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))bis(2-methylpropanoate) (27) [ka] Synthesis of trans-4-propylcyclohexyl 2-(tert-butoxycarbonylamino)-2-methylpropanoate (27a)

[0385] To a mixture of trans-4-propylcyclohexan-1-ol (1.0 g, 7.03 mmol), 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (2.14 g, 10.5 mmol), and DMAP (1.72 g, 14.1 mmol) in acetonitrile (30 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.18 g, 14.1 mmol) at room temperature. The mixture was stirred at room temperature for 15 hours, quenched with water, and concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with brine, dried over sodium sulfate, concentrated in vacuo, and purified by silica gel chromatography (0 to 70% hexanes in EtOAc) to give intermediate 27a. 1 H NMR (400 MHz, acetonitrile-d3) δ 5.58 (bs, 1H), 4.61 (m, 1H), 1.96-1.83 (m, 2H), 1.85-1.73 (m, 2H), 1.45-1.14 (m, 2H), 1.05 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). LCMS: MS m / z = 327.77 [M+1]; t R = 1.98 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min–1.8 min 2–100% acetonitrile, 1.8 min–1.85 min 100%–2% acetonitrile, 1.85 min–2.00 min 2% ACN. [ka] Synthesis of trans-4-propylcyclohexyl 2-amino-2-methylpropanoate hydrochloride (27b)

[0386] Intermediate 27a (1.46 g, 4.46 mmol) in DCM (10 mL) was slowly added with 4 M HCl in dioxane (6 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours, concentrated in vacuo, coevaporated with DCM several times, suspended in ether, stirred for 5 minutes, and filtered. The filter cake was washed several times with ether and dried under high vacuum for 15 hours to give Intermediate 27b. 1 H NMR(400MHz,chloroform-d)δ 8.98(bs,3H),4.76(m,1H),2.02(m,2H),1.80(m,2H),1.72(s,6H),1.48(m,2H),1.38-1.12(m,5H),0.99(m,2H),0.89(t,J=7.2Hz,3H).LCMS:MS m / z=227.89[M+1-HCl];t R = 1.19 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min to 1.8 min, 2 to 100% acetonitrile, 1.8 min to 1.85 min, 100% to 2% acetonitrile, 1.85 min to 2.00 min, 2% ACN at 1800 μL / min. [ka]

[0387] A mixture of PMPA (300 mg, 1.04 mmol), Intermediate 27b (600 mg, 2.27 mmol), 2,2'-dipyridyl disulfide (768 mg, 3.49 mmol), and triphenylphosphine (914 mg, 3.49 mmol) was flushed with nitrogen several times and dissolved in pyridine (5 mL). Triethylamine (0.8 mL, 5.77 mmol) was added. The resulting mixture was stirred at 90 °C for 20 h, concentrated in vacuo, coevaporated several times with toluene, and purified on silica gel (0-15% MeOH in DCM) to give the title compound (27). 1H NMR (400 MHz, acetonitrile-d3) δ 8.24(s,1H),8.06(s,1H),6.01(s,2H),4.62(m,2H),4.34(dd,J=14.5,3.2Hz, 1H),4.17(dd,J=14.5,7.0Hz,1H),3.94(m,1H),3.74(d,J=10.6Hz,1H),3.66(d d,J=12.7,8.9Hz,1H),3.55(d,J=10.7Hz,1H),3.46(dd,J=12.6,9.8Hz,1H),1. 96-1.87(m,4H),1.85-1.72(m,4H),1.57-0.95(m,33H),0.91(t,J=7.3Hz,6H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.59. LCMS: MS m / z = 706.37 [M+1]; t R = 1.89 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 7.84 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 28: Dihexyl 2,2′-(((((1-(6-acetamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (28) [ka]

