Combination therapy for HIV with adenosine derivative and capsid inhibitor

Abstract

This invention relates to a method for treating or preventing RNA virus infections and retroviral diseases (such as HIV and AIDS), comprising administering to an individual in need an effective amount of the (a) capsid inhibitor and (b) adenosine derivative disclosed herein. This invention also provides compositions comprising an effective amount of the adenosine derivative and an effective amount of the capsid (CA) inhibitor.

Description

[Technical Field]

[0001] This invention relates to an adenosine derivative prodrug that can inhibit reverse transcriptase. This invention also relates to a pharmaceutical composition comprising an adenosine derivative prodrug and a capsid inhibitor, which can be used to treat or prevent acquired immunodeficiency syndrome (AIDS), HIV-1, HIV-2, multidrug-resistant HIV, or combinations thereof. [Previous Technology]

[0002] Retroviruses such as human immunodeficiency virus (HIV) have been associated with immunosuppressive diseases known as acquired immunodeficiency syndrome (AIDS). Several strains of retroviruses, such as HIV type 1 (HIV-1) and type 2 (HIV-2), are known to be associated with these diseases. Individuals infected with HIV retroviruses may initially be asymptomatic, but subsequently develop AIDS-related complications (ARC), and then AIDS. HIV replication from host cells requires the integration of the viral genome into the host cell's DNA. A key step in this process involves the transcription of the viral RNA genome into DNA via an enzyme called reverse transcriptase (RT).

[0003] Reverse transcriptases typically possess a variety of enzymatic functions, which can (1) act as an RNA-dependent DNA polymerase for a single-stranded DNA copy (first DNA) of viral RNA, (2) act as a ribonuclease that destroys the initial viral RNA and releases the DNA just generated from that initial RNA, and (3) act as a DNA-dependent DNA polymerase that uses 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 an integrase.

[0004] 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).

[0005] The adenosine derivative EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine, also known as MK-8591, islatravir) is a long-acting (LA) NRTI that has been shown to have anti-HIV activity by preventing translocation inhibition of reverse transcriptase (US 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 herein by reference in its entirety). This compound has broad inhibitory activity and efficacy against different subtypes and mutations (including HIV-1, HIV-2, and multidrug-resistant (MDR) and wild-type (WT) strains, as well as reverse transcriptase inhibitor-resistant (RTI) viruses). Some modified EFdA analogues and prodrugs have been described in U.S. Patent Publication No. 2018 / 0002366, which is incorporated herein by reference in its entirety.

[0006] A common problem arising from the treatment of HIV infection with antiretroviral inhibitory compounds is the resistance of these viruses to these inhibitors. This resistance is usually the result of mutations in the reverse transcriptase region of the pol gene. Continued use of antiviral compounds (such as inhibitory compounds) to prevent HIV infection will inevitably lead to the emergence of new drug-resistant HIV strains. Therefore, the need for novel RT inhibitors effective against HIV strains (including mutant HIV and multidrug-resistant HIV strains) persists.

[0007] Another common problem is medication adherence. Medication adherence is crucial for individuals with HIV to achieve successful treatment throughout their lives. Adherence to daily regimens can be challenging, as daily reminders of the patient's HIV status can negatively impact their quality of life. Increasing patient adherence to medication regimens can potentially be achieved by reducing the frequency of administration. Therefore, it is necessary to identify long-acting compounds or regimens (e.g., once-weekly, once-monthly, or once-every-two-months therapy) to overcome these challenges associated with daily oral medication use. [Summary of the Invention]

[0008] The present invention, