Combination therapy against HIV using adenosine derivatives and capsid inhibitors

Abstract

The present disclosure relates to methods of treating or preventing RNA viral infections and retroviral diseases such as HIV and AIDS comprising administering to a subject in need thereof an effective amount of (a) a capsid inhibitor and (b) an adenosine derivative disclosed herein. Also provided are compositions comprising an effective amount of an adenosine derivative and an effective amount of a capsid (CA) inhibitor.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application Serial No. 63 / 141,445, filed January 25, 2021, which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to an adenosine derivative prodrug that can inhibit reverse transcriptase. This disclosure also relates to pharmaceutical compositions comprising an adenosine derivative prodrug and a capsid inhibitor, which may be used to treat or prevent acquired immunodeficiency syndrome (AIDS), HIV-1, HIV-2, multidrug-resistant HIV, or combinations thereof. Background Technology

[0004] Retroviruses such as human immunodeficiency virus (HIV) are associated with an immunosuppressive disease called acquired immunodeficiency syndrome (AIDS). Several retroviral strains, such as HIV type 1 (HIV-1) and type 2 (HIV-2), are known to be associated with this disease. Individuals infected with HIV retroviruses may initially be asymptomatic but subsequently develop AIDS-related syndrome (ARC), which then progresses to AIDS. HIV replication in host cells requires the integration of the viral genome into the host cell's DNA. A key step in this process involves the viral RNA genome being transcribed into DNA via an enzyme called reverse transcriptase (RT).

[0005] Reverse transcriptases typically possess multiple enzymatic functions, acting as (1) RNA-dependent DNA polymerases that synthesize single-stranded DNA copies (first DNA) of viral RNA, (2) ribonucleases that break down the original viral RNA and release the DNA just generated from it, and (3) DNA-dependent DNA polymerases that use the first DNA strand as a template to generate a second complementary DNA strand. The two DNA strands then form a double-stranded DNA, which is integrated into the host cell's genome by integrase.

[0006] Many compounds can inhibit reverse transcriptase (RT) activity. These compounds can be used to treat HIV infection in humans by inhibiting HIV replication in infected cells or individuals. Examples of compounds approved for the treatment of HIV infection and AIDS include nucleoside RT inhibitors (NRTIs) such as 3'-azido-3'-deoxythymidine (AZT, also known as zidovudine (ZDV), azidothymidine (AZT)), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), d4T, 3TC, abacavir, emtricitabine, and tenofovir disoproxil fumarate, and non-nucleoside RT inhibitors (NNRTIs) such as nevirapine, delavirdine, efavirenz, rilpivirine, and doravirine (DHHS Guidelines: https: / / aidsinfo.nih.gov / understanding-hiv-aids, Iyidogan & Anderson, Viruses, 6, 4095-4139, 2014, doi:10.3390 / v6104095; Hayakawa et al., Antiviral Chem & Chemotherapy, 15: 169-187, 2004; Ohrul et al., J. Med. Chem. 43, 4516-4525, 2000; Pauwels, Antiviral Research, 71, 77-89, 2006.).

[0007] The adenosine derivative EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine, also known as MK-8591, islatrivir) is a long-acting (LA) NRTI that has been shown to have anti-HIV activity via inhibition of reverse transcriptase by blocking translocation (U.S. Patent Nos.: 7,339,053, 7,625,877, 8,039,614. Singh et al., Pharmaceuticals, 12, 62, 2019, DOI: 10.3390 / ph12020062, each of which is incorporated by reference herein in its entirety). This compound has broad inhibitory activity and potency against different subtypes and mutations, including HIV-1, HIV-2, and multi-drug resistant (MDR) and wild-type (WT) strains, as well as reverse transcriptase inhibitor (RTI)-resistant viruses. Some modified EFdA analogs and prodrugs are described in U.S. Patent Publication No.: 2018 / 0002366, incorporated by reference herein in its entirety.

[0008] A common problem with the treatment of HIV infection with antiretroviral inhibitory compounds is the development of viral resistance to the inhibitors. This resistance is often the result of mutations occurring in the pol gene reverse transcriptase segment. Continued use of antiviral compounds, such as inhibitory compounds, to prevent HIV infection will inevitably lead to the emergence of new HIV resistant strains. Thus, there is a continuing need for new RT inhibitors effective against HIV strains, including mutant HIV and multi-drug resistant HIV strains.

[0009] Another common problem is medication adherence. Medication adherence is critical for individuals with HIV to have a successful therapy over their lifetime. Adherence to a daily regimen can be challenging and also negatively impacts the patient’s quality of life as they are reminded of their HIV status every day. By reducing the frequency of dosing, patient adherence to a drug regimen can potentially be increased. Thus, there is a need to identify long-acting compounds or regimens (e.g., once-a-week, once-a-month, or once- every-two-months therapy) for patients to overcome these challenges associated with taking oral medications every day. SUMMARY

[0010] The present disclosure addresses these and other problems, and relates to adenosine derivatives and compositions thereof useful for the treatment of retroviral diseases such as HIV and AIDS, and RNA viral infections.

[0011] In some embodiments, the present disclosure provides a composition comprising an effective dose of:

[0012] (a) a capsid (CA) inhibitor; and

[0013] (b) an adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof,

[0014] wherein the adenosine derivative is a compound having the structure of Formula (1):

[0015]

[0016] or a pharmaceutically acceptable salt, tautomer, or solvate thereof,

[0017] wherein:

[0018] R 1 , R 1 , and R 2 are each independently -H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , or -Z-L 4-R 5 , provided that at least one of R 1 and R 2 is not H;

[0019] R 3 , R 3’ , and R 4 are each independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0020]

[0021] R 6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0022] -L 1 -R 5 is -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -(C1-C10 alkylene)-S-R 5 , -(C2-C10 alkenylene)-N(R 7 )-R 5 , -(C2-C10 alkenylene)-O-R 5 , -(C2-C10 alkenylene)-S-R 5 , -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5 , -C(O)O-L 2 -S-R 5 , -C(O)O-L 2 -C(O)O-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -O-R5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -S-R 5 , -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -O-R 5 , -C(O)N(R 7 )-L 2 -S-R 5 , -C(O)N(R 7 )-L 2 -C(O)O-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -, -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 , -C(O)O-L 2 -N(R 7 )C(O)O-R 5 , -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -O-R 5 or -C(O)N(R 7 )-L 2 -C(O)N(R8 )-L 3 -S-R 5 ;

[0023] -Z- is -C(O)-, -C(O)O-, or -C(O)N(R 7 )-;

[0024] -L 4 -R 5 is -(C1-C10alkylene)-N(R 7 )-R 5 , -(C1-C10alkylene)-O-R 5 , -(C1-C10alkyl)-S-R 5 , -(C2-C10alkenylene)-N(R 7 )-R 5 , -(C2-C10alkenylene)-O-R 5 , or -(C2-C10alkenylene)-S-R 5 ;

[0025] R 7 and R 8 are each independently H, C1-C10alkyl, or C2-C10alkenyl;

[0026] R 9 is independently H, -F, C1-C10alkyl, or C2-C10alkenyl;

[0027] L 2 and L 3 are each -(C1-C10alkylene)- or -(C2-C10alkenylene)-; and

[0028] X is a halogen atom.

[0029] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0030] In some embodiments, the present disclosure provides a method of treating or preventing an HIV infection, comprising administering to a subject in need thereof an effective amount of:

[0031] (a) a capsid (CA) inhibitor; and

[0032] (b) an adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof,

[0033] wherein the adenosine derivative is of Formula (1) having the structure:

[0034]

[0035] or a pharmaceutically acceptable salt, tautomer, or solvate thereof,

[0036] wherein:

[0037] R 1 , R1’ and R 2 are each independently H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , or -Z-L 4 -R 5 , provided that at least one of R 1 and R 2 is not H;

[0038] R 3 , R 3’ , and R 4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0039] R 5 is:

[0040]

[0041] R 6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0042] -L 1 -R 5 is -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -(C1-C10 alkylene)-S-R 5 , -(C2-C10 alkenylene)-N(R 7 )-R 5 , -(C2-C10 alkenylene)-O-R 5 , -(C2-C10 alkenylene)-S-R 5 , -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5 , -C(O)O-L 2-S-R 5 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 2 -C(O)N(R 7 )-R 5 -C(O)N(R 2 )-L 7 -N(R 3 )-R 7 -C(O)N(R 5 )-L 2 -C(O)N(R 7 )-L 3 -O-R 5 -C(O)N(R 2 )-L 7 -S-R 3 -C(O)N(R 5 )-R 7 -C(O)N(R 5 )-L 7 -N(R 2 )-R 7 -C(O)N(R 5 )-L 7 -O-R 2 -C(O)N(R 5 )-L 7 -S-R 2 -C(O)N(R 5 )-L 7 -C(O)O-R 2 -C(O)N(R 5 )-L 7 -C(O)N(R 2 )-R 8 -C(O)N(R 5 )-L 7 -C(O)N(R 2 )-L 8 -N(R 3 )-R 7 -C(O)N(R 5 )-L 2 -N(R 7 )C(O)O-R 5 -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 -C(O)N(R 2 )-L 7)C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -O-R 5 or -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -S-R 5 ;

[0043] -Z- is -C(O)-, -C(O)O- or -C(O)N(R 7 )-;

[0044] -L 4 -R 5 is -(C1-C10alkylene)-N(R 7 )-R 5 , -(C1-C10alkylene)-O-R 5 , -(C1-C10alkylene)-S-R 5 , -(C2-C10alkenylene)-N(R 7 )-R 5 , -(C2-C10alkenylene)-O-R 5 or -(C2-C10alkenylene)-S-R 5 ;

[0045] R 7 and R 8 are each independently H, C1-C10alkyl or C2-C10alkenyl;

[0046] R 9 is independently H, -F, C1-C10alkyl or C2-C10alkenyl;

[0047] L 2 and L 3 are each -(C1-C10alkylene)- or -(C2-C10alkenylene)-; and

[0048] X is a halogen atom.

[0049] In some embodiments of formula (1), R 1 , R 1’ and R2 each independently is:

[0050]

[0051]

[0052] In some embodiments, the adenosine derivative is selected from the group consisting of:

[0053] Formula (2-A):

[0054]

[0055] Formula (3-A):

[0056]

[0057] Formula (4-A):

[0058]

[0059] Formula (5-A):

[0060]

[0061] Formula (6-A):

[0062]

[0063] Formula (7-A):

[0064]

[0065] Formula (8-A):

[0066]

[0067] Formula (4-C):

[0068]

[0069] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0070] In some embodiments, the adenosine derivative is a compound having the structure:

[0071]

[0072] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0073] In some embodiments, the CA inhibitor is a compound having the structure:

[0074] In some embodiments, the CA inhibitor is a compound having the structure:

[0075] Or its pharmaceutically acceptable salts, tautomers or solvates. Attached Figure Description

[0076] Figure 1 Representative, non-limiting examples of the average three-dimensional surface plot of the interaction between Equation 4-A and the antiviral drug lenakavir. Detailed Implementation

[0077] The following is a more detailed description of various concepts and implementation schemes of the methods and apparatus according to this disclosure. It should be understood that the various aspects of the subject matter described above and discussed in more detail below can be implemented in any of a variety of ways, as the subject matter is not limited to any particular implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes.

[0078] Definitions

[0079] As used herein, the term "alkyl" or "alkyl group" refers to a fully saturated straight-chain or branched hydrocarbon chain having one to twelve carbon atoms and connected to the remainder of the molecule by single bonds. This includes alkyl groups containing any number of carbon atoms from 1 to 12. Alkyl groups containing a maximum of 12 carbon atoms are C1-C1. 12 Alkyl groups, those containing a maximum of 10 carbon atoms, are C1-C6. 10 Alkyl groups, specifically C1-C6 alkyl groups containing up to six carbon atoms, and C1-C5 alkyl groups containing up to five carbon atoms, are defined as alkyl groups. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include all the portions described above for C1-C5 alkyl groups, but also include C6 alkyl groups. C1-C 10 Alkyl groups include all the portions described above for C1-C5 and C1-C6 alkyl groups, but also include C7, C8, C9, and C6 alkyl groups. 10 Alkyl groups. Similarly, C1-C 12 Alkyl groups include all the foregoing portions, but also include C. 11 and C 12 Alkyl group. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in the specification, the alkyl group may optionally be substituted.

[0080] As used herein, the term "alkylene" or "alkylene chain" refers to a fully saturated straight chain or branched divalent hydrocarbon chain radical and has one to twelve carbon atoms. C1-C 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical (such as those described herein) through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical can be through one carbon or any two carbons within the chain. Unless otherwise specifically noted in the specification, the alkylene chain can be optionally substituted.

[0081] As used herein, the term "alkenyl" or "alkenyl group" refers to a straight chain or branched aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having a specified number of carbon atoms. For example, "C2-C10 alkenyl" (or "C2-C10 alkenyl") refers to a straight chain or branched alkenyl group having from 2 to 10 carbon atoms. In another example, C2-C6 alkenyl can have 1-butene, 2-butene, 3-butene, isobutene, 1-propene, 2-propene, and ethene (or vinyl). The points of attachment of the alkylene chain to the rest of the molecule and to the radical can be through one carbon or any two carbons within the chain. Unless otherwise specifically noted in the specification, the alkylene chain can be optionally substituted. 10 Non-limiting examples of alkenyl include ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical (such as those described herein) through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical can be through one carbon or any two carbons within the chain. Unless otherwise specifically noted in the specification, the alkylene chain can be optionally substituted.

[0082] As used herein, the term "alkenylene" or "alkenylene chain" refers to an unsaturated straight chain or branched divalent hydrocarbon chain radical having one or more alkenes and two to twelve carbon atoms. C2-C 12 Non-limiting examples of alkenylene include ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical (such as those described herein) through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical can be through one carbon or any two carbons within the chain. Unless otherwise specifically noted in the specification, the alkylene chain can be optionally substituted.

[0083] As used herein, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting only of carbon and hydrogen atoms, which can include fused or bridged ring systems having three to twenty carbon atoms (such as having three to ten carbon atoms), and which is attached to the rest of the molecule through a single bond. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. In some embodiments, "cycloalkyl" refers to any monocyclic alkane having a specified number of carbon atoms within the range. For example, "C3-C10 cycloalkyl" (or "C3-C10 cycloalkyl") refers to a monocyclic cycloalkyl group having from 3 to 10 carbon atoms. In another example, C3-C6 cycloalkyl can have cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specifically noted in the specification, the cycloalkyl group can be optionally substituted. 10"Cycloalkyl" refers to a monocyclic alkyl group of an alkane having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specifically stated in the specification, the cycloalkyl group may optionally be substituted.

[0084] As used herein, the terms "heterocyclic alkyl", "heterocyclic ring" or "heterocycle" refer to a saturated or partially saturated 3- to 20-membered ring consisting of 2 to 19 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which are connected to the remainder of the molecule by single bonds. Unless otherwise specifically stated in the specification, heterocyclic alkyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl may optionally be oxidized, for example to form an N-oxide, sulfoxide, or sulfone, and / or the nitrogen atom may optionally be quaternized, for example to form a quaternary ammonium cation. Examples of such heterocyclic alkyl include, but are not limited to, dioxolane, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydro Isoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolylalkyl, piperidinyl, piperazineyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In some embodiments, "3- to 10-membered heterocyclic alkyl" refers to a cycloalkyl group containing one or more heteroatoms selected from the group consisting of N, O, and S. In some embodiments, "heterocyclic alkyl," "heterocyclic ring," or "heterocycle" refers to a 3- to 10-membered ring structure having a carbon atom and one or more heteroatoms selected from N, O, S, or combinations thereof as members of the ring structure. Unless otherwise specifically stated in the specification, heterocyclic alkyl groups may optionally be substituted and include saturated and / or unsaturated rings.

[0085] As used herein, the term “halogen” (or “halogenated group”) refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I)).

[0086] As used herein, the term "aryl" refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, which is connected to the remainder of the molecule by a single bond. For the purposes of this disclosure, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, those derived from anthracene, acenaphthene, phenanthrene, anthracene, azulene, benzene, etc. aryl groups of fluorene, asymmetric-indacene, symmetric-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, "aryl" refers to phenyl or one or more fused cyclic hydrocarbon ring systems in which at least one ring is aromatic. Unless otherwise specifically noted in the specification, "aryl" groups can be optionally substituted.

[0087] As used herein, the term "heteroaryl" refers to a 5- to 20-membered ring system comprising hydrogen atoms, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring, which is attached to the rest of the molecule by a single bond. For purposes of the present disclosure, the heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can optionally be oxidized, for example, to form N-oxides, sulfoxides, or sulfones, and / or the nitrogen atoms can optionally be quaternized, for example, to form quaternary ammonium cations. Non-limiting examples of heteroaryl groups include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl or 1,2,4-triazolyl), tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl (i.e., 1,2,3-, 1,2,4-, 1,2,5-(furazanyl), or 1,3,4-isomer), oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-membered heterobicyclic fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthrydinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxazinyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromanyl, isochromanyl, benzothiophenyl, benzofuranyl, imidazo[l,2-a]pyridinyl, benzotriazolyl, indolinyl, isoindolinyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, and 2,3-dihydrobenzo-l,4-dioxinyl. Unless otherwise specifically noted in the specification, heteroaryl groups can be optionally substituted.

[0088] It should be understood that unless specifically noted otherwise in a particular context, any of the various cyclic rings and ring systems described herein can be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom), provided that the attachment is chemically permissible.

[0089] As used herein, the term "substituted" means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to, halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl groups, alkoxy groups, and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by the following groups: -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h . "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by the following groups: -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h. In the foregoing, R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thio, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the above substituents can also be optionally substituted with one or more of the above substituents.

[0090] As used herein, the term “isomer” refers to structural isomers, such as groups or atoms located at different positions in a molecule; stereoisomers, such as chiral isomers, enantiomers, diastereomers, and cis / trans isomers; tautomers, such as amino tautomers, imino tautomers, or combinations thereof. In a non-limiting example, the adenosine derivatives of the present disclosure can have amino tautomers, imino tautomers, or combinations thereof. In another non-limiting example, where -OH substituents are allowed to occur on the heteroaromatic ring and keto-enol tautomerism can exist, it is understood that the substituents can actually exist in whole or in part as oxo (=O). Mixtures of isomers can also be suitable. Mixtures of isomers can include all proportions of the corresponding isomers. Salts of isomers can also be suitable. The adenosine derivatives of the present disclosure can include isomers thereof, one or more salts thereof, one or more solvates thereof (including hydrates), solvated salts thereof, or mixtures thereof. Absolute stereochemistry or isomeric configuration can be determined by X-ray crystallography, vibrational circular dichroism (VCD) spectroscopy, or combinations thereof.

[0091] The adenosine derivatives can be identified by a name based on the nomenclature recommended by the International Union of Pure and Applied Chemistry (IUPAC) or based on the nucleoside (nucleoside-based nomenclature). The adenosine derivatives can also be identified by a chemical structure diagram. Unless explicitly indicated to the contrary in a particular context, the names and structures can be used interchangeably.

[0092] Any atom in the compounds disclosed herein can occur in its natural isotopic abundance, or one or more atoms can be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. The disclosure is intended to include all suitable isotopic variations of the compounds disclosed herein.

[0093] The compounds can be administered in the form of a pharmaceutically acceptable salt or solvate. The term "pharmaceutically acceptable salt" refers to a salt or solvate that is not biologically or otherwise undesirable (e.g., that is neither toxic nor otherwise deleterious to the recipient or subject thereof). Mixtures of the compounds disclosed herein with one or more of their salts or solvates are also contemplated herein. Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1- sulfonates, naphthalene-2-sulfonates, and mandelates.

[0094] In addition, the compounds disclosed herein can exist in amorphous forms and / or one or more crystalline forms, or a combination thereof.

[0095] The term "retrovirus" or "retroviral infection" refers to a virus that uses RNA as its genetic material. When a retrovirus infects a cell, the retrovirus makes a DNA copy of its genome and inserts it into the host cell's DNA.

[0096] The term "RNA virus infection" refers to a disease caused by an RNA virus, such as the common cold, influenza, SARS, COVID-19, hepatitis C, hepatitis E, West Nile fever, Ebola virus disease, rabies, poliomyelitis, and measles.

