Prodrugs of phosphonamide nucleotide analogues and pharmaceutical use thereof

Abstract

To provide a method for treating a disease.SOLUTION: There are disclosed compounds, compositions, and method useful for treating a viral infection, such as human immunodeficiency virus (HIV) and / or hepatitis B virus (HBV) infection. In particular, there are disclosed prodrugs of phosphonamide nucleotide analogues and methods for their preparation and use as therapeutic or prophylactic agents. The present disclosure is directed to novel prodrugs of the nucleotide analogue reverse transcriptase inhibitor tenofovir and pharmaceutically acceptable salts thereof. In some embodiments, the compounds may be used to treat HIV infections, to inhibit the activity of HIV reverse transcriptase, and / or to reduce HIV replication.SELECTED DRAWING: None

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 Aug. 7, 2020, and the entire disclosure thereof is incorporated herein by reference for all purposes.

[0002] (Field of the Invention) Compounds, compositions, and methods useful for treating viral infections such as human immunodeficiency virus (HIV) infection are disclosed.

Background Art

[0003] Human immunodeficiency virus (HIV) infection and related diseases are major public health problems worldwide. The 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 effectiveness, especially when used in combination with, for example, protease inhibitors and integrase inhibitors. A cure for HIV is not known, and thus, individuals infected with HIV may require lifelong treatment. Improvements in treatment methods for HIV and other viral infections are desired.

Summary of the Invention

Means for Solving the Problems

[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 for treating HIV infection, inhibiting the activity of HIV reverse transcriptase, and / or reducing 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 at a frequency of less than once a day, for example, on a weekly, monthly, or longer interval basis.

[0005] In one embodiment, there is provided a compound having the following formula (I) or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[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 additive.

[0007] In another embodiment, there is provided a pharmaceutical composition comprising means for maintaining a therapeutically effective concentration of TFV-DP in PBMC for a prolonged period and a pharmaceutically acceptable additive, wherein the means for maintaining a therapeutically effective concentration of TFV-DP in PBMC for a prolonged period is a compound of formula I or a pharmaceutically acceptable salt thereof.

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

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

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

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

[0012] In another embodiment, a method for treating an HIV infection is provided by administering to a subject in need of treatment for an 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 additive.

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

[0014] In another embodiment, a method for preventing an HIV infection is provided by administering to a subject at risk of an 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 additive.

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

[0016] In another embodiment, a method of treating an HIV infection is provided by administering to a subject in need of treatment for 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 additive.

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

[0018] In another embodiment, a method of preventing an HIV infection is provided 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 additive.

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

[0022] In another embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating an 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 additive for use in treating an 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 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 additive 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 additive for use in the treatment of 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 comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive for use in medical therapy.

[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 a treatment. In particular, a method of 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), the method comprising administering to the mammal a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

[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 additive for use in a method of 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, there is provided a kit or article of manufacture comprising a composition effective to treat or prevent an HIV infection, and a packaging material comprising a label indicating that the composition can be used to treat or prevent an infection by HIV. Exemplary compositions include a compound of formula I or a pharmaceutically acceptable salt thereof disclosed herein.

[0035] In another embodiment, there is provided a method of inhibiting the replication of HIV. The method comprises exposing the virus to an effective amount of a compound of formula I or a salt thereof under conditions in which 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 the 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 following embodiments, some of which may be apparent from or learned by practice of the description of the claimed embodiments. These may be realized and achieved by the processes and compositions particularly pointed out in the detailed description and claims. The foregoing summary is to be considered as some brief and general overviews of some of the embodiments disclosed herein, and is made with the understanding that the appended claims are not intended to limit in any way the scope of the legally granted rights or the scope of equivalents.

Mode for Carrying Out the Invention

[0038] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, one skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The following description of some embodiments is to be taken as illustrative of the present disclosure and is made with the understanding that the appended claims are not intended to be limited to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. The embodiments illustrated under any heading may be combined with the embodiments illustrated under any other heading. The embodiments illustrated under any heading may be combined with the embodiments illustrated under any other heading. Definitions

[0039] Unless the context requires otherwise, throughout this specification and the claims, the word "comprise" and variations thereof, such as "comprises" and "comprising" are to be construed in an open and inclusive sense, that is to say, "including, but not limited to". 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 the embodiment is included in at least one embodiment disclosed herein. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0041] The terms "about" or "approximately" when used in relation to a quantity include the recited value and have the meaning determined by the context (e.g., including the degree of error associated with the measurement of a particular quantity).

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

[0043] "Alkyl" is saturated and has from 1 to 12 carbon atoms (C 1-12 alkyl), and in certain embodiments has from 1 to 8 carbon atoms (C 1-8 alkyl), or has from 1 to 6 carbon atoms (C 1-6(alkyl), having 1 to 4 carbon atoms (C 1-4 (alkyl), or having 5 to 8 carbon atoms (C 5-8 (alkyl), which is bonded to the remainder of the molecule by a single bond, and refers to a linear or branched hydrocarbon radical, for example, 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, etc.

[0044] "Alkylene" is saturated and has 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 alkylene), and refers to a divalent linear or branched hydrocarbon radical. Examples include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2), 1-methylethylene (-CH(CH3)CH2), butylene (-CH2CH2CH2CH2-), 1-methylpropylene (-CH(CH3)CH2CH2), 1,1-dimethylethylene (-C(CH3)2CH2), and 1,2-dimethylethylene (-CH(CH3)CH( CH3). Unless otherwise specified, the definitions of propylene and butylene include all possible isomeric forms of the group in question having the same number of carbons. Thus, for example, propylene 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 agent) effective to inhibit the formation and / or replication of a virus in a subject, such as a human, including but not limited to agents that interfere with the mechanism of action of either the host or the virus required for virus formation and / or replication in the subject, such as a human.

[0047] The term "aryl" refers to a single aromatic ring, or a bicyclic or polycyclic ring. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals or ortho, spiro, or bridged bicyclic or polycyclic radicals having about 9 to 14 atoms, wherein at least one ring is an aromatic ring (e.g., one or more aryl rings or aryl rings fused to a carbocyclic ring). Such bicyclic or polycyclic rings may be optionally substituted on any carbocyclic moiety of the bicyclic or polycyclic ring with one or more (e.g., 1, 2, or 3) oxo groups. It should be understood that the point of attachment of the bicyclic or polycyclic radical defined above can be at any position of the ring, including the aryl or carbocyclic moiety of the ring. Exemplary 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 "arylalkylene" typically has 1 to 6 carbon atoms (i.e., aryl(C 1-6(alkylene). Examples of the arylalkylene group include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethane-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl, etc. The arylalkylene can contain 6 to 20 carbon atoms. For example, the alkylene portion of the arylalkylene group has 1 to 6 carbon atoms, and the aryl portion has 5 to 14 carbon atoms.

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

[0050] As used herein, "bicycloalkyl" refers to a hydrocarbon radical having the specified number of carbon atoms and two rings, which rings may be crosslinked, fused, or spirocyclic with respect to each other. In certain embodiments, the bicycloalkyl has 7 to 12 carbon atoms, 6 to 12 carbon atoms, 6 to 10 carbon atoms, or 5 to 10 carbon atoms, is saturated, and is bonded to the remainder of the molecule by a single bond. A crosslinked bicycloalkyl has two rings connected via two non-adjacent shared atoms. A fused bicycloalkyl has two rings connected via a shared bond. A spirocyclic bicycloalkyl (denoted "spirocycloalkyl") has two rings connected via a single shared atom. For example, bicycloheptyl can be, as exemplified below, either crosslinked bicycloheptyl, fused bicycloheptyl, or spirocycloheptyl.

Chemical formula

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

[0052] As used herein, "combination therapy" refers to a situation where a subject is simultaneously exposed to two or more treatment or prevention regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously, in some embodiments, such regimens may be administered sequentially (e.g., all of the "doses" of the first regimen are administered before any dose of the second regimen is administered), and in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, "administration" of combination therapy may include administration of one or more agents or modalities to a subject that is receiving administration of 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, but in some embodiments, two or more agents or their active moieties may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0053] "C u-v " or a prefix such as "(C u -C v )" indicates that the group that follows has u to v carbon atoms. For example, "C 1-6 alkyl group" indicates that the alkyl group has 1 to 6 carbon atoms.

[0054] "Carbon ring" refers to a non-aromatic hydrocarbon ring having 3 to 15 carbon atoms, and in certain embodiments, having 3 to 10 carbon atoms, or 3 to 7 carbon atoms, or 3 to 6 carbon atoms, being saturated or partially unsaturated, and bonded to the remainder of the molecule by single bonds. Examples of carbon rings include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0055] "Cycloalkyl" refers to a saturated non-aromatic cyclic hydrocarbon radical having 3 to 15 carbon atoms (C 3-15 cycloalkyl), and in certain embodiments, having 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), and being bonded to the remainder of the molecule by single bonds. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohex yl, 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, the cyclobutylene radical includes the following:

Chemical formula

[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 an appropriate unit dosage amount (in whole or in part) to be administered according to a dosage regimen that has been determined to correlate with a desired or beneficial result when administered to the relevant population (i.e., with a prophylactic or therapeutic dosing regimen). One of ordinary 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 the ring structures described herein that contain a carbocyclic, heterocyclic, aromatic, and / or heteroaromatic ring linked through two adjacent atoms. For example, the bicyclic compounds shown below each incorporate a cyclopropane fused to cyclohexane, a pyrrolidine fused to benzene, and a thiophene fused to furan.

Chemical formula

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

[0060] "Haloalkyl" refers to alkyl as defined herein, wherein one or more hydrogen atoms are replaced by halo substituents. For example, C 1-6 Haloalkyl is C 1-6 alkyl, and one or more of the hydrogen atoms are replaced by halo substituents. Such a range includes one halo substituent on the alkyl group to complete 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, and the like.

[0061] "Heterocyclyl" or "heterocycle" refers to a non-aromatic radical or ring having 3 to 15 atoms, wherein 1 to 6 atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and are bonded to the remainder of the molecule by single bonds. In certain embodiments, "heterocyclyl" has 3 to 10 atoms where 1 to 4 atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, or 3 to 7 atoms where 1 to 2 atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in heterocyclyl may optionally be oxidized, and the nitrogen atoms may optionally be 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 a partially saturated ring where so designated. Examples of such heterocyclyl 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 can reduce or eliminate 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, e.g., laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and wild animals.

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

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

[0068] "Pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for delivering a biologically active compound to a mammal, e.g., a human. Such media include all pharmaceutically acceptable additives.

[0069] "Pharmaceutically acceptable additives" include any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifying agent, or other pharmacologically inactive substances that are formulated in combination with the pharmacologically active components of a pharmaceutical composition, are compatible with the other components of the formulation, and are suitable for use in humans or livestock without undue toxicity, irritation, allergic - reaction, etc., but are not limited to these.

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

[0071] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 + (wherein X is C 1-4Salts derived from suitable bases such as (which is alkyl) are included. Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, 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, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid and other organic carboxylic acids, methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid and other organic sulfonic acids, and salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. Pharmaceutically acceptable salts of hydroxy group-containing compounds include Na + and NX4 + (wherein X is independently selected from H or C 1-4 alkyl group) and the anions of the compounds combined with suitable cations such as are included.

[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 pharmaceutically unacceptable acids or bases may also find use, for example, in the preparation or purification of compounds of formula I or another compound of the embodiments disclosed herein. All salts, whether or not derived from physiologically acceptable acids or bases, 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 the embodiments disclosed herein. Examples of metal salts prepared in this way are Li + 、Na + 、and K +It is a salt containing. By adding a suitable metal compound, a metal salt with lower solubility can be precipitated from a solution of a salt with higher solubility.

[0074] In addition, the salt may be formed by adding a specific organic acid and inorganic acid, such as HCl, HBr, H2SO4, H3PO4, or an organic sulfonic acid, to a basic center, typically an amine. Finally, it should be understood that the compositions herein include the compounds disclosed herein in non-ionized and zwitterionic forms.

[0075] "Prevent" or "preventing" means any treatment of a disease or condition that does not cause the clinical symptoms of the disease or condition to develop. In some embodiments, the compound can be administered to a subject (including humans) at risk of a disease or condition. As used herein, "prevent ing" and the term "prevention" refer to administering a compound, composition, or pharmaceutically acceptable salt according to the embodiments disclosed herein before or after an individual is exposed to HIV or HBV, but before the symptoms of HIV infection or HBV infection appear and / or before the virus is detected in the blood. The term also refers to preventing the appearance of symptoms of the disease and / or preventing the virus from reaching a detectable level in the blood. The term includes pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and both event-driven ) or "on-demand" prophylaxis. The terms also refer to preventing perinatal transmission of HIV from mother to infant by administering to the mother before delivery and the infant within a few days after birth. The term also refers to preventing transmission of HIV by blood transfusion.

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

[0077] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed on each other. 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, the human subject is an adult, adolescent, or pediatric subject. In some embodiments, the subject is afflicted with a relevant disease or condition. In some embodiments, the subject is susceptible to a disease or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease or condition. In some embodiments, the subject does not exhibit symptoms or characteristics of a disease or condition. In some embodiments, the subject is a person having one or more characteristics typical of susceptibility or risk of a disease or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who has been administered and / or has already been administered a diagnostic agent and / or a therapeutic agent and / or a prophylactic agent.

[0079] As used herein, the term "therapeutically effective amount" is an amount that produces the desired effect for which it is administered. In some embodiments, the term "therapeutically effective amount" or "therapeutically effective dosage" means an amount sufficient when administered to a population afflicted with or susceptible to a disease or condition according to a therapeutic dosing regimen for treating the disease or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity of one or more symptoms of a disease or condition, stabilizes one or more of their characteristics, and / or delays their onset. One of ordinary skill in the art will understand that the term "therapeutically effective amount" does not actually require the success of treatment achieved in a particular individual. Rather, a therapeutically effective amount can be an amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. In some embodiments, reference to a therapeutically effective amount can be reference to an 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.). One of ordinary skill in the art will understand that in some embodiments, a therapeutically effective amount can be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective amount can 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 a beneficial or desired result, including a clinical result. A beneficial or desirable clinical result can include one or more of the following: namely, a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or attenuating the degree of the disease or condition), b) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition), and / or c) alleviating the disease, i.e., causing regression of the clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, improving the quality of life, and / or extending survival). As used herein, the terms "treatment" and "treating" include administering a compound, composition, or pharmaceutically acceptable salt according to the embodiments disclosed herein to alleviate or eliminate symptoms of HIV infection or HBV infection and / or to reduce the 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 the specified number of carbon atoms and three rings, which rings may be cross-linked, fused, spirocyclic, or a combination thereof with respect to each other. In certain embodiments, the tricycloalkyl has 10 to 16 carbon atoms, or 9 to 12 carbon atoms, is saturated, and is attached to the remainder of the molecule by a single bond. For example, tricyclodecyl may be, as shown below, cross-linked tricyclodecyl, fused tricyclodecyl, dispirocyclodecyl, or mixed (e.g., cross-linked-fused) tricyclodecyl, respectively.