[0388] To a solution of 1 (100 mg, 0.210 mmol) in pyridine (1 mL) was added acetic anhydride (0.03 mL, 0.320 mmol). The resulting solution was stirred at room temperature for 2 h and purified by preparative HPLC (10-100% ACN in water for 8 min, 100% ACN for 18 min) to give the title compound (28). 1 H NMR(400MHz,acetonitrile-d3)δ 9.13(s,1H),8.61(s,1H),8.34(s,1H),4.43(dd,J=14.5,3.2Hz,1H),4.26(dd,J=14.5,7 .1Hz,1H),4.17-4.01(m,4H),3.97(m,1H),3.75(d,J=10.8Hz,1H),3.69(dd,J=12.8,8.6 Hz,1H),3.59(d,J=10.8Hz,1H),3.45(dd,J=12.7,9.8Hz,1H),2.48(s,3H),1.62(m,4H), 1.52(s,3H),1.45(s,6H),1.42-1.23(m,15H),1.20(d,J=6.3Hz,3H),0.95-0.88(m,6H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.75. LCMS: MS m / z = 668.42 [M+1]; t R = 1.90 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 6.66 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 29: Dihexyl 2,2′-(((((1-(6-butylamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (29) [ka]

[0389] To a solution of 1 (100 mg, 0.210 mmol) in pyridine (1 mL) was added butyryl chloride (0.033 mL, 0.320 mmol). The resulting solution was stirred at room temperature for 2 h and purified by preparative HPLC (10–100% ACN in water for 8 min, 100% for 15 min) to give the title compound (29). 1 H NMR(400MHz,acetonitrile-d3)δ 8.98(s,1H),8.61(s,1H),8.32(s,1H),4.43(dd,J=14.5,3.1Hz,1H),4.25(dd,J=14.5,7.2H z,1H),4.17-4.01(m,4H),3.96(m,1H),3.78-3.64(m,2H),3.57(d,J=10.8Hz,1H),3.44(dd,J =12.7,9.9Hz,1H),2.77(t,J=7.4Hz,2H),1.74(m,2H),1.63(m,4H),1.52(s,3H),1.48-1.42 (m,6H),1.43-1.23(m,15H),1.20(d,J=6.2Hz,3H),1.02(t,J=7.4Hz,3H),0.96-0.84(m,6H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.756. LCMS: MS m / z = 696.31 [M+1]; t R= 2.02 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 7.02 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 30: Dihexyl 2,2′-(((((1-(6-dodecanamido-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (30) [ka]

[0390] To a solution of 1 (100 mg, 0.210 mmol) in pyridine (1 mL) was added lauryl chloride (0.07 mL, 0.320 mmol). The resulting mixture was stirred at room temperature for 2 h, quenched by the addition of methanol, concentrated in vacuo, and purified by silica gel chromatography (MeOH in DCM 0-15%) to give the title compound (30). 1H NMR (400 MHz, acetonitrile-d3) δ 8.96 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 4.43 (dd, J = 14.5, 3.1 Hz, 1H), 4.30-4.23 (m, 1H), 4.17-4.01 (m, 4H), 3.96 (m, 1H), 3.77-3.64 (m, 2H), 3.54 (d, J = 10.8 Hz, 1H), 3 .43(dd,J=12.7,9.9Hz,1H),2.78(t,J=7.5Hz,2H),1.78-1.53(m,6H),1.52(s,3H) ,1.46-1.40(m,6H),1.40-1.25(m,31H),1.20(d,J=6.2Hz,3H),0.93-0.83(m,9H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.71. LCMS: MS m / z = 808.83 [M+1]; t R = 2.58 min. LC system: Dionex Ultimate 3000 UHPLC; column: Phenomenex Kinetex 2.6μ C18 100A, 50 x 3.0 mm; solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; gradient: 1100 μL / min, 0 min - 40% acetonitrile, 0.2 min - 1.55 min - 40% - 100% acetonitrile, 1.55 min - 2.80 min - 100% acetonitrile, 2.80 - 2.81 min - 100% - 40% acetonitrile. HPLC: t R = 8.92 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 31: Dihexyl 2,2′-(((((1-(6-((propoxycarbonyl)amino)-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (31) [ka]