[0097] The term "HIV infection" refers to the illness caused by the human immunodeficiency virus (HIV), such as HIV-1 and HIV-2. In some cases, HIV infection can be caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV. The term "AIDS" refers to Acquired Immunodeficiency Syndrome, which is caused by HIV infection and is a later form of the disease.

[0098] The term "prodrug" refers to a compound that can be converted into the bioactive compound described herein under physiological conditions or by solvent degradation. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. A prodrug can be a biologically inactive or substantially inactive compound that can be metabolized in the body (i.e., in vivo) to produce a drug with desired activity. The term "substantially inactive" means that, based on a percentage by weight of the prodrug, the prodrug may have about 1% to about 10% of the activity of the corresponding drug or its activity after metabolism in vivo. In some embodiments, the term "substantially inactive" means that, based on a percentage by weight of the prodrug, the prodrug has less than about 5% of the activity of the corresponding drug or its activity after metabolism in vivo. When the molar amounts of the prodrug and its bioactive compound are equal, their doses are considered equivalent doses.

[0099] The terms “anti-HIV agent,” “antiviral agent,” or grammatical variations refer to compounds, mixtures of one or more compounds, formulations, chemical agents, or biological agents (such as antibodies, proteins, peptides, nucleotides, other biological compounds, or combinations thereof) that can directly or indirectly and effectively inhibit HIV, treat or prevent HIV infection, and / or treat, prevent, or delay the onset or progression of AIDS and / or diseases or disorders arising from or associated with it, RNA virus infection, or combinations thereof. Anti-HIV agents may include HIV antiviral agents, immunomodulators, anti-infective agents, vaccines, or combinations thereof that can be used to treat HIV infection or AIDS. Examples of antiviral agents for the treatment of HIV infection or AIDS include, but are not limited to, abacavir (ABC), under their respective trademarks or registered trademarks of their respective owners. ), Abacavir + Lamivudine ( Abacavir + Lamivudine + Zidovudine Amponavir ( ), Azanavir ), AZT (zidovudine, azidothymidine or ), caravirine, darunavir ( ), ddC (zacitabine, dideoxycytidine or ), ddI (desoxyinosine, dideoxyinosine or ), ddI (enteric-coated, Videox) ), deraviridine (DLV or Dolutegravir Doravirine (MK-1439), Efavirenz (EFV) ), Efavirenz + Emtricitabine + Tenofovir DF ), EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine), erteiravir, cabozantivir, dolutegravir, bicretiravir, emtricitabine (FTC, ), Emtricitabine + Tenofovir DF ), etimivirine ( ), Enfuwedi ( ), enteric-coated hydroxyinosine (Videx) ), Etravirine (TMC-125), Fosanavir Calcium ( Indinavir Lamivudine (3TC, Lamivudine + Zidovudine ), Lopinavir, Lopinavir + Ritonavir ( Maravero ), Nefinavir ), NVP, PPL-100 (also known as PL-462) (Ambrilia), raltirapvir (MK-0518 or Isentress) TM Rilpivirine ( ), ritonavir ( ), saquinavir or Stavudine (d4T, didehydrodeoxythymidine or) Tenofovir DF (DF = dipyridoxine fumarate, TDF, Tenofovir (hexadecyloxypropyl (CMX-157), tenofovir alafenamide fumarate (GS-7340), telanavir ( ) and vicriviroc. Some of the anti-HIV agents shown above can be used in the form of a salt; for example, abacavir sulfate, delavirdine mesylate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate, saquinavir mesylate, or other salts. The anti-HIV agents can have one or more activities, such as entry inhibitors (EIs), fusion inhibitors (FIs); integrase inhibitors (InIs); protease inhibitors (PIs); nucleoside reverse transcriptase inhibitors (nRTIs or NRTIs); or non-nucleoside reverse transcriptase inhibitors (nnRTIs or NNRTIs). The anti-HIV agents can comprise two or more agents disclosed herein. The adenosine derivatives of the present disclosure can be anti-HIV agents that are with or combined with other anti-HIV agent(s).

[0100] Unless expressly stated to the contrary, all ranges cited herein are inclusive. It is to be understood that any ranges cited herein include all sub-ranges within the range. For example, a dosage in the range of 100 to 2000 mg is intended to mean 100 mg, 101 mg, 101.1 mg, 101.01 mg, and the like, and a dosage of 2000 mg, including all dosages within the range. In another non-limiting example, a time range of 1 to 8 days is intended to mean 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, and 8 days, including all time sub-ranges or each individual time point or points within the range. In yet another non-limiting example, a heteroaromatic ring described as containing 1 to 4 range of heteroatoms is intended to mean that the ring can contain 1, 2, 3, or 4 heteroatoms. It is also to be understood that any ranges cited herein include all sub-ranges within the range. Thus, for example, a heterocyclic ring described as containing 1 to 4 heteroatoms is intended to include as aspects thereof heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, or 4 heteroatoms. In other examples, C1-C10 alkyl means an alkyl group comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms (including all sub-ranges). Thus, C1-C10 alkyl can be a linear or branched methyl, ethyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, and C10 alkyl. C1-C10 alkyl can be a linear or branched -CH2-, -C2H4-, -C3H6-, -C4H8-, -C5H10-, -C6H12-, -C7H14-, -C8H16-, -C9H18-, or -C10H20-. 10 12 17 18 18 10 20 ​​​​​​Similarly, C2-C10alkenyl means straight-chained or branched alkenyl groups comprising 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms, including all subranges. Straight-chained or branched alkenyl groups can be suitable. C3-C10cycloalkyl means straight-chained or branched cycloalkyl groups comprising 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms.

[0101] Unless otherwise indicated, the open terms such as “contain,” “containing,” “include,” “including,” and the like are meant to be inclusive.

[0102] The singular forms “a,” “an,” and “the” used herein are intended to include plural references unless the context clearly indicates otherwise. Thus, the numerical parameters set forth in the specification and claims are approximations that can vary as desired. These and other modifications will be apparent to the skilled artisan.

[0103] The term “about” and its grammatical equivalents as used herein in connection with a reference numerical value and its grammatical equivalents can include a range of values plus or minus 10% from that value, such as a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. For example, the quantity “about 10” includes quantities from 9 to 11.

[0104] The term “injection” refers to intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active ingredient can be coated with a material to protect it from acids and other natural conditions that can inactivate it. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, and includes, without limitation, injection, either intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinally, intrathecal, epidural and intrastemal injection and infusion. Other non-parenteral routes can include, such as topical, epidermal, or mucosal administration routes, such as intranasal, oral, vaginal, rectal, sublingual, or topical administration. The pharmaceutical composition can be in the form of a sterile aqueous solution or suspension. The pharmaceutical composition can be formulated as a microemulsion, liposome, or other ordered structure suitable for high drug concentration.

[0105] Compounds of the present disclosure

[0106] In some embodiments, the present disclosure provides an adenosine derivative having the structure of Formula (1):

[0107]

[0108] or a pharmaceutically acceptable salt, tautomer, or solvate thereof,

[0109] wherein:

[0110] R 1 , R 1 , and R 2 are each independently -H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , or -Z-L 4 -R 5 , provided that at least one of R 1 and R 2 is not H;

[0111] R 3 , R 3’ , and R 4 are each independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0112] R 5 is:

[0113]

[0114] R 6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0115] -L 1 -R 5 is -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -(C1-C10 alkylene)-S-R 5 , -(C2-C10 alkenylene)-N(R 7 )-R 5 , -(C2-C10 alkenylene)-O-R 5 , -(C2-C10 alkenylene)-S-R 5 , -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5-C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 3 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 3 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 3 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 8 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 8 -C(O)O-R 3 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 8 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -O-R 5 or -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -S-R 5 ;

[0116] -Z- is -C(O)-, -C(O)O- or -C(O)N(R 7 )-;

[0117] -L 4 -R 5 is -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -(C1-C10 alkylene)-S-R 5 , -(C2-C10 alkenylene)-N(R 7 )-R 5 , -(C2-C10 alkenylene)-O-R 5 or -(C2-C10 alkenylene)-S-R 5 ;

[0118] R 7 and R 8 are each independently H, C1-C10 alkyl or C2-C10 alkenyl;

[0119] R 9 is independently H, -F, C1-C10 alkyl or C2-C10 alkenyl;

[0120] L 2 and L 3 are each divalent -(C1-C10 alkylene)-, or -(C2-C10 alkenylene)-; and

[0121] X is a halogen atom.

[0122] The adenosine derivatives of the present disclosure can be free of a monophosphate group, a diphosphate group, a triphosphate group, or a combination thereof. In some embodiments, the R 1 1’ 2 group of the adenosine derivatives of the present disclosure is free of a monophosphate group, a diphosphate group, a triphosphate group, or a combination thereof. Non-limiting examples of adenosine derivatives having a halogen atom are shown in formulae (1)-(8) and (4-B).

[0123] In some embodiments of formula (1), the C1-C10 alkyl and C2-C10 alkenyl are linear or branched. In some embodiments, the compound of formula (1) comprises a combination of C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, and heteroaryl groups.

[0124] In some embodiments, R 1 and R 1’ are each independently selected from one of formulae 9-24. In some embodiments, R 2 is H, -COO(C1-C3 alkyl), or In some embodiments, R 2 is H.

[0125] In some embodiments, R 2 is selected from one of formulae 9-24. In some embodiments, R 1 and R 1’ are each independently H, -COO(C1-C3 alkyl), or In some embodiments, R 1 is H, -COO(C1-C3 alkyl), or and R 1’ is H. In some embodiments, R 1’ is H, -COO(C1-C3 alkyl), or and R 1 is H.

[0126] In some embodiments, R 3 and R 3’ are each independently H, C1-C5 alkyl, C2-C5 alkenyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 3 and R 3’ are each independently H, C1-C5 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 3 and R 3’ ​​each independently H or C1-C5 alkyl. In some embodiments, R 3 and R 3’ each independently H or C1-C3 alkyl. In some embodiments, R 3 and R 3’ each independently H, methyl, ethyl, or isopropyl.

[0127] In some embodiments, R 4 is H, C1-C5 alkyl, C2-C5 alkenyl, C3-C6 cycloalkyl, 3- to 6- membered heterocycloalkyl, phenyl, or 5- to 6- membered heteroaryl. In some embodiments, R 4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, 3- to 6- membered heterocycloalkyl, phenyl, or 5- to 6- membered heteroaryl. In some embodiments, R 4 is H or C1-C5 alkyl. In some embodiments, R 4 is H or C1-C3 alkyl. In some embodiments, R 4 is H, methyl, ethyl, or isopropyl.

[0128] In some embodiments of Formula (1), R 1 is H and R 2 is -C(O)N(R 3 )(R 3’ ). In some embodiments, R 1 is -C(O)N(R 3 )(R 3’ ) and R 2 is H. In some embodiments, R 3 is C1-C5 alkyl or C3-C6 cycloalkyl and R 3’ is H. In some embodiments, R 3 is methyl, ethyl, or isopropyl and R 3’ is H. In some embodiments, R 3 is methyl and R 3’ is H.

[0129] In some embodiments of Formula (1), R 1 is H and R 2 is -R 5 or -L 1 -R 5 . In some embodiments, R 1 is -L 1 -R 5 and R 2 is H. In some embodiments, -L 1 -R 5 is -C(O)N(R 7)-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -OR 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-C(O)O-R 5 , -C(O)N(R 7 )-L 2 -N(R 8 )-C(O)N(R 8 )-R 5 or -C(O)O-L 2 -N(R 8 )-C(O)N(R 8 )-R 5 In some embodiments, R 5 is In some embodiments, R 6 is C1-C5 alkyl. In some embodiments, R 6 is methyl, ethyl, or isopropyl. In some embodiments, R 6 is methyl. In some embodiments, R 7 is H or Me. In some embodiments, R 9 is H, F, or C1-C5 alkyl. In some embodiments, R 9 is H, F, or Me. In some embodiments, R 9 is H. In some embodiments, L 2 is C2-C5 alkylene. In some embodiments, L 2 is ethylene or propylene. In some embodiments, L 2 is ethylene.

[0130] In some embodiments of formula (1), R 1 is -C(O)O-R 5 or -R 5 and R 2 is H. In some embodiments, R 1 is H and R 2 is -C(O)O-R 5 or -R 5 . In some embodiments, R 5 is In some embodiments, R 6is C1-C5 alkyl. In some embodiments, R 6 is methyl, ethyl, or isopropyl. In some embodiments, R 6 is methyl. In some embodiments, R 9 is H, F, or Me. In some embodiments, R 9 is H.

[0131] In some embodiments of formula (1), R 1 is -L 1 -R 5 . In some embodiments, R 1’ is H or -L 1 -R 5 . In some embodiments, R 1’ is H. In some embodiments, R 1’ is -L 1 -R 5 . In some embodiments, R 1 is -L 1 -R 5 and R 1’ is H. In some embodiments, R 1 is -L 1 -R 5 and R 1’ is -L 1 -R 5 . In some embodiments, R 1 is -L 1 -R 5 , R 1’ is H and R 2 is H. In some embodiments, R 1 is -L 1 -R 5 , R 1’ is -L 1 -R 5 and R 2 is H. In some embodiments, -L 1 -R 5 is selected from the group consisting of -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5 , -C(O)O-L 2 -C(O)O-R 5-C(O)OL 2 -C(O)N(R 7 )-R 5 -C(O)N(R) 7 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )-R 5 -C(O)N(R) 7 )-L 2 -OR 5 -C(O)OL 2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -C(O)OR 5 and -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-R 5 -. In some implementations, -L 1 -R 5 Choose from the following groups: -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL 2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5, -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 and -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 - In some embodiments, -L 1 -R 5 is -C(O)O-R 5 . In some embodiments, R 2 is H.

[0132] The divalent linker L 1 may also comprise one or more repeats of the same group or a combination of different groups. In some embodiments, L 1 comprises -C(O)O- and C1-C10 alkylene. In some embodiments, L 1 comprises two or more repeats of -C(O)O-. In some embodiments, L 1 comprises two or more repeats of -C(O)O(CH2) n -. In some embodiments, L 1 comprises two or more repeats of -C(O)N(R 7 )-. In some embodiments, L 1 comprises two or more repeats of -C(O)N(R 7 )(CH2) n -. In some embodiments, L 1 comprises a combination of -C(O)O-, C1-C10 alkylene, and -C(O)N(R 7 )-. In some embodiments, L 1 comprises a combination of -C(O)O-, -(CH2) n -, and -C(O)N(R 7 )-. In some embodiments, L 1 comprises a combination of -C(O)N(R 7 )- and C1-C10 alkylene. In some embodiments, L 1 comprises two or more repeats of -C(O)O(CH2) n -C(O)N(R 7 )-. In some embodiments, L 1is -C(O)O-. In some embodiments, L 1 is -C(O)N(R 7 )-. In some embodiments, n is an integer from 0 to 10. In some embodiments, n is an integer from 1 to 3. As understood in the art, the above combinations are non-limiting examples, and other chemically possible combinations of L 1 are contemplated by the present disclosure.

[0133] In some embodiments, R 6 is H, C1-C5 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 6 is H, C1-C10 alkyl, C2-C10 alkenyl, or C3-C10 cycloalkyl. In some embodiments, R 6 is H, C1-C5 alkyl, C2-C5 alkenyl, or C3-C6 cycloalkyl. In some embodiments, R 6 is H, C1-C3 alkyl, or C2-C4 alkenyl. In some embodiments, R 6 is C1-C10 alkyl. In some embodiments, R 6 is C1-C5 alkyl. In some embodiments, R 6 is C1-C3 alkyl. In some embodiments, R 6 is selected from the group consisting of H, methyl, ethyl, isopropyl, and cyclopropyl. In some embodiments, R 6 is methyl, ethyl, or isopropyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is isopropyl.

[0134] In some embodiments, R 7 and R 8 are each independently H, C1-C10 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 7 and R 8 are each independently H, C1-C5 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 7 and R 8 are each independently H or C1-C5 alkyl. In some embodiments, C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R 7 and R 8 are each independently H, methyl, ethyl, isopropyl, or cyclopropyl.

[0135] In some embodiments, R 7H or C1-C10 alkyl. In some embodiments, R 7 H or C1-C5 alkyl. In some embodiments, C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 7 H or Me. In some embodiments, R 7 H.

[0136] H or C1-C10 alkyl. In some embodiments, R 8 H or C1-C10 alkyl. In some embodiments, R 8 H or C1-C5 alkyl. In some embodiments, R 8 H or Me. In some embodiments, R 8 H.

[0137] H, F, C1-C10 alkyl, or C2-C10 alkenyl. In some embodiments, R 9 H, F, C1-C5 alkyl, or C2-C5 alkenyl. In some embodiments, R 9 H, F, C1-C5 alkyl, or C2-C5 alkenyl. In some embodiments, R 9 H, F, or C1-C5 alkyl. In some embodiments, R 9 H, F, or C1-C3 alkyl. In some embodiments, R 9 H or C1-C3 alkyl. In some embodiments, R 9 C1-C3 alkyl. In some embodiments, R 9 H, F, or Me. In some embodiments, R 9 H, F, Me, or isopropyl. In some embodiments, R 9 H or Me. In some embodiments, R 9 H or F. In some embodiments, R 9 H.

[0138] The adenosine derivatives of the present disclosure can include one or more isomers thereof. Isomers can include chiral isomers (also known as stereoisomers) comprising one or more chiral centers, tautomers that can interconvert via repositioning of hydrogen atoms and double bonds, such as amino tautomers, imino tautomers, or combinations thereof. In non-limiting examples, the adenosine derivatives can have amino tautomers, imino tautomers, or combinations thereof. In further non-limiting examples, the adenosine derivatives can include enantiomers, diastereomers, and cis / trans isomers, tautomers, or combinations thereof. Also included are isomers that can have reverse transcriptase inhibitor (RTI) activity in vivo.

[0139] In some embodiments of formula (1), X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine (which may be alternatively referred to as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I)). In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is Br.

[0140] In some embodiments, the adenosine derivative of this disclosure comprises R 1 R 1’ and R 2 The R 1 R 1’ and R 2 Each independently contains one or more 5- to 10-membered heterocyclic rings. In some embodiments, R 1 R 1’ Or R 2 Each independently comprises a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, or a 6-10-membered heterocyclic ring. In some embodiments, R 1 R 1’ and R 2 Each independently contains a 6-10-membered heterocyclic ring. In some embodiments, R 1 R 1’ and R 2 Each independently contains a 5-membered heterocyclic ring. In some embodiments, R 1 R 1’ and R 2 Each of the components independently comprises a 6-membered heterocyclic ring. The heterocyclic rings of this disclosure may have one or more substituents. In some embodiments, the 5-membered heterocyclic ring comprises 1 to 4 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the 5-membered heterocyclic ring comprises 1 to 3 O atoms. In some embodiments, the 5-membered ring is a cyclic carbonate. In a further embodiment, R... 1 R 1’ and R 2 Each of the above independently comprises a 5-membered heterocyclic ring of formulas 9-24 disclosed herein. In even further embodiments, the adenosine derivatives of this disclosure comprise R 1 R 1’ and R 2 The R 1 R 1’ and R 2 Each independently contains the previously mentioned -R 5 -L 1 -R 5 -ZL 4 -R 5 Group. In some embodiments, -R 5 -L 1-R 5 , -Z-L 4 -R 5 is selected from the group consisting of formulae 9-24:

[0141]

[0142]

[0143] In some embodiments, -R 5 , -L 1 -R 5 , -Z-L 4 -R 5 is selected from the group consisting of:

[0144]

[0145] In some embodiments, the adenosine derivative of the present disclosure comprises R 1 and R 1’ , each independently H, -C(O)N(R 3 )(R 3’ ), or -C(O)OR 4 ; and R 2 , which is -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , or one of formulae 9-24.

[0146] In some embodiments, the adenosine derivative of the present disclosure comprises R 1 and R 1’ , each independently -C(O)N(R 3 )(R 3’ ) or -C(O)OR 4 ; and R 2 , which is H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , or one of formulae 9-24.

[0147] In some embodiments, the adenosine derivative of the present disclosure comprises R 2 , which is H, -C(O)N(R 3 )(R 3’ ), or -C(O)OR 4 ; and R 1 , which is -C(O)N(R 3 )(R 3’ ) or -C(O)OR 4 , or one of formulae 9-24.

[0148] In some embodiments, the adenosine derivatives of the present disclosure comprise R 2 which is -C(O)N(R 3 )(R 3’ ) or -C(O)OR 4 ; and R 1 which is H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , or one of Formulae 9-24.