Chemical formula

[0082] The embodiments disclosed herein also mean that all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers are included. Examples of isotopes that can be incorporated into the disclosed compounds include 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 I are included. In certain embodiments, these radiolabeled compounds are useful, for example, in determining or measuring the effectiveness of a compound by characterizing the site or mode of action or the binding affinity for a pharmacologically important site of action. Certain isotopically labeled compounds of Formula I, for example, those incorporating a radioisotope, are useful in drug research and / or substrate tissue distribution studies. The radioisotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in terms of the ease of their incorporation and the means of detection.

[0083] In certain embodiments, substitution with a heavier isotope such as deuterium, i.e., 2 H, can provide certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life can be increased or the required dose can be decreased. Thus, in some situations, heavier isotopes may be preferred.

[0084] Substitution with a positron-emitting isotope, for example, 11 C, 18 F, 15O, and 13 N may be useful in positron emission tomography (PET ) studies for examining substrate receptor occupancy. The isotopically labeled compounds of Formula I can be prepared by using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents, by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples below.

[0085] The methods, compositions, kits, and articles of manufacture provided herein use or contain a compound (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, and n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds are useful for increasing the half-life of a compound or a pharmaceutically acceptable salt thereof when administered to a mammal, as they enhance resistance to metabolism. 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 include the in vivo metabolites of the compounds of the present disclosure. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compounds, mainly due to enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by a process that involves administering a compound according to the embodiments disclosed herein to a mammal for a period sufficient to obtain its metabolites. Such products are typically identified by administering a radiolabeled compound according to the embodiments disclosed herein to an animal such as a rat, mouse, guinea pig, monkey, or human at a detectable dose, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0087] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may contain one or more asymmetric centers and, thus, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry, or as (D)- or (L)- with respect to amino acids. 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 a chiral synthon or chiral reagent or resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or racemic compounds (or salts or derivatives thereof) using, for example, chiral high pressure liquid chromatograph (HPLC). Resolution of the racemic compound of the conductor is included. When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center and are not otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. Compound

[0088] This specification provides compounds that function as anti-HIV agents or anti-HBV agents, pharmaceutical compositions containing such compounds, optionally in combination with one or more (e.g., 2, 3, or 4) additional therapeutic agents, and methods of using such compounds and compositions. Embodiments of all compounds described herein include any pharmaceutically acceptable salts thereof, their stereoisomers, or mixtures of their stereoisomers.

[0089] In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided,

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

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

Chemical formula

Chemical formula

[0091] In some embodiments, the compound of formula I is a compound of formula (II) or

Chemical formula

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

[0093] In some embodiments of the compound of formula I, II, or formula III, or a pharmaceutically acceptable salt thereof, R 1 and R 2 are 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 3-7Selected from cycloalkylene and 5- to 7-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, each 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, and C 7-12 spirocycloalkyl-C 1-4 Alkylene is optionally substituted with 1 to 3 R a as defined above. In some embodiments, R a and R 1 are independently C 2 alkyl, aryl-C 1-8 alkylene, C 1-4 cycloalkyl, C 3-7 cycloalkyl-C 3-7 alkylene, aryl-C 1-4 cycloalkylene, C 3-7 spirocycloalkyl, C 7-12 spirocycloalkyl-C 7-12 alkylene, bridged C 1-4 bicycloalkyl-C 5-10 alkylene, fused C 1-4 bicycloalkyl, C 5-10 dispirocycloalkyl-C 10-16 alkylene, bridged C 1-4 tricycloalkyl-C 9-12 alkylene, C 1-4 cycloalkyl-C 3-7 cycloalkylene, and selected from 5- to 7-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, each C 3-7 alkyl, aryl-C 1-8 alkylene, C 1-4 cycloalkyl, C 3-7 cycloalkyl-C 3-7 alkylene, aryl-C 1-4 cycloalkylene, C 3-7 cycloalkylene, C7-12 Spirocycloalkyl, and C 7-12 Spirocycloalkyl-C 1-4 Alkylene is optionally substituted with 1 to 3 R a and R is as defined above. In some embodiments, R a and R 1 are independently selected from C 2 alkyl, C 1-8 cycloalkyl, C 3-7 cycloalkyl-C 3-7 alkylene, C 1-4 spirocycloalkyl, C 7-12 spirocycloalkyl-C 7-12 alkylene, and bridged C 1-4 bicycloalkyl-C 5-10 alkylene, and each C 1-4 alkyl, C 1-8 cycloalkyl, C 3-7 cycloalkyl-C 3-7 alkylene, C 1-4 spirocycloalkyl, and C 7-12 spirocycloalkyl-C 7-12 alkylene is optionally substituted with 1 to 3 R 1-4 and R is as defined above. In some embodiments, R a and R a are independently selected from C 1 alkyl, C 2 cycloalkyl, C 5-8 cycloalkyl-C 5-7 alkylene, C 5-7 spirocycloalkyl, C 1-4 spirocycloalkyl-C 7-9 alkylene, and bridged C 7-9 bicycloalkyl-C 1-4 alkylene, and each C 5-7 alkyl, C 1-4 cycloalkyl, C 5-8 cycloalkyl-C 5-7 alkylene, C 5-7 spirocycloalkyl, C 1-4 spirocycloalkyl-C 7-9 alkylene, and C 7-9 spirocycloalkyl-C1-4 Alkylene, and bridged C 5-7 Bicycloalkyl-C 1-4 The alkylene is optionally substituted with 1 to 3 Rs a and R is as defined above. 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 a 5- to 7-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, 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 The alkylene is optionally substituted with 1 to 3 Rs a and Ra 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, C 7-12 spirocycloalkyl, C 7-12 spirocycloalkyl-C 1-4 alkylene, and bridged C 5-10 bicycloalkyl-C 1-4 alkylene are selected from, 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 optionally substituted with 1 to 3 R a s, where R a is as defined above. In some embodiments, R 1 and R 2 are the same, and C 3-7 cycloalkyl-C1 -4 alkylene, C 7-12 spirocycloalkyl, C 7-12 spirocycloalkyl-C 1-4 alkylene, and bridged C 5-10 bicycloalkyl-C 1-4 alkylene are selected from, and each C 3-7 cycloalkyl-C 1-4 alkylene, C 7-12 spirocycloalkyl, and C 7-12 spirocycloalkyl-C 1-4 alkylene is optionally substituted with 1 to 3 R a s, where R a is as defined above. In some embodiments, R 1 and R 2 are the same, and C 1-8 alkyl and C 3-7Selected from cycloalkyl, each C 1-8 alkyl and C 3-7 cycloalkyl is optionally substituted with 1 to 3 R a as defined above. a In some embodiments of the compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof, R

[0095] and R 1 are independently selected from 2

Chemical formula

[0096] is selected from 1

Chemical formula

[0097] is selected from 2

Chemical formula

[0098] and R 1 are the same and 2 are selected from

Chemical formula

Chemical formula

[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 are both methyl. In some embodiments, R 3 and R 5 are both ethyl. In some embodiments, R 3 and R5 Both are cyclopropyl. In some embodiments, R 3 and R 5 are both 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 are both methyl. In some embodiments, R 4 and R 6 are both ethyl. In some embodiments, R 4 and R 6 are both cyclopropyl. In some embodiments, R 4 and R 6 are both 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 are both methyl. In some embodiments, R 3 and R 4 are both ethyl. In some embodiments, R 3 and R 4 are both cyclopropyl. In some embodiments, R 3 and R 4 are both 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, R5 and R 6 are both methyl. In some embodiments, R 5 and R 6 are both ethyl. In some embodiments, R 5 and R 6 are both cyclopropyl. In some embodiments, R 5 and R 6 are both 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 atom to which they are attached form a 3- to 5-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R b wherein R 5 and R 6 are independently selected from 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 optionally substituted with one to three R b and each R b is as defined above. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, and this cyclopropane ring or cyclobutane ring is optionally substituted with one to three R b wherein R b is as defined above. In some aspects, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one to three R In some aspects, R b and R 3 and R 4together with the carbon atoms to which they are attached form a cyclobutane ring optionally substituted with 1 to 3 R b In some embodiments, the cyclopropane ring or cyclobutane ring is unsubstituted. In some embodiments, the cyclopropane ring or cyclobutane ring is substituted with 1 R b In some embodiments, the cyclopropane ring or cyclobutane ring is substituted with 2 R b In some embodiments, the cyclopropane ring or cyclobutane ring is substituted with 3 R b In some embodiments, R 5 and R 6 are independently selected from 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 optionally substituted with 1 to 3 R b In some embodiments, R 5 and R 6 are independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with 1 to 3 R b In some aspects, R 3 and R 4 together with the carbon atoms to which they are attached form a cyclopropane ring or cyclobutane ring, and this cyclopropane ring or cyclobutane ring is optionally substituted with 1 to 3 R b and R 5 and R 6 are independently selected from methyl, ethyl, cyclopropyl and benzyl, and each methyl, ethyl, cyclopropyl and benzyl is optionally substituted with 1 to 3 R b In some embodiments of the compounds of formula I, II, or III, or a pharmaceutically acceptable salt thereof, R 3

[0104] ​and R 4 is, independently, C 1-4 alkyl, C 3-6 cycloalkyl, and aryl-C 1-4 alkylene selected from, each C 1-4 alkyl, C 3-6 cycloalkyl, and aryl-C 1-4 alkylene is optionally substituted with 1 to 3 R b s, and R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 5-membered saturated or partially unsaturated carbocyclic ring optionally substituted with 1 to 3 R b s, and R b is as defined above. In some embodiments, R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, and this cyclopropane ring or cyclobutane ring is optionally substituted with 1 to 3 R b s, and R b is as defined above. In some aspects, R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with 1 to 3 R b s. In some aspects, R 5 and R 6 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with 1 to 3 R b s. In some embodiments, the cyclopropane ring or the cyclobutane ring is unsubstituted. In some embodiments, the cyclopropane ring or the cyclobutane ring is substituted with one R b . In some embodiments, the cyclopropane ring or the cyclobutane ring is substituted with two R b s. In some embodiments, the cyclopropane ring or the cyclobutane ring is substituted with three R b s. In some embodiments, R 3 and R 4 are, independently, C 1-3 alkyl, C3-5 Cycloalkyl, and aryl-C 1-4 selected from alkylene, each C 1-4 alkyl, C 3-6 Cycloalkyl, and aryl-C 1-4 alkylene is optionally substituted with 1 to 3 R b In some embodiments, R 3 and R 4 are independently selected from methyl, ethyl, cyclopropyl, and benzyl, and each methyl, ethyl, cyclopropyl, and benzyl is optionally substituted with 1 to 3 R b In some embodiments, R 3 and R 4 are independently selected from methyl, ethyl, cyclopropyl and benzyl, and each methyl, ethyl, cyclopropyl and benzyl is optionally substituted with 1 to 3 R b and is optionally substituted with 1 to 3 R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, and this cyclopropane ring or cyclobutane ring is optionally substituted with 1 to 3 R b .

[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 atom to which they are attached form a 3- to 5-membered saturated or partially unsaturated carbon ring optionally substituted with 1 to 3 R b , and R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 5-membered saturated or partially unsaturated carbon ring optionally substituted with 1 to 3 R b . In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, and this cyclopropane ring or cyclobutane ring is optionally substituted with 1 to 3 R bis optionally replaced with R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring, and this cyclopropane ring or cyclobutane ring is optionally substituted with 1 to 3 R b where R b is as defined above. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with 1 to 3 R b In some embodiments, R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropane ring. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with 1 to 3 R b In some embodiments, R 5 and R 6 together with the carbon atom to which they are attached form a cyclobutane ring. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with 1 to 3 R b where R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with 1 to 3 R b In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with 1 to 3 R b where R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with 1 to 3 R b In some embodiments, R 3 and R 4together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with 1 to 3 R b and R 5 and R 6 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with 1 to 3 R b . In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with 1 to 3 R b and R 5 and R 6 together with the carbon atom to which they are attached form a cyclobutane ring optionally substituted with 1 to 3 R b .

[0106] In some embodiments of the compounds of formula I, II, or III, or pharmaceutically acceptable salts 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 compounds of formula I, II, or III, or pharmaceutically acceptable salts 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 each C 1-3 alkyl, C 3-5 cycloalkyl, or aryl-C 1-4 alkylene, and each C 1-3 alkyl, C3-5 Cycloalkyl, or aryl-C 1-4 Alkylene is optionally substituted with 1 to 3 Rs b wherein R is as defined above. In some embodiments, R b is as defined above. In some embodiments, R 3 , R 4 , R 5 , and R 6 are each methyl, ethyl, cyclopropyl, or benzyl, and each methyl, ethyl, cyclopropyl, or benzyl is optionally substituted with 1 to 3 Rs b wherein R is as defined above. In some embodiments, 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 are each cyclopropyl. In some embodiments, R 3 , R 4 , R 5 , and R 6 are each benzyl.

[0108] In some embodiments of the compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof, R 7 is hydrogen. In some embodiments, R 7 is R 8 .

[0109] In some embodiments of the compounds of formula I, II, or III, R 8 is -L1 -L 2 -L 3 -R 8a It is. In some embodiments, R 8 is -L 1 -(L 3 ) n -R 8a It is. In some embodiments, R 8 is -L 1 -(L 2 ) m -R 8a It is. In some embodiments, R 8 is -L 1 -L 3 -R 8a It is. In some embodiments, R 8 is -L 1 -L 2 -R 8a It is. In some embodiments, R 8 is -L 1 -R 8a It is. In some embodiments, R 8 is R 8a It is. In some embodiments, R 8 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0110] In some embodiments of the compounds of formula I, II, or III, or pharmaceutically acceptable salts 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 compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof, L 2 is selected from -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-, -CH2-CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-CH2-C(CH3)2-, -CH2-C(CH3)2-CH2-CH2-, and -CH2-CH2-CH2-C(CH3)2-. In some embodiments, L 2 is selected from -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-C(CH3)2-, -CH2-C(CH3)2-CH2-, -CH2-CH2-C(CH3)2-, and -CH2-C(CH3)2-CH2-CH2-. In some embodiments, L 2 is -CH2-. In some embodiments, L 2 is -CH2-CH2-. In some embodiments, L 2 is -CH2-CH2-CH2-. In some embodiments, L 2 is -CH2-C(CH3)2-. In some embodiments, L 2 is -CH2-C(CH3)2-CH2-. In some embodiments, L 2 is -CH2-CH2-C(CH3)2-. In some embodiments, L 2 is -CH2-C(CH3)2-CH2-CH2-.

[0112] In some embodiments of the compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof, L 3 is -C(O)O-. In some embodiments, L3 is

Chem.

[0113] In some embodiments of the compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof, R 8a is C 1-12 alkyl, aryl, -C(O)-C 1-4 alkyl, -S-C(O)-C 1-4 alkyl,

Chem.

Chem.

[0114] In some embodiments of the compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof, each R a is independently selected from C 1-4 alkyl, halo, and C 1-4 haloalkyl. In some embodiments, each R a is independently C 1-4 alkyl. In some embodiments, each R a is independently halo. In some embodiments, each R a is independently C 1-4 haloalkyl. In some embodiments, each R a is independently -O-C 1-4 alkyl. In some embodiments, each R ais independently selected from methyl, ethyl, n-propyl, isopropyl, fluoro, methoxy, and trifluoromethyl.