[0391] To a solution of 1 (200 mg, 0.32 mmol) in pyridine (1 mL) was added propyl chloroformate (118 mg, 0.96 mmol). The resulting mixture was stirred at room temperature for 2 h, and the reaction was quenched by adding water. The mixture was concentrated and purified by preparative HPLC (10-100% ACN in water for 5 min and 100% ACN for 18 min) to give the title compound (31). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.88 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 4.43 (dd, J = 14.5, 3.2 Hz, 1H), 4.25 (dd, J = 14.5, 7.2 Hz, 1H), 4.20-4.01 (m, 6H), 4.01-3.91 (m, 1H), 3.75 (d, J = 10.9 Hz, 1H), 3.69 (dd, J = 12.8, 8.6 Hz, 1H), 3. 58(d,J=10.9Hz,1H),3.44(dd,J=12.8,9.9Hz,1H),1.73(m,2H),1.69-1.58(m,4H),1.52(s,3H), 1.45(s,6H),1.41-1.26(m,15H),1.20(d,J=6.2Hz,3H),1.00(t,J=7.4Hz,3H),0.93-0.83(m,6H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.86. LCMS: MS m / z = 712.31 [M+1]; tR = 1.84 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min, 2-100% acetonitrile, 1.8 min - 1.85 min, 100% - 2% acetonitrile, 1.85 min - 2.00 min, 2% ACN. HPLC: t R = 7.12 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 32: Dihexyl 2,2′-(((((1-(6-(((pentyloxy)carbonyl)amino)-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (32) [ka]

[0392] To a solution of 1 (200 mg, 0.32 mmol) in pyridine (1 mL) was added pentyl chloroformate (144 mg, 0.96 mmol). The resulting mixture was stirred at room temperature for 2 h, quenched by adding water, and purified by preparative HPLC (10-100% ACN in water for 5 min and 100% ACN for 18 min) to give the title compound (32). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.74(s,1H),8.61(s,1H),8.30(s,1H),4.43(dd,J=14.5,3.1Hz,1H),4.30-4.17 (m,3H),4.17-4.01(m,4H),3.96(m,1H),3.74(d,J=10.8Hz,1H),3.68(dd,J=12.8 ,8.6Hz,1H),3.56(d,J=10.8Hz,1H),3.43(dd,J=12.7,9.9Hz,1H),1.77-1.56(m ,6H),1.52(s,3H),1.47-1.26(m,25H),1.20(d,J=6.2Hz,3H),0.98-0.85(m,9H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.80. LCMS: MS m / z = 740.39 [M+1]; t R= 1.96 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 7.61 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 33: Dihexyl 2,2′-(((((1-(6-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (33) [ka]

[0393] To a mixture of 1 (200 mg, 0.32 mmol) and triphosgene (38 mg, 0.128 mmol) in DCM (4 mL) was added DMAP (234 mg, 1.92 mmol) slowly in portions at room temperature. The resulting mixture was stirred at room temperature for 15 min, and 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (60 mg, 0.46 mmol) was added at room temperature. The resulting mixture was stirred for 2 h, concentrated in vacuo, and purified by silica gel column chromatography (0–15% MeOH in DCM) and preparative HPLC (10–100% ACN in water for 8 min, 100% ACN for 15 min) to give the title compound (33). 1H NMR (400 MHz, acetonitrile-d3) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 5.02 (s, 2H), 4.44 (dd, J = 14.5, 3.2 Hz, 1H), 4.26 (dd, J = 14.5, 7.2 Hz, 1H), 4.16-4.02 (m, 4H), 3.96 (m, 1H), 3.79-3.61 (m, 2H), 3.55 (d,J=10.7Hz,1H),3.44(dd,J=12.7,9.8Hz,1H),2.21(s,3H),1.70-1.55(m,4H),1.5 2(s,3H),1.45(s,6H),1.42-1.26(m,15H),1.20(d,J=6.2Hz,3H),0.95-0.83(m,6H). 31 P NMR (162 MHz, acetonitrile-d3) δ 17.63. LCMS: MS m / z = 782.17 [M+1]; t R = 2.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 1800 μL / min, 0 min - 1.8 min 2 - 100% acetonitrile, 1.8 min - 1.85 min 100% - 2% acetonitrile, 1.85 min - 2.00 min 2% ACN. HPLC: t R = 7.05 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μ C18 100A, 100 × 4.6 mm; Solvent: acetonitrile with 0.1% TFA, water with 0.1% TFA; Gradient: 0 min to 8.5 min, 2 to 98% ACN at 1.5 mL / min. Example 34: Dicyclopentyl 2,2'-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (34) [ka] Synthesis of cyclopentyl 2-amino-2-methyl-propanoate hydrochloride (34a)