[0149] In some embodiments, the adenosine derivatives of the present disclosure comprise R 1 and R 1’ each of which is H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , -Z-L 4 -R 5， , or one of Formulae 9-24; and R 2 which is -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , -Z-L 4 -R 5 , or one of Formulae 9-24.

[0150] In some embodiments, the adenosine derivatives of the present disclosure comprise R 1 which is -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , -Z-L 4 -R 5 , or one of Formulae 9-24; and R 2 which is H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , -Z-L 4 -R 5 , or one of Formulae 9-24.

[0151] In some embodiments, R 1 , R 1’ , and R 2 are each independently selected from one of formulas 9-24.

[0152] In some embodiments, the present disclosure relates to an adenosine derivative having the structure of formula (1a):

[0153]

[0154] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 1 and X are as defined above for formula (1).

[0155] In some embodiments, the present disclosure relates to an adenosine derivative having the structure of formula (1b):

[0156]

[0157] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 and X are as defined above for formula (1).

[0158] In some embodiments, the adenosine derivative of the present disclosure is selected from the group consisting of:

[0159] Formula (2):

[0160]

[0161] Formula (3):

[0162]

[0163] Formula (4):

[0164]

[0165] Formula (5):

[0166]

[0167] Formula (6):

[0168]

[0169] Formula (7):

[0170]

[0171] Formula (8):

[0172]

[0173] Formula (4-B):

[0174]

[0175] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X is as described herein.

[0176] In some embodiments, X is CI, F, or Br. In some embodiments, X is F.

[0177] In further embodiments, the adenosine derivative of the present disclosure is selected from the group consisting of:

[0178] Formula (2-A):

[0179]

[0180] Formula (3-A):

[0181]

[0182] Formula (4-A):

[0183]

[0184] Formula (5-A):

[0185]

[0186] Formula (6-A):

[0187]

[0188] Formula (7-A):

[0189]

[0190] Formula (8-A):

[0191]

[0192] Formula (4-C):

[0193]

[0194] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0195] In some embodiments, the adenosine derivative of the present disclosure is a compound selected from the group consisting of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2- ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl isopropylcarbamate, isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6- yl)carbamate, (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl carbonic acid ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester, (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl methylcarbamate, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6- yl)amino)methyl)-5-methyl-1,3-dioxol-2-one, (2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)ethyl)carbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, 4-[methyl-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl]amino]butanoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl] methyl ester, and pharmaceutically acceptable salts thereof.

[0196] In some embodiments, the adenosine derivative of the present disclosure is an isomer of Formula (1)-(8), Formula (1a), Formula (1b), or Formula (1-A)-(8-A). In some embodiments, the isomer is a stereoisomer, such as an enantiomer or a diastereomer. In some embodiments, the isomer is an inhibitor of reverse transcriptase with in vivo activity.

[0197] The adenosine derivatives of the present disclosure can undergo conversion to a target drug and can comprise in vivo reverse transcriptase inhibitor activity, in vivo reverse transcriptase chain terminator activity, in vivo DNA translocation inhibitor activity, or a combination thereof.

[0198] The adenosine derivatives of the present disclosure can be prodrugs, which are inactive or have limited activity in their original (i.e., parent) form as shown herein, and can be metabolized in vivo to exhibit the desired activity of the target drug, including reverse transcriptase inhibitor activity, reverse transcriptase chain terminator activity, DNA translocation inhibitor activity, or a combination thereof.

[0199] Without wishing to be bound by a particular mechanism or theory, Applicants have found that the adenosine derivatives of the present disclosure can be metabolized in vivo to produce a compound or mixture of compounds similar or identical to the target drug 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) having reverse transcriptase inhibitor and other antiviral activity.

[0200] As disclosed herein, the adenosine derivatives of the present disclosure can include an isomer (e.g., an enantiomer, a diastereomer, and / or a tautomer) thereof, one or more pharmaceutically acceptable salts thereof, one or more solvates (including hydrates) thereof, a solvated salt thereof, or a mixture thereof.

[0201] The adenosine derivatives are also described in WO 2021 / 021717, which is incorporated by reference in its entirety.

[0202] Compositions of the present disclosure

[0203] The present disclosure provides pharmaceutical compositions comprising an adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0204] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an effective dose of (a) a capsid (CA) inhibitor; and (b) an adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0205] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (1) an effective dose of (a) a capsid (CA) inhibitor; and (b) an adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof; and (2) a pharmaceutically acceptable carrier.

[0206] In some embodiments, the CA inhibitor is lenacapavir. Lenacapavir as used herein refers to a compound having the following structure:

[0207]

[0208] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, or a combination thereof. Lenacapavir available commercially can be suitable for use in the disclosed compositions.

[0209] In some embodiments, the pharmaceutical composition of the present disclosure comprises an effective dose of (a) an anti-HIV agent; and (b) an adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0210] In some embodiments, the anti-HIV agent is selected from the group consisting of abacavir, abacavir sulfate, lamivudine, amprenavir, atazanavir, atazanavir sulfate, AZT, bevirimat, cabotegravir, darunavir, dideoxycytidine, dideoxyinosine, doravirine, dorzalex, efavirenz, emtricitabine, fumarate tenofovir disoproxil, tenofovir alafenamide, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, etifelbavir, incivek, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobicistat, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, tipranavir, vicriviroc, one or more capsid (CA) inhibitors, GS-6207 (lenacapavir), and combinations thereof. In some embodiments, the anti-HIV agent is a capsid (CA) inhibitor. In some embodiments, the anti-HIV agent is lenacapavir.

[0211] In some embodiments, the anti-HIV agent is a reverse transcriptase inhibitor. In some embodiments, the reverse transcriptase inhibitor is selected from the group consisting of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC), d4T, 3TC, abacavir, emtricitabine, fumarate tenofovir disoproxil, nevirapine, delavirdine, efavirenz, rilpivirine, and doravirine.

[0212] The compositions of the present disclosure can be used to treat a disease, including but not limited to acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, multi-drug resistant HIV, or an RNA viral infection. In some embodiments, the disease is human immunodeficiency virus 1 (HIV-1). In some embodiments, the HIV-1 is multi-drug resistant.

[0213] In some embodiments, the compositions of the present disclosure comprise an adenosine derivative of Formula (1):

[0214]

[0215] or a pharmaceutically acceptable salt, tautomer, or solvate thereof,

[0216] wherein:

[0217] R 1 , R 1’ , and R 2 are each independently H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , or -Z-L 4 -R 5 , wherein at least one of R 1 and R 2 is not H;

[0218] R 3 , R 3’ , and R 4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0219] R 5 is:

[0220]

[0221] R 6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0222] -L 1 -R 5 is -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -(C1-C10 alkyl)-S-R 5 , -(C2-C10 alkenylene)-N(R 7 )-R 5 , -(C2-C10 alkenylene)-O-R 5 , -(C2-C10 alkenylene)-S-R 5 , -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5-C(O)O-R 2 -S-R 5 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 3 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 3 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 3 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 8 -C(O)O-R 5 -C(O)O-R 7 -C(O)O-R 2 -C(O)O-R 8 -C(O)O-R 3 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R 8 -C(O)O-R 2 -C(O)O-R 7 -C(O)O-R 5 -C(O)O-R2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -O-R 5 or -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -S-R 5 ;

[0223] -Z- is -C(O)-, -C(O)O- or -C(O)N(R 7 )-;

[0224] -L 4 -R 5 is -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -(C1-C10 alkylene)-S-R 5 , -(C2-C10 alkenylene)-N(R 7 )-R 5 , -(C2-C10 alkenylene)-O-R 5 or -(C2-C10 alkenylene)-S-R 5 ;

[0225] R 7 and R 8 are each independently H, C1-C10 alkyl or C2-C10 alkenyl;

[0226] R 9 is independently H, -F, C1-C10 alkyl or C2-C10 alkenyl;

[0227] L 2 and L 3 are each divalent -(C1-C10 alkylene)-, or -(C2-C10 alkenylene)-; and

[0228] X is a halogen atom.

[0229] In some embodiments of formula (1), the C1-C10 alkyl and C2-C10 alkenyl groups are straight-chain or branched. In some embodiments, the adenosine derivative of the pharmaceutical composition comprises a combination of C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl, and heteroaryl groups.

[0230] In some embodiments, the adenosine derivatives disclosed herein include a divalent linker L 1 It contains one or more repetitions of the same group as disclosed herein, or a combination of different groups. Connector L 1 Non-limiting examples of other chemically possible combinations include those described above, such as those in equation (1).

[0231] In some implementation schemes, R 1 R 1’ and R 2 Each independently as R 5 -L 1 -R 5 or -ZL 4 -R 5 In some implementations, R 5 -L 1 -R 5 and -ZL 4 -R 5 The structure is:

[0232]

[0233]

[0234] In some embodiments, the pharmaceutical compositions of this disclosure comprise the adenosine derivatives disclosed herein, wherein R 1 and R 1’ It is H, -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 And R 2 It is -C(O)N(R) 3 (R) 3’ -C(O)OR 4 , or one of formulas 9-24.

[0235] In some embodiments, the pharmaceutical compositions of this disclosure comprise the adenosine derivatives disclosed herein, wherein R 1 It is -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 And R 2 It is H, -C(O)N(R)3 )(R 3’ ), -C(O)N(R 4 )(R

[0236] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative disclosed herein, wherein R 2 is H, -C(O)N(R 3 )(R 3’ ), or -C(O)OR 4 and R 1 is -C(O)N(R 3 )(R 3’ ), or -C(O)OR 4 , or one of Formula 9-24.

[0237] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative disclosed herein, wherein R 2 is -C(O)N(R 3 )(R 3’ ), or -C(O)OR 4 and R 1 and R 1 are each independently H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , or one of Formula 9-24.

[0238] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative disclosed herein, wherein R 1 and R 1’ are each independently H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , -Z-L 4 -R 5 , or one of Formula 9-24 and R 2 is -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , -Z-L 4 -R 5 , or one of Formula 9-24.

[0239] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative disclosed herein, wherein R1 -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , -Z-L 4 -R 5 , or one of Formula 9-24, and R 2 is H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , -Z-L 4 -R 5 , or one of Formula 9-24.

[0240] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative disclosed herein, wherein R 1 , R 1’ , and R 2 are each independently selected from one of Formula 9-24.

[0241] In some embodiments, R 3 , R 3’ , and R 4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, or C3-C10 cycloalkyl. In some embodiments, R 3 , R 3’ , and R 4 are each independently H, C1-C5 alkyl, C2-C5 alkenyl, or C3-C6 cycloalkyl. In some embodiments, R 3 , R 3’ , and R 4 are each independently H or C1-C5 alkyl. In some embodiments, the C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 , R 3’ , and R 4 are each independently H, methyl, or isopropyl.

[0242] In some embodiments, R 6 is H, C1-C5 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 6 is H, C1-C10 alkyl, C2-C10 alkenyl, or C3-C10 cycloalkyl. In some embodiments, R 6H, C1-C5 alkyl, C2-C5 alkenyl, or C3-C6 cycloalkyl. In some embodiments, R 6 H, C1-C3 alkyl, or C2-C4 alkenyl. In some embodiments, R 6 C1-C10 alkyl. In some embodiments, R 6 C1-C5 alkyl. In some embodiments, R 6 C1-C3 alkyl. In some embodiments, R 6 is selected from the group consisting of H, methyl, ethyl, isopropyl, and cyclopropyl. In some embodiments, R 6 methyl, ethyl, or isopropyl. In some embodiments, R 6 methyl. In some embodiments, R 6 isopropyl.

[0243] In some embodiments, R 7 and R 8 each independently is H, C1-C10 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 7 and R 8 each independently is H, C1-C5 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 7 and R 8 each independently is H or C1-C5 alkyl. In some embodiments, C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R 7 and R 8 each independently is H, methyl, ethyl, isopropyl, or cyclopropyl.

[0244] In some embodiments, R 7 is H or C1-C10 alkyl. In some embodiments, R 7 is H or C1-C5 alkyl. In some embodiments, C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 7 is H or Me. In some embodiments, R 7 is H.

[0245] In some embodiments, R 8 is H or C1-C10 alkyl. In some embodiments, R 8 is H or C1-C5 alkyl. In some embodiments, R 8 is H or Me. In some embodiments, R 8 is H.

[0246] In some embodiments, R 9H, F, C1-C10 alkyl, or C2-C10 alkenyl. In some embodiments, R 9 H, F, C1-C5 alkyl, or C2-C5 alkenyl. In some embodiments, R 9 H, F, or C1-C5 alkyl. In some embodiments, R 9 H, F, or C1-C3 alkyl. In some embodiments, R 9 H, or C1-C3 alkyl. In some embodiments, R 9 C1-C3 alkyl. In some embodiments, R 9 H, F, or Me. In some embodiments, R 9 H, F, Me, or isopropyl. In some embodiments, R 9 H, or Me. In some embodiments, R 9 H, or F. In some embodiments, R 9 H.

[0247] In some embodiments, X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine (alternatively referred to as fluorine (F), chlorine (CI), bromine (Br), and iodine (I)). In some embodiments, X is F. In another embodiment, X is CI. In yet another embodiment, X is Br. Non-limiting examples of adenosine derivatives of the present disclosure are disclosed herein.

[0248] In some embodiments, the compositions of the present disclosure comprise an adenosine derivative of formula (1a):

[0249]

[0250] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 1 and X are as defined above for formula (1).

[0251] In some embodiments, the compositions of the present disclosure comprise an adenosine derivative of formula (1b):

[0252]

[0253] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 and X are as defined above for formula (1).

[0254] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having a formula selected from the group consisting of:

[0255] Formula (2):

[0256]

[0257] Formula (3):

[0258]

[0259] Formula (4):

[0260]

[0261] Formula (5):

[0262]

[0263] Formula (6):

[0264]

[0265] Formula (7):

[0266] and

[0267] Formula (8):

[0268]

[0269] Formula (4-B):

[0270]

[0271] or a pharmaceutically acceptable salt, tautomer, solvate, or combination thereof.

[0272] In some embodiments, X is CI, F, or Br. In some embodiments, X is F.

[0273] In some embodiments, the pharmaceutical composition of the present disclosure comprises an adenosine derivative having a formula selected from the group consisting of:

[0274] Formula (2-A):

[0275]

[0276] Formula (3-A):

[0277]

[0278] Formula (4-A):

[0279]

[0280] Formula (5-A):

[0281]

[0282] Formula (6-A):

[0283]

[0284] Formula (7-A):

[0285]

[0286] Formula (8-A):

[0287]

[0288] Formula (4-C):

[0289]

[0290] stereoisomers thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

[0291] In some embodiments, the adenosine derivative of the pharmaceutical composition is a compound of Formula (1)-(8), Formula (1a), Formula (1b), Formula (1-A)-(8-A), Formula (4-B), or Formula (4-C).

[0292] In some embodiments, the adenosine derivative of the pharmaceutical composition is an isomer of Formula (1)-(8), Formula (1a), Formula (1b), Formula (1-A)-(8-A), Formula (4-B), or Formula (4-C). Isomers described above, such as tautomers, enantiomers, diastereomers, cis / trans isomers, or combinations thereof can be suitable. In some embodiments, the isomer is a stereoisomer, such as an enantiomer or a diastereomer. In some embodiments, the isomer is an inhibitor of reverse transcriptase with in vivo activity.

[0293] As disclosed herein, the pharmaceutical compositions of the present disclosure can comprise an adenosine derivative selected from the group consisting of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl isopropylcarbamate, isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate, (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl carbonic acid ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester, (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl methylcarbamate, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-1,3-dioxol-2-one, (2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)ethyl)carbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, 4-[methyl-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl]amino]butanoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl] methyl ester, and pharmaceutically acceptable salts thereof.

[0294] As disclosed above, the pharmaceutical compositions of the present disclosure comprising an adenosine derivative can be free of a monophosphate group, a diphosphate group, a triphosphate group, or a combination thereof. In some embodiments, the R 1 and / or R 2 group of the adenosine derivatives disclosed herein is free of a monophosphate group, a diphosphate group, a triphosphate group, or a combination thereof.

[0295] In some embodiments, the pharmaceutical compositions of the present disclosure comprise 10 mg to 2000 mg, such as about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg (including all ranges and values therebetween) of an adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the pharmaceutical compositions of the present disclosure comprise 100 mg to 2000 mg, 100 mg to 1900 mg, 100 mg to 1800 mg, 100 mg to 1700 mg, 100 mg to 1600 mg, 100 mg to 1500 mg, 100 mg to 1400 mg, 100 mg to 1300 mg, 100 mg to 1200 mg, 100 mg to 1100 mg, 100 mg to 1000 mg, 100 mg to 900 mg, 100 mg to 800 mg, 100 mg to 700 mg, 100 mg to 600 mg, 100 mg to 500 mg, 100 mg to 400 mg, or 100 mg to 300 mg, 200 mg to 1000 mg, 300 mg to 1000 mg, 400 mg to 1000 mg, 500 mg to 1000 mg, 600 mg to 1000 mg, 700 mg to 1000 mg, 800 mg to 1000 mg, 900 mg to 1000 mg, 200 mg to 1200 mg, 300 mg to 1200 mg, 400 mg to 1200 mg, 500 mg to 1200 mg, 600 mg to 1200 mg, 700 mg to 1200 mg, 800 mg to 1200 mg, 900 mg to 1200 mg, 1000 mg to 1200, 200 mg to 2000 mg, 300 mg to 2000 mg, 400 mg to 2000 mg, 500 mg to 2000 mg, 600 mg to 2000 mg, 700 mg to 2000 mg, 800 mg to 2000 mg, 900 mg to 2000 mg, or 1000 mg to 2000 mg of an adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the pharmaceutical compositions comprise 700 mg to 2000 mg of an adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the pharmaceutical compositions comprise 700 mg to 1200 mg of an adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0296] In some embodiments, the pharmaceutical composition of the present disclosure comprises 10 mg to 2000 mg, such as about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg (including all ranges and values therebetween) of the anti-HIV agent. In some embodiments, the pharmaceutical composition comprises 100 mg to 2000 mg, 100 mg to 1800 mg, 100 mg to 1600 mg, 100 mg to 1500 mg, 100 mg to 1400 mg, 100 mg to 1200 mg, 100 mg to 1100 mg, 100 mg to 1000 mg, 100 mg to 900 mg, 100 mg to 800 mg, 100 mg to 700 mg, 100 mg to 600 mg, 100 mg to 500 mg, 100 mg to 400 mg, or 100 mg to 300 mg, 200 mg to 1200 mg, 300 mg to 1200 mg, 400 mg to 1200 mg, 500 mg to 1200 mg, 600 mg to 1200 mg, 700 mg to 1200 mg, 800 mg to 1200 mg, 900 mg to 1200 mg, 1000 mg to 1200, 1000 mg to 2000 mg of the anti-HIV agent. In some embodiments, the pharmaceutical composition comprises 700 mg to 1000 mg of the anti-HIV agent.

[0297] In some embodiments, the pharmaceutical composition of the present disclosure comprises 10 mg to 2000 mg, such as about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg of a CA inhibitor, such as entecavir. In some embodiments, the pharmaceutical composition comprises 100 mg to 2000 mg, 100 mg to 1800 mg, 100 mg to 1600 mg, 100 mg to 1500 mg, 100 mg to 1400 mg, 100 mg to 1200 mg, 100 mg to 1100 mg, 100 mg to 1000 mg, 100 mg to 900 mg, 100 mg to 800 mg, 100 mg to 700 mg, 100 mg to 600 mg, 100 mg to 500 mg, 100 mg to 400 mg, or 100 mg to 300 mg, 200 mg to 1200 mg, 300 mg to 1200 mg, 400 mg to 1200 mg, 500 mg to 1200 mg, 600 mg to 1200 mg, 700 mg to 1200 mg, 800 mg to 1200 mg, 900 mg to 1200 mg, 1000 mg to 1200, 1000 mg to 2000 mg of a CA inhibitor, such as entecavir. In some embodiments, the pharmaceutical composition comprises 700 mg to 1000 mg of a CA inhibitor.

[0298] The pharmaceutical composition of the present disclosure can further comprise a pharmaceutically acceptable carrier.