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

[0116] In some embodiments of the compounds of Formula I, II, or III, or pharmaceutically acceptable salts thereof, each R c is independently C 1-4 alkyl. In some embodiments, each R c is independently -OC(O)-C 1-4 alkyl. In some embodiments, each R c is independently methyl or -OC(O)-methyl.

[0117] In some embodiments of the compounds of Formula I, II, or III, or pharmaceutically acceptable salts 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 the compounds of Formula I, II, or III, or pharmaceutically acceptable salts 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 compounds of Formula I, II, or III, or pharmaceutically acceptable salts thereof, R 1 and R 2 are the same, and R 3 , R 4 , R 5 , and R 6 are the same. In some embodiments, R 1 and R 2are the same, and R 3 , R 4 , R 5 , and R 6 are each methyl or cyclopropyl. In some embodiments, R 1 and R 2 are the same, and R 3 , R 4 , R 5 , and R 6 are each cyclopropyl. In some embodiments, R 1 and R 2 are the same, and R 3 , R 4 , R 5 , and R 6 are each methyl.

[0120] In some embodiments of the compounds of Formula I, II, or III, or pharmaceutically acceptable salts 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 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 are each cyclopropyl. In some embodiments, R 7 is hydrogen, and R 3 , R 4 , R 5 , and R 6 are each methyl.

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

Chemical formula

[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, a compound of Formula I or III is a compound of Formula (V):

Chem.

[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 .

[0127] In some embodiments, the compound is of the formula:

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0128] In some embodiments, the compound is of the formula:

Chem.

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

[0130] Any one compound of Formula I, II, III, IV, and V as shown above, and any specific group or substituent shown herein in the compounds of Formula I, II, III, IV, and V as shown above (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 ), R 7 , R 8 , and its substituents) of any embodiment can be independently combined with other embodiments of any one compound of Formula I, II, III, IV, and V and / or substituents to form embodiments not specifically described above. Additionally, the list of substituents for any specific R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , and R 8 If a particular R group is not listed, each individual substituent may be deleted from a particular embodiment and / or claim, and the remaining list of substituents is understood to be within the scope of the embodiments disclosed herein.

[0131] The compounds of formulas I, II, III, IV, and V, or pharmaceutically acceptable salts thereof, are prodrugs in which the pro moiety is rapidly cleaved in the intracellular environment to yield tenofovir (TFV). In some embodiments, the compounds of formulas I, II, III, IV, and V, or pharmaceutically acceptable salts thereof, are suitable for use in long-acting formulations. In certain patients, for example, patients with difficult or limited access to medical care, it can be difficult to comply with a daily oral treatment or prophylaxis regimen to treat or prevent viral infections (e.g., HIV infection). Drugs that provide favorable pharmaceutical or physical science properties for sustained release (e.g., improved efficacy, long-acting pharmacokinetics, low solubility, reduced solubility, enhanced plasma stability, and / or other properties) are suitable for less frequent dosing and can provide better patient compliance. Such improvements in turn result in optimization of drug exposure and limitation of the emergence of drug resistance.

[0132] Although not bound by theory, 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 maintenance of intracellular levels of tenofovir diphosphate (TFV-DP), a pharmacologically active agent, thereby allowing for long-term maintenance of therapeutically effective concentrations of TFV-DP in relevant cell types and rendering 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 has been considered in Remenar, Mol. Pharmaceutics 2014, 11, 1739-1749. Pharmaceutical composition

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

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

[0135] In some embodiments, a composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof in a modified form does 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 disclosure does not contain an agent that affects (e.g., delays, inhibits, or blocks) the metabolism of the compound of the disclosure or any other active ingredient administered separately, sequentially, or simultaneously therewith. In one aspect, it is also understood that any of the methods, kits, articles of manufacture, etc. detailed herein do not contain an agent that affects (e.g., delays, inhibits, or blocks) the metabolism of the compound of the disclosure or any other active ingredient administered separately, sequentially, or simultaneously therewith.

[0136] In some embodiments, the above-described pharmaceutical composition is for use in humans or animals.

[0137] The present disclosure further includes a compound of the present disclosure for administration as a single active ingredient of a pharmaceutically acceptable composition that can be prepared by conventional methods known in the art, for example, by binding the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or additive, or by mixing it therewith.

[0138] In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient having a synergistic effect with other active ingredients in known drugs, or the co-administration of a compound of the present disclosure with such drugs. Method of treatment HIV infection

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

[0142] In some embodiments, the provided composition is combined with one, two, three, or four additional therapeutic agents selected from an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a Nef inhibitor, a latent infection reactivator, an HIV bNAb, an agonist of TLR7, TLR8, and TLR9, an HIV vaccine, a cytokine, an immune checkpoint inhibitor, an FLT3 ligand, a bispecific antibody that mobilizes T cells and NK cells, a chimeric T cell receptor that targets an HIV antigen, a pharmacokinetic enhancer, and other drugs for treating HIV, and combinations thereof.

[0143] In some embodiments, the provided composition is combined with one, two, three, or four additional therapeutic agents selected from an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a Nef inhibitor, a latent infection reactivator, an HIV bNAb, an agonist of TLR7, TLR8, and TLR9, an HIV vaccine, a cytokine, an immune checkpoint inhibitor, an FLT3 ligand, a bispecific antibody that mobilizes T cells and NK cells, a chimeric T cell receptor that targets an HIV antigen, a pharmacokinetic enhancer, and other drugs for treating HIV, and combinations thereof.

[0144] In some embodiments, the provided composition is 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 for treating and / or preventing hepatitis B virus (HBV) infection in a subject. In some embodiments, a method for treating and / or preventing HBV infection in a subject comprises administering to the subject a composition provided herein. In some embodiments, a method for treating HBV infection in a subject in need thereof comprises administering to the subject a composition provided herein.

[0146]

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

[0148] In some embodiments, the composition provided is an HBV combination drug, an HBV vaccine, an HBV polymerase inhibitor, an HBV capsid modulator, an agonist of TLR7, TLR8, and TLR9, a cytokine, an immune checkpoint inhibitor, FLT3 ligand, an interferon α receptor ligand, interferon α, interferon λ, a hyaluronidase inhibitor, a hepatitis B surface antigen (HBsAg) inhibitor, an HBV X protein (HBx) inhibitor, a cyclophilin inhibitor, an HBV virus entry inhibitor, an antisense oligonucleotide, short interfering RNA (siRNA), and DNA-directed RNA interference (ddRNAi), an endonuclease modulator, a ribonucleotide reductase inhibitor, an HBV E antigen (HBeAg) inhibitor, a covalently closed circular DNA (cccDNA) inhibitor, a farnesoid X receptor agonist, HBV protein, HBx) inhibitor, a cyclophilin inhibitor, an HBV virus entry inhibitor, an anti- sense oligonucleotide, short interfering RNA (short interfering RNA, siRNA ) and DNA-directed RNA interference (DNA directed RNA interference, ddRNAi), an endonuclease modulator, a ribonucleotide reductase inhibitor, an HBV E antigen (HBV E antigen, HBeAg) inhibitor, a covalently closed circular DNA (covalently closed circular DNA, cccDNA) inhibitor, a farnesoid X receptor agonist, HBV Bispecific antibodies that recruit antibodies, 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 (BTK) inhibitors, epigenetic regulators, inducers of tertiary lymphoid aggregates, antagonists of IAP / XIAP, nucleic acid polymers (e.g., NAP (nucleic acid polymer) and STOPS), modulators of lipid metabolism or transport, arginase inhibitors, and other drugs for treating HBV, and are combined with one, two, three, or four additional therapeutic agents selected from these and combinations thereof.

[0149] In some embodiments, the provided composition is 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, the provided composition is 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, provided is a method 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 a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In one embodiment, provided is a method 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 a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

[0152] In one embodiment, provided is a pharmaceutical composition 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 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 a therapeutically effective amount of one, two, three, or four additional therapeutic agents suitable for treating HIV infection.

[0154] In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with one, two, three, or four additional therapeutic agents. In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with two additional therapeutic agents. In other embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with three additional therapeutic agents. In further embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are 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 combination HIV therapy

[0155] In certain embodiments, the compounds disclosed herein are administered with one, two, three, or four additional therapeutic agents. Co-administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally refers to simultaneously or sequentially administering the compounds disclosed herein and the one, two, three, or four additional therapeutic agents such that a therapeutically effective amount of both the compounds disclosed herein and the one, two, three, or four additional therapeutic agents are present in the body of the patient. When administered sequentially, the combination may be administered in more than one dose.

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

[0157] In certain embodiments, a kit is provided that comprises 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, a reverse transcriptase HIV nucleoside or nucleotide inhibitor, 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 is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, HIV Tat or Rev inhibitor, immunomodulator, immunotherapeutic agent, antibody-drug conjugate, gene modifier, gene editor (CRISPR / Cas9, zinc finger nuclease, homing nuclease, synthetic nuclease, TALEN, etc.), cell therapy (chimeric antigen receptor T cell, CAR-T, and genetically engineered T cell receptor, TCR-T, autologous T cell therapy, genetically engineered B cell, etc.), latent infection reactivator, immune-based therapy, phosphatidylinositol 3-kinase (PI3K) inhibitor, HIV antibody, bispecific antibody and "antibody-like" therapeutic protein, HIV p17 matrix protein inhibitor, IL-13 antagonist, peptidylprolyl cis-trans isomerase A modulator, protein disulfide isomerase inhibitor, complement C5a receptor antagonist, DNA methyltransferase inhibitor, fatty acid synthase inhibitor, HIV vif gene modulator, Vif dimerization antagonist, HIV-1 viral infectivity factor inhibitor, HIV-1 Nef modulator, TNF alpha ligand inhibitor, HIV Nef inhibitor, Hck tyrosine kinase modulator, mixed lineage kinase-3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain-containing protein 1 modulator, HIV ribonuclease H inhibitor, IFN antagonist, retrocyclin modulator, CD3 antagonist, CDK-4 inhibitor, CDK-6 inhibitor, CDK-9 inhibitor, CXCR4 modulator, dendritic ICAM-3-grabbing non-integrin 1 inhibitor, HIV GAG protein inhibitor, HIVIt 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 additional therapeutic agents are selected from HIV combination drugs, other HIV therapeutic drugs, 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, latent infection reactivators, capsid inhibitors, immune system therapeutic drugs, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0161] In some embodiments, the additional therapeutic agent consists of a group selected from HIV combination drugs, other HIV therapeutic drugs, 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, latent infection reactivators, capsid inhibitors, immune system therapeutic drugs, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0162] In some embodiments, the additional therapeutic agent or additional therapeutic agents are selected from an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of reverse transcriptase of HIV, a nucleoside or nucleotide inhibitor of reverse transcriptase of HIV, an HIV integrase inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a Nef inhibitor, a latent infection reactivator, an HIV bNAb, an agonist of TLR7, TLR8, and TLR9, an HIV vaccine, a cytokine, an immune checkpoint inhibitor, an FLT3 ligand, a bispecific antibody that mobilizes T cells and NK cells, a chimeric T cell receptor that targets an HIV antigen, a pharmacokinetic enhancer, 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 additional therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir. HIV combination drug

[0165] Examples of combination drugs 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); DESCCOVY® (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® (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 Bicistat; atazanavir sulfate and bicistat; atazanavir sulfate and ritonavir; darunavir and bicistat; 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, 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 + albuvertide, Elpida (elsulfabirin; VM-1500; VM-1500A, but not limited to these. Other HIV drugs

[0166] Examples of other drugs for treating HIV include, but are not limited to, 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 (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 peptides, 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 conjugate (AVC), and VIR-576. HIV protease inhibitor

[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 + 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 inhibitor

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

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

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

[0171] Examples of reverse transcriptase inhibitors, HIV nucleoside or nucleotide inhibitors include adefovir, adefovir dipivoxil, azidothymidine, 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), abacavir, abacavir sulfate, alozidothymidine, apricitabine, censidothymidine, didanosine, elvucitabine, festinavir, fosalbutidoxil, CMX-157, dapivirine, doravirine, etodidothymidine-ravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozibutidoxil, lamivudine, hoffadide, stubidothymidine, zalcitabine, lobatofovir etalafernamide (GS-9131), GS-9148, MK-8504, islatravir, MK-8583, VM-2500, and KP-1461, but are not limited thereto. HIV integrase inhibitor

[0172] Examples of HIV integrase inhibitors include, but are not limited to, 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, bictegravir, AVX-15567, cabotegravir (long-acting injection), 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, stilbenedisulfonic acid, T-169, STP-0404, VM-3500, and cabotegravir.

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

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

[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), adaptavire (RAP-101), nelfinavir (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, 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 CADA analogs.

[0179] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicide, Radha-108 (receptor) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicine, fostemsavir 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 inhibitor

[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 such as GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as bortezomib, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 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, G DC-0917, HGS1029, AT-406, Debio-1143), PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 regulatory 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 indolactam, prostratin, ingenol B, and DAG-lactone. Histone deacetylase (HDAC) inhibitor

[0184] In some embodiments, the agents described herein are combined with inhibitors of histone deacetylases, such as histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene number 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, givinostat, mocetinostat, panobinostat, pracinostat, xenoSTAT (JNJ-26481585), resminostat, ricolinostat, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat. Capsid inhibitor

[0185] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (nucleocapsid p7, NCp7) inhibitors such as azodicarboxamide, HIV p24 capsid protein inhibitors, lenacapavir (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 the compounds described in (GSK International Publication No. 2019 / 087016). Immune checkpoint modulator

[0186] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of an inhibitory immune checkpoint protein or receptor, and / or one or more stimulators, activators, or agonists of a stimulatory immune checkpoint protein or receptor. Blocking or inhibiting an inhibitory immune checkpoint can reliably regulate the activation of T cells or NK cells and prevent immune escape of infected cells. Activating or stimulating a stimulatory immune checkpoint can enhance the effect of an immune checkpoint inhibitor in an anti-infective agent. In various embodiments, the immune checkpoint protein or receptor regulates the T cell response (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, the immune checkpoint protein or receptor regulates the NK cell response (e.g., as reviewed 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 and Immunoglobulin Domain Containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain Main T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); Immunoglobulin superfamily member 11 (IGSF11, VSIG3); Natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-related 2 (HHLA2, B7H7); Inducible T cell co-stimulatory molecule (ICOS, CD278); Inducible T cell co-stimulatory 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 (BTLA)); 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; Necltin 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 member 6 (SLAMF6, CD352); 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, 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, 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 T cell activation inhibitor 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-related immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); Lymphocyte activation 3 (LAG3, CD223); Hepatitis A virus cellular 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, the 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 co-stimulatory molecule (ICOS, CD278); Inducible T cell co-stimulatory 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, for example, 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 long cytoplasmic tail (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); killer cell immunoglobulin-like receptor, three Ig domains, and 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 stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory 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, for example, 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, one or more immune checkpoint inhibitors are PD-L1(C It comprises a proteinaceous inhibitor of D274), PD-1 (PDCD1), or CTLA4 (e.g., an antibody or a fragment thereof, or an antibody mimetic). In some embodiments, one or more immune checkpoint inhibitors comprise an organic small 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 inhibitors of CTLA4 that can be co-administered include, but are not limited to, 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, PBI-5D3H5, BPI-002, and bispecific 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 inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include pembrolizumab, nivolumab, semiprimab, 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, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (budigalimab), PD1 -PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), 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 bispecific inhibitor 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) are included, but are not limited to these.