[0394] 2-Amino-2-methyl-propanoic acid (1.0 g, 9.70 mmol) was suspended in cyclopentanol (17.6 mL, 194 mmol). Thionyl chloride (1.4 mL, 19.4 mmol) was added slowly over 3 minutes. The resulting mixture was heated at 70° C. for 3 days. The mixture was diluted with ethyl acetate / hexane (1:1, 20 mL) and water (20 mL). The organic phase was extracted with water (20 mL). The combined aqueous phase was washed with ethyl acetate / hexane (1:1, 3×20 mL), diethyl ether (3×20 mL), and dichloromethane (3×20 mL). Residual solvent in the aqueous phase was removed under reduced pressure. The volume was reduced to 20 mL under reduced pressure. The aqueous phase was diluted with acetonitrile (10 mL) and lyophilized. The solid was washed, stirred with hexane for 15 minutes, and isolated by filtration to give Intermediate 34a. 1 H NMR(400MHz,DMSO-d6)δ 8.54(s,3H),5.18(m,1H),1.94-1.78(m,2H),1.76-1.62(m,4H),1.62-1.52(m,2H),1.45(s,6H). [ka]

[0395] PMPA (100 mg, 0.384 mmol), triphenylphosphine (344 mg, 1.39 mmol), 2,2'-dipyridyl disulfide (307 mg, 1.39 mmol), and Intermediate 34a (289 mg, 1.39 mmol) were suspended in pyridine (4 mL) under argon. Triethylamine (0.38 mL, 2.79 mmol) was added. The resulting mixture was heated at 75 °C for 3 days. Pyridine was removed under reduced pressure. The residue was coevaporated with toluene (2 × 10 mL). The residue was applied to a silica plug using an ISCO solid-packed cartridge with 40% then 100% ethyl acetate / hexane. The material remaining on the solid-packed cartridge was subjected to flash chromatography (0–20% methanol / dichloromethane). The product-containing fractions were combined, and the solvent was removed under reduced pressure. The residue was subjected to preparative HPLC (Gemini, 10 μM, NX-C18, 110 Å 250 × 30 mm column, 40% to 100% acetonitrile / water gradient over 20 min.) The product-containing fractions were combined and subjected to lyophilization to give the title compound (34). 1 H NMR (400 MHz, methanol-d4) δ 8.30 (s, 1H), 8.23 ​​(s, 1H), 5.20 (m, 1H), 5.15 (m, 1H), 4.43 (dd, J = 14.5, 3.1 Hz, 1H), 4.34 (d, J = 11.9 Hz, 0.39H), 4.27 (dd, J = 14.5, 7.4 Hz, 1H), 4.12 (s, 0.24H), 4.08-3.96 (m, 1H), 3.08-3.96 (m, 1H). 80(dd,J=12.8,8.5Hz,1H),3.55(dd,J=12.8,10.2Hz,1H),1.89(m,5H),1.82-1.69(m,6H) ,1.66(m,5H),1.55(s,3H),1.47(s,3H),1.45(s,3H),1.40(s,3H),1.26(d,J=6.2Hz,3H). 31 P NMR (162 MHz, methanol-d4) δ 20.98-20.75 (m). LCMS: MS m / z = 594.58 [M+1]; t R= 1.145 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: Acetonitrile with 0.1% trifluoroacetic acid, Water with 0.1% trifluoroacetic acid; Gradient: 1.8 mL / min, 0 min - 0.2 min 10% acetonitrile, 0.2 min - 1.85 min 10% - 100% acetonitrile, 1.85 min - 2.14 min 100% acetonitrile, 2.14 min - 2.15 min 100% - 10% acetonitrile, 2.15 min - 2.25 min 10% acetonitrile. HPLC: t R = 2.706 min; HPLC system: Agilent 1100 series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: A = acetonitrile with 5% water and 0.1% TFA, B = 5% acetonitrile, water with 0.1% TFA; gradient: 2 mL / min, 0 min–4.0 min 2–95% B, 4.0 min–5.0 min 95% B, 5.0 min–5.25 min 95–98% B, 5.25–5.50 min 98%–2% B. Example 35: Dicyclobutyl 2,2'-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (35) [ka] Synthesis of isobutyl 2-amino-2-methyl-propanoate hydrochloride (35a)