[0299] Non-limiting examples of pharmaceutically acceptable carriers include pharmaceutical excipients, surfactants, emulsifiers, fillers, carriers, isotonic agents, dispersants, viscosity adjusting agents, resuspension agents, buffers, or combinations thereof. Pharmaceutical excipients generally do not have the properties of pharmaceutically or drug active ingredients (also known as active pharmaceutical ingredients (APIs)) and are generally used to simplify the manufacturing process or packaging of active ingredients, or to deliver APIs to patients or other subjects. Pharmaceutically acceptable carriers, excipients, or inactive ingredients from the Inactive Ingredients Database available from the US FDA (https: / / www.fda.gov / drugs / drug-approvals-and-databases / inactive-ingredients-database-download) can be suitable. Some Generally Recognized As Safe (GRAS) food substances available from the GRAS Substances (SCOGS) database of the US FDA (https: / / www.fda.gov / food / generally-recognized-safe-gras / gras-substances-scogs-database) can also be suitable.

[0300] In some embodiments of the present disclosure, the pharmaceutically acceptable carrier includes acacia, animal oil, benzyl alcohol, benzyl benzoate, calcium stearate, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, cyclodextrin, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, glyceryl stearate, glyceryl monooleate, glyceryl monostearate aqueous, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-beta-cyclodextrin (HPBCD), hydroxypropyl methylcellulose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohols, lecithin, medium chain triglycerides, metallic soaps, methylcellulose, mineral oil, monosodium phosphate, monoethanolamine, oleic acid, polyethylene glycol (PEG 3350, PEG 4000, PEG 6000), polyoxyethylene-polyoxypropylene copolymer (poloxamer), polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene stearates, polysorbates, polyoxyethylene (20) sorbitan monolaurate (Tween 20, polysorbate 20), polyoxyethylene (20) sorbitan monooleate (Tween 80, polysorbate 80), povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium monobasic phosphate, sodium dihydrogen phosphate, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth, triethanolamine, vegetable oil, water, xanthan gum, or combinations thereof.

[0301] In further embodiments, the pharmaceutically acceptable carrier includes dextrose, glycerin, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-beta-cyclodextrin (HPBCD), hydroxypropyl methylcellulose (hydroxypropyl methylcellulose (HPMC)), polyoxyethylene (20) sorbitan monolaurate (Tween 20, polysorbate 20), polyethylene glycol (PEG 400, PEG 3350, PEG 4000, PEG 6000), polyoxyethylene-polyoxypropylene copolymer (poloxamer 188, poloxamer 407), polyoxyethylene (20) sorbitan monooleate (Tween 80, polysorbate 80), saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium lauryl sulfate, sodium monobasic phosphate, sodium dihydrogen phosphate, or combinations thereof.

[0302] In some embodiments, an adenosine derivative (such as a compound of Formula (1)-(8), Formula (1a), Formula (1b), or Formula (1-A)-(8-A)), and an anti-HIV agent (such as a CA inhibitor) are combined in a single formulation that can be administered to a subject. In some embodiments, an adenosine derivative and an anti-HIV agent such as a CA inhibitor are provided in separate formulations that can be administered simultaneously or sequentially to a subject. The pharmaceutical compositions of the present disclosure can also be administered with one or more additional anti-HIV agents in separate formulations that can be administered simultaneously to a subject.

[0303] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject simultaneously with, prior to, or after a CA inhibitor. In some embodiments, each of an adenosine derivative and a CA inhibitor are periodically administered to a subject.

[0304] The pharmaceutical compositions of the present disclosure are suitable for oral, intravenous, intramuscular, subcutaneous, parenteral administration, intraspinal or epicutaneous administration (e.g., by injection or infusion). Depending on the route of administration, the active ingredient can be coated with a material to protect it from acids and other natural conditions that can inactivate it. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, and includes, without limitation, injection, either intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion. Alternatively, the pharmaceutical composition can be administered via a non-parenteral route, such as a topical, epicutaneous, or mucosal administration route, such as by intranasal, oral, vaginal, rectal, sublingual, or topical administration. The pharmaceutical composition can be in the form of a sterile aqueous solution or suspension. The pharmaceutical composition can also be formulated as a microemulsion, liposome, or other ordered structure suitable for high drug concentration.

[0305] Methods of the present disclosure

[0306] In some embodiments, the present disclosure provides a method of treating or preventing an HIV infection comprising administering to a subject in need thereof an effective dose of (a) an anti-HIV agent; and (b) an adenosine derivative disclosed herein, a composition thereof, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0307] In some embodiments, the present disclosure provides a method of treating an HIV infection comprising administering to a subject in need thereof an effective dose of (a) an anti-HIV agent; and (b) an adenosine derivative disclosed herein, a composition thereof, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0308] In some embodiments of the disclosed methods, the anti-HIV agent is selected from the group consisting of abacavir, abacavir sulfate, lamivudine, amprenavir, atazanavir, atazanavir sulfate, AZT, bevirimat, cabotegravir, darunavir, dideoxycytidine, dideoxyinosine, doravirine, doravirine, efavirenz, emtricitabine, fumarate tenofovir disoproxil, tenofovir alafenamide, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, elvitegravir, etravirine, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobicistat, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, tipranavir, vicriviroc, one or more capsid (CA) inhibitors, and GS-6207 (lenacapavir), or combinations thereof. In some embodiments, the anti-HIV agent is a capsid (CA) inhibitor. Capsid inhibitors (also known as HIV-1 capsid inhibitors) are disclosed in WO2018 / 0145021, which is incorporated by reference herein in its entirety for all purposes. In some embodiments, the capsid inhibitor is a capsid polymerization inhibitor or capsid disruption compound, an HIV nucleocapsid p7 (NCp7) inhibitor, or an HIV p24 capsid protein inhibitor. In some embodiments, the CA inhibitor is lenacapavir. In some embodiments, the anti-HIV agent is lenacapavir.

[0309] Lenacapavir as used herein refers to a compound having the following structure:

[0310]

[0311] or a pharmaceutically acceptable salt, tautomer, or solvate thereof. Commercially available lenacapavir can be suitable for use in the disclosed methods.

[0312] In some embodiments, the present disclosure provides a method of treating or preventing an HIV infection comprising administering to a subject in need thereof an effective dose of (a) a capsid (CA) inhibitor; and (b) an adenosine derivative disclosed herein, a composition thereof, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the capsid inhibitor is lenacapavir.

[0313] In some embodiments, the present disclosure provides a method of treating an HIV infection comprising administering to a subject in need thereof an effective dose of (a) a capsid (CA) inhibitor; and (b) an adenosine derivative disclosed herein, a composition thereof, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the capsid inhibitor is lenacapavir.

[0314] In some embodiments, the capsid (CA) inhibitor, such as the above-mentioned tenofovir, is administered to the subject at a dose (effective dose) of 100 mg to 2000 mg, 100 mg to 1800 mg, 100 mg to 1600 mg, 100 mg to 1500 mg, 100 mg to 1400 mg, 100 mg to 1200 mg, 100 mg to 1100 mg, 100 mg to 1000 mg, 100 mg to 900 mg, 100 mg to 800 mg, 100 mg to 700 mg, 100 mg to 600 mg, 100 mg to 500 mg, 100 mg to 400 mg, or 100 mg to 300 mg, 200 mg to 1200 mg, 300 mg to 1200 mg, 400 mg to 1200 mg, 500 mg to 1200 mg, 600 mg to 1200 mg, 700 mg to 1200 mg, 800 mg to 1200 mg, 900 mg to 1200 mg, 1000 mg to 1200, 1000 mg to 2000 mg. In some embodiments, the CA inhibitor is administered to a subject in need thereof at an effective dose ranging from 700 mg to 1000 mg using the administration schedule described above and below. In some embodiments, the CA inhibitor is administered to the subject in a single dose ranging from 100 mg to 2000 mg every 6 months. The CA inhibitor can be administered to the subject via one or more injections.

[0315] In some embodiments, the effective dose of a capsid (CA) inhibitor, such as the above-mentioned entecavir, administered to a subject ranges from 100 mg to 2000 mg once every 1 to 7 days to about once every 8 weeks. In some embodiments, the effective dose of a CA inhibitor is 300 mg daily, once every two days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W). In some embodiments, the effective dose of a CA inhibitor is 400 mg daily, once every two days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W). In some embodiments, the effective dose of a CA inhibitor is 500 mg daily, once every two days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W). In some embodiments, the effective dose of a CA inhibitor is 600 mg daily, once every two days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W). In some embodiments, the effective dose of a CA inhibitor is 800 mg daily, once every two days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W). In some embodiments, the effective dose of a CA inhibitor is 900 mg daily, once every two days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W).In some embodiments, an effective dose of the CA inhibitor is 1000 mg daily, once every two days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W). In some embodiments, an effective dose of the CA inhibitor ranges from 700 mg to 2000 mg once a month (QM). In some embodiments, an effective dose of the CA inhibitor ranges from 700 mg to 2000 mg once a month (QM). The CA inhibitor can be administered to the subject orally, with or without food. The CA inhibitor can also be administered to the subject via injection, such as subcutaneous injection in the abdomen.

[0316] In some embodiments, the lenacapavir is administered orally to the subject. In some embodiments, the lenacapavir is administered orally to the subject at a dose of 100 mg to 1000 mg per day. In some embodiments, the lenacapavir is administered orally at a dose of 300 mg to 600 mg per day. In some embodiments, the lenacapavir is administered orally at a dose of 300 mg to 600 mg per day.

[0317] In some embodiments, the lenacapavir is administered subcutaneously by injection. In some embodiments, the lenacapavir is administered subcutaneously. In some embodiments, the lenacapavir is administered subcutaneously at a dose of 500 mg to 1500 mg per day. In some embodiments, the lenacapavir is administered subcutaneously at a dose of 800 mg to 100 mg per day. In some embodiments, the lenacapavir is administered subcutaneously at a dose of 927 mg per day.

[0318] The adenosine derivative suitable for use in the disclosed methods can be any adenosine derivative disclosed herein, a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0319] In some embodiments, the adenosine derivative for use in the disclosed methods is a compound of Formula (1):

[0320]

[0321] or a pharmaceutically acceptable salt, tautomer, or solvate thereof,

[0322] wherein:

[0323] R 1 , R 1’ , and R 2 each independently is -H, -C(O)N(R 3 )(R 3’ ), -C(O)OR4 , -R 5 , -L 1 -R 5 or -Z-L 4 -R 5 wherein R 1 and R 2 are not both H;

[0324] R 3 , R 3’ and R 4 are each independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0325] R 5 is:

[0326]

[0327] R 6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0328] -L 1 -R 5 is -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -(C1-C10 alkyl)-S-R 5 , -(C2-C10 alkenylene)-N(R 7 )-R 5 , -(C2-C10 alkenylene)-O-R 5 , -(C2-C10 alkenylene)-S-R 5 , -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5 , -C(O)O-L 2 -S-R 5 , -C(O)O-L 2 -C(O)O-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L3 -N(R 7 )-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -O-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -S-R 5 , -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -O-R 5 , -C(O)N(R 7 )-L 2 -S-R 5 , -C(O)N(R 7 )-L 2 -C(O)O-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -, -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 , -C(O)O-L 2 -N(R 7 )C(O)O-R 5 , -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2-C(O)N(R 8 )-L 3 -O-R 5 or -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -S-R 5 ;

[0329] -Z- is -C(O)-, -C(O)O-, or -C(O)N(R 7 )-;

[0330] -L 4 -R 5 is -(C1-C10alkylene)-N(R 7 )-R 5 , -(C1-C10alkylene)-O-R 5 , -(C1-C10alkylene)-S-R 5 , -(C2-C10alkenylene)-N(R 7 )-R 5 , -(C2-C10alkenylene)-O-R 5 , or -(C2-C10alkenylene)-S-R 5 ;

[0331] R 7 and R 8 are each independently H, C1-C10alkyl, or C2-C10alkenyl;

[0332] R 9 is independently H, -F, C1-C10alkyl, or C2-C10alkenyl;

[0333] L 2 and L 3 are each bivalent -(C1-C10alkylene)-, or -(C2-C10alkenylene)-; and

[0334] X is a halogen atom.

[0335] In some embodiments, the adenosine derivative used in the disclosed methods is a compound of Formula (1)-(8), Formula (1a), Formula (1b), Formula (1-A)-(8-A), Formula (4-B), or Formula (4-C). In some embodiments, the adenosine derivative used in the disclosed methods is a compound of Formula (4-A) or Formula (4-C). In some embodiments, the adenosine derivative used in the disclosed methods is a compound of Formula (4-A) having the structure , or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0336] In some embodiments of the methods of the present application, the adenosine derivative is an isomer of Formula (1)-(8), Formula (1a), Formula (1b), Formula (1-A)-(8-A), Formula (4-B), or Formula (4-C). The isomers described above, such as tautomers, stereoisomers, cis / trans isomers, or combinations thereof can be suitable. In some embodiments, the stereoisomers of the adenosine derivatives disclosed herein are enantiomers and / or diastereomers. In some embodiments, the isomer is an inhibitor of reverse transcriptase with in vivo activity.

[0337] In some embodiments of the methods of the present application, the adenosine derivative of Formula (1) comprises a linear or branched C1-C10 alkyl and / or C2-C10 alkenyl. In some embodiments, the adenosine derivative comprises a combination of C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, and heteroaryl.

[0338] In some embodiments of the methods of the present application, the adenosine derivative comprises a linker L 1 comprising one or more repetitions of the same group as disclosed herein or a combination of different groups. The linker L 1 Non-limiting examples of other chemically possible combinations include those described above, such as those in Formula (1).

[0339] In some embodiments, X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine (alternatively referred to as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I)). In one embodiment, X is F. In another embodiment, X is Cl. In yet another embodiment, X is Br. Non-limiting examples of the adenosine derivatives of the present disclosure are disclosed herein.

[0340] In some embodiments, the adenosine derivative for use in the disclosed methods is a compound of Formula (1a):

[0341]

[0342] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 1 and X are as defined above for Formula (1).

[0343] In some embodiments, the adenosine derivative for use in the disclosed methods is a compound of Formula (1b):

[0344]

[0345] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2and X is as defined above for formula (1).

[0346] In some embodiments, the methods disclosed herein include an adenosine derivative having a formula selected from the group consisting of:

[0347] Formula (2):

[0348]

[0349] Formula (3):

[0350]

[0351] Formula (4):

[0352]

[0353] Formula (5):

[0354]

[0355] Formula (6):

[0356]

[0357] Formula (7):

[0358] and

[0359] Formula (8):

[0360]

[0361] Formula (4-B):

[0362]

[0363] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0364] In some embodiments, X is CI, F, or Br. In some embodiments, X is F.

[0365] In some embodiments, the methods disclosed herein include an adenosine derivative having a formula selected from the group consisting of:

[0366] Formula (2-A):

[0367]

[0368] Formula (3-A):

[0369]

[0370] Formula (4-A):

[0371]

[0372] Formula (5-A):

[0373]

[0374] Formula (6-A):

[0375]

[0376] Formula (7-A):

[0377]

[0378] Formula (8-A):

[0379]

[0380] Formula (4-C):

[0381]

[0382] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0383] In some embodiments, the methods of the present disclosure comprise an adenosine derivative selected from the group consisting of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl isopropylcarbamate, isopropyl (9-((2R,4S,5R)-5- ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl) carbamate, (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran- 2-yl)methyl carbonic acid ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester, (2R,3S,5R)-5-(6- amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl methyl carbamate, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-1,3-dioxol-2-one, (2-(methyl((5-methyl-2- oxo-1,3-dioxol-4-yl)methyl)amino)ethyl)carbamic acid ((2R,3S,5R)-5-(6-amino-2-fluoro- 9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester, 4-[methyl-[(5-methyl- 2-oxo-1,3-dioxol-4-yl)methoxycarbonyl]amino]butanoic acid [(2R,3S,5R)-5-(6-amino-2- fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester, and pharmaceutically acceptable salts thereof.

[0384] As disclosed above, the adenosine derivatives suitable for use in the disclosed methods can not contain a monophosphate group, a diphosphate group, a triphosphate group, or a combination thereof. In some embodiments, the R 1 and / or R 2 groups of the adenosine derivatives disclosed herein do not contain a monophosphate group, a diphosphate group, a triphosphate group, or a combination thereof.

[0385] In some embodiments, the adenosine derivative, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, is administered to the subject at a dose (effective dose) in the range of about 10 mg to about 2000 mg, such as about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg, including all ranges and values therebetween. In some embodiments, the adenosine derivative, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, is administered to the subject at a dose (effective dose) in the range of 100 mg to 2000 mg, 100 mg to 1900 mg, 100 mg to 1800 mg, 100 mg to 1700 mg, 100 mg to 1600 mg, 100 mg to 1500 mg, 100 mg to 1400 mg, 100 mg to 1300 mg, 100 mg to 1200 mg, 100 mg to 1100 mg, 100 mg to 1000 mg, 100 mg to 900 mg, 100 mg to 800 mg, 100 mg to 700 mg, 100 mg to 600 mg, 100 mg to 500 mg, 100 mg to 400 mg, or 100 mg to 300 mg, 200 mg to 1000 mg, 300 mg to 1000 mg, 400 mg to 1000 mg, 500 mg to 1000 mg, 600 mg to 1000 mg, 700 mg to 1000 mg, 800 mg to 1000 mg, 900 mg to 1000 mg, 200 mg to 1200 mg, 300 mg to 1200 mg, 400 mg to 1200 mg, 500 mg to 1200 mg, 600 mg to 1200 mg, 700 mg to 1200 mg, 800 mg to 1200 mg, 900 mg to 1200 mg, 1000 mg to 1200, 200 mg to 2000 mg, 300 mg to 2000 mg, 400 mg to 2000 mg, 500 mg to 2000 mg, 600 mg to 2000 mg, 700 mg to 2000 mg, 800 mg to 2000 mg, 900 mg to 2000 mg, or 1000 mg to 2000 mg. In some embodiments, the adenosine derivative, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, is administered to the subject at a dose (effective dose) in the range of 700 mg to 2000 mg.In some implementations, the adenosine derivative or its pharmaceutically acceptable salt, tautomer, or solvate is administered to the subject at a dose (effective dose) ranging from 700 mg to 1200 mg.

[0386] In some embodiments, the adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvation thereof is administered to the subject via intramuscular (IM), subcutaneous (SC), intravenous (IV), oral, implantation, or a combination thereof. In some embodiments, the adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvation thereof is administered to the subject via IM and / or SC. Implantation may include an implantable device or film containing the pharmaceutical compositions disclosed herein. Implantation may include vaginal rings, films, membranes, patches, other devices, or combinations thereof.

[0387] In some embodiments, the methods disclosed herein include administering an effective dose via oral administration and / or injection. In some embodiments, the methods disclosed herein include administering an effective dose via oral administration. In some embodiments, the methods disclosed herein include administering an effective dose to a subject orally (e.g., by taking one or more tablets) once weekly (QW) to once every eight weeks (Q8W). In some embodiments, the methods disclosed herein include administering an effective dose to a subject by injection (e.g., by injecting once or more every month, every two months, every three months, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, every eleven months, or every twelve months). In some embodiments, the effective dose is administered via subcutaneous and / or intramuscular injection.

[0388] In some embodiments, the capsid (CA) inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject simultaneously or sequentially. In some embodiments, the CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject simultaneously. The term "simultaneously" means that the CA inhibitor or composition and the adenosine derivative or composition thereof are administered to the subject at the same time or within a time period of a few seconds (such as 0 to 60 seconds) to a few minutes (such as 1 to 5 minutes). In some embodiments, the CA inhibitor or composition and the adenosine derivative or composition thereof are administered to the subject sequentially within a time period ranging from 0.1 minutes to 72 hours, 0.1 minutes to 48 hours, 0.1 minutes to 24 hours, 0.1 minutes to 12 hours, 0.1 minutes to 4 hours, 0.1 minutes to 1 hour, 0.1 minutes to 30 minutes, 0.1 minutes to about 5 minutes, or 0.1 minutes to about 1 minute. When using tablet forms, one or more tablets comprising the CA inhibitor and one or more tablets comprising the adenosine derivative are administered to the subject by oral ingestion at one time or within the time period described above. Any of the time ranges disclosed herein are inclusive. In some embodiments, the CA inhibitor or composition thereof is administered prior to the administration of the adenosine derivative or composition thereof. In some embodiments, the CA inhibitor or composition thereof is administered after the administration of the adenosine derivative or composition thereof.