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

[0194] In various embodiments, the agents described herein are agonists of one or more members of the TNF receptor superfamily (TNFRSF), e.g., TNFRSF1A (NCBI gene number 7132), TNFRSF1B (NCBI gene number 7133), TNFRSF4 (OX40, CD134; NCBI gene number 7293), TNFRSF5 (CD40; NCBI gene number 958), TNFRSF6 (FAS, NCBI gene number 355), TNFRSF7 (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 (NGFR, CD271, NCBI gene number 4804), TNFRSF17 (BCMA, CD269, NCBI gene number 608), TNFRSF18 (GITR, CD357, NCBI gene number 8784), TNFRSF19 (NCBI gene number 55504), TNFRSF21 (CD358, DR6, NCBI gene number 27242), and TNFRSF25 (DR3, NCBI gene number 8718), and are combined with one or more agonists thereof.

[0195] Exemplary anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tabalixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in International Publication No. 2016 / 179517, International Publication No. 2017 / 096179, International Publication No. 2017 / 096182, International Publication No. 2017 / 096281, and International Publication No. 2018 / 089628.

[0196] Exemplary anti-TNFRSF5 (CD40) antibodies that can 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 balstilimab (CDX-1127) is co-administered.

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

[0199] Exemplary anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication No. 2017 / 096179, International Publication No. 2017 / 096276, International Publication No. 2017 / 096189, and International Publication No. 2018 / 089628. In some embodiments, an antibody or fragment thereof that targets TNFRSF4 (OX40) and TNFRSF18 (GITR) simultaneously is co-administered. Such antibodies are described, for example, in International Publication No. 2017 / 096179 and International Publication No. 2018 / 089628. Bispecific and trispecific natural killer (NK) cell engagers Ja

[0200] In various embodiments, the agents described herein are bispecific NK-cell engagers (BiKEs) or trispecific NK-cell engagers (TriKEs) (e.g., those without Fc) or bispecific antibodies (e.g., those with Fc) against NK cell activating receptors such as 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 receptor FcγR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptor (KIR) (KIR-2DS and KIR-3DS), DNAM- 1, and CD137 (41BB). 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-related antigens as described herein. BiKEs and TriKEs 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 (TRiKEs) 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 ID 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 vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916. Toll-like receptor (TLR) agonist

[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 number 7096), TLR2 (NCBI gene number 7097), TLR3 (NCBI gene number 7098), TLR4 (NCBI gene number 7099), TLR5 (NCBI gene number 7100), TLR6 (NCBI gene number 10333), TLR7 (NCBI gene number 51284), TLR8 (NCBI gene number 51311), TLR9 (NCBI gene number 54106), and / or TLR10 (NCBI gene number 81793). Exemplary TLR7 agonists that can be co-administered are 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 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. 20090047249 (Gilead Sciences), U.S. Patent Application Publication No. 20140045849 (Janss en), U.S. Patent Application Publication No. 20140073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Compounds disclosed in 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 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics) are included, but not limited thereto. Examples of TLR7 / TLR8 agonists include NKTR-262, telratolimod, and BDB-001.Examples of TLR8 agonists 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 the compounds disclosed in US Patent Application Publication No. 20140045849 (Janssen), US Patent Application Publication No. 20140073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), US Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), US Patent Application Publication No. 20080234251 (Array Biopharma), US Patent Application Publication No. 20080306050 (Array Biopharma), US Patent Application Publication No. 20100029585 (Ventirx Pharma), US Patent Application Publication No. 20110092485 (Ventirx Pharma), US Patent Application Publication No. 20110118235 (Ventirx Pharma), US Patent Application Publication No. 20120082658 (Ventirx Pharma), US Patent Application Publication No. 20120219615 (Ventirx Pharma), US Patent Application Publication No. 20140066432 (Ventirx Pharma), US Patent Application Publication No. 20140088085 (Ventirx Pharma), US Patent Application Publication No. 20140275167 (Novira Therapeutics), and US Patent Application Publication No. 20130251673 (Novira Therapeutics).Examples of TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, retenimode, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitimode (MGN-1703), CYT-003, CYT-003-QbG10, chilothrimod, and PUL-042. Examples of TLR3 agonists include rintatrimod, 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 inhibitor or antagonist

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

[0204] In some embodiments, the agents described herein are combined with a stimulator of interferon gene (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 (potential HIV), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP), and cyclic di-AMP. In some embodiments, the agents described herein are combined with an RIG-I modulator such as RGT-100, or an 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 anti-TIM-3 antibodies such as TSR-022, LY-3321367, MBG-453, INCAGN-2390.

[0206] In certain embodiments, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation) antibody such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385. Interleukin agonist

[0207] In certain embodiments, the agents described herein include interleukin agonists such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists; examples of IL-2 agonists such as proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214), modified variants of IL-2 (e.g., THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, 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 sympolin (pegylated Il-15), P-22339, and examples of IL-15 agonists such as IL-15-PD-1 fusion protein N-809, and an example of IL-7 is CYT-107.

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

[0209] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panolisib, perifosine, pictilisib, piraralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, Examples include, but are not limited to, 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. α-4 / β-7 antagonist

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

[0211] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include, but are not limited to, DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies), TMB-360, and those targeting HIV gp120 or gp41, antibody mobilizing 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-targeted antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, KLIC target clone 3 human monoclonal antibodies (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0212] A variety of bNAbs can be used. Examples include those described in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, International Publication No. 2014 / 063059, International Publication No. 2012 / 158948, International Publication No. 2015 / 117008, and International Application No. US2015 / 41272, and International Publication No. 2017 / 096221, but are not limited thereto, and include antibody 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 those described in Klein et al., Nature, 492(7427):118-22(2012), Horwitz et al., Proc Natl Acad Sci U S A, 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), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81, etc. (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to V1V2-glycan), 2G12 (binds to 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 broad neutralizing antibodies that can be used as a second therapeutic agent in combination therapy are described, for example, in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, and International Publications Nos. 2012 / 154312, 2012 / 158948, 2013 / 086533, 2013 / 142324, 2014 / 063059, 2014 / 089152, 2015 / 048462, 2015 / 103549, 2015 / 117008, 2016 / 014484, 2016 / 154003, 2016 / 196975, 2016 / 149710, 2017 / 096221, 2017 / 133639, 2017 / 133640, which are hereby incorporated by reference in their entirety for all purposes. Additional examples are described in 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 U S A, 110(41):16538-43(2013), Scheid, et al., Science, 333:1633-1637(2011), Scheid, et al., Nature, 458:636-640(2009), Eroshkin et

[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, PGT122, 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 (ipilimumab), 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, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E, and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34, and VRC34.01, 10E8, 10E8v4, 10E8- Examples include, but are not limited to, 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 enhancer

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

[0218] Examples of additional therapeutic agents include those disclosed 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), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim), but are not limited thereto. 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 (such as adenovirus vectors like Ad5, Ad26, or Ad35), simian adenoviruses (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus-based vaccines, enterovirus-based vaccines, gorilla adenovirus vaccines, lentivirus vector-based vaccines, arenavirus vaccines (e.g., LCMV, Pichinde), two-segment or three-segment arenavirus-based vaccines, trimeric HIV-1 vaccines, measles virus-based vaccines, flavivirus vector-based vaccines, tobacco mosaic virus vector-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara, MVA), orthopoxvirus-derived NYVAC, avipoxvirus-derived ALVAC (canarypox virus) strain; fowlpox virus-based vaccines, rhabdovirus-based vaccines, e.g., VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines, e.g., 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; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines, but are not limited to these. Modified vaccinia virus Ankara, MVA, orthopox virus-derived NYVAC, avipoxvirus-derived ALVAC (canarypox virus) strain; fowlpox virus-based vaccines, rhabdovirus-based vaccines, e.g., VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines, e.g., 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; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines, but are not limited to these. Modified vaccinia virus Ankara, MVA, orthopoxvirus-derived NYVAC, avipoxvirus-derived ALVAC (canarypox virus) strain; fowlpox virus-based vaccines, rhabdovirus-based vaccines, e.g., VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines, e.g., 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; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines, but are not limited to these.

[0220] Examples of vaccines include AAVLP-HIV vaccine, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664gp140 adjuvant vaccine, BG505 SOSIP.GT1.1 gp140 adjuvant vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA tripleplex 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 liposome subunit vaccine, Remune, ITV-1, 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 expressing SCaVII and Sev vector vaccine, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.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 virus-like particle vaccines such as 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 (such as 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, multi-clade 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 60mer series 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-stimulating anti-CD4 vaccine, MVA-BN HIV-1 vaccine regimen, UBI HIV gp120, mRNA-based prophylactic vaccine, VPI-211, and TBL-1203HI are included. Combined therapy with contraception

[0221] In certain embodiments, the agents described herein are combined with a contraception or birth control regimen. Therapeutic agents for use in contraception (birth control) that can be combined with the agents of the present disclosure include cyproterone acetate, desogestrel, ethinyl estradiol, ethinodiol, etonogestrel, levomefolate acid, levonorgestrel, lynestrenol, misoprostol, nomegestrol acetate, norelgestromin, norethisterone, norethindrone, norethynodrel, norethoxyfen, segesterone acetate, and any combination thereof.

[0222] In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are 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); DESCCOVY® (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 and elvitegravir; tenofovir alafenamide + elvitegravir (rectal preparation, HIV infection), tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; pegylated raltegravir; raltegravir and lamivudine; maraviroc; tenofovir + emtricitabine + maraviroc, enfuvirtide; ALUVIA® (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; Prolactin; Tipranavir; Tipranavir Calcium; Efavirenz; Etravirine; Nelfinavir; Nelfinavir Mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir Mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine Mesylate; Radha-108 (receptol); Lamivudine and Tenofovir Disoproxil Fumarate; Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate; Phosphazide; Lamivudine, Nevirapine, and Zidovudine; Abacavir, and Abacavir Sulfate, is combined with one, two, three, or four additional therapeutic agents selected from the group consisting of

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

[0224] In another embodiment, the agent or its pharmaceutical composition disclosed herein 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, the agent or its pharmaceutical composition disclosed herein is combined with a first additional therapeutic agent (contraceptive) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethinodiol, etonogestrel, levomefolate, levonorgestrel, linestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, norethinodrel, 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 therapies and cell therapies include gene modification to silence genes; genetic approaches to directly kill infected cells; replacing most of the patient's own immune system to enhance the immune response against infected cells, or activating the patient's own immune system to kill infected cells, or injecting immune cells designed to find and kill infected cells; genetic approaches to modify cell activity to further alter the endogenous immune responsiveness to infection. Examples of cell therapies include LB-1903, ENOB-HV-01, GOVX-B01, HSPC overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies include AGS-004. Examples of CCR5 gene editors include SB-728T. Examples of CCR5 gene inhibitors include Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy transduced autologous CD34+ hematopoietic progenitor cells (HIV infection / HIV-related lymphoma). In some embodiments C34-CCR5 / C34-CXCR4-expressing CD4+ T cells are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the 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, e.g., an HIV-targeted gene editor. In various embodiments, the genome editing system can be selected from the group consisting of CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and meganuclease complexes. Exemplary HIVs targeting the CRISPR / Cas9 system include, but are not limited to, EBT-101. CAR-T cell therapy

[0228] In some embodiments, the agents described herein are chimeric antigen receptors. A collection of immune effector cells engineered to express a specific antigen receptor (CAR) The CAR can be co-administered with a group of antibodies, and 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-induced binding site on gp120, an N-glycan on gp120, V2 of gp120, a membrane proximal region on gp41. The immune effector cell is a T cell or a NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof. The cell 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 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 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] The compounds 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 a 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 comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0233] In one embodiment, the additional therapeutic agent or additional therapeutic agents of the kit are an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an immunomodulatory agent, an immunotherapeutic agent, an antibody-drug conjugate, a gene modifier, a gene editor (CRISPR / Cas9, zinc finger nuclease, homing nuclease, synthetic nuclease, TALENs, etc.), a cell therapy (chimeric antigen receptor T cells, CAR-T, and genetically engineered T cell receptor, TCR-T, autologous T cell therapy, etc.), a compound targeting the HIV capsid, a latent infection reactivator, a capsid polymerization inhibitor, an HIV bNAb, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a broadly neutralizing HIV antibody, a bispecific antibody, and an “antibody-like” therapeutic protein, an HIV p17 matrix protein inhibitor, an IL-13 antagonist, a peptidylprolyl cis-trans isomerase A modulator, a protein disulfide isomerase inhibitor, a complement C5a receptor antagonist, a DNA methyltransferase inhibitor, an HIV vif gene modulator, a Vif dimerization antagonist, an HIV viral infectivity factor inhibitor, a TAT protein inhibitor, an HIV Nef modulator, an Hck tyrosine kinase modulator, a mixed lineage kinase-3 (MLK-3) inhibitor, an HIV splicing inhibitor, a Rev protein inhibitor, an integrin antagonist, a nucleoprotein inhibitor, a splicing factor modulator, a COMM domain-containing protein 1 modulator, an HIV ribonuclease H inhibitor, a retrocyclin modulator, a CDK-9 inhibitor, a dendritic ICAM-3-grabbing non-integrin 1 inhibitor, an HIV GAG protein inhibitor, an HIVIt is an anti-HIV agent selected from a POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxythymidine 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 combinations thereof.

[0234] In some embodiments, the additional therapeutic agent or additional plurality of therapeutic agents of the kit are selected from HIV combination drugs, other HIV therapeutic drugs, 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, latent infection reactivators, capsid inhibitors, immune system therapeutic drugs, 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 particular 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 a further 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 nucleosides or nucleotide inhibitors of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV nucleo It includes an osid or nucleotide inhibitor and an HIV capsid inhibitor. In certain embodiments, the kit includes 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 includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor. In certain embodiments, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAbs. In certain embodiments, the kit includes 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 includes 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 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. Combination therapy for HBV

[0237] In certain embodiments, a method for treating or preventing HBV infection is provided, the method comprising administering to a human a therapeutically effective amount of a composition described herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating HBV infection is provided, the method comprising administering to a human a therapeutically effective amount of a composition described herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) 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 the composition described herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) 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, immunomodulators, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (DART®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editors (CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs, etc.), CAR-T (chimeric antigen receptor T cells), and TCR-T (engineered T cell receptor) agents for cell therapy, or any combination thereof.