[0396] 2-Amino-2-methylpropanoic acid (2.5 g, 24.2 mmol) was suspended in 2-methylpropan-1-ol (22 mL, 282 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4 N, 60 mL, 242 mmol). The resulting mixture was heated at 65 °C for 5 days. 1,4-Dioxane was removed under reduced pressure. The mixture was diluted with ethyl acetate / hexane (1:1, 50 mL) and water (50 mL). The organic phase was extracted with water (50 mL). The combined aqueous phase was washed with ethyl acetate / hexane (1:1, 3 × 50 mL), diethyl ether (3 × 50 mL), and dichloromethane (3 × 50 mL). Residual solvent in the aqueous phase was removed, and the volume was reduced to 50 mL under reduced pressure. The aqueous phase was diluted with acetonitrile (20 mL) and water (10 mL) and subjected to lyophilization. The solid was stirred with hexane (20 mL) and isolated by filtration with a hexane wash to give intermediate 35a. 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,3H),3.98(d,J=6.5Hz,2H),1.93(m,1H),1.49(s,6H),0.92(d,J=6.7Hz,6H). [ka]

[0397] PMPA (100 mg, 0.384 mmol), triphenylphosphine (341 mg, 1.74 mmol), 2,2'-dipyridyl disulfide (307 mg, 1.39 mmol), and Intermediate 35a (289 mg, 1.39 mmol) were suspended in pyridine (4 mL) under argon. Triethylamine (0.475 mL, 3.48 mmol) was added. The reaction was heated at 90 °C for 18 h. Pyridine was removed under reduced pressure. The residue was coevaporated with toluene (3 × 10 mL). The residue was applied to a silica plug using an ISCO solid-packed cartridge with 40% then 100% ethyl acetate / hexane. The material remaining on the solid-packed cartridge was subjected to flash chromatography (0–20% methanol / dichloromethane). Fractions containing the product were combined, and the solvent was removed under reduced pressure. The residue was subjected to preparative HPLC (Gemini, 10 μM, NX-C18, 110 Å 250 × 30 mm column, 40% to 100% acetonitrile / water gradient over 20 min.) The product-containing fractions were combined and subjected to lyophilization to give the title compound (35). 1 H NMR(400MHz, methanol-d4)δ 8.34(s,1H),8.28(s,1H),4.45(dd,J=14.5,3.0Hz,1H),4.29(dd,J=14.5,7.4Hz,1H),4.05-3.88(m,5H),3.88-3.75(m,1H),3.5 5(dd,J=12.8,10.2Hz,1H),2.03-1.90(m,2H),1.59(s,3H),1.51(s,3H),1.50(s,3H),1.26(d,J=6.2Hz,3H),1.02-0.92(m,12H). 31 P NMR (162 MHz, methanol-d4) δ 20.78 (t, J = 9.3 Hz). LCMS: MS m / z = 570.14 [M+1]; t R= 1.350 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18 100A, 50 × 3.0 mm; Solvent: Acetonitrile with 0.1% trifluoroacetic acid, Water with 0.1% trifluoroacetic acid; Gradient: 1.8 mL / min, 0 min - 0.2 min 10% acetonitrile, 0.2 min - 1.85 min 10% - 100% acetonitrile, 1.85 min - 2.14 min 100% acetonitrile, 2.14 min - 2.15 min 100% - 10% acetonitrile, 2.15 min - 2.25 min 10% acetonitrile. HPLC: t R = 2.673 min; HPLC system: Agilent 1100 series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: A = acetonitrile with 5% water and 0.1% TFA, B = 5% acetonitrile, water with 0.1% TFA; gradient: 2 mL / min, 0 min–4.0 min 2–95% B, 4.0 min–5.0 min 95% B, 5.0 min–5.25 min 95–98% B, 5.25–5.50 min 98%–2% B. Example 36: Dipropyl 2,2'-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (36) [ka] Synthesis of 2-amino-2-methyl-propanoate hydrochloride (36a)