[0389] In some embodiments, the capsid (CA) inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject once every 1 to 12 months. In some embodiments, the CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject once every 3 months, once every 4 months, once every 5 months, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, or once every 12 months. In some embodiments, the CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject once every 6 months. The CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject simultaneously or sequentially as described above and hereafter. In some embodiments, the CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject once every 1 to 8 weeks. In some embodiments, the CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject once a week (QW), once every two weeks (Q2W), once every 3 weeks (Q3W), once every 4 weeks (Q4W), once every 5 weeks (Q5W), once every 6 weeks (Q6W), once every 7 weeks (Q7W), or once every 8 weeks (Q8W). In some embodiments, the CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject once a month (QM). In some embodiments, the CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject orally using one or more tablets. In some embodiments, the CA inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject orally using one or more tablets once a week (QW). The administration schedules and frequencies described above and hereafter are collectively referred to herein as “administration schedule(s)” or “administering schedule(s)”, in the plural or singular form.

[0390] In some embodiments, the capsid (CA) inhibitor or composition thereof and the adenosine derivative or composition thereof are administered to the subject simultaneously or sequentially using a combination of oral and injection administration as described above and hereafter. In some embodiments, the CA inhibitor or composition thereof is administered to the subject via injection every 6 months, and the adenosine derivative or composition thereof is administered to the subject orally once a week (QW), once every two weeks (Q2W), once every 3 weeks (Q3W), once every 4 weeks (Q4W), once every 5 weeks (Q5W), once every 6 weeks (Q6W), once every 7 weeks (Q7W), or once every 8 weeks (Q8W). In some embodiments, the CA inhibitor or composition thereof is administered to the subject via injection or orally every month (QM), and the adenosine derivative or composition thereof is administered to the subject orally once a month (QM).

[0391] In some embodiments, the effective dose of the capsid (CA) inhibitor ranges from 300 mg to 2000 mg once a week (QW) to once every 8 weeks (Q8W) and the effective dose of the adenosine derivative or composition thereof ranges from 100 mg to 2000 mg of the adenosine derivative once a week (QW) to once every 8 weeks (Q8W). In some embodiments, the effective dose of the CA inhibitor ranges from 300 mg to 2000 mg once a month (QM) and the effective dose of the adenosine derivative or composition thereof ranges from 100 mg to 2000 mg of the adenosine derivative once a month (QM). In some embodiments, the effective dose of the CA inhibitor ranges from 300 mg to 1200 mg once a month (QM) and the effective dose of the adenosine derivative ranges from 100 mg to 1200 mg of the adenosine derivative once a month (QM).

[0392] In some embodiments, the effective dose of the anti-HIV agent and the adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, provides a synergistic effect in the treatment of a disease, wherein the disease is Acquired Immunodeficiency Syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multi-drug resistant HIV, or an RNA viral infection. In some embodiments, the effective dose of the CA inhibitor and the adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, provides a synergistic effect in the treatment of a disease, wherein the disease is Acquired Immunodeficiency Syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multi-drug resistant HIV, or an RNA viral infection. In some embodiments, the disease is HIV-1. In some embodiments, the CA inhibitor is

[0393] Effective doses of the capsid (CA) inhibitor, alone or in combination, and effective doses of the adenosine derivative disclosed herein are suitable. For example, the effective dose of the CA inhibitor is administered once a week (QW), and the effective dose of the adenosine derivative is administered once a week (QW) to once every 8 weeks (Q8W). In another example, the effective dose of the adenosine derivative is administered once a week (QW), and the effective dose of the CA inhibitor is administered once a week (QW) to once every 8 weeks (Q8W). Once a week (QW) combination is preferred. In some embodiments, the effective dose of the CA inhibitor ranges from 300 mg to 600 mg once a week (QW), and the effective dose of the adenosine derivative ranges from 600 mg to 900 mg of the adenosine derivative once a week (QW). In some embodiments, the effective dose of the CA inhibitor ranges from 300 mg to 600 mg once a week (QW) via one or more oral tablets, and the effective dose of the adenosine derivative ranges from 600 mg to 900 mg of the adenosine derivative once a week (QW) via one or more tablets. In some embodiments, the effective dose of the CA inhibitor ranges from 600 mg to 2000 mg once a month (QM), the effective dose of the adenosine derivative ranges from 600 mg to 2000 mg of the adenosine derivative once a month (QM), or a combination thereof. In some embodiments, the effective dose of the CA inhibitor ranges from 300 mg to 600 mg of ledipasvir once a week (QW), and the effective dose of the adenosine derivative ranges from 100 mg to 2000 mg of the adenosine derivative once a week (QW) to once every 8 weeks (Q8W). In some embodiments, the effective dose of the CA inhibitor ranges from 900 mg to 2000 mg of ledipasvir once a month (QM), and the effective dose of the adenosine derivative ranges from 100 mg to 1200 mg of the adenosine derivative once a week (QW) to 100 mg to 2000 mg of the adenosine derivative once every 8 weeks (Q8W).

[0394] In some embodiments, at least one of the capsid (CA) inhibitor or a composition thereof and the adenosine derivative or a composition thereof is administered to the subject once a month (QM). In some embodiments, the CA inhibitor or a composition thereof is administered to the subject once a month (QM), and the adenosine derivative or a composition thereof is administered to the subject once a week (QW) to once every 12 months (as described above and below). In some embodiments, the adenosine derivative or a composition thereof is administered to the subject once a month (QM), and the CA inhibitor or a composition thereof is administered to the subject once a week (QW) to once every 12 months (as described above and below). In some embodiments, both the adenosine derivative or a composition thereof and the CA inhibitor or a composition thereof are administered to the subject once a month (QM).

[0395] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose of 900 mg once per week (QW) with a CA inhibitor such as GS-6207 (ledipasvir) at a dose ranging from 100 mg to 900 mg once every 3 months.

[0396] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose of 900 mg once per week (QW) with a CA inhibitor such as GS-6207 (ledipasvir) at a dose ranging from 100 mg to 900 mg once every 3 months.

[0397] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose of 900 mg once per week (QW) with a CA inhibitor such as GS-6207 (ledipasvir) at a dose ranging from 100 mg to 900 mg once every 3 months.

[0398] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose of 900 mg once per week (QW) with a CA inhibitor such as GS-6207 (ledipasvir) at a dose ranging from 100 mg to 900 mg once every 3 months.

[0399] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose of 900 mg once per week (QW) with a CA inhibitor such as GS-6207 (ledipasvir) at a dose ranging from 100 mg to 900 mg once every 3 months.

[0400] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose of 900 mg once per week (QW) with a CA inhibitor such as GS-6207 (ledipasvir) at a dose ranging from 100 mg to 900 mg once every 3 months.

[0401] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose of 900 mg once per week (QW) with a CA inhibitor such as GS-6207 (ledipasvir) at a dose ranging from 100 mg to 900 mg once every 3 months.

[0402] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose of 900 mg once per week (QW) with a CA inhibitor such as GS-6207 (ledipasvir) at a dose ranging from 100 mg to 900 mg once every 3 months.

[0403] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose ranging from 600 mg to 2000 mg once every 1 month with a CA inhibitor such as GS-6207 (ledipasvir) at a dose of 900 mg to 2000 mg once every 6 months.

[0404] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose ranging from 600 mg to 1200 mg once every two weeks with a CA inhibitor such as GS-6207 (ledipasvir) at a dose of 900 mg to 2000 mg once every 6 months.

[0405] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose ranging from 600 mg to 1200 mg once every two weeks with a CA inhibitor such as GS-6207 (ledipasvir) at a dose of 900 mg to 2000 mg once every 6 months.

[0406] In some embodiments, an adenosine derivative of the present disclosure is administered to a subject at a dose ranging from 600 mg to 1200 mg once every two weeks with a CA inhibitor such as GS-6207 (ledipasvir) at a dose of 900 mg to 2000 mg once every 6 months.

[0407] In some embodiments, the HIV infection is caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, or multi-drug resistant HIV.

[0408] In some embodiments, the subject is a person with high HIV treatment experience, a person who has received a large amount of treatment and has multi-drug resistant HIV, a person who is HIV positive, a person who is exposed to pre-exposure prophylaxis (PrEP) by taking one or more anti-HIV drugs, a woman at risk of HIV or a man at risk of HIV.

[0409] In some embodiments, the capsid inhibitor and the adenosine derivative, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, disclosed herein, when administered to a subject according to the methods disclosed herein, provide synergistic antiviral activity in treating HIV, AIDS, or RNA viruses. In some embodiments, the synergistic antiviral activity is measured by synergy volume. In some embodiments, a synergy volume of 50-100 indicates synergistic antiviral activity. In some embodiments, a synergy volume >100 indicates highly synergistic antiviral activity. As used herein, synergy is achieved when the combined effect of the adenosine derivative and the capsid inhibitor is greater than the additive effect of each drug alone.

[0410] In some embodiments, the methods of the present disclosure further comprise measuring a sample of the subject to determine a measured level of a target drug in the sample, wherein the target drug can have the formula (T-1):

[0411]

[0412] an isomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, X is a halogen selected from the group consisting of F, Cl, Br, and I. In some embodiments, X is I.

[0413] In some embodiments, the target drug has the formula (T-1A):

[0414]

[0415] an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0416] In some embodiments, the target drug is (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (also known as 4'-ethynyl-2-fluoro-2'-deoxyadenosine, EFdA) or a pharmaceutically acceptable salt thereof.

[0417] In some embodiments, the target drug is a degradation or metabolite of compound (T-1), (T-1A), or EFdA.

[0418] The sample is a blood sample, a urine sample, a bodily fluid sample, a tissue sample, or a combination thereof from a subject, such as a patient.

[0419] The measured level of the target drug is determined using an analytical method known to one of skill in the art, such as, but not limited to, HPLC, GC, MS, GC-MS, or a combination thereof.

[0420] The methods of the present disclosure further comprise, if the measured level of the target drug is different from the predetermined target level of the target drug, adjusting the effective dose to produce a modified effective dose, and administering the modified effective dose to the subject.

[0421] In some embodiments, the target drug is a compound of formula (T-1A):

[0422]

[0423] an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0424] In some embodiments, the target drug is (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (also known as 4'-ethynyl-2-fluoro-2'-deoxyadenosine, EFdA), or a pharmaceutically acceptable salt thereof.

[0425] In some embodiments, the target drug is a degradation or metabolite of compound (T-1), (T-1A), or EFdA.

[0426] The sample can be a blood sample, a urine sample, a bodily fluid sample, a tissue sample, or a combination thereof from a subject, such as a patient.

[0427] The measured level of the target drug can be determined with an analytical method known to one of skill in the art, such as, but not limited to, HPLC, GC, MS, GC-MS, or a combination thereof.

[0428] The method of the present disclosure can further comprise adjusting the effective dose to produce a modified effective dose if the measured level of the target drug is different from the predetermined target level of the target drug, and administering the modified effective dose to the subject.

[0429] In some embodiments, the method of the present disclosure further comprises administering to the subject an effective dose of one or more additional anti-HIV agents selected from the group consisting of abacavir, abacavir sulfate, lamivudine, amprenavir, atazanavir, atazanavir sulfate, AZT, bevirimat, cabotegravir, darunavir, dideoxycytidine, dideoxyinosine, doravirine, dorzolamide, efavirenz, emtricitabine, fumarate tenofovir disoproxil, tenofovir alafenamide, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, etifelbavir, incivek, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobicistat, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, tipranavir, and vicriviroc, or a combination thereof. Other anti-HIV agents identified or developed, or combinations thereof, can also be suitable.

[0430] The present disclosure further relates to the use of any of the adenosine derivatives and capsid (CA) inhibitors disclosed herein, optionally with one or more pharmaceutically acceptable carriers, in the manufacture of a medicament for the treatment of a disease, wherein the disease is Acquired Immune Deficiency Syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multi-drug resistant HIV, or an RNA viral infection. Any of the foregoing adenosine derivatives can be suitable. Any of the foregoing pharmaceutically acceptable carriers can be suitable.

[0431] The present disclosure further relates to a method for preventing an infection in a subject in need thereof, the method comprising administering to the subject an effective dose of any of the pharmaceutical compositions or therapeutic compositions disclosed herein, wherein the subject does not have detectable symptoms of the infection. In some embodiments, the infection comprises a disease selected from the group consisting of Acquired Immune Deficiency Syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multi-drug resistant HIV, an RNA viral infection, or a combination thereof.

[0432] Detectable symptoms can include, but are not limited to, symptoms of Acquired Immune Deficiency Syndrome (AIDS), infection with the HIV virus (including wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multi-drug resistant HIV), or a combination thereof. Detection of the HIV virus can be accomplished by PCR, reverse PCR, immuno-detection of antigens or antibodies associated with AIDS or HIV.

[0433] Without being bound by any particular theory, it is an advantage of the compositions and methods of the present application that the adenosine derivatives disclosed herein can be rapidly converted to the target drug. As demonstrated below in the Examples, greater than about 60% of the adenosine derivatives of the present disclosure are surprisingly and unexpectedly converted to the target drug within about 30 minutes of contact with human plasma.

[0434] One advantage of the combination of an adenosine derivative and a capsid (CA) inhibitor such as GS-6207 (ledipasvir) can be the potential benefit of preventing HIV infection via pre-exposure prophylaxis (or PrEP), a way for people who do not have HIV but are at substantial risk of becoming infected with HIV to prevent HIV infection by routinely taking medication. Currently, a drug available under the brand name Truvada contains two drugs (tenofovir and emtricitabine) that can be used in combination with other drugs to treat HIV. These drugs can work to prevent the virus from establishing a permanent infection when a person is exposed to HIV. The combination of an adenosine derivative and a capsid (CA) inhibitor such as GS-6207 (ledipasvir) disclosed herein can provide additional PrEP for HIV prevention, preferably on a once-weekly (QW) schedule. PrEP is known to be very effective at preventing HIV when taken consistently. If it is not taken consistently, PrEP is much less effective. The once-weekly (QW) schedule of the combination of an adenosine derivative and a capsid (CA) inhibitor such as GS-6207 (ledipasvir) disclosed herein can provide convenience and help maintain consistent medication intake, and thereby help HIV prevention.

[0435] Numbered embodiments of the disclosure

[0436] Other subject matter contemplated by the present disclosure is set forth in the following numbered embodiments:

[0437] 1. A method of treating or preventing an HIV infection comprising administering to a subject in need thereof an effective amount of:

[0438] (a) a capsid inhibitor; and

[0439] (b) an adenosine derivative, wherein the adenosine derivative is a compound of Formula (1):

[0440]

[0441] or a pharmaceutically acceptable salt or solvate thereof,

[0442] wherein:

[0443] R 1 , R 1 , and R 2 each independently is H, -C(O)N(R 3 )(R 3’ ), -C(O)OR 4 , -R 5 , -L 1 -R 5 , or -Z-L 4 -R 5 , provided that R 1 and R 2at least one of R, R, and R is not H;

[0444] R 3 , R 3’ , and R 4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0445]

[0446] R 6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, or heteroaryl;

[0447] -L 1 -R 5 is -(C1-C10 alkylene)-N(R 7 )-R 5 , -(C1-C10 alkylene)-O-R 5 , -(C1-C10 alkylene)-S-R 5 , -(C2-C10 alkenylene)-N(R 7 )-R 5 , -(C2-C10 alkenylene)-O-R 5 , -(C2-C10 alkenylene)-S-R 5 , -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5 , -C(O)O-L 2 -S-R 5 , -C(O)O-L 2 -C(O)O-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -O-R 5 , -C(O)O-L 2 -C(O)N(R 7)-L 3 -S-R 5 , -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -O-R 5 , -C(O)N(R 7 )-L 2 -S-R 5 , -C(O)N(R 7 )-L 2 -C(O)O-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -, -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 , -C(O)O-L 2 -N(R 7 )C(O)O-R 5 , -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -O-R 5 or -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -S-R 5 ;

[0448] -Z- is -C(O)-, -C(O)O- or -C(O)N(R 7 )-;

[0449] -L 4 -R 5 is -(C1-C10alkylene)-N(R 7 )-R 5 , -(C1-C10alkylene)-O-R 5 , -(C1-C10alkylene)-S-R 5 , -(C2-C10alkenylene)-N(R 7 )-R 5 , -(C2-C10alkenylene)-O-R 5 or -(C2-C10alkenylene)-S-R 5 ;

[0450] R 7 and R 8 are each independently H, C1-C10alkyl or C2-C10alkenyl;

[0451] R 9 is independently H, -F, C1-C10alkyl or C2-C10alkenyl;

[0452] L 2 and L 3 are each divalent -(C1-C10alkylene)-, or -(C2-C10alkenylene)-; and

[0453] X is a halogen atom.

[0454] 2. The method of embodiment 1, wherein R 1 and R 2 are each independently H, -R 5 , -L 1 -R 5 or -Z-L 4 -R 5 .

[0455] 3. The method of embodiment 1 or 2, wherein R 1 and R 2 are each independently H, -R 5 or -L 1 -R 5 .

[0456] 4. The method of any one of embodiments 1-3, wherein R 1 is -L 1 -R 5 .

[0457] 5. The method of any one of embodiments 1-4, wherein R 1’ is -L 1 -R 5 .

[0458] 6. The method of any one of embodiments 1-4, wherein R 1’ is H.

[0459] 7. The method of any one of embodiments 1-6, wherein -L 1 -R 5 is selected from the group consisting of: -(Ci-Cio alkylene)-N(R 7 )-R 5 , -(Ci-Cio alkylene)-O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5 , -C(O)O-L 2 -C(O)O-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)O-R 5 , -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2-C(O)O-R 5 and -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -.

[0460] 8. The method of any one of embodiments 1-7, wherein -L 1 -R 5 is selected from the group consisting of -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -N(R 7 )C(O)O-R 5 , -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , and -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -.

[0461] 9. The method of any one of embodiments 1-7, wherein -L 1 -R 5 is -C(O)O-R 5 .

[0462] 10. The method of any one of embodiments 1-9, wherein R 2 is H.

[0463] 11. The method of any one of embodiments 1-10, wherein R 3 and R 3’ are each independently H, C1-C10 alkyl, or C3-C6 cycloalkyl.

[0464] 12. The method of any one of embodiments 1-10, wherein R 3 and R 3’ each independently is H or C1-C3 alkyl.

[0465] 13. The method of embodiment 1, wherein R 4 is C1-C10 alkyl or C3-C6 cycloalkyl.

[0466] 14. The method of embodiment 1 or 2, wherein -Z-L 4 -R 5 is Z-(C1-C10 alkylene)-N(R 7 )-R 5 or Z-(C1-C10 alkylene)-O-R 5 .

[0467] 15. The method of any one of embodiments 1, 2, and 14, wherein -Z- is -C(O)N(R 7 )-.

[0468] 16. The method of any one of embodiments 1-15, wherein R 6 is C1-C5 alkyl.

[0469] 17. The method of embodiment 16, wherein R 6 is methyl.

[0470] 18. The method of any one of embodiments 1-17, wherein R 7 is H or C1-C5 alkyl.

[0471] 19. The method of embodiment 18, wherein R 7 is H or methyl.

[0472] 20. The method of any one of embodiments 1-19, wherein R 8 is H or C1-C5 alkyl.

[0473] 21. The method of embodiment 20, wherein R 8 is H or methyl.

[0474] 22. The method of any one of embodiments 1-21, wherein R 9 is H or Me.

[0475] 22a. The method of embodiment 22, wherein R 9 is H.

[0476] 23. The method of any one of embodiments 1-22a, wherein X is F.

[0477] 24. The method of embodiment 1, wherein the adenosine derivative has the structure:

[0478]

[0479] Formula (4-C):

[0480]

[0481] Formula (6-A):

[0482]

[0483] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0484] 25. The method of embodiment 1, wherein the adenosine derivative is: ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl ((5-methyl-2-oxo-l,3-dioxol-4-yl)methyl) carbonate,

[0485] 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-l,3-dioxol-2-one, or

[0486] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-((((5-methyl-2-oxo-l,3- dioxol-4-yl)methoxy)carbonyl)oxy)tetrahydrofuran-2-yl)methyl ((5-methyl-2-oxo-l,3- dioxol-4-yl)methyl) carbonate,

[0487] or a pharmaceutically acceptable salt or solvate thereof.