[0240] In some embodiments, the additional therapeutic agent or additional therapeutic agents are HBV combination drugs, HBV vaccines, HBV polymerase inhibitors, HBV capsid modulators, agonists of TLR7, TLR8, and TLR9, cytokines, immune checkpoint inhibitors, FLT3 ligand, interferon α receptor ligand, interferon α, interferon λ, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, HBV X protein (HBx) inhibitors, cyclophilin inhibitors, HBV virus entry inhibitors, antisense oligonucleotides, short interfering RNAs (siRNAs) and DNA-directed RNA interference Selected from interfering (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, indoleamine-2,3-dioxygenase (IDO1) pathway inhibitors, anti-OX40, anti-CD40, anti-CD160, HBV gene editors, PAPD5 / PAPD7 inhibitors, ZCCHC14 inhibitors, Bruton 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 additional therapeutic 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-IFNα; and INO-1800 (INO-9112 and RG7944). Other HBV drugs

[0244] Examples of other drugs for the treatment of HBV include α-hydroxy tropolone, amdoxovir, β-hydroxy cytosine nucleoside, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), JNJ-56136379, nitazoxanide, biliranapant, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotide, mibotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, allopheron, 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, DasKloster 0014-01, 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, and U.S. Patent Application Publication No. 20150210682 (Roche), U.S. Patent Application Publication No. 2016 / 0122344 (Roche), International Publication No. 2015173164, International Publication No. 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), International Publication No. 16128335(A1) (Roche), International Publication No. 16120186(A1) (Roche), U.S. Patent Application Publication No. 2016237090(A) (Roche), International Publication No. 16107833(A1) (Roche), International Publication No. 16107832(A1) (Roche), U.S. Patent Application Publication No. 2016176899(A) (Roche), International Publication No. 16102438(A1) (Roc Examples include, but are not limited to, the compounds described in WO 2016 / 012470 (A1) (Roche), US Patent Application Publication No. 2016 / 0220586 (A) (Roche), and US Patent Application Publication No. 2015 / 031687 (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 preventive 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 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 Examples include, but are not limited to, HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac B, Hebsulin, Recombivax HB, Revac B mcf, Revac 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, but are not limited to, HBsAG-HBIG complex, 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 inhibitor

[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 octadecyl oxyethyl ester, CMX-157, bicifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filoscirivibin, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil asparagine orotate, and HS-10234, but are not limited thereto. Immunomodulators

[0248] Examples of immunomodulators include linterferon modulator, imidol 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, 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, but are not limited thereto. Toll-like receptor (TLR) modulator

[0249] In various embodiments, the agents described herein are combined with agonists of toll-like receptors (TLRs), such as agonists of TLR1 (NCBI Gene ID 7096), TLR2 (NCBI Gene ID 7097), TLR3 (NCBI Gene ID 7098), TLR4 (NCBI Gene ID 7099), TLR5 (NCBI Gene ID 7100), TLR6 (NCBI Gene ID 10333), TLR7 (NCBI Gene ID 51284), TLR8 (NCBI Gene ID 51311), TLR9 (NCBI Gene ID 54106), and / or TLR10 (NCBI Gene ID 81793). Exemplary TLR7 agonists that can be co-administered are 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 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. 20090047249 (Gilead Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), US Patent Application Publication No. 20100029585 (Ventirx Pharma), US Patent Application Publication No. 20110092485 (Ventirx Pharma), US Patent Application Publication No. 20110118235 (Ventirx Pharma), US Patent Application Publication No. 20120082658 (Ventirx Pharma), US Patent Application Publication No. 20120219615 (Ventirx Pharma), US Patent Application Publication No. 20140066432 (Ventirx Pharma), US Patent Application Publication No. 20140088085 (Ventirx Pharma), United States Examples of compounds disclosed in Patent Application Publication No. 20140275167 (Novira Therapeutics) and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics) include, but are not limited to, these. TLR7 / TLR8 agonists that can be co-administered are NKTR-262, telratolimod, and BDB-001. Examples of TLR8 agonists that can 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 compounds disclosed in U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), International Publication No. 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 (Ventirx Pharma), Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics).Exemplary TLR9 agonists that can be co-administered include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, lenitimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitimimod (MGN-1703), CYT-003, CYT-003-QbG10, chilsonimod, and PUL-042. Examples of TLR3 agonists include lintrimod, 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 ligand.

[0250] Examples of interferon alpha receptor ligand include interferon alpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®), pegylated interferon alpha-1b, interferon alpha1b (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 (YPEG-rhIFNalpha-2b), MOR-22, peg interferon alpha-2b (PEG-INTRON®), Bioferon, Novaferon, Inmuta Gro (Inmutag) (Interferon), MULTIFERON®, Interferon α-n1 (HUMOFERON®), Interferon β-1a (AVONEX®), Shaferon, Interferon α-2b (Axxo), Alfaferone, Interferon α-2b (BioG eneric Pharma), Interferon-α2 (CJ), Laferonum, VIPEG, BLAUFERON-A, B LAUFERON-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), Inter feron α 2a, Optipeg A, Realfa 2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), ropeg Interferon α-2b, rHSA-IFN α-2a (recombinant human serum albumin Interferon α2a fusion protein), rHSA-IFN α 2b, recombinant human Interferon α-(1b, 2a, 2b), peg Interferon α-2b (Amega), peg Interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon α-2b (Changchun In Institute of Biological Products, Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN (SINOGEN), Fukangtai, Pegstat, rHSA-IFN α-2b, SFR-9216, and Interapo (Interapa), among others, but not limited thereto. Hyaluronidase inhibitor

[0251] Examples of hyaluronidase include, but are not limited to, Astoremer. Hepatitis B surface antigen (HBsAg) inhibitor

[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, 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, ipilimumab, belatacept, PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155. Cyclophilin inhibitor

[0255] Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and those described in U.S. Patent No. 8513184 (Gilead Sciences), U.S. Patent Application Publication No. 20140030221 (Gilead Sciences), U.S. Patent Application Publication No. 20130344030 (Gilead Sciences), and U.S. Patent Application Publication No. 20130344029 (Gilead Sciences), but are not limited thereto. HBV virus entry inhibitor

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

[0257] Examples of virus mRNA-targeted antisense oligonucleotides include, but are not limited to, ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004. Antisense oligonucleotides targeting 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, ARB-1467.

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

[0260] Examples of endonuclease modulators include, but are not limited to, PGN-514. Ribonucleotide reductase inhibitor

[0261] Examples of ribonucleotide reductase inhibitors include, but are not limited to, Trimidox. HBV E antigen inhibitor

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

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

[0264] Examples of farnesoid x receptor agonists include, for example, 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, although not limited thereto. 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 Zute Examples include, but are not limited to, ctra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, Igantibe, Niuliva, CT-P24, Hepatitis B Immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

[0267] Examples of fully human monoclonal antibodies include, but are not limited to, HBC-34. CCR2 chemokine antagonist

[0268] Examples of CCR2 chemokine antagonists include, but are not limited to, propagermanium. Thymosin agonist

[0269] Examples of thymosin agonists include, but are not limited to, timalfasin, recombinant thymosin α1 (GeneScience). Cytokine

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

[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, morphothiazine 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 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), International Publication No. 2014037480 (Roche), U.S. Patent Application Publication No. 20130267517 (Roche), International Publication No. 2014131847 (Janssen), International Publication No. 2014033176 (Janssen), International Publication No. 2014033170 (Janssen), International Publication No. 2014033167 (Janssen), International Publication No. 2015 / 059212 (Janssen), International Publication No. 2015118057 (Janssen), International Publication No. 2015011281 (Janssen), International Publication No. 2014184365 (Janssen), International Publication No. 2014184350 (Janssen), International Publication No. 2014161888 (Janssen), International Publication 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. 20 Compounds described in US Patent Application Publication No. 20150259324 (Novira), US Patent Application Publication No. 20150132258 (Novira), US Patent No. 9181288 (Novira), International Publication No. 2014184350 (Janssen), International Publication No. 2013144129 (Roche), International Publication No. 2017198744 (Roche), US Patent Application Publication No. 20170334882 (Novira), US Patent Application Publication No. 20170334898 (Roche), International Publication No. 2017202798 (Roche), International Publication No. 2017214395 (Enanta), International Publication No. 2018001944 (Roche), International Publication No. 2018001952 (Roche), International Publication No. 2018005881 (Novira), International Publication No. 2018005883 (Novira), International Publication No. 2018011100 (Roche), International Publication No. 2018011160 (Roche), International Publication No. 2018011162 (Roche), International Publication No. 2018011163 (Roche), International Publication No. 2018036941 (Roche), International Publication No. 2018043747 (Kyoto Univ), US Patent Application Publication No. 20180065929 (Janssen), International Publication No. 2016168619 (Indiana University), International Publication No. 2016195982 (The Penn State Foundation), International Publication No. 2017001655 (Janssen), International Publication No. 2017048950 (Assembly Biosciences), International Publication No. 2017048954 (Assembly Biosciences), International Publication No. 2017048962 (Assembly Biosciences), US Patent Application Publication No. 20170121328 (Novira), US Patent Application Publication No. 20170121329 (Novira) are included, but not limited thereto.

[0273] Examples of transcription inhibitors include, but are not limited to, the compounds described below: WO 2017 / 013046 (Roche), WO 2017 / 016960 (Roche), WO 2017 / 017042 (Roche), WO 2017 / 017043 (Roche), WO 2017 / 061466 (Toyoma chemicals), WO 2016 / 177655 (Roche), WO 2016 / 161268 (Enanta), WO 2017 / 001853 (Redex Pharma), WO 2017 / 211791 (Roche), WO 2017 / 216685 (Novartis), WO 2017 / 216686 (Novartis), WO 2018 / 019297 (Ginkgo Pharma), WO 2018 / 022282 (Newave Pharma), US Patent Application Publication No. 2018 / 0030053 (Novartis), WO 2018 / 045911 (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 stimulants of NOD2 include, but are not limited to, SB-9200. Phosphatidylinositol 3-kinase (PI3K) inhibitor

[0276] Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, a Ruperisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584, copanlisib, CAI otolate, perifosine, RG-7666, GSK-2636771, DS-7423, panolisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, piraralisib, BAY-1082439, pexidartinib 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, boxalisib, and CLR-1401, among others, are included, but not limited to these. Inhibitor of the indoleamine-2,3-dioxygenase (IDO1) pathway

[0277] In various embodiments, the agents described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID 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 vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916. Recombinant thymosin α-1

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

[0279] Examples of BTK inhibitors include, but are not limited to, 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 Pharmaceutical), U.S. Patent Application Publication No. 20130079327 (Ono Pharmaceutical), and U.S. Patent Application Publication No. 20130217880 (Ono Pharmaceutical). KDM inhibitor

[0280] Examples of KDM5 inhibitors include, but are not limited to, the compounds described in International Publication No. 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140275092 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), 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 International Publication No. 2014164708 (Quanticel).

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

[0282] Examples of STING agonists include, but are not limited to, SB-11285, AdVCA0848, STINGVAX, and the compounds described in International Publication No. 2018 / 065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), International Publication No. 2018 / 009466 (Aduro Biotech), International Publication No. 2017 / 186711 (InvivoGen), International Publication No. 2017 / 161349 (Immune Sensor), International Publication No. 2017 / 106740 (Aduro Biotech), U.S. Patent Application Publication No. 2017 / 0158724 (Glaxo Smithkline), International Publication No. 2017 / 075477 (Aduro Biotech), U.S. Patent Application Publication No. 2017 / 0044206 (Merck), International Publication No. 2014 / 179760 (University of California), International Publication No. 2018 / 098203 (Janssen), International Publication No. 2018 / 118665 (Merck), International Publication No. 2018 / 118664 (Merck), International Publication No. 2018 / 100558 (Takeda), International Publication No. 2018 / 067423 (Merck), International Publication No. 2018 / 060323 (Boehringer). Non-nucleoside reverse transcriptase inhibitor (NNRTI)

[0283] Examples of NNRTIs include, but are not limited to, the compounds described in WO 2018 / 118826 (Merck), WO 2018 / 080903 (Merck), WO 2018 / 119013 (Merck), WO 2017 / 100108 (Idenix), WO 2017 / 027434 (Merck), WO 2017 / 007701 (Merck), and WO 2008 / 005555 (Gilead). HBV replication inhibitor

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

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

[0286] Gene therapy and cell therapy include gene modification to silence genes; genetic approaches to directly kill infected cells; replacement of most of the patient's own immune system to enhance the immune response against infected cells, or injection of immune cells designed to activate the patient's own immune system to kill or find and kill infected cells; and genetic approaches to modify cell activity to further alter the endogenous immune response to infection. Gene editor

[0287] Examples of genome editing systems include the CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system; for example, cccDNA elimination by targeted cleavage and hepatitis B virus (HBV) viral genes Modifying one or more of these is possible, but not limited thereto. Modifying the PreC, C, X, PreS1, PreS2, S, P, or SP gene (e.g., knockout and / or knockdown) means (1) reducing or eliminating PreC, C, X, PreS1, PreS2, S, P, or SP gene expression, (2) interfering with the function of precore, core, X protein, long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and / or hepatitis B splice protein (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and / or HBSP), or (3) reducing or eliminating the intracellular, serum, and / or parenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHB, Pol, and / or HBSP proteins. Knockdown of one or more of the PreC, C, X, PreS1, PreS2, S, P, and / or SP genes is performed by targeting the genes within HBV cccDNA and / or the genes integrated with HBV DNA. 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 that express an HBV-specific T cell receptor. The TCR-T cells are genetically engineered to target HBV-derived peptides (e.g., peptides presented by HLA / pMHC) 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 compound described herein or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and one or two additional therapeutic agents selected from immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies and bispecific antibodies comprising HBV antibodies targeting hepatitis B virus surface antigens including anti-HBsAg (small, medium, large), and "antibody-like" therapeutic proteins (e.g., DARTs (registered trademark), DUOBODIES (registered trademark), BITES (registered trademark), XmAbs (registered trademark), TandAbs (registered trademark), Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I-like receptors, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of NOD2, and one or two additional therapeutic agents selected from HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigens, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).

[0291] In another specific embodiment, the compound described herein or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and one or two additional therapeutic agents selected from immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies and bispecific antibodies comprising HBV antibodies targeting hepatitis B virus surface antigens including anti-HBsAg (small, medium, large), and "antibody-like" therapeutic proteins (e.g., DART (registered trademark), DUOBODIES (registered trademark), BITES (registered trademark), XmAbs (registered trademark), TandAbs (registered trademark), Fa It is combined with at least a second additional therapeutic agent selected from b derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I-like receptors, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO1 inhibitors, and stimulators of NOD2.

[0292] In another specific embodiment, the compounds or pharmaceutically acceptable salts thereof described herein are combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from an HBV virus entry inhibitor, an NTCP inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody targeting the surface antigen of hepatitis B virus including anti-HBsAg (small, medium, large), siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleotide protein modulators (HBV core or capsid protein inhibitors).