[0398] 2-Amino-2-methylpropanoic acid (1 g, 9.7 mmol) was suspended in propan-1-ol (17.6 mL, 278 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4N, 12.1 mL, 48.5 mmol). The resulting mixture was heated at 40 °C for 5 days. 1,4-Dioxane was removed under reduced pressure. The mixture was diluted with ethyl acetate / hexane (1:1, 50 mL) and water (50 mL). The organic phase was extracted with water (50 mL). The combined aqueous phase was washed with ethyl acetate / hexane (1:1, 3 × 50 mL), diethyl ether (3 × 50 mL), and dichloromethane (3 × 50 mL). Residual solvent in the aqueous phase was removed, and the volume was reduced to 50 mL under reduced pressure. The aqueous phase was diluted with acetonitrile (20 mL) and water (10 mL) and subjected to lyophilization. The solid was stirred with hexane (20 mL) and isolated by filtration with a hexane wash to give intermediate 36a. 1 H NMR(400MHz,DMSO-d6)δ 8.76-8.33(m,3H),4.14(t,J=6.5Hz,2H),1.64(m,2H),1.49(s,6H),0.92(t,J=7.4Hz,3H). [ka]

[0399] PMPA (100 mg, 0.384 mmol), triphenylphosphine (344 mg, 1.39 mmol), 2,2'-dipyridyl disulfide (307 mg, 1.39 mmol), and Intermediate 36a (341 mg, 1.88 mmol) were suspended in pyridine (4 mL) under argon. Triethylamine (0.475 mL, 3.48 mmol) was added. The reaction was heated at 90 °C for 16 h. Pyridine was removed under reduced pressure. The residue was coevaporated with toluene (3 × 10 mL). The residue was applied to a silica plug using an ISCO solid-packed cartridge with 40% then 100% ethyl acetate / hexane. The material remaining on the solid-packed cartridge was subjected to flash chromatography (0–20% methanol / dichloromethane). The product-containing fractions were combined, and the solvent was removed under reduc...

Claims

1. A compound of formula (III), 【Chemistry 1】 During the ceremony, R １ and R ２ is independently １－１２ Alkyl, aryl-C １－４ Alkylene, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, aryl-C ３－７ Cycloalkylene, C ７－１２ Spirocycloalkyl, C ７－１２ Spirocycloalkyl-C １－４ Alkylene, Bridge C ５－１０ Bicycloalkyl, bridged C ５－１０ Bicycloalkyl-C １－４ Alkylene, fused C ５－１０ Bicycloalkyl, C １０－１６ Dispirocycloalkyl, C １０－１６ Dispirocycloalkyl-C １－４ Alkylene, Bridge C ９－１２ Tricycloalkyl, Bridged C ９－１２ Tricycloalkyl-C １－４ Alkylene, C ３－７ Cycloalkyl-C ３－７ cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; １－１２ Alkyl, aryl-C １－４ Alkylene, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, aryl-C ３－７ Cycloalkylene, C ７－１２ Spirocycloalkyl, and C ７－１２ Spirocycloalkyl-C １－４ Alkylene is one to three R ａ and optionally substituted with R ３ , R ４ , R ５ and R ６ is independently １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ alkylene; each C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ Alkylene is one to three R ｂ or optionally substituted with R ３ and R ４ together with the carbon atom to which they are attached, 1 to 3 R ｂ forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R ５ and R ６ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ alkylene; each C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ Alkylene is one to three R ｂ or R ３ and R ４ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ alkylene; each C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ Alkylene is one to three R ｂ and R ５ and R ６ together with the carbon atom to which they are attached, 1 to 3 R ｂ or forming a 3-6 membered saturated or partially unsaturated carbocyclic ring optionally substituted with R ３ and R ４ together with the carbon atom to which they are attached, 1 to 3 R ｂ forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R ５ and R ６ together with the carbon atom to which they are attached, 1 to 3 R ｂ forming a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with R ７ is hydrogen or R ８ and R ８ is -L 1 -R 8a, L １ is selected from a bond, —C(O)—, and —C(O)O—; R ８ａ is C1-8 alkyl, aryl, -C(O)-aryl, -C(O)-C １－４ Alkyl, -S-C(O)-C １－４ Alkyl, 【Chemistry 4】 Aryl is selected from one or two R ｃ and optionally substituted with Each R ａ is independently １－４ Alkyl, halo, C １－４ Haloalkyl, and —O—C １－４ alkyl, Each R ｂ is independently １－４ is alkyl, Each R ｃ is independently １－４ Alkyl or -OC(O)-C １－４ is alkyl, p is 0, 1, or 2; or a pharma- ceutically acceptable salt thereof.