[0488] 26. The method of any one of embodiments 1-25, wherein the adenosine derivative is an in vivo reverse transcriptase inhibitor activity, an in vivo reverse transcriptase chain terminator activity, an in vivo DNA translocation inhibitor activity, or a combination thereof.

[0489] 27. The method of any one of embodiments 1-26, wherein the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

[0490] 28. The method of any one of embodiments 1-27, wherein the capsid (CA) inhibitor and the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, are administered to the subject simultaneously or sequentially.

[0491] 29. The method of embodiment 28, wherein the CA inhibitor and the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, are administered to the subject sequentially over a period of time ranging from 0.1 minutes to 72 hours.

[0492] 30. The method of any one of embodiments 1-29, wherein the CA inhibitor and the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, are administered to the subject once a day to once every 12 months.

[0493] 31. The method of embodiment 30, wherein the CA inhibitor and the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, are administered to the subject once every 6 months.

[0494] 32. The method of embodiment 30, wherein the CA inhibitor and the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, are administered to the subject once every 1 to 8 weeks.

[0495] 33. The method of embodiment 30, wherein at least one of the CA inhibitor and the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject once a month.

[0496] 34. The method of any one of embodiments 1-33, wherein the CA inhibitor is a compound having the structure:

[0497]

[0498] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0499] 35. The method of embodiment 34, wherein the effective dose of the CA inhibitor is a single dose ranging from 100 mg to 2000 mg administered every 6 months.

[0500] 36. The method of embodiment 34, wherein the effective dose of the CA inhibitor ranges from 200 mg to 1200 mg administered every 1 to 7 days.

[0501] 37. The method of embodiment 34, wherein the effective dosage of the CA inhibitor ranges from 300 mg to 1200 mg administered once a week (QW) and the effective dosage of the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, ranges from 100 mg to 2000 mg administered once a week (QW) to once every 8 weeks (Q8W).

[0502] 38. The method of embodiment 34, wherein the effective dosage of the CA inhibitor ranges from 900 mg to 2000 mg administered once a month (QM) and the effective dosage of the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, ranges from 100 mg to 2000 mg administered once a week (QW) to once every 8 weeks (Q8W).

[0503] 39. The method of any one of embodiments 1-38, wherein the HIV infection is caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, or multi-drug resistant HIV.

[0504] 40. The method of any one of embodiments 1-39, wherein the subject is a person with a high HIV treatment experience, a person who has received a large amount of treatment and has multi-drug resistant HIV, a person who is HIV positive, a person who is exposed to pre-exposure prophylaxis (PrEP) by taking one or more anti-HIV drugs, a woman at risk of HIV, or a man at risk of HIV.

[0505] 40a. The method of any one of embodiments 1-40, wherein the capsid inhibitor is administered orally.

[0506] 40b. The method of any one of embodiments 1-40, wherein the capsid inhibitor is administered parenterally.

[0507] 40c. The method of embodiment 40b, wherein the parenteral administration is by intramuscular and / or subcutaneous injection.

[0508] 40d. The method of any one of embodiments 1-40, wherein the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

[0509] 40e. The method of any one of embodiments 1-40, wherein the adenosine derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered parenterally.

[0510] 40f. The method of embodiment 40e, wherein the parenteral administration is by intramuscular and / or subcutaneous injection.

[0511] 41. A pharmaceutical composition comprising an effective amount of:

[0512] (a) Capsid (CA) inhibitors; and

[0513] (b) Adenosine derivatives or their pharmaceutically acceptable salts, tautomers or solvates.

[0514] The adenosine derivative thereon is a compound having the structure of formula (1):

[0515]

[0516] in,

[0517] R 1 R 1 'and R 2 Each independently represents H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 or -ZL 4 -R 5 The premise is R 1 and R 2 At least one of them is not H;

[0518] R 3 R 3’ and R 4 Each of them is independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0519] R 5 yes:

[0520]

[0521] R 6 It is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0522] -L 1 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkylene)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5, -(C2-C10alkenylene)-O-R 5 , -(C2-C10alkenylene)-S-R 5 , -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5 , -C(O)O-L 2 -S-R 5 , -C(O)O-L 2 -C(O)O-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -O-R 5 , -C(O)O-L 2 -C(O)N(R 7 )-L 3 -S-R 5 , -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -O-R 5 , -C(O)N(R 7 )-L 2 -S-R 5 , -C(O)N(R 7 )-L 2 -C(O)O-R 5 , -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -, -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R7 )-R 5 -C(O)OL 2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -OR 5 or -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -SR 5 ;

[0523] -Z- is -C(O)-, -C(O)O-, or -C(O)N(R) 7 )-;

[0524] -L 4 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkyl)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5 or -(C2-C10 imidene)-SR 5 ;

[0525] R 7 and R 8 Each is independently H, C1-C10 alkyl, or C2-C10 alkenyl;

[0526] R 9 It can be independently H, -F, C1-C10 alkyl or C2-C10 alkenyl;

[0527] L 2 and L 3 each is -(C1-C10alkylene)- or -(C2-C10alkenylene)-; and

[0528] X is a halogen atom.

[0529] 42. The composition of embodiment 41, wherein R 1 and R 2 each independently is H, -R 5 , -L 1 -R 5 , or -Z-L 4 -R 5 .

[0530] 43. The composition of embodiment 41 or 42, wherein R 1 and R 2 each independently is H, -R 5 , or -L 1 -R 5 .

[0531] 44. The composition of any one of embodiments 41-43, wherein R 1 is -L 1 -R 5 .

[0532] 45. The composition of any one of embodiments 41-44, wherein R 1’ is -L 1 -R 5 .

[0533] 46. The composition of any one of embodiments 41-44, wherein R 1’ is H.

[0534] 47. The composition of any one of embodiments 41-46, wherein -L 1 -R 5 is selected from the group consisting of -(C1-C10alkylene)-N(R 7 )-R 5 , -(C1-C10alkylene)-O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -O-R 5 , -C(O)O-L 2 -C(O)O-R 5 , -C(O)O-L2 -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)O-R 5 , -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -C(O)O-R 5 , and -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -.

[0535] 48. The composition of any of embodiments 41-47, wherein -L 1 -R 5 is selected from the group consisting of -C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )-R 5 , -C(O)O-L 2 -N(R 7 )C(O)O-R 5 , -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 , -C(O)O-L 2 -N(R 7)C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , and -C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -.

[0536] 49. The composition of any of embodiments 41-47, wherein -L 1 -R 5 is -C(O)O-R 5 .

[0537] 50. The composition of any of embodiments 41-49, wherein R 2 is H.

[0538] 51. The composition of any of embodiments 41-50, wherein R 3 and R 3’ are each independently H, C1-C10 alkyl, or C3-C6 cycloalkyl.

[0539] 52. The composition of any of embodiments 41-50, wherein R 3 and R 3’ are each independently H or C1-C3 alkyl.

[0540] 53. The composition of embodiment 41, wherein R 4 is C1-C10 alkyl or C3-C6 cycloalkyl.

[0541] 54. The composition of embodiment 41 or 42, wherein -Z-L 4 -R 5 is Z-(C1-C10 alkylene)-N(R 7 )-R 5 or Z-(C1-C10 alkylene)-O-R 5 .

[0542] 55. The composition of embodiment 54, wherein -Z- is -C(O)N(R 7 )-.

[0543] 56. The composition of any one of embodiments 41-55, wherein R 6 is C1-C5 alkyl.

[0544] 57. The composition of embodiment 56, wherein R 6 is methyl.

[0545] 58. The composition of any one of embodiments 41-57, wherein R 7 is H or C1-C5 alkyl.

[0546] 59. The composition of embodiment 58, wherein R 7 is H or methyl.

[0547] 60. The composition of any one of embodiments 41-59, wherein R 8 is H or C1-C5 alkyl.

[0548] 61. The composition of embodiment 60, wherein R 8 is H or methyl.

[0549] 62. The composition of any one of embodiments 41-61, wherein R 9 is H or Me.

[0550] 62a. The composition of embodiment 62, wherein R 9 is H.

[0551] 63. The composition of any one of embodiments 41-62a, wherein X is F.

[0552] 64. The composition of embodiment 41, wherein the adenosine derivative is a compound having the structure:

[0553] Formula (2):

[0554]

[0555] Formula (3):

[0556]

[0557] Formula (4):

[0558]

[0559] Formula (5):

[0560]

[0561] Formula (6):

[0562]

[0563] Formula (7):

[0564]

[0565] Formula (8):

[0566]

[0567] Formula (4-B):

[0568]

[0569] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0570] 65. The composition of embodiment 41, wherein the adenosine derivative is a compound of Formula (2-A):

[0571]

[0572] Formula (3-A):

[0573]

[0574] Formula (4-A):

[0575]

[0576] Formula (5-A):

[0577]

[0578] Formula (6-A):

[0579]

[0580] Formula (7-A):

[0581]

[0582] Formula (8-A):

[0583]

[0584] Formula (4-C):

[0585]

[0586] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0587] 66. The composition of any one of embodiments 41-65, wherein the adenosine derivative is ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl ((5-methyl-2-oxo-l,3-dioxol-4-yl)methyl) carbonate, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-l,3-dioxol-2-one, ((2R,3S,5R)-5-(6-amino- 2-fluoro-9H-purin-9-yl)-2-ethynyl-3-((((5-methyl-2-oxo-l,3-dioxol-4-yl)methoxy) carbonyl)oxy)tetrahydrofuran-2-yl)methyl ((5-methyl-2-oxo-l,3-dioxol-4-yl)methyl) carbonate, or a combination thereof.

[0588] 67. The composition of embodiment 41, wherein R 5 , -L 1 -R 5 or -Z-L 4 -R 5 is:

[0589]

[0590]

[0591] 68. The composition of any one of embodiments 41-67, wherein the CA inhibitor is a compound having the structure:

[0592]

[0593] or a pharmaceutically acceptable salt or solvate thereof.

[0594] 69. The composition of any one of embodiments 41-68, further comprising a pharmaceutically acceptable carrier.

[0595] 70. The composition of any one of embodiments 41-69, wherein the effective dose of the adenosine derivative is 200 mg to 2000 mg and the effective amount of the capsid inhibitor is 300 mg to 2000 mg.

[0596] 71. The composition of any one of embodiments 41-70, wherein the pharmaceutical composition is suitable for oral administration.

[0597] 72. The composition of any one of embodiments 41-70, wherein the pharmaceutical composition is suitable for parenteral administration.

[0598] 73. The composition of embodiment 72, wherein the parenteral administration is by intramuscular and / or subcutaneous injection.

[0599] Examples

[0600] The application is further defined by the following non-limiting examples. It should be understood that these examples, while indicating preferred embodiments of the application, are given by way of illustration only. From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of the application, and without departing from the spirit and scope thereof, can make various changes and modifications of the application to adapt it to various uses and conditions.

[0601] Properties of the adenosine derivatives of the disclosure

[0602] Properties of the adenosine derivatives are listed in Table 1.

[0603] Table 1. Nomenclature and properties.

[0604]

[0605]

[0606] Example 1:

[0607] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2- yl)methyl isopropylcarbamate

[0608]

[0609] Preparation of [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purin-9-yl]-2- ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (4-nitrophenyl) ester

[0610]

[0611] To a solution of tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]carbamate (80 mg, 0.203 mmol, 1 eq) in pyridine (0.8 mL) was added chloroformic acid (4-nitrophenyl) ester (41 mg, 0.203 mmol, 1 eq) at 10 °C. The mixture was stirred at 10 °C for 16 h, water (10 mL) was added and extracted with EtOAc (10 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give crude carbonic acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purin-9-yl]-2-ethynyl-3- hydroxy-tetrahydrofuran-2-yl] methyl ester (4-nitrophenyl) ester (114 mg, crude) as a yellow oil which was used in the next reaction without further purification. LCMS (ESI) m / z, C 24 H 23 FN6O9: Calculated 558.2, Found (M+H) + : 559.1.

[0612] Preparation of tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (isopropylcarbamoyloxymethyl)tetrahydrofuran-2-yl]-2-fluoropurin-6-yl]carbamate

[0613]

[0614] To a mixture of carbonic acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2- fluoro-purin-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl] methyl ester (4- nitrophenyl) ester (10 mg, 0.018 mmol, 1 eq) and triethylamine (3.6 mg, 0.035 mmol, 2 eq) in THF (0.5 mL) was added propan-2-amine (1.3 mg, 0.021 mmol, 1.2 eq). The mixture was stirred at 15 °C for 2.5 h, water (5 mL) was added and extracted with EtOAc (2 x 10 mL). The organic layer was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 15%-45%, 11 min) to give tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (isopropylcarbamoyloxymethyl)tetrahydrofuran-2-yl]-2-fluoropurin-6-yl]carbamate (3.6 mg, 45.0% yield) as a white solid. LCMS (ESI) m / z, C21 H 27 FN606: Calculated 478.2, measured (M+H) + : 479.3; (M+Na) + : 501.2.

[0615] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl isopropylcarbamate

[0616]

[0617] To a solution of tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (isopropylcarbamoyloxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6- yl]carbamate (3.6 mg, 0.0075 mmol, 1 eq) in DCM (0.5 mL) was added TFA (77 mg, 0.68 mmol, 0.05 mL, 89.8 eq) at 10 °C. The mixture was stirred at 10 °C for 40 h. The mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Agela DuraShell 150 mm x 25 mm x 5 um; mobile phase: [water (0.05% HC1) - ACN]; B%: 10% - 40%, 8 min) to give ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl isopropylcarbamate (1.2 mg, 40.0% yield) as a white solid. LCMS (ESI) m / z, C 16 H 19 FN604: Calculated 378.2, measured (M+H) + : 379.3; (M+Na) + : 401.2. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 1H NMR (DMSO-d6, 400 MHz) 8.27 (s, 1H), 7.85 (br s, 2H), 7.13 (br d, J = 4.8 Hz, 1H), 6.24 (dd, J = 7.6, 5.2 Hz, 1H), 4.55 (br t, J = 6.8 Hz, 1H), 4.35 (br d, J = 11.6 Hz, 1H), 4.00 (br d, J = 11.6 Hz, 1H), 3.61 (s, 1H), 2.70-2.79 (m, 1H), 2.40-2.43 (m, 1H), 0.98-1.07 (m, 7H). 19F NMR(376MHz,DMSO-d6)δ(ppm)-51.79(s).

[0618] Example 2:

[0619] Preparation of methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester

[0620]

[0621] Methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester was prepared using the same procedure as isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, but with propane-2-amine replaced by methylamine. LCMS(ESI) m / z, C 14 H 15 FN6O4: Calculated value 350.1, measured value (M+H) + :351.2. 1 HNMR(400MHz,DMSO-d6)δ(ppm)8.26(s,1H),7.87(br s,2H),7.13(br d,J=4.4Hz,1H),6.24(dd,J=7.6,5.0Hz,1H),5.76(br d,J=4.4Hz,1H),4.55(br d,J=5.2Hz,1H),4.35(d,J=11.6Hz,1H),4.03(d,J=11.6Hz,1H),3.60(s,1H),2.70-2.79(m,1H),2.54(s,3H),2.40-2.45(m,1H). 19 F NMR(376MHz,DMSO-d6)δ(ppm)-51.75(s).

[0622] Example 3:

[0623] (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate isopropyl ester

[0624]

[0625] Preparation of 4-methylbenzoic acid (2R, 3S, 5R)-5-[6-[bis(isopropoxy carbonyl) amino]-2-fluoro-9H-purin-9-yl]-2-ethynyl-2-(((4-methylbenzoyl)oxy) methyl)- tetrahydrofuran-3-yl ester

[0626]

[0627] To a mixture of 4-methylbenzoic acid [(2R, 3S, 5R)-5-(6-amino-2-fluoro-purin-9-yl)- 2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (50 mg, 0.094 mmol, 1 eq) and Et3N (10 mg, 0.094 mmol, 1 eq) in DCM (1 mL) was added isopropyl chloroformate (23 mg, 0.19 mmol, 2 eq) at 0 °C, the mixture was stirred at 15 °C for 16 h. The mixture was concentrated under reduced pressure and added 2 mL water, extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure to give 4-methylbenzoic acid (2R, 3S, 5R)-5-(6-(bis(isopropoxy carbonyl) amino)-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(((4-methylbenzoyl)oxy) methyl) tetrahydrofuran-3-yl ester as a crude product, which was used in the next reaction without further purification. LCMS (ESI) m / z, C 36 H 36 FN5O9: Calc. 701.3, Found (M+H) + : 702.1.

[0628] Preparation of isopropyl (9-((2R, 4S, 5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate

[0629]

[0630] To a solution of (2R,3S,5R)-5-[6-[bis(isopropoxy carbonyl)amino]-2-fluoro-9H-purin-9-yl]-2- ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl] 4-methylbenzoate (66 mg, 0.094 mmol) in THF (1 mL) at -20 °C was added NaOMe (34 mg, 0.19 mmol, 30%, 2 eq) and the resulting mixture was stirred at -20 °C for 16 h. Additional NaOMe (17 mg, 0.095 mmol, 30%, 1 eq) was added and the mixture was stirred at -20 °C for another 40 h. The mixture was neutralized with AcOH (0.1 mL), concentrated under reduced pressure and purified by flash silica gel chromatography (Silica Flash Column, eluted with 0-8% MeOH / DCM gradient at 20 mL / min) and again by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150x30 5u; Mobile Phase: [Water (10 mM NH4HC03)-ACN]; B%: 5%-30%, 7 min) to give isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate (3.5 mg, 11% yield) as a white solid. LCMS (ESI) m / z, C 4g Silica Flash Column, eluted with 0-8% MeOH / DCM gradient at 20 mL / min) and again by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150x30 5u; Mobile Phase: [Water (10 mM NH4HC03)-ACN]; B%: 5%-30%, 7 min) to give isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate (3.5 mg, 11% yield) as a white solid. LCMS (ESI) m / z, C 16 H 18 FN5O9: calc. 379.1 (meas. (M+Na + : 402.1). 1 H NMR (400 MHz, CDC13) d (ppm) 8.17 (s, 1H), 7.98 (s, 2H), 6.41 (dd, J = 8.8, 5.6 Hz, 1H), 5.13 (dt, J = 12.4, 6.4 Hz, 1H), 5.04 (dd, J = 11.0, 3.0 Hz, 1H), 4.70-4.75 (m, 1H), 4.09 (dd, J = 12.4, 2.4 Hz, 1H), 3.84-3.93 (m, 1H), 3.06-3.15 (m, 1H), 2.83 (s, 1H), 2.48-2.56 (m, 2H), 1.36 (d, J = 6.0 Hz, 6H). 19 F NMR (376 MHz, CDC13) d (ppm) -46.89 (s).

[0631] Example 4 (Method 1):

[0632] Carbonic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl ester ((5-methyl-2-oxo-1,3- dioxol-4-yl)methyl) ester

[0633] Carbonic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl ester ((5-methyl-2-oxo-1,3- dioxol-4-yl)methyl) ester

[0634]

[0635] Preparation of S-ethyl chlorothioformate

[0636]

[0637] To a mixture of ethanethiol (16 g, 257.5 mmol, 19.1 mL, 1 eq), triethylamine (26.1 g, 257.5 mmol, 35.8 mL, 1 eq) in THF (1 L) at -15 °C was added bis(trichloromethyl)carbonate (76.4 g, 257.5 mmol, 1 eq) in THF (50 mL). The mixture was warmed to 18 °C and stirred at 18 °C for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to give S-ethyl chlorothioformate (13 g, crude) as a yellow oil which was used directly in the next reaction without further purification.