[0293] In certain embodiments, the compounds or pharmaceutically acceptable salts thereof described herein 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. 8722054 (Gilead Sciences), U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), International Publication No. 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. 8513184 (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 (Gilead(Sciences), US Patent Application Publication No. 20140275167 (Novira Therapeutics), US Patent Application Publication No. 20130251673 (Novira Therapeutics), US Patent Application Publication No. 2014 / 0343032 (Roche), International Publication No. 2014037480 (Roche), US Patent Application Publication No. 2013 / 0267517 (Roche), International Publication No. 2014131847 (Janssen), International Publication No. 2014033176 (Janssen), International Publication No. 2014033170 (Janssen), International Publication No. 2014033167 (Janssen), International Publication No. 2015 / 059212 (Janssen), International Publication No. 2015118057 (Janssen), International Publication No. 2015011281 (Janssen), International Publication No. 2014184365 (Janssen), International Publication No. 2014184350 (Janssen), International Publication No. 2014161888 (Janssen), International Publication No. 2013096744 (Novira), US Patent Application Publication No. 20150225355 (Novira), US Patent Application Publication No. 20140178337 (Novira), US Patent Application Publication No. 20150315159 (Novira), US Patent Application Publication No. 20150197533 (Novira), US Patent Application Publication No. 20150274652 (Novira), US Patent Application Publication No. 20150259324, (Novira), US Patent Application Publication No. 20150132258 (Novira), US Patent Application Publication 9181288 (Novira), International Publication No. 2014184350 (Janssen), International Publication No. 2013144129 (Roche), US Patent Application Publication No. 20100015178 (Incyte), US Patent Application Publication No. 2016137652 (Flexus Biosciences, Inc.), International Publication No. 2014073738 (Flexus Biosciences, Inc.), International Publication No. 2015188085 (Flexus Biosciences, Inc.), US Patent Application Publication No. 2014 / 0330015 (Ono Pharmaceutical), US Patent Application Publication No. 2013 / 0079327 (Ono Pharmaceutical), US Patent Application Publication No. 2013 / 0217880 (Ono pharmaceutical), International Publication No. 2016057924 (Genentech / Constellation Pharmaceuticals), US Patent Application Publication No. 20140275092 (Genentech / Constellation Compounds such as those described in U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), 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), International Publication No. 2014164708 (Quanticel), U.S. Patent No. 9186337 (B2) (Oryzon Genomics), and other drugs for treating HBV, and are combined with combinations thereof. Administration Route of administration

[0294] The compounds 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 suitable for the condition being 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 the suitable route may vary, for example, depending 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 are orally administrable and can be administered orally.

[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 administration of 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, a 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 a 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 over a desired period or duration, such as, for example, at least once a day, at least once a week, at least once a month, at least once every about 2 months, at least once every about 3 months, at least once every about 4 months, at least once every about 6 months, or at least once every about 12 months or more. In some embodiments, the compound is administered daily or on an 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 2 months. In some embodiments, the compound is administered every 3 months. In some embodiments, the compound is administered every 4 months. In some embodiments, the compound is administered every 5 months. In some embodiments, the compound is administered every 6 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 once per month. In some embodiments, the 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 once every about 2 months, or at least once every about 3 months, or at least once every about 4 months, or at least once every about 6 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 a subject at least once per month. 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 a subject at least once every about 2 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 a subject at least once every about 3 months.

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

[0300] In some embodiments, a compound (e.g., a compound of Formula I, II, III, IV, or V) or a pharmaceutically acceptable salt thereof disclosed herein 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, for example, a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, (1) before an event that exposes an individual to HIV (or increases the risk of an individual who would otherwise be HIV-infected), e.g., 2 hours, 1 day, 2 days, 5 days, or more than 7 days before the event; and / or (2) during an event that exposes an individual to HIV (or increases the risk of an individual who would otherwise be HIV-infected) (or an event that occurs repeatedly two or more times); and / or (3) after an event that exposes an individual to HIV (or increases the risk of an individual who would otherwise be HIV-infected) (or after the last event of a series of events that occur repeatedly). In some embodiments, event-driven administration is performed prior to the subject's exposure to HIV. In some embodiments, event-driven administration is performed after the subject's exposure to HIV. In some embodiments, event-driven administration is performed both prior to 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] Examples of event-driven dosing regimens include administering a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to HIV exposure (e.g., sexual activity including first sexual intercourse with a sex partner known to be HIV positive), then 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 activity with a sex partner known to be HIV positive), and then administering an additional dose of a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, after the final exposure (e.g., sexual activity with a sex partner known to be HIV positive), and then administering a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, one last time 24 hours after that.

[0305] Further examples of event-driven dosing regimens include administering 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 activity with a sex partner known to be HIV positive), administering daily during the exposure period (e.g., sexual activity with a sex partner known to be HIV positive including last sexual intercourse), and then administering a final dose approximately 24 hours after the final exposure (which may be an increased dose such as a double dose).

[0306] In certain embodiments, for example, 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, for example, 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 would increase the individual's risk of contracting HIV (e.g., before exposure to the HIV virus by sex or other means). In some embodiments, a 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 exposure to the HIV virus by sex or other means). In certain embodiments, when a 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., before the event), it is administered daily before the event (e.g., sexual activity). In certain embodiments, when a 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), 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, a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is administered daily during the HIV exposure period. In certain embodiments where a compound of formula I, II, III, IV, or V is administered prior to exposure, The compound of formula V, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., as a single dose) during the period of HIV exposure (e.g., during sexual intercourse 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 period of sexual intercourse with a sex partner known to be HIV-positive). In some embodiments, the administration is continued 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 hereby incorporated 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 the 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 the risk of contracting HIV is at least about 75%. In some embodiments, the reduction in the risk of contracting HIV is about 80%, about 85%, or about 90%. Formulation

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

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

[0313] In certain embodiments, the active ingredient (e.g., 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 formulation is administered subcutaneously to a subject. In certain embodiments, the formulation is administered intramuscularly to a subject.

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

[0316] In addition to the ingredients specifically described above, the compositions of these embodiments can include other agents conventional in the art with respect to the type of composition in question. For example, it should be understood that those suitable for oral administration can include flavoring agents. Kits and Manufactured Articles

[0317] Kits containing a compound of the present disclosure, or a mirror image isomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the foregoing are also included in the present disclosure. In one embodiment, the kit further includes instructions for use. In one aspect, the kit includes a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog, and a label and / or instructions for use of the compound in the treatment of indications such as the diseases or health disorders described herein. In one embodiment, a kit is provided that includes a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

[0318] Also provided herein are manufactured articles containing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog, in a suitable container. The container can be a vial, jar, ampule, prefilled syringe, implant, or drip 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 further comprise one, two, three, or four additional therapeutic agents as previously described herein. The kit may further comprise instructions for use, for example, for use in the inhibition of HIV integrase, such as in the treatment of HIV infection or AIDS, or for use as a research tool. The instructions for use are generally a written description, although an electronic storage medium (e.g., magnetic disk or optical disk) containing the description is also acceptable.

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

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

Table 1-1

Table 1-2

[0322] The following examples are provided for illustrative purposes only and not for limitation.

Example

[0323] General Scheme A

Chem.

Chem.

[0324] R 1 and R 2 Compounds of formula A in which are different can be prepared according to General Scheme B from PMPA, the intermediate of formula b, and the intermediate of formula b (R 1 ≠R 2It can be prepared in one step from an alcohol different from that used to prepare 1 and R 2 This can be done by obtaining a compound of formula A where R General Scheme C

Chemical formula

[0325] The compound of formula C can be prepared in one step from the compound of formula A according to General Scheme C. The compound of formula A can be mixed with an anhydride and pyridine to obtain the compound of formula C. Alternatively, the compound of formula A can be mixed with an acid chloride and pyridine to obtain the compound of formula C. Alternatively, the compound of formula A can be mixed with a carboxylic acid, EDCI, DMAP and ACN to obtain the compound of formula C. R A is defined by R 1 when L 8 is -C(O)-. General Scheme D

Chemical formula

[0326] The compound of formula D can be prepared in three steps from the compound of formula A according to General Scheme D (this is done in addition to the one-step preparation according to General Scheme C using the appropriate R A ). The compound of formula A can be mixed with a 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 alkylated by mixing with an alkyl halide defined by R 8a , sodium iodide, potassium carbonate and DMF to obtain the compound of formula D. General Scheme E

Chem.

[0327] The compound of formula E can be prepared in one step from the compound of formula A according to General Scheme E. The compound of formula A can be mixed with chloroformate and pyridine to obtain the compound of formula E. Alternatively, the compound of formula A can be mixed with alcohol, triphosgene, DMAP and DCM to obtain the compound of formula E. L 1 When L is -C(O)O-, R B is R 8 defined by General Scheme F

Chem.

[0328] The compounds of formula F-1, F-2 and F-3 can be prepared in one step from the compound of formula A according to General Scheme F. The compound of formula A can be mixed with the alkyl halide defined by R 8a , cesium carbonate and DMF to obtain the compounds of formula F-1, F-2 and F-3. Alternatively, the compound of formula A can be mixed with the alkyl halide defined by R 8a , potassium bicarbonate and NMP to obtain the 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)

Chem.

[0329] A suspension of 2-amino-2-methyl-propanoic acid (5 g, 48.5 mmol) in 1-hexanol (49.5 g, 485 mmol) was added with thionyl chloride (7.07 mL, 97 mmol) in a sealed tube under an argon atmosphere at 5 °C over 10 minutes. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was heated to 90 °C for 16 hours. The reaction mixture was cooled to room temperature and the reaction was 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 obtain Intermediate 1a. 1 H 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).

Chemical formula

[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'-dipyridyldisulfide (307 mg, 1.39 mmol) and triethylamine (0.38 mL, 2.79 mmol) were combined in pyridine (2 mL) under argon. The reaction mixture 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 saturated aqueous sodium bicarbonate (5 mL×2), water (5 mL) and dried over sodium sulfate. After removing the desiccant, 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 solution containing the product was concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110Å 100×30 mm column, gradient of 25% to 100% acetonitrile in water over 30 min) to give the title compound (1). 1 H NMR (400 MHz, 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 = 6.2 Hz, 3H), 0.84 (td, J = 6.9, 2.1 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 18.41 (t, J = 10.2 Hz). 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 containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: At 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 containing 0.1% TFA, water containing 0.1% TFA; Gradient: At 2 mL / min, 0 min - 5.0 min 2 - 98% ACN, 5.0 min - 6.0 min 98% ACN. 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) [Chemical formula] Synthesis of 2-ethylbutyl 2-amino-2-methylpropanoate hydrochloride (2a)

[0331] Thionyl chloride (28.3 mL, 388 mmol) was added to a suspension of 2-amino-2-methyl-propanoic acid (20 g, 194 mmol) in 2-ethylbutan-1-ol (85.3 g, 835 mmol) at 5 °C over 10 minutes in a sealed tube under an argon atmosphere. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was heated to 90 °C for 16 hours. The reaction mixture was cooled to room temperature and the reaction was 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 obtain intermediate 2a. 11H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 3H), 4.08 (d, J = 5.5 Hz, 2H), 1.49 (s, 7H), 1.33 (p, J = 7.3 Hz, 4H), 0.86 (t, J = 7.5 Hz, 6H). [Chemical formula]

[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'-dipyridyldisulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (2). 1 1H NMR (400 MHz, 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 = 6.2 Hz, 3H), 0.83 (td, J = 7.4, 3.3 Hz, 12H). 31 31P NMR (162 MHz, DMSO-d6) δ 18.43 (t, J = 10.2 Hz). LCMS: MS m / z = 626.38 [M+1], t R= 1.74 minutes; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: at 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 minutes; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: at 2 mL / min, 0 min - 5.0 min 2 - 98% ACN, 5.0 min - 6.0 min 98% ACN. 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)

Chemical formula

[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), thionyl chloride (28.3 mL, 38.8 mmol) was added dropwise at 5 °C for 10 minutes in a sealed tube under an argon atmosphere. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was heated to 90 °C for 16 hours. The reaction mixture 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 obtain intermediate 3a. 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 3H), 7.46 - 7.33 (m, 5H), 5.26 (s, 2H), 1.49 (s, 6H). [Chem.]

[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'-dipyridyldisulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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 C18-110Å 100×30 mm column, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (3). 1 H NMR (400 MHz, 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 = 6.2 Hz, 3H). 31 P NMR (162 MHz, DMSO-d6) δ 18.71 (t, J = 9.2 Hz). 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 containing 0.1% acetic acid, 0.1% ace Water containing acid; gradient: 2 μL / min, 2 - 100% acetonitrile from 0 min to 2.0 min, 100% acetonitrile from 2.0 min to 3.05 min, 100% - 2% acetonitrile from 3.05 min to 3.2 min, 2% ACN from 3.2 min to 3.5 min. HPLC: t R = 2.91 min; HPLC system: Agilent 1100 series; column: Gemini 5μ C18 110A, 50×4.6 mm; solvents: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 2 mL / min, 2 - 98% ACN from 0 min to 5.0 min, 98% ACN from 5.0 min to 6.0 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)

Chem.

[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), thionyl chloride (28.3 mL, 38.8 mmol) was added dropwise at 5 °C over 10 min under an argon atmosphere in a sealed tube. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture 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 obtain intermediate 4a. 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 3H), 4.17 (t, J = 6.5 Hz, 2H), 1.68 - 1.57 (m, 2H), 1.48 (s, 6H), 1.36 - 1.28 (m, 4H), 0.92 - 0.86 (m, 3H).

Chem.

[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'-dipyridyldisulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (4). 1 H NMR (400 MHz, 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 = 6.7 Hz, 4H), 1.45 - 1.35 (m, 12H), 1.27 (p, J = 3.6 Hz, 8H), 1.06 (d, J = 6.2 Hz, 3H), 0.90 - 0.79 (m, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 18.43 (t, J = 10.1 Hz). 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 containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: at 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 containing 0.1% TFA, water containing 0.1% TFA; Gradient: at 2 mL / min, 0 min - 5.0 min 2 - 98% ACN, 5.0 min - 6.0 min 98% ACN. 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)

Chemical formula

[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), thionyl chloride (2.83 mL, 38.8 mmol) was added dropwise at 5 °C over 10 min under an argon atmosphere in a sealed tube. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture 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. 11H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 3H), 3.88 (s, 2H), 1.51 (s, 6H), 0.94 (s, 9H).

Chem.

[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'-dipyridyldisulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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 C18-110Å 100×30 mm column, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (5). 1 1H NMR (400 MHz, 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 = 6.2 Hz, 3H), 0.89 (d, J = 5.1 Hz, 18H). 31 31P NMR (162 MHz, DMSO-d6) δ 18.52 - 18.37 (m). LCMS: MS m / z = 589.12 [M+1], t R= 1.57 minutes; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: at 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 minutes; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: at 2 mL / min, 0 min - 5.0 min 2 - 98% ACN, 5.0 min - 6.0 min 98% ACN. 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)

Chemical Structure

[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), thionyl chloride (2.83 mL, 38.8 mmol) was added dropwise at 5 °C over 10 minutes under an argon atmosphere in a sealed tube. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was heated to 90 °C for 16 hours. The reaction mixture 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 obtain intermediate 6a. 11H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.54 (m, 3H), 4.20 (t, J = 6.7 Hz, 2H), 1.75 - 1.62 (m, 1H), 1.52 (q, J = 6.7 Hz, 2H), 1.48 (s, 6H), 0.90 (d, J = 6.6 Hz, 6H).

Chem.