2. R １ and R ２ But independently, C １－８ Alkyl, aryl-C １－４ Alkylene, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, aryl-C ３－７ Cycloalkylene, C ７－１２ Spirocycloalkyl, C ７－１２ Spirocycloalkyl-C １－４ Alkylene, Bridge C ５－１０ Bicycloalkyl, bridged C ５－１０ Bicycloalkyl-C １－４ Alkylene, fused C ５－１０ Bicycloalkyl, C １０－１６ Dispirocycloalkyl, C １０－１６ Dispirocycloalkyl-C １－４ Alkylene, Bridge C ９－１２ Tricycloalkyl, Bridged C ９－１２ Tricycloalkyl-C １－４ Alkylene, C ３－７ Cycloalkyl-C ３－７ cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; １－８ Alkyl, aryl-C １－４ Alkylene, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, aryl-C ３－７ Cycloalkylene, C ７－１２ Spirocycloalkyl, and C ７－１２ Spirocycloalkyl-C １－４ Alkylene is 1 to 3 R ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

3. R １ and R ２ But independently, C １－８ Alkyl, aryl-C １－４ Alkylene, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, aryl-C ３－７ Cycloalkylene, C ７－１２ Spirocycloalkyl, C ７－１２ Spirocycloalkyl-C １－４ Alkylene, Bridge C ５－１０ Bicycloalkyl-C １－４ Alkylene, fused C ５－１０ Bicycloalkyl, C １０－１６ Dispirocycloalkyl-C １－４ Alkylene, Bridge C ９－１２ Tricycloalkyl-C １－４ Alkylene, C ３－７ Cycloalkyl-C ３－７ cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; １－８ Alkyl, aryl-C １－４ Alkylene, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, aryl-C ３－７ Cycloalkylene, C ７－１２ Spirocycloalkyl, and C ７－１２ Spirocycloalkyl-C １－４ Alkylene is 1 to 3 R ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

4. R １ and R ２ But independently, C １－８ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, C ７－１２ Spirocycloalkyl, C ７－１２ Spirocycloalkyl-C １－４ Alkylene and bridge C ５－１０ Bicycloalkyl-C １－４ alkylene; each C １－８ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, C ７－１２ Spirocycloalkyl, and C ７－１２ Spirocycloalkyl-C １－４ Alkylene is 1 to 3 R ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

5. R １ and R ２ But independently, C ５－８ Alkyl, C ５－７ Cycloalkyl, C ５－７ Cycloalkyl-C １－４ Alkylene, C ７－９ Spirocycloalkyl, C ７－９ Spirocycloalkyl-C １－４ Alkylene and bridge C ５－７ Bicycloalkyl-C １－４ alkylene; each C ５－８ Alkyl, C ５－７ Cycloalkyl, C ５－７ Cycloalkyl-C １－４ Alkylene, C ７－９ Spirocycloalkyl, C ７－９ Spirocycloalkyl-C １－４ Alkylene and bridge C ５－７ Bicycloalkyl-C １－４ Alkylene is 1 to 3 R ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

6. R １ and R ２ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein:

7. R １ and R ２ The compound according to any one of claims 1 to 5, wherein A commercially acceptable salt.

8. R １ and R ２ are the same, and C １－８ Alkyl, aryl-C １－４ Alkylene, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, aryl-C ３－７ Cycloalkylene, C ７－１２ Spirocycloalkyl, C ７－１２ Spirocycloalkyl-C １－４ Alkylene, Bridge C ５－１０ Bicycloalkyl-C １－４ Alkylene, fused C ５－１０ Bicycloalkyl, C １０－１６ Dispirocycloalkyl-C １－４ Alkylene, Bridge C ９－１２ Tricycloalkyl-C １－４ Alkylene, C ３－７ Cycloalkyl-C ３－７ cycloalkylene, and 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S; １－８ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, C ７－１２ Spirocycloalkyl, and C ７－１２ Spirocycloalkyl-C １－４ Alkylene is 1 to 3 R ａ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, optionally substituted with