[0638] To a mixture of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (13 g, 99.9 mmol, 1 eq) in Et2O (800 mL) at 0 °C was added pyridine (7.90 g, 99.9 mmol, 8.1 mL, 1 eq) and S-ethyl chlorothioformate (12.45 g, 99.9 mmol, 1.0 eq) in Et2O (200 mL) and the mixture was stirred at 0 °C for 1 h and warmed to 18 °C and stirred at 18 °C for 16 h. The mixture was filtered and concentrated in vacuo, then taken up in DCM (150 mL) and washed with saturated aqueous NaHCO3 (150 mL x 2), water (150 mL x 2). The mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (Silica Flash Column, eluted with 0-15% ethyl acetate / petroleum ether gradient at 70 mL / min) to give ethyl thioformate (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (9.2 g, 42.2% yield) as a light yellow oil. 120 g Silica Flash Column, eluted with 0-15% ethyl acetate / petroleum ether gradient at 70 mL / min) to give ethyl thioformate (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (9.2 g, 42.2% yield) as a light yellow oil. 1H NMR (400 MHz, CDC13) δ 4.95 (s, 2H), 2.89 (q, J = 7.2 Hz, 2H), 2.19 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0639] Preparation of chloroformic acid (5-methyl-2-oxo-1,3-indenyl-4-yl)methyl ester

[0640]

[0641] To a mixture of ethylsulfanylformic acid (5-methyl-2-oxo-1,3-indenyl-4-yl)methyl ester (500 mg, 2.29 mmol, 1 eq) in DCM (50 mL) was added sulfuryl chloride (618.5 mg, 4.58 mmol, 0.46 mL, 2 eq). The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was washed with water (50 mL x 2), 5% aq Na2CO3(50 mL x 2), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give chloroformic acid (5-methyl-2-oxo-1,3-indenyl-4-yl)methyl ester (350 mg, crude) as a yellow oil. The product was dissolved in 10 mL DCM and stored in the freezer.

[0642] Preparation of tert-butyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(((((5-methyl-2-oxo-1,3- indenyl-4-yl)methoxy)carbonyl)oxy)methyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6- yl)carbamate

[0643]

[0644] To a mixture of tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]carbamate (100 mg, 0.25 nmol, 1 eq) in pyridine (2 mL) at 20 °C was added chloroformic acid (5-methyl-2-oxo-1,3- indenyl-4-yl)methyl ester (140 mg, 0.73 mmol, 4 mL, 2.86 eq, 35 mg / mL in DCM), the mixture was stirred at 20 °C for 16 h. The mixture was concentrated under reduced pressure, and purified by flash silica gel chromatography (DCM / MeOH, 95 / 5) to give tert-butyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(((((5-methyl-2-oxo-1,3-indenyl-4- yl)methoxy)carbonyl)oxy)methyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate (100 mg, 0.25 mmol, 1 eq) as a white solid. 4g Silica Flash Column, eluted with a gradient of 0-5% MeOH / DCM at 25 mL / min) to give [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purin-9-yl]-2-ethynyl-3- hydroxy-tetrahydrofuran-2-yl]methyl carbonote (5-methyl-2-oxo-1,3-dioxol-4- yl)methyl ester as a yellow solid (45 mg, 32.2% yield). LCMS (ESI) m / z, C 23 H 24 FN5O6: calc. 449.1, found (M+H) 10 : 450.1. + : 550.1.

[0645] Preparation of Carbonic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2- ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester ((5-methyl-2-oxo-1,3- dioxol-4-yl)methyl) ester

[0646]

[0647] To a mixture of Carbonic acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2- fluoro-purin-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (5- methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (45 mg, 0.082 mmol, 1 eq) in toluene (1 mL) at 20 °C was added TFA (154 mg, 1.35 mmol, 0.1 mL, 16.5 eq). The mixture was stirred at 20 °C for 16 h and then concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Column: Boston Green ODS 150x30mmx5um; Mobile Phase: [water(0.2%FA)-ACN]; B%: 13%-43%, 8 min) to give Carbonic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2- ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester ((5-methyl-2-oxo-1,3- dioxol-4-yl)methyl) ester as a white solid (11 mg, 25.4% yield). LCMS (ESI) m / z, C 18 H 16 FN5O6: calc. 449.1, found (M+H) + : 450.1. 19 F NMR (376 MHz, CD3OD) d (ppm) -53.00 (s). 1H NMR (400 MHz, CD3CN) 7.92 (s, 1H), 6.41-6.21 (m, 3H), 4.87 (d, J = 5.2 Hz, 2H), 4.77-4.67 (m, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.30 (d, J = 11.6 Hz, 1H), 3.75 (d, J = 6.4 Hz, 1H), 3.00 (s, 1H), 2.89-2.81 (m, 1H), 2.61-2.52 (m, 1H), 2.10 (s, 3H).

[0648] Example 4 (Method 2):

[0649] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2- yl)methyl) carbonate (4-nitrophenyl) ester

[0650]

[0651] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl) carbonate (4-nitrophenyl) ester

[0652]

[0653] To a mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ol (100 mg, 0.34 mmol, 1 eq) in pyridine (5 mL) was added chloroformic acid (4-nitrophenyl) ester (82 mg, 0.41 mmol, 1.2 eq) and the mixture was stirred at 26 °C for 16 h. Chloroformic acid (4-nitrophenyl) ester (82 mg, 0.41 mmol, 1.2 eq) was added and the mixture was stirred at 26 °C for 24 h. The reaction solution was purified by flash column chromatography (Silica, eluted with 0-5% DCM / MeOH gradient at 25 mL / min) to give ((2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy- tetrahydrofuran-2-yl)methyl) carbonate (4-nitrophenyl) ester (80 mg, 51.2% yield) as a white solid. LCMS (ESI) m / z, C 4g Silica Flash Column, eluted with 0-5% DCM / MeOH gradient at 25 mL / min) to give ((2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2- yl)methyl) carbonate (4-nitrophenyl) ester (80 mg, 51.2% yield) as a white solid. LCMS (ESI) m / z, C 19 H 15 FN607: Calc. 458.4, Found (M+H) +:459.1.

[0654] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl carbonate ((5-methyl-2-oxo-1,3-dioxol-4- yl)methyl) ester

[0655]

[0656] To a mixture of [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3- hydroxy-tetrahydrofuran-2-yl]methyl carbonate (4-nitrophenyl) ester (150 mg, 0.298 mmol, 1 eq) and 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (96 mg, 0.745 mmol, 2.5 eq) in THF (3 mL) was added DMAP (3.6 mg, 0.023 mmol, 0.1 eq) and the mixture was stirred at 25 °C for 2 h. The reaction solution was purified by flash silica gel chromatography (Silica Flash Column, eluted with 0-2.5% DCM / MeOH gradient at 25 mL / min) to give [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3- hydroxy-tetrahydrofuran-2-yl]methyl carbonate (5-methyl-2-oxo-1,3-dioxol-4- yl)methyl ester (85 mg, 63.5% yield) as a white solid. LCMS (ESI) m / z, C 24g Silica Flash Column, eluted with 0-2.5% DCM / MeOH gradient at 25 mL / min) to give [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3- hydroxy-tetrahydrofuran-2-yl]methyl carbonate (5-methyl-2-oxo-1,3-dioxol-4- yl)methyl ester (85 mg, 63.5% yield) as a white solid. LCMS (ESI) m / z, C 18 H 16 FN508 Calcd 449.4, Found 450.1 (M+H) + . 1 H NMR (400 MHz, CD3CN) d (ppm) 7.91 (s, 1H), 6.42-6.16 (m, 3H), 4.93-4.79 (m, 2H), 4.76-4.67 (m, 1H), 4.53-4.46 (m, 1H), 4.34-4.25 (m, 1H), 3.77-3.69 (m, 1H), 3.00 (s, 1H), 2.90-2.78 (m, 1H), 2.62-2.50 (m, 1H), 2.10 (s, 3H). 19 F NMR (376 MHz, CD3CN) d (ppm) -52.87 (s, 1F).

[0657] Example 4 (Method 3):

[0658] Carbonic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3- hydroxytetrahydrofuran-2-yl)methyl ester ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester

[0659]

[0660] Preparation of carbonic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2- ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester (4-nitrophenyl) ester

[0661]

[0662] To a mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ol (5 g, 17.05 mmol, 1 eq) in pyridine (50 mL) was added dropwise chloroformic acid (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester (16.42 g, 85.25 mmol, 5 eq) in DCM (16 mL) at 0 °C over a period of 2 h, after which the mixture was stirred at 16 °C for 10 min. The mixture was diluted with DCM (200 mL) and washed with water (150 mL), brine (150 mL x 2), dried over Na2S04, filtered and concentrated. The resulting residue was purified by flash silica gel chromatography (Silica Flash Column, eluted with 0-5% MeOH / DCM gradient at 65 mL / min) to give carbonic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy- tetrahydrofuran-2-yl] methyl ester (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester (5.10 g, 11.35 mmol, 66.6% yield) as a light yellow solid. LCMS (ESI) m / z, C 80g Silica Flash Column, eluted with 0-5% MeOH / DCM gradient at 65 mL / min) to give carbonic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy- tetrahydrofuran-2-yl] methyl ester (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester (5.10 g, 11.35 mmol, 66.6% yield) as a light yellow solid. LCMS (ESI) m / z, C 18 H 16 FN5O8: Calculated 449.4, found (M+H) 450.1. + : 450.1. 1H NMR (400 MHz, CD3CN) d (ppm) 7.92 (s, 1H), 6.34 (br s, 2H), 6.29-6.23 (m, 1H), 4.93-4.81 (m, 2H), 4.77-4.69 (m, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.30 (d, J = 11.6 Hz, 1H), 3.74 (d, J = 6.4 Hz, 1H), 3.00 (s, 1H), 2.91-2.79 (m, 1H), 2.62-2.51 (m, 1H), 2.10 (s, 3H). 19 F NMR (376 MHz, CD3CN) d (ppm) -52.84 (s, 1F).

[0663] Re-crystallization of carbonic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester (4-nitrophenyl) ester

[0664]

[0665] A mixture of carbonic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3- hydroxy-tetrahydrofuran-2-yl] methyl ester (5-methyl-2-oxo-1,3-benzodioxol-4-yl) methyl ester (9.5 g, 21.14 mmol, 1 eq) in MeCN (50 mL) and EtOAc (50 mL) was heated at 80 °C for 30 min and observed that the solid dissolved. After cooling to room temperature (20 °C), the mixture was stirred at 20 °C for 16 h. The mixture was filtered and the filter cake was dried under vacuum to give carbonic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl] methyl ester (5-methyl-2-oxo-1,3-benzodioxol-4-yl) methyl ester (8.0 g, 17.80 mmol, 84.2% yield) as a white solid. LCMS (ESI) m / z, C 18 H 16 FN5O8: Calc. 449.4, Found (M+H) + : 450.1. 1H NMR (400 MHz, CD3CN) d (ppm) 7.92 (s, 1H), 6.31 (br s, 2H), 6.27-6.24 (m, 1H), 4.92-4.81 (m, 2H), 4.77-4.69 (m, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.30 (d, J = 11.6 Hz, 1H), 3.73 (d, J = 6.4 Hz, 1H), 3.00 (s, 1H), 2.89-2.81 (m, 1H), 2.62-2.51 (m, 1H), 2.10 (s, 3H). 19 F NMR (376 MHz, CD3CN) d (ppm) -52.84 (s, 1F).

[0666] Example 5 (Method 1):

[0667] 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-1,3-dioxol-2-one

[0668]

[0669] Preparation of tert-butyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)((5-methyl-2-oxo-1,3- dioxol-4-yl)methyl)carbamate

[0670]

[0671] To a mixture of tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]carbamate (100 mg, 0.25 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (70 mg, 0.51 mmol, 2 eq) and 4- (bromomethyl)-5-methyl-1,3-dioxol-2-one (147 mg, 0.76 mmol, 3 eq). The reaction mixture was then heated at 60 °C for 12 h, concentrated, and then diluted with H2O (30 mL). The resulting mixture was extracted with EtOAc (30 x 3 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (0-10% MeOH in DCM) to give tert-butyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)((5-methyl-2-oxo-1,3- dioxol-4-yl)methyl)carbamate (100 mg, 0.22 mmol, 88% yield) as a white solid. 4g Silica Flash Column, eluted with a gradient of 0-10% methanol / dichloromethane at 30 mL / min) to give N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]-N-[(5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl]carbamate tert-butyl as a light yellow oil (45 mg, 35.0% yield). 1 H NMR (400 MHz, CDC13) δ (ppm) 8.02 (s, 1H), 6.40-6.43 (m, 1H), 5.02 (s, 2H), 4.70-4.73 (m, 2H), 4.09 (d, J = 12 Hz, 1H), 3.90-3.92 (m, 1H), 3.11-3.14 (m, 1H), 2.85 (s, 1H), 2.50-2.55 (m, 1H), 2.45 (bs, 1H), 2.22 (s, 3H), 1.53 (s, 9H).

[0672] Preparation of 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)amino)methyl)-5- methyl-1,3-dioxol-2-one

[0673]

[0674] To a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]-N-[(5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl]carbamate tert-butyl (40 mg, 0.079 mmol, 1 eq) in dichloromethane (DCM) (3 mL) at 25 °C was added TFA (0.5 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated and purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(0.2%FA)-ACN]; B%: 15%-45%, 8 min) to give 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)amino)methyl)-5- methyl-1,3-dioxol-2-one (1.7 mg, 5% yield) as a white solid. LCMS (ESI) m / z, C 17 H 16 FN5O6: calculated 405.1, measured (M+H)+ 406.1. (M+Na) + 428.1. 1 H NMR (400 MHz, CD3OD) d (ppm) 8.26 (s, 1H), 6.38-6.35 (m, 1H), 4.76-4.72 (m, 1H), 4.51 (s, 1H), 3.87-3.84 (d, J = 12 Hz, 1H), 3.78-3.75 (d, J = 12 Hz, 1H), 3.09 (s, 2H), 2.80-2.75 (m, 1H), 2.64-2.57 (m, 1H), 2.24 (s, 3H). 19 F NMR (376 MHz, CD3OD) d (ppm) -53.00.

[0675] Example 5 (Method 2):

[0676] 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-1,3-dioxol-2-one

[0677]

[0678] Preparation of tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]-N-[(5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl]carbamate

[0679]

[0680] To a solution of tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]carbamate (300 mg, 0.76 mmol, 1 eq) in DMF (5 mL) was added NaHC03(128 mg, 1.52 mmol, 2 eq) followed by 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (294 mg, 1.52 mmol, 2 eq). The mixture was stirred at 25 °C for 48 h. The mixture was concentrated. The resulting residue was purified by flash silica gel chromatography (MeOH / DCM, 1 : 99) to give tert-butyl N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]-N-[(5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl]carbamate (300 mg, 0.71 mmol, 93% yield) as a white solid. 4g Silica Flash Column, eluting with a gradient of 0-100% ethyl acetate / petroleum ether at 20 mL / min) to give N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]-N-[(5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl]carbamate tert-butyl (200 mg, 52% yield) as a white solid. 1 H NMR (400 MHz, CDC13) δ (ppm) 7.98 (s, 1H), 6.45-6.33 (m, 1H), 4.99 (s, 1H), 5.03-4.94 (m, 1H), 4.78 (br d, J = 11.2 Hz, 1H), 4.71 (br s, 1H), 4.16-4.02 (m, 2H), 3.11 (br s, 1H), 2.80 (s, 1H), 2.49 (br d, J = 7.2 Hz, 1H), 2.42 (br s, 1H), 2.19 (s, 3H), 1.55 (s, 9H).

[0681] Preparation of 4-[[[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]amino]methyl]-5- methyl-1,3-dioxol-2-one

[0682]

[0683] To a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]-N-[(5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl]carbamate tert-butyl (50 mg, 0.10 mmol, 1 eq) in CH3CN (5 mL) was added ZnBr2(45 mg, 0.20 mmol, 2 eq). The mixture was stirred at 25 °C for 48 h. The reaction was filtered and the filtrate was concentrated. The resulting residue was purified by prep-HPLC (FA condition; Column: 3_Phenomenex Luna C18 75x30mmx3um; Mobile Phase: [water(0.2%FA)-ACN]; B%: 22%-52%, 6 min) to give 4-[[[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purin-6-yl]amino]methyl]-5- methyl-1,3-dioxol-2-one (19.8 mg, 48.8% yield) as a white solid. LCMS (ESI) m / z, C17 H 16 FN5O6: Calculated 405.34, found (M+H) + : 406.1. 1 H NMR (400 MHz, CD3OD) d (ppm) 8.26 (s, 1H), 6.38-6.35 (m, 1H), 4.76-4.72 (m, 1H), 4.51 (br s, 2H), 3.87-3.84 (d, J = 12 Hz, 1H), 3.78-3.75 (d, J = 12 Hz, 1H), 3.09 (s, 1H), 2.80-2.75 (m, 1H), 2.64-2.57 (m, 1H), 2.24 (s, 3H). 19 F NMR (376 MHz, CD3OD) d (ppm) -52.33.

[0684] Example 6:

[0685] Conversion and stability of adenosine derivative prodrugs

[0686] The stability of the prodrugs and conversion of the prodrugs to the target drug, adenosine derivative (EFdA) (Formula T-1A), were measured in plasma and liver S9 assays, and the data are given in Table 2.

[0687] Plasma stability

[0688] Prior to the experiment, the pooled frozen plasma was thawed at 37 °C in a water bath. The plasma was centrifuged at 4000 rpm for 5 minutes and if there were clots, the clots were removed. If necessary, the pH was adjusted to 7.4 ± 0.1.

[0689] Preparation of test compound and positive control (propantheline): 1 mM intermediate solution was prepared by diluting 10 pL of stock solution with 90 pL MeOH; 1 mM positive control propantheline intermediate solution was prepared by diluting 10 pL of stock solution with 90 pL ultrapure water. 100 pM dosing solution was prepared by diluting 20 pL of intermediate solution (1 mM) with 180 pL MeOH. 2 pL of dosing solution (100 pM) was spiked in duplicate in 98 pL of blank plasma to reach a final concentration of 2 pM and the samples were incubated at 37 °C in a water bath. At each time point (0, 10, 30, 60, and 120 minutes), 400 pL of stop solution (0.1% FA in MeOH containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) was added to precipitate the proteins and mixed well. The sample plate was centrifuged at 4,000 rpm for 10 minutes. An aliquot of supernatant (100 pL) was transferred from each well to another plate.

[0690] Data Analysis: The % remaining of test compound after incubation in plasma was calculated using the following equation:

[0691] % Remaining = 100 x (PAR at specified incubation time / PAR at TO time)

[0692] Where PAR is the peak area ratio of analyte to internal standard (IS) (LC / MS / MS mobile phase conditions: water with 0.1% formic acid / acetonitrile with 0.1% formic acid. Specified incubation time points are TO (0 min), Tn (n = 0, 10, 30, 60, 120 min).

[0693] Liver S9 stability

[0694] Intermediate solution: 5 pL of compound from stock solution (10 mM) or control (7-ethoxy coumarin) was diluted with 495 pL MeOH (concentration: 100 pM, 1% DMSO, 99% MeOH). Stop solution: cold ACN (containing 100 ng / mL tolbutamide and labetalol as internal standards). 2 pL of test compound or control working solution per well was added to all plates except matrix blank (TO, T5, T10, T20, T30, T60, NCF60). 600 pL / well stop solution (4°C cold, containing 100 ng / mL tolbutamide / 100 ng / mL labetalol) was added to the TO plate to stop the reaction, which was then placed on ice. 840 pL / well S9 solution was dispensed into a 96-well plate as a reservoir according to the plate map. 100 pL / well was then added to each plate by Apricot. The S9 solution and compound were incubated at 37°C for approximately 10 minutes, except for NCF60 and TO. After adding S9 solution and 98 pL PB buffer to NCF60, the timer 1 was started at 37°C without pre-warming. After 60 minutes, 600 pL / well stop solution was added to stop the reaction. After pre-warming, 760 pL / well cofactor solution was dispensed into a 96-well plate as a reservoir according to the plate map. 98 pL / well was then added to each plate with Apricot to start the reaction. The reaction was incubated at 37°C, timer 2 was started, and 600 pL / well stop solution (4°C cold, containing 100 ng / mL tolbutamide and labetalol) was added to stop the reaction. The samples were centrifuged at 4000 rpm for 20 minutes. While centrifuging, 8x new 96-well plates were loaded with 300 pL HPLC water, and then 100 pL supernatant was transferred to mix with water for LC / MS / MS and to Bioanalytical Services for LC-MS / MS analysis. The t 1 / 2 and CL: First order kinetic equation:

[0695]

[0696]

[0697] CL int(S9) = Vd.k e

[0698] Vd = 1 mL / mg

[0699] Stability results of exemplary compounds in human plasma and human liver S9 are listed in Table 2 below.

[0700] Table 2. Conversion and half-life data.

[0701]

[0702] Half-life ranges: A: >200 min; B: 50-200 min; C: <50 min.