[0340] PMPA (100 mg, 0.35 mmol) and intermediate 6a (219 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (6). 1 1H NMR (400 MHz, 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 = 6.3 Hz, 3H), 0.89 - 0.84 (m, 12H). 31 31P NMR (162 MHz, 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 containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: at 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 containing 0.1% TFA, water containing 0.1% TFA; Gradient: at 2 mL / min, 0 min - 5.0 min 2 - 98% ACN, 5.0 min - 6.0 min 98% ACN. 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)

Chemical formula

[0341] 2-Amino-2-methyl-propanoic acid (2 g, 9.84 mmo in DCM (50 mL) (l) To a solution of 3-ethylpentan-1-ol (1.37 g, 11.8 mmol) and HATU (2.34 g, 9.84 mmol), TEA (5.37 mL, 39.4 mmol) was added, 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 4N HCl (48.5 mL, 194 mmol) in dioxane. 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 (400 MHz, DMSO-d6) δ 8.57 (s, 3H), 4.20 (t, J = 6.8 Hz, 2H), 1.61 - 1.54 (m, 2H), 1.48 (s, 5H), 1.35 - 1.26 (m, 6H), 0.87 - 0.81 (m, 6H). [Chemical formula]

[0342] PMPA (100 mg, 0.35 mmol) and intermediate 7b (335 mg, 1.41 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 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, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (7). 1 1H NMR (400 MHz, 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 = 6.2 Hz, 3H), 0.83 - 0.77 (m, 12H). 31 31P NMR (162 MHz, DMSO-d6) δ 18.44 (t, J = 9.6 Hz). LCMS: MS m / z = 654.17 [M+1], t R= 1.92 minutes; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: at 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 minutes; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: at 2 mL / min, 0 min - 5.0 min 2 - 98% ACN, 5.0 min - 6.0 min 98% ACN. 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)

Chemical formula

[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 4N HCl (19.4 mL, 77.6 mmol) in dioxane under an argon atmosphere in a sealed tube. The reaction mixture was heated to 90 °C for 16 hours. The reaction mixture 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 obtain intermediate 8a. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 3H), 4.23 (t, J = 7.1 Hz, 2H), 1.56 (t, J = 7.1 Hz, 2H), 1.46 (s, 6H), 0.93 (s, 9H).

Chemical formula

[0344] PMPA (100 mg, 0.35 mmol) and intermediate 8a (315 mg, 1.41 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (8). 1 H NMR (400 MHz, 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 = 7.2 Hz, 4H), 1.45 - 1.34 (m, 12H), 1.06 (d, J = 6.2 Hz, 3H), 0.89 (d, J = 3.7 Hz, 18H). 31 P NMR (162 MHz, DMSO-d6) δ 18.47 (t, J = 9.6 Hz). 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: Kinete x 2.6μ XB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: At 2 μL / min, from 0 min to 2.0 min, 2 - 100% acetonitrile, from 2.0 min to 3.05 min, 100% acetonitrile, from 3.05 min to 3.2 min, 100% - 2% acetonitrile, from 3.2 min to 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 containing 0.1% TFA, water containing 0.1% TFA; Gradient: At 2 mL / min, from 0 min to 5.0 min, 2 - 98% ACN, from 5.0 min to 6.0 min, 98% ACN. 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) [Chemical formula]

[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 twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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 C18-110Å 100×30 mm column, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (9). 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.13 (s, 1H), 7.17 (s, 2H), 4.29 (dd, J = 14.3, 3.8 Hz, 1H), 4.18 (dd, J = 14.4, 6.0 Hz, 1H), 4.12 (d, J = 10.6 Hz, 1H), 4.02 (d, J = 10.6 Hz, 1H), 3.98 - 3.92 (m, 1H), 1.45 - 1.30 (m, 30H), 1.07 (d, J = 6.3 Hz, 3H). 31 P NMR (162 MHz, 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 containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: At 2 μL / min, 2 - 100% acetonitrile from 0 min to 2.0 min, 100% acetonitrile from 2.0 min to 3.05 min, 100% - 2% acetonitrile from 3.05 min to 3.2 min, 2% ACN from 3.2 min to 3.5 min. HPLC: t R = 2.86 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: At 2 mL / min, 2 - 98% ACN from 0 min to 5.0 min, 98% ACN from 5.0 min to 6.0 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)

Chemical formula

[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 4N HCl (5.58 mL, 22.3 mmol) in dioxane under an argon atmosphere in a sealed tube. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture 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 obtain intermediate 10a. 1 H NMR (400 MHz, DMSO-d6) δ 4.02 (t, J = 6.5 Hz, 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 = 7.5 Hz, 3H). [Chem.]

[0347] PMPA (100 mg, 0.35 mmol) and intermediate 10a (248 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (10). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.24 (s, 1H), 8.04 (s, 1H), 6.14 (s, 2H), 4.33 (dd, J = 14.5, 3.3 Hz, 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 = 6.3 Hz, 3H), 0.95 - 0.87 (m, 6H), 0.83 (t, J = 7.4 Hz, 30H), 0.78 (t, J = 7.4 Hz, 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 cis Item: Agilent 1260 Infinity II HPLC; MS System: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50mm×2.1mm; Solvent: Acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: At 2 μL / min, 10% - 100% acetonitrile from 0 to 1.00 minutes, 100% acetonitrile from 1.00 to 1.35 minutes, 100 - 10% acetonitrile from 1.35 to 1.36 minutes. HPLC: t R = 3.55 minutes; HPLC System: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50×4.6mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: At 2 mL / min, 2 - 98% ACN from 0 minutes to 5.0 minutes, 98% ACN from 5.0 minutes to 6.0 minutes. 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)

Chemical Structure

[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 4N HCl (5.58 mL, 22.3 mmol) in dioxane in a sealed tube under an argon atmosphere. The reaction mixture was heated to 90 °C for 16 hours. The reaction mixture 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 obtain intermediate 11a. 11H NMR (400 MHz, 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 = 12.9 Hz, 1H), 2.76 (d, J = 12.9 Hz, 1H), 1.59 - 1.50 (m, 2H), 1.31 - 1.24 (m, 6H), 1.22 (s, 3H), 0.90 - 0.83 (m, 3H).

Chem.

[0349] PMPA (100 mg, 0.35 mmol) and intermediate 11a (275 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature, 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 organic matter was concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18 - 110 Å 100×30 mm column, gradient of 25% - 100% acetonitrile in water over 30 min) to obtain the title compound (11). 1 1H NMR (400 MHz, 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 = 8.7 Hz, 2H), 3.11 - 2.87 (m, 4H), 1.55 - 1.39 (m, 10H), 1.27 - 1.14 (m, 12H), 0.97 (d, J = 6.3 Hz, 3H), 0.86 - 0.78 (m, 6H).31 1H NMR (162 MHz, 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, 50 mm × 2.1 mm; solvent: acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; gradient: at 2 μL / min, 10% - 100% acetonitrile from 0 to 1.00 min, 100% acetonitrile from 1.00 to 1.35 min, 100 - 10% acetonitrile from 1.35 to 1.36 min. HPLC: t R = 3.86 min; HPLC system: Agilent 1100 series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 2 mL / min, 2 - 98% ACN from 0 min to 5.0 min, 98% ACN from 5.0 min to 6.0 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).

Chemical formula

[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), TEA (5.37 mL, 39.4 mmol) was added, 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 4N HCl (48.5 mL, 194 mmol) in dioxane. 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 (400 MHz, 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).

Chemical Structure

[0351] PMPA (100 mg, 0.35 mmol) and intermediate 12b (290 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 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 C18-110Å 100×30 mm column, 30 min gradient of 25% - 100% acetonitrile in water) to give the title compound (12). 1 H NMR (400 MHz, 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, 3.8 Hz, 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 (162 MHz, DMSO-d6) δ 18.27 (t, J = 9.5 Hz). 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 containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: at 2 μL / min, from 0 min to 2.0 min, 2 to 100% acetonitrile, from 2.0 min to 3.05 min, 100% acetonitrile, from 3.05 min to 3.2 min, 100% to 2% acetonitrile, from 3.2 min to 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 containing 0.1% TFA, water containing 0.1% TFA; Gradient: at 2 mL / min, from 0 min to 5.0 min, 2 to 98% ACN, from 5.0 min to 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)

Chemical formula

[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 4N HCl (9.7 mL, 38.8 mmol) in dioxane under an argon atmosphere in a sealed tube. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture 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 obtain intermediate 13a. 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 3H), 4.04 (d, J = 6.0 Hz, 2H), 1.61 - 1.41 (m, 10H), 1.40 - 1.31 (m, 2H), 1.25 - 1.08 (m, 3H), 0.88 (d, J = 11.2 Hz, 6H).

Chemical formula

[0353] PMPA (100 mg, 0.35 mmol) and intermediate 13a (276 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 minutes under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture 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 organic matter was concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini, 5 μm C18-110Å 100×30 mm column, gradient of 25% - 100% acetonitrile in water over 30 minutes) to obtain the title compound (13). 1 H NMR (400 MHz, 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 = 7.1 Hz, 8H), 1.06 (d, J = 6.2 Hz, 3H), 0.87 (d, J = 2.2 Hz, 6H), 0.84 (d, J = 2.4 Hz, 6H). 31 P NMR (162 MHz, DMSO-d6) δ 18.35 (t, J = 9.7 Hz). 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 containing 0.1% TFA, water containing 0.1% TFA; Gradient: at 2 mL / min, 2 - 98% ACN from 0 min to 5.0 min, 98% ACN from 5.0 min to 6.0 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)

Chemical formula

[0354] 2 - Amino - 2 - methyl - propanoic acid (1 g, 9.7 mmol) and 2 - cyclohexylethanol (3.73 g, 29.1 mmol) were dissolved in 4N HCl (9.7 mL, 38.8 mmol) in dioxane under an argon atmosphere in a sealed tube. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture 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 obtain intermediate 14a. 1 H NMR (400 MHz, DMSO - d6) δ 8.64 (s, 3H), 4.20 (t, J = 6.7 Hz, 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).

Chemical formula

[0355] PMPA (100 mg, 0.35 mmol) and Intermediate 14a (223 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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, gradient of 25% - 100% acetonitrile in water over 30 min) to give the title compound (14). 1 H NMR (400 MHz, 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, 10 H), 1.51 - 1.27 (m, 18H), 1.24 - 1.11 (m, 6H), 1.07 (d, J = 6.3 Hz, 3H), 0.96 - 0.82 (m, 4H). 31 P NMR (162 MHz, DMSO-d6) δ 18.43 (t, J = 9.7 Hz). 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, 50 mm × 2.1 mm; Solvent: Acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: At 2 μL / min, 10% - 100% acetonitrile from 0 to 1.00 min, 100% acetonitrile from 1.00 to 1.35 min, 100 - 10% acetonitrile from 1.35 to 1.36 min. HPLC: t R = 3.34 min; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50 × 4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: At 2 mL / min, 2 - 98% ACN from 0 min to 5.0 min, 98% ACN from 5.0 min to 6.0 min. Example 15: Bis(cyclohexylmethyl) 2,2’ - ((((R)-1-(6 - amino - 9H - purin - 9 - yl)propan - 2 - yloxy)methyl)phosphoryl)bis(azanediyl))(2S,2’S)-bis(2 - methyl - 3 - phenylpropanoate) (15) [Chemical formula] 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 4N HCl (5.58 mL, 22.3 mmol) in dioxane in a sealed tube under an argon atmosphere. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture 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 obtain intermediate 15a. 11H NMR (400 MHz, 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, 6.2 Hz, 1H), 3.87 (dd, J = 10.6, 6.1 Hz, 1H), 3.15 (s, 2H), 1.72 - 1.46 (m, 9H), 1.27 - 1.09 (m, 3H), 1.03 - 0.85 (m, 2H).

Chem.

[0357] PMPA (100 mg, 0.35 mmol) and intermediate 15a (326 mg, 1.04 mmol) were suspended in 2 mL of toluene and concentrated twice under reduced pressure. Pyridine (1 mL) and triethylamine (0.38 mL, 2.79 mmol) were added, and the reaction mixture was heated to 70 °C for 5 min under an argon atmosphere. A solution of triphenylphosphine (457 mg, 1.74 mmol) and 2,2'-dipyridyldisulfide (384 mg, 1.74 mmol) in pyridine (1 mL) was added. The reaction mixture was stirred at 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 saturated aqueous sodium bicarbonate (5 mL × 2) and 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, gradient of 25% - 100% acetonitrile in water over 30 min) to obtain the title compound (15). 11H NMR (400 MHz, 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, 3.4 Hz, 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 = 6.2 Hz, 3H), 1.04 - 0.87 (m, 4H). 31 31P 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: LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; column: Kinetix 2.6u C18 100A, 50 mm × 2.1 mm; solvent: acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; gradient: at 2 μL / min, 10% - 100% acetonitrile from 0 to 1.00 min, 100% acetonitrile from 1.00 to 1.35 min, 100 - 10% acetonitrile from 1.35 to 1.36 min. HPLC: t R = 3.34 min; HPLC system: Agilent 1100 series; column: Gemini 5μ C18 110A, 50 × 4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 2 mL / min, 2 - 98% ACN from 0 min to 5.0 min, 98% ACN from 5.0 min to 6.0 min. 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] (1R,2R)-1-((tert-butoxycarbonyl)amino)-2-ethylcyclopropane-1-carboxylic acid (1.0 g, 4.36 mmHg) in acetonitrile (30 mL). To a mixture of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (813 mg, 5.234 mmol), n-hexanol (0.82 mL, 6.542 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (813 mg, 5.234 mmol) 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 under vacuum. The resulting residue was purified by silica gel column chromatography (0-70% 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 slowly added 4M HCl in dioxane (1.9 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h, concentrated in vacuo, co-evaporated several times with DCM, and dried under high vacuum for 15 h 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).

Chemical Structure

[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'-dipyridyldisulfide (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 h, concentrated in vacuo, and purified by silica gel column chromatography (0 - 15% MeOH in DCM) to give a mixture of products, which was separated by preparative HPLC (35% - 90% ACN containing 0.1% TFA in water containing 0.1% TFA). Each compound was dissolved in ACN (3 mL), and triethylamine (3 drops) was added to form the free form, and re-purified by normal phase HPLC (10 - 100% ACN in water for 12 min, 100% ACN for 5 min) to give 16 and 17. ol) was added. The reaction mixture was stirred at 90 °C for 18 h, concentrated in vacuo, and purified by silica gel column chromatography (0 - 15% MeOH in DCM) to give a mixture of products, which was separated by preparative HPLC (35% - 90% ACN containing 0.1% TFA in water containing 0.1% TFA). Each compound was dissolved in ACN (3 mL), and triethylamine (3 drops) was added to form the free form, and re-purified by normal phase HPLC (10 - 100% ACN in water for 12 min, 100% ACN for 5 min) to give 16 and 17.

[0361] 16: 11H 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 31P 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 2.6 μ XB-C18 100A, 50 × 3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 6.64 min (45%) and 6.68 min (55%); HPLC system: 1290 Infinity II.; column: Phenomenex 2.6 μ C18 100A, 100 × 4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 min.