9. R １ and R ２ are the same, and C １－８ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, C ７－１２ Spirocycloalkyl, C ７－１２ Spirocycloalkyl-C １－４ Alkylene and bridge C ５－１０ Bicycloalkyl-C １－４ alkylene; each C １－８ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkylene, C ７－１２ Spirocycloalkyl, and C ７－１２ Spirocycloalkyl-C １－４ Alkylene is 1 to 3 R ａ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, optionally substituted with

10. R １ and R ２ But independently, 【Chemistry 5】 【Chemistry 6】 The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, selected from:

11. R １ and R ２ are the same, and 【Chemistry 7】 【Chemistry 8】 The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, selected from:

12. R ３ , R ４ , R ５ and R ６ are each independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is selected from 1 to 3 R ｂ 12. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

13. R ３ and R ５ The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein:

14. R ３ and R ５ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein both are methyl.

15. R ４ and R ６ The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein:

16. R ４ and R ６ or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 12 and 15, wherein: are both ethyl or both benzyl.

17. R ３ and R ４ The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein:

18. R ３ and R ４ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 12 and 17, wherein:

19. R ５ and R ６ The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein:

20. R ５ and R ６ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 12 and 19, wherein:

21. R ３ and R ４ together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, said cyclopropane ring or said cyclobutane ring being ｂ and R ５ and R ６ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ alkylene; each C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ Alkylene is 1 to 3 R ｂ 12. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

22. R ５ and R ６ is independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is selected from 1 to 3 R ｂ 22. The compound of claim 21, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

23. R ３ and R ４ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ alkylene; each C １－４ Alkyl, C ３－６ Cycloalkyl and aryl-C １－４ Alkylene is 1 to 3 R ｂ and R ５ and R ６ together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, said cyclopropane ring or said cyclobutane ring being ｂ 12. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

24. R ３ and R ４ is independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is selected from 1 to 3 R ｂ 24. The compound of claim 23, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

25. R ３ and R ４ together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, said cyclopropane ring or said cyclobutane ring being ｂ and R ５ and R ６ together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, said cyclopropane ring or said cyclobutane ring being ｂ 12. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

26. Each R ｂ is independently methyl or ethyl, or a pharma- ceutically acceptable salt thereof.

27. R ３ , R ４ , R ５ , and R ６ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein:

28. R ３ , R ４ , R ５ , and R ６ 28. The compound of claim 27, or a pharma- ceutically acceptable salt thereof, wherein each is methyl or cyclopropyl.

29. R ３ , R ４ , R ５ , and R ６ or a pharma- ceutically acceptable salt thereof.

28. The compound of claim 27, wherein each is methyl; or a pharma- ceutically acceptable salt thereof.

30. R ８ but, 【Chemistry 13】 【Chemistry 14】 30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, selected from:

31. R ８ but, 【Chemical 15A】 30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, selected from:

32. R ７ The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

33. formula: 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 or a pharma- ceutically acceptable salt thereof.

34. formula: 【Chemistry 24】 or a pharma- ceutically acceptable salt thereof.

35. formula: 【Chemistry 25】 or a pharma- ceutically acceptable salt thereof.

36. formula: 【Chemistry 26】 or a pharma- ceutically acceptable salt thereof.

37. formula: 【Chemistry 27】 or a pharma- ceutically acceptable salt thereof.

38. formula: 【Chemistry 28】 or a pharma- ceutically acceptable salt thereof.

39. formula: 【Chemical Formula 29】 or a pharma- ceutically acceptable salt thereof.

40. formula: 【Chemistry 30】 or a pharma- ceutically acceptable salt thereof.

41. formula: 【Chemistry 31】 or a pharma- ceutically acceptable salt thereof.

42. formula: 【Chemistry 32】 or a pharma- ceutically acceptable salt thereof.

43. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 42 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

44. 44. The pharmaceutical composition of claim 43, further comprising one, two, three, or four additional therapeutic agents.

45. 45. The pharmaceutical composition of claim 44, wherein the additional therapeutic agent or agents is an anti-HIV agent.

46. 45. The pharmaceutical composition of claim 44, wherein the additional therapeutic agent or agents is an anti-HBV agent.

47. 43. A composition for treating HIV infection, comprising a compound according to any one of claims 1 to 42, or a pharma- ceutically acceptable salt thereof.

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