[0703] The data indicate that adenosine derivatives 4-A and 4-C can be efficiently converted to the target drug in human plasma and liver S9 assays, and that 6-A can be efficiently converted to the target drug in the liver S9 assay.

[0704] Example 7:

[0705] Antiviral activity of prodrugs in combination with lenacapavir (GS-6207) and the antiviral activity of the combination of prodrugs with lenacapavir (GS-6207) against HIV-1 laboratory strain HIV-1 NL4-3 in MT-4 cells.

[0706] Method Compound preparation: Compound stocks (10 mM in DMSO) of prodrug Formula 4-A and lenacapavir were prepared and aliquoted. The stocks were stored at -20 °C until the day of the assay. The compound stocks were used to make fresh working drug dilutions on each day of the assay setup. Each aliquot of the compound stock was used only once and was discarded after the experiment. Fresh assay working dilutions were prepared for each experiment using a previously unused aliquot of the stock to avoid compound degradation. Each dilution of Formula 4-A was tested in combination with five dilutions of the second anti-HIV drug, the capsid inhibitor lenacapavir. In all cases, the final DMSO concentration was <0.25%, which has been previously shown to have no effect in the described assay.

[0707] Virus strains and cell lines: The viruses and cell lines used for these evaluations were obtained from the NIH AIDS Research and Reference Reagent Program (Germantown, Maryland). Evaluations were performed using a cell protection (CPE) assay method.

[0708] For each antiviral assay, pre-titrated aliquots of virus were removed from the freezer (-80°C) and quickly thawed. The virus was resuspended and diluted into tissue culture medium such that the amount of virus added to each well was that determined to produce 85% to 95% loss of cell viability due to virus-induced cytopathic effect (CPE assay).

[0709] Antiviral efficacy assay in MT4 T cells: MT4 cells were passaged in T-75 flasks prior to use in antiviral assays. The day before the assay, cells were split 1 :2 to ensure they were in exponential growth phase at the time of infection. Total cells and viability were quantified using a hemocytometer and trypan blue exclusion assay. Cells to be used in the assay needed to have greater than 95% cell viability. Cells were resuspended in tissue culture medium and added to drug-containing microtiter plates in a volume of 110 μl / well and a seeding density of 5.0 x 105cells / well. 3 The assay was performed in duplicate.

[0710] For each assay, pre-titrated aliquots of HIV-1 NL4-3 virus were removed from the freezer (-80°C) and allowed to slowly thaw to room temperature in a biological safety cabinet. The virus was resuspended and diluted into tissue culture medium such that the amount of virus added to each well in a 50 μL volume was that determined to produce 85% to 95% cell killing at 6 days post-infection. TCID50assays were performed in MT4 cells by endpoint titration. 50 Calculations indicated that the multiplicity of infection for these assays was approximately 0.01.

[0711] Five concentrations of Ledecavir were tested in all possible combinations with eight concentrations of Formula 4-A using a checkerboard format. Combination antiviral efficacy was evaluated on three replicate assay plates (i.e., triplicate measurements) that included cell control wells (cells only) and virus control wells (cells plus virus). Combination cytotoxicity was evaluated in parallel on two replicate assay plates (i.e., duplicate measurements) that included cell control wells. Compound color control plates were included for background subtraction when color was observed at the concentrations of compounds used in the experiment. Antiviral efficacy and cytotoxicity were monitored at the end of the experiment by MTS staining.

[0712] MTS staining for cell viability: At the termination of the assay, the wells were stained with the soluble tetrazolium-based dye MTS reagent (Promega, Madison, WI) and incubated for 4 hours at 37°C. The amount of formazan product produced by viable cells was quantified by measuring the absorbance at 490 nm using a microplate reader. 96 Reagent, Promega under their respective registered trademarks) to determine cell viability and quantify compound toxicity. MTS is metabolized by the mitochondrial enzymes of metabolically active cells to produce a soluble formazan product, allowing rapid quantitative analysis of cell viability and compound cytotoxicity. At the end of the assay, 20 μΐ^of MTS reagent was added to each well and the microtiter plate was then incubated at 37 °C, 5% C02 for 4-6 hours for the HIV cell protection assay; the incubation interval was chosen based on the empirically determined optimal dye reduction time. The sealed plate was inverted several times to mix the soluble formazan product using a adhesive plate sealer instead of a lid, and the plate was read spectrophotometrically at 490 / 650 nm using a Molecular Devices SpectraMax i3 plate reader.

[0713] Data Analysis: Combination antiviral assays were performed as described above with MT4 cells and HIV-1 NL4-3. For each combination assay, five concentrations of the compound were tested in all possible combinations with eight concentrations of the compound of Formula 4-A. Three replicates were used to determine the combination antiviral efficacy and two replicates were used to determine the combination cytotoxicity in uninfected MT4 cells. Each combination assay was performed twice unless otherwise noted.

[0714] The drug combination assay data was then analyzed using the MacSynergy II program for data analysis and statistical evaluation. Briefly, the MacSynergy II program calculates the theoretical additive interaction of drugs based on the Bliss independent mathematical definition of the expected effect of drug-drug interactions. The Bliss independent model is based on statistical probability and assumes that drugs act independently to affect viral replication; this independent effect model is also known as the dual-site (DS) model and was used for all combination analyses reported herein.

[0715] Theoretical additive interactions were calculated from the dose response curves of each drug used alone. This calculated additive surface, which represents the predicted or additive interaction, was then subtracted from the experimentally determined dose response surface to reveal non-additive activity regions. If the interaction was simply additive, the resulting surface would appear as a horizontal plane at 0% inhibition on the graph calculated above. Any peak above this additivity plane indicates synergy. Similarly, any depression below the additivity plane indicates antagonism. The data was statistically evaluated using the 95% confidence interval around the experimental dose-response surface, and the volume of the peaks / depressions was calculated and used to quantify the volume of synergy / antagonism produced. The volume of peaks observed in the synergy plots (in units of concentration by concentration by percent; e.g., μΜ x μΜ x %) was summed and divided by 100 to give the percent synergy observed for each combination. Similarly, the volume of depressions observed in the antagonism plots was summed and divided by 100 to give the percent antagonism observed for each combination. 2 %, nM 2The peak volumes are the three-dimensional counterparts of the 3-dimensional dose response surface area and are quantitative measures of synergy or antagonism. For these studies, synergy was defined as a drug combination that produced a synergy number greater than 50. Mild synergistic activity and highly synergistic activity were operationally defined as producing synergy numbers of 50-100 and >100, respectively. Additive drug interactions have synergy numbers in the range of -50 to 50, while those with synergy numbers of -50 to -100 were considered mildly antagonistic and those <-100 were considered highly antagonistic.

[0716] Results: Formula 4-A showed synergistic anti-viral activity when combined with tenofovir in dual drug combination anti-HIV studies against HIV-1 NL4-3 virus in MT4 cells (Table 3).

[0717] Table 3: Summary of anti-viral efficacy results of formula 4-A in combination with tenofovir in MT4 T cells.

[0718]

[0719] 1 Synergy was defined as a drug combination that produced a synergy number greater than 50. Mild synergistic activity and highly synergistic activity were defined as producing synergy numbers of 50-100 and >100, respectively.

[0720] Additive drug interactions have synergy numbers in the range of -50 to 50, while those with synergy numbers of -50 to -100 were considered mildly antagonistic and those <-100 were considered highly antagonistic.

[0721]

[0722] Representative examples of average three-dimensional contour plots of formula 4-A and tenofovir anti-viral drugs interacting with HIV-1 NL-43 in MT4 cells are shown in Figure 6. Figure 1

[0723] Example 8:

[0724] Plasma exposures in beagle dogs following oral administration of prodrug

[0725] Pharmacokinetics of EFdA and prodrug formula 4-A were studied in dogs following oral administration of 5 mg-equivalent / kg EFdA dose.

[0726] Formulation: Prodrug was formulated as a 1.65 mg / mL solution in 20% PEG400 in water within 0.5 hours prior to dosing.

[0727] ​​Dose administration and sample collection: The life stages of this study were conducted at Charles River Laboratory (CRL) in Worcester, MA in accordance with CRL Institutional Animal Care and Use Committee (IACUC) standard animal procedures and in compliance with IACUC guidelines of the Animal Welfare Act, Guide for the Care and Use of Laboratory Animals, and were approved by the IACUA committee. Male beagle dogs (10+ / -2 kg) that were fasted were used for the study. Each drug was administered as a single dose by oral gavage (5 ml / kg). The prodrug Formula 4-A dose (8.25 mg / kg) was an equivalent dose to 5 mg / kg EFdA. Plasma samples were collected at 0 (pre-dose), 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours post-dose. Blood (approximately 0.1 to 0.2 mL) was immediately processed into plasma by centrifugation at 3,500 rpm for 10 minutes at 5°C immediately after collection. Plasma samples were frozen and kept at -70°C until analysis. To stabilize the prodrug at the time of sample collection and subsequent analysis, the following stabilization reagents were added to the blood collection K2EDTA tubes on wet ice prior to sample collection: for every 100 mL of blood, 15 mL of a pre-made inhibitor cocktail consisting of: 1 mM DFP, 100 mM chlorpyrifos, 100 mM 2-hydroxyquinoline, 100 mM PCMB, 1 mM paraoxon, 100 mM PMSF, 100 mM NaF, 30.0 mM EDTA, and 15 mM citric acid, 10 mL of 0.2 M isorile, and 10 mL of 0.2 M BNPP solution.

[0728] Determination of EFdA and prodrugs in plasma: Briefly, plasma (20 μΐ) was mixed with 100 μΐ of acetonitrile to precipitate proteins. In line with the sample collection procedure, the same cocktail regimen was also added to stabilize the prodrugs in the standard samples and QC samples.

[0729] Bioanalysis: Quantitative analysis of plasma samples was performed using a Sciex API-6500 heavy quadrupole mass spectrometer coupled with a Shimadzu HPLC system (Framingham, MA 01701). The column was a Waters HSS T3 column (2.1 x 50 mm, 1.8 mm). The mobile phase used was: A, 5% acetonitrile in 2 mM ammonium formate buffer; B, 95% acetonitrile in 2 mM ammonium formate buffer (pH 6.0). The flow rate was 0.6 mL / min and the total run time was 3.0 minutes. The HPLC gradient started at 98% A / 2% B for 0.20 minutes, then a linear gradient increase to 25% over the next 1.40 minutes; the gradient was then increased to 100% mobile phase B over the next 1.0 minute, then held for an additional 0.2 minutes, then ramped down to 2% mobile phase B over the next 0.2 minutes. Detection of prodrug and EFdA was achieved by using positive ion electrospray mass spectrometry mode with unit resolution mode. Multiple reaction monitoring (MRM) mode was used to quantify both prodrug and EFdA, for example, the MRM transition for EFdA was 294.0-153.90 Da, while the transition for prodrug 4-A was 450.0-153.9 Da. Peak areas were integrated by the Sciex program version 1.6.3, where the concentration was determined from the linear regression of the peak area ratio (peak area of EFdA / peak area of the corresponding IS) versus the nominal concentration of the plasma calibration standards, weighted by 1 / x2. Calculations were performed on non-rounded numbers. In summary, The precision and accuracy of the calibration standards and QC samples were determined.

[0730] Pharmacokinetic calculations: Non-compartmental (NCA) analysis of EFdA and prodrug individual plasma concentration-time data was performed using the WinNonlin module in the Phoenix PK / PD platform (version 8.3.0.5005, Certara Inc., Princeton, NJ 08540). Calculations were performed prior to rounding, and nominal sampling times were used in the pharmacokinetic analysis. Exposure was expressed as the area under the concentration curve from 0 hours to 24 hours (AUC 0-24h ) in plasma. AUC values were calculated using the linear trapezoidal rule.

[0731] Plasma Concentrations: The results of the PK study are given in Tables 3 and 4. These data demonstrate in vivo that prodrug Formula 4-A can be readily delivered orally and can release EFdA in vivo effectively with minimal prodrug detected in the systemic circulation. For example, EFdA released in vivo from prodrug Formula 4-A can be significantly more than EFdA released in vivo from an equivalent dose of EFdA, i.e., 91%, 102%, 55%, 79%, and 200% more at the 0.25, 0.5, 1, 2, and 4 hour time points, respectively (see Table 4). Further, prodrug Formula 4-A can produce higher AUC and Cmaxvalues than an equivalent dose of EFdA. max (see Table 4).

[0732] Table 4: Plasma Concentrations of EFdA and Prodrug Formula 4-A Following Single Oral Dose to Male Beagle Dogs

[0733]

[0734]

[0735] BQL = Below Quantitation Level; NA = Not Applicable

[0736] Table 5: EFdA Exposure in Plasma from Oral Administration of EFdA and Prodrug Formula 4-A in Dogs

[0737] Compound Dose (mg / kg) AUC (ng*hr / mL) C max (ng / mL) EFdA 5 792 392 Prodrug Formula 4-A 8.25 (~5 mg eq EFdA) 1432 753

[0738] Example 9:

[0739] Plasma Exposure Following Combined Administration of Example 4-A and Ledipasvir via Intravenous Infusion in Sprague-Dawley Rats

[0740] The pharmacokinetics of EFdA and prodrug Formula 4-A and ledipasvir were investigated in rats following IV infusion administration alone or in combination at a dose of 1.0 mg / kg each.

[0741] Formulation: The prodrugs and ledipasvir were formulated separately as 1.0 mg / mL solutions in 20% PEG 400, 10% Solutol aqueous solution, either alone or in combination, within 0.5 hours prior to dosing.

[0742] Dose administration and sample collection: The life stages of this study were conducted at WuXi Biologics (Wuxi), Shanghai, China, in accordance with the WuXi Institutional Animal Care and Use Committee (IACUC) standard animal procedures and in compliance with the IACUC guidelines of the Animal Welfare Act, Guide for the Care and Use of Laboratory Animals, and were approved by the IACUA committee. Male Sprague-Dawley rats (0.262 + / - 0.019 kg) were used for the study. Each drug was administered as a single dose by a 30-min IV infusion (1 ml / kg) either alone or in combination. Plasma samples were collected at 0 (pre-dose), 5, 10, 15, and 30 min, 1 h, 2 h, 4 h, 7 h, 12 h, and 24 h post-dose. Blood (approximately 0.1 mL) was immediately processed to plasma by centrifugation at 3,200 g for 10 min at 4 °C within half an hour of collection. Plasma samples were frozen and kept at -70 °C until analysis. To stabilize the prodrugs at the time of sample collection and subsequent analysis, the following stabilization reagents were added to the blood collection K2EDTA tubes on wet ice prior to sample collection: for every 100 mL of blood, 10 mL of pre-made inhibitor cocktail consisting of 600 mM citric acid, 400 mM PMSF, 400 mM NaF, and 400 mM Dichlorvos.

[0743] Determination of EFdA and prodrugs in plasma: Briefly, plasma (20 μΐ) was mixed with 100 μΐ of acetonitrile to precipitate proteins. In line with the sample collection procedure, the same cocktail regimen was also added to stabilize the prodrugs in the standard samples and QC samples.

[0744] Bioanalysis: Sciex API-6500 Plus triple quadrupole mass spectrometer and Waters Acquity UPLC system (Framingham, MA 01701) were combined for quantitative analysis of plasma samples. The column was a Waters HSS T3 column (2.1 x 50 mm, 1.8 micron). The mobile phase used was: A, water with 0.1% formic acid; B, acetonitrile with 0.1% formic acid. For analysis of EFdA and prodrugs in plasma, the flow rate was 0.6 mL / min and the total run time was 2.0 minutes. The HPLC gradient started at 100% A for 0.30 minutes, followed by a linear gradient increase to 40% B over the next 0.7 minutes; the gradient was then increased to 100% mobile phase B over the next 0.7 minutes, and then held for another 0.2 minutes before ramping down to 100% mobile phase A over the next 0.1 minutes. Detection of prodrugs and EFdA was achieved using positive ion electrospray mass spectrometry mode with unit resolution mode. Multiple reaction monitoring (MRM) mode was used to quantify both prodrugs and EFdA, for example, the MRM transition for EFdA was 294.0-154.2 Da, while the transition for prodrug 4-A was 449.3-164.9 Da. For analysis of ledipasvir in plasma, the flow rate was 0.7 mL / min and the total run time was 1.5 minutes. The HPLC gradient started at 95% A / 5% B for 0.50 minutes, followed by a linear gradient increase to 10% B over the next 0.2 minutes; the gradient was then maintained at 100% mobile phase B over the next 0.7 minutes, before ramping down to 95% mobile phase A over the next 0.1 minutes. Detection of ledipasvir was achieved using positive ion electrospray mass spectrometry mode with unit resolution mode. Multiple reaction monitoring (MRM) mode was used to quantify ledipasvir, for example, the MRM transition for ledipasvir was 968.1-869.4 Da. Peak areas were integrated by the Sciex program Version 1.6.3, where the concentration was determined from the peak area ratio (peak area of EFdA / peak area of corresponding IS) versus the nominal concentration of the plasma calibration standards with a weighted (1 / x2) linear regression. Calculations were performed on non-rounded numbers. In summary, The precision and accuracy of the calibration standards and QC samples were determined.

[0745] Pharmacokinetic calculations: Non-compartmental (NCA) analysis of EFdA and prodrug individual plasma concentration-time data was performed using the WinNonlin module in the Phoenix PK / PD platform (version 8.3.0.5005, Certara Inc., Princeton, NJ 08540). Calculations were performed prior to rounding, and nominal sampling times were used in the pharmacokinetic analysis. Exposure is expressed as the area under the concentration curve from 0 hours to 24 hours in plasma (AUCo-24h). AUC values were calculated using the linear trapezoidal rule.

[0746] Plasma concentrations: Results of the PK study are shown in Tables 6-13. These data demonstrate in vivo that prodrug Formula 4-A can be readily delivered orally and can be efficiently released EFdA in vivo in the absence or presence of ledipasvir with little prodrug detected in the systemic circulation. Furthermore, the pharmacokinetic profile of ledipasvir is not affected by co-administration of prodrugs such as Formula 4-A.

[0747] Table 6. Plasma concentrations of EFdA and prodrug Formula 4-A following single IV infusion doses administered to male Sprague-Dawley rats when dosed alone.

[0748]

[0749] Table 7. Plasma concentrations of EFdA and prodrug Formula 4-A following single IV infusion doses administered to male Sprague-Dawley rats when dosed with ledipasvir.

[0750]

[0751] Table 8. Plasma prodrug Formula 4A concentrations in rat plasma (ng / mL) when dosed alone.

[0752]

[0753] Table 9. Plasma prodrug Formula 4A concentrations in rat plasma (ng / mL) when dosed with ledipasvir.

[0754]

[0755] Table 10. Plasma concentrations of ledipasvir in rat plasma when dosed alone.

[0756]

[0757] Table 11. Plasma concentrations of ledipasvir in rat plasma when dosed with prodrug Formula 4-A.

[0758]

[0759]

[0760] BQL = below quantification level; ND = not determined

[0761] Table 12: Plasma intra-EFdA exposures for IV administration of prodrug Formula 4-A alone or in combination with ledipasvir in rats

[0762] Dosing Method Dose (mg / kg) AUC (ng*hr / mL) C max (ng / mL) Alone 1 147 179 In combination with 1 149 177

[0763] Table 13: Plasma intra-ledipasvir exposures for IV administration of ledipasvir alone or in combination with prodrug Formula 4-A in rats

[0764] Dosing Method Dose (mg / kg) AUC (ng*hr / mL) C max (ng / mL) Alone 1 7976 903 In combination with Prodrug Formula 4-A 1 7483 645

[0765] incorporated by reference

[0766] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. Use of an adenosine derivative in combination with a capsid inhibitor in the manufacture of a medicament for treating or preventing an HIV infection in a subject, wherein (a) the adenosine derivative is a compound of Formula (4-A): (4-A) or a pharmaceutically acceptable salt thereof; (b) the capsid inhibitor is a compound having the structure: (5-A) or a pharmaceutically acceptable salt thereof.

2. The use of claim 1, wherein the capsid inhibitor and the adenosine derivative are administered sequentially to the subject over a period of time ranging from 0.1 minutes to 72 hours. (4-A) the adenosine derivative is administered orally.

4. The use of any one of claims 1-2, wherein the HIV infection is caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multi-drug resistant HIV. ​ ​ 3. The use of any one of claims 1-2, wherein, ​ ​

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