[0362] 17: 1 1H NMR (400 MHz, acetonitrile-d3) δ 8.23 (s, 1H), 8.03 (s, 1H), 6.07 (s, 2H), 4.35 (dd, J = 14.5, 3.2 Hz, 1H), 4.21 - 4.07 (m, 4H), 4.08 - 3.84 (m, 4H), 3.73 (dd, J = 12.7, 8.4 Hz, 1H), 3.51 (dd, J = 12.6, 10.1 Hz, 1H), 1.72 - 1.09 (m, 26H), 0.98 - 0.84 (m, 12H). 311H 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 2.6 μ XB-C18 100A, 50 × 3.0 mm; solvents: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 6.81 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6 μ C18 100A, 100 × 4.6 mm; solvents: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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) [Chemical formula] 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 slowly added 4 M HCl in dioxane (6.5 mL, 26.06 mmol) at room temperature. The resulting mixture was heated at 80 °C for 15 h and concentrated at 65 °C under high vacuum. The solid residue was triturated with ether, the filter cake was washed with ether and dried under high vacuum for 15 h 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). [Chemical formula] [Chemical formula]

[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 containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: At 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. H PLC: t R = 6.50 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6μ C18 100A, 100×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: At 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 min.

[0366] 19: 1 1H NMR (400 MHz, acetonitrile-d3) δ 8.22 (s, 1H), 8.04 (s, 1H), 6.23 (s, 2H), 4.34 (dd, J = 14.5, 3.2 Hz, 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, 10.2 Hz, 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 = 6.2 Hz, 3H), 0.98 - 0.85 (m, 6H). 31 31P 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 containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: At 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R=6.56 minutes; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6μ C18 100A, 100×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chemical Structure

[0367] The intermediate 20a was obtained from 1 - aminocyclopropane - 1 - carboxylic acid by the same 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).

Chemical Structure

[0368] A mixture of PMPA (170 mg, 0.59 mmol), Intermediate 1a (199 mg, 0.89 mmol), 2,2'-dipyridyldisulfide (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 (12 min with 10 - 100% ACN in water and 5 min with 100% ACN) to afford 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; solvents: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. 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; solvents: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chem.

[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 hours, quenched with water, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (0 - 70% EtOAc in hexane) to give the 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).

Chem.

[0370] To a mixture of Intermediate 21a (451 mg, 1.28 mmol) in DCM (10 mL), 4M HCl in dioxane (1.6 mL) was slowly added at room temperature. The resulting mixture was stirred at room temperature for 15 h, concentrated in vacuo, co-evaporated several times with DCM, and dried under high vacuum for 15 h to obtain 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).

Chemical Structure

[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 (MeOH 0 - 15% in DCM) to obtain a mixture of two products, which was separated by preparative HPLC (ACN 10 - 100% in water for 12 min, 100% for 5 min) to obtain 21 and 22.

[0372] 21: 11H NMR (400 MHz, 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, 3.2 Hz, 1H), 4.17 (dd, J = 14.5, 7.1 Hz, 1H), 3.94 (m, 1H), 3.77 - 3.62 (m, 2H), 3.55 (d, J = 10.7 Hz, 1H), 3.47 (dd, J = 12.6, 9.8 Hz, 1H), 2.18 (m, 2H), 2.10 - 1.89 (m, 8H), 1.57 - 1.27 (m, 20H), 1.19 (d, J = 6.2 Hz, 3H). 31 31P 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 2.6 μ XB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 6.12 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6 μ C18 100A, 100×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 min.

[0373] 22: 1 1H 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]; t 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 containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 6.25 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6μ C18 100A, 100×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chemical Structure

[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 under vacuum. The resulting residue was purified by silica gel column chromatography (0 - 50% EtOAc in hexane) to afford 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).

Chemical Structure

[0375] To a mixture of intermediate 23a (490 mg, 1.71 mmol) in DCM (10 mL) was slowly added 4M HCl in dioxane (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 15 h, concentrated in vacuo, co-evaporated several times with DCM, and dried under high vacuum for 15 h to afford 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).

Chemical Structure

[0376] To a mixture of L-phenylalanine (2.5 g, 15.1 mmol) and n-hexanol (30 mL), SOCl2 (4.4 mL, 60.5 mmol) was slowly added at room temperature. The resulting mixture was heated at 80 °C for 15 h and concentrated at 65 °C under high vacuum. 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 h to obtain Intermediate 23c. 1 H NMR (400 MHz, methanol-d4) δ 7.42 - 7.29 (m, 3H), 7.28 - 7.22 (m, 2H), 4.29 (t, J = 7.0 Hz, 1H), 4.17 (m, 2H), 3.21 (m, 2H), 1.58 (m, 2H), 1.35 - 1.25 (m, 6H), 0.91 (t, J = 6.85 Hz, 3H).

Chemical Structure

Chemical Structure

[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'-dipyridyldisulfide (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 min. Intermediate 23c (299 mg, 1.04 mmol) in pyridine (0.5 mL) was added. The mixture was heated at 8 0 °C for 3 h, concentrated in vacuo, and purified by silica gel chromatography (MeOH in DCM 0 - 25%) into two products, which were further purified by HPLC (for 23, 12 min with ACN in water 10 - 100%, 5 min with 100% ACN, and for 24, 17 min with ACN in water 10 - 100%) to obtain 23 and 24.

[0378] 23: 1 1H NMR (400 MHz, 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), 4.89 (m, 1H), 4.39 - 3.95 (m, 4H), 3.94 - 3.68 (m, 4H), 3.61 (dd, J = 12.8, 8.8 Hz, 0.5H), 3.54 - 3.41 (m, 3.5H), 3.24 (dd, J = 12.7, 10.4 Hz, 0.5H), 3.15 (d, J = 11.3 Hz, 0.5H), 3.06 - 2.90 (m, 1.5H), 2.82 (dd, J = 13.5, 8.1 Hz, 0.5H), 1.92 - 1.77 (m, 2H), 1.65 - 1.46 (m, 4H), 1.43 - 1.19 (m, 12H), 1.11 (t, J = 6.0 Hz, 3H), 0.92 - 0.83 (m, 3H). 31 31P 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 2.6 μ XB-C18 100A, 50 × 3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 5.57 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6 μ C18 100A, 100 × 4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 min.

[0379] 24: 11H 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, 3.3 Hz, 1H), 4.17 (dd, J = 14.5, 7.1 Hz, 1H), 3.94 (m, 1H), 3.82 (dt, J = 10.6, 5.7 Hz, 4H), 3.75 (d, J = 10.7 Hz, 1H), 3.67 (dd, J = 12.7, 8.8 Hz, 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 = 6.2 Hz, 3H). 31 31P 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 2.6 μ XB-C18 100A, 50 × 3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 3.81 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6 μ C18 100A, 100 × 4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chemical formula

[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), SOCl2 (0.72 mL, 9.89 mmol) was slowly added at room temperature. The resulting mixture was heated at 80 °C for 15 h and concentrated at 70 °C under high vacuum. Hexane was added to the obtained residue, and the mixture was stirred for 30 min. The precipitated solid was filtered. The filter cake was washed several times with ether and dried under high vacuum for 15 h to obtain 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.

Chemical Structure

[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 several times with nitrogen gas, 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 (MeOH 0 - 20% in DCM) and preparative HPLC (ACN 10 - 100% in water for 12 min and ACN 100% for 5 min) to obtain the title compound (25). 11H NMR (400 MHz, acetonitrile-d3) δ 8.24 (s, 1H), 8.06 (s, 1H), 6.15 (s, 2H), 4.34 (dd, J = 14.4, 3.2 Hz, 1H), 4.22 - 4.03 (m, 5H), 3.94 (m, 1H), 3.77 - 3.61 (m, 2H), 3.56 (d, J = 10.6 Hz, 1H), 3.44 (dd, J = 12.7, 9.8 Hz, 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 = 6.3 Hz, 3H). 19 19F NMR (376 MHz, acetonitrile-d3) δ -67.52 (d, J = 5.3 Hz). 31 31P NMR (162 MHz, acetonitrile-d3) δ 17.83. LCMS: MS m / z = 706.31 [M+1]; t R = 1.57 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6 μ XB-C18 100A, 50 × 3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 5.53 min; HPLC system: 1290 Infinity II. ; column: Phenomenex 2.6 μ C18 100A, 100 × 4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chemical Structure

[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 - 70% EtOAc in hexane) to give intermediate 26a. 1 H 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]; t 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; solvents: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min.

Chemical Structure

[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 h, concentrated in vacuo, co-evaporated with DCM several times, suspended in ether, stirred for 5 min, and filtered. The filter cake was washed several times with ether and dried under high vacuum for 15 h 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), 1.7 4 - 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 2.6 μ XB-C18 100A, 50 × 3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min.

Chemical formula

[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 several times with nitrogen 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, co-evaporated with toluene several times, and produced by silica gel chromatography (0 - 20% MeOH in DCM) and preparative HPLC (12 min with 10 - 100% ACN in water and 5 min with 100% ACN) to give the title compound (26).1 1H NMR (400 MHz, 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, 3.2 Hz, 1H), 4.17 (dd, J = 14.5, 7.3 Hz, 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 = 6.2 Hz, 3H). 19 19F NMR (376 MHz, acetonitrile-d3) δ -74.27. 31 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 containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 5.50 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6μ C18 100A, 100×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chemical Structure

[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 h, 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 - 70% hexane 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, 22H), 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 2.6 μ XB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min.

Chemical formula

[0386] Intermediate 27a (1.46 g, 4.46 mmol) in DCM (10 mL) and 4 M HCl in dioxane (6 mL) were slowly added at room temperature. The resulting mixture was stirred at room temperature for 4 h, concentrated in vacuo, co-evaporated with DCM several times, suspended in ether, stirred for 5 min, and filtered. The filter cake was washed several times with ether and dried under high vacuum for 15 h to give Intermediate 27b. 1 H NMR (400 MHz, 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 = 7.2 Hz, 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 2.6 μ XB-C18 100A, 50×3.0 mm; solvents: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gra dient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. [Chemical formula]

[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 several times with nitrogen 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, co-evaporated with toluene several times, and purified by silica gel (0 - 15% MeOH in DCM) to give the title compound (27). 11H 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, 3.2 Hz, 1H), 4.17 (dd, J = 14.5, 7.0 Hz, 1H), 3.94 (m, 1H), 3.74 (d, J = 10.6 Hz, 1H), 3.66 (dd, J = 12.7, 8.9 Hz, 1H), 3.55 (d, J = 10.7 Hz, 1H), 3.46 (dd, J = 12.6, 9.8 Hz, 1H), 1.96 - 1.87 (m, 4H), 1.85 - 1.72 (m, 4H), 1.57 - 0.95 (m, 33H), 0.91 (t, J = 7.3 Hz, 6H). 31 31P 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 2.6 μ XB-C18 100A, 50 × 3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 7.84 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6 μ C18 100A, 100 × 4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chemical Structure

[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 (8 min with 10 - 100% ACN in water and 18 min with 100% ACN) to give the title compound (28). 1 H NMR (400 MHz, acetonitrile - d3) δ 9.13 (s, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 4.43 (dd, J = 14.5, 3.2 Hz, 1H), 4.26 (dd, J = 14.5, 7.1 Hz, 1H), 4.17 - 4.01 (m, 4H), 3.97 (m, 1H), 3.75 (d, J = 10.8 Hz, 1H), 3.69 (dd, J = 12.8, 8.6 Hz, 1H), 3.59 (d, J = 10.8 Hz, 1H), 3.45 (dd, J = 12.7, 9.8 Hz, 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 = 6.3 Hz, 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 containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 6.66 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6μ C18 100A, 100×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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) [Chemical formula]

[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 hours and purified by preparative HPLC (8 minutes with 10 - 100% ACN in water and 15 minutes with 100% ACN) to obtain the title compound (29). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.98 (s, 1H), 8.61 (s, 1H), 8.32 (s, 1H), 4.43 (dd, J = 14.5, 3.1 Hz, 1H), 4.25 (dd, J = 14.5, 7.2 Hz, 1H), 4.17 - 4.01 (m, 4H), 3.96 (m, 1H), 3.78 - 3.64 (m, 2H), 3.57 (d, J = 10.8 Hz, 1H), 3.44 (dd, J = 12.7, 9.9 Hz, 1H), 2.77 (t, J = 7.4 Hz, 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 = 6.2 Hz, 3H), 1.02 (t, J = 7.4 Hz, 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 containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: At 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 7.02 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6μ C18 100A, 100×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: At 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chem.

[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 adding methanol, concentrated in vacuo, and purified by silica gel chromatography (0 - 15% MeOH in DCM) to afford the title compound (30). 11H 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, 9.9 Hz, 1H), 2.78 (t, J = 7.5 Hz, 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 = 6.2 Hz, 3H), 0.93 - 0.83 (m, 9H). 31 31P 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 2.6 μ C18 100A, 50 × 3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: at 1100 μL / min, 40% acetonitrile from 0 min to 0.2 min, 40% - 100% acetonitrile from 0.2 min to 1.55 min, 100% acetonitrile from 1.55 min to 2.80 min, 100% - 40% acetonitrile from 2.80 to 2.81 min. HPLC: t R = 8.92 min; HPLC system: 1290 Infinity II.; column: Phenomenex 2.6 μ C18 100A, 100 × 4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: at 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 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)

Chemical Structure

[0391] To a solution of 1 (200 mg, 0.32 mmol) in pyridine (1 mL), propyl chloroformate (118 mg, 0.96 mmol) was added. 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 afford 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 = 10.9 Hz, 1H), 3.44 (dd, J = 12.8, 9.9 Hz, 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 = 6.2 Hz, 3H), 1.00 (t, J = 7.4 Hz, 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 containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R= 7.12 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6 μ C18 100A, 100×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: 1.5 mL / min, 2 - 98% ACN from 0 min to 8.5 min. Example 32: Dihexyl 2,2'-(((((1-(6-(((pentyloxy)carbonyl)amino)-9H-purin-9-yl)propan-2-yl)oxy)methyl)pho sphoryl)bis(azanediyl))(R)-bis(2-methylpropanoate) (32) [Chemical formula]

[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 hours, the reaction was quenched by adding water, and purified by preparative HPLC (ACN 10 - 100% in water for 5 minutes and ACN 100% for 18 minutes) to obtain the title compound (32). 1 1H NMR (400 MHz, acetonitrile-d3) δ 8.74 (s, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 4.43 (dd, J = 14.5, 3.1 Hz, 1H), 4.30 - 4.17 (m, 3H), 4.17 - 4.01 (m, 4H), 3.96 (m, 1H), 3.74 (d, J = 10.8 Hz, 1H), 3.68 (dd, J = 12.8, 8.6 Hz, 1H), 3.56 (d, J = 10.8 Hz, 1H), 3.43 (dd, J = 12.7, 9.9 Hz, 1H), 1.77 - 1.56 (m, 6H), 1.52 (s, 3H), 1.47 - 1.26 (m, 25H), 1.20 (d, J = 6.2 Hz, 3H), 0.98 - 0.85 (m, 9H). 31 31P 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 containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: At 1800 μL / min, 2 - 100% acetonitrile from 0 min to 1.8 min, 100% - 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min. HPLC: t R = 7.61 min; HPLC system: 1290 Infinity II.; Column: Phenomenex 2.6μ C18 100A, 100×4.6 mm; Solvent: Acetonitrile containing 0.1% ...

Claims

【Claim 1】 The invention described in the specification.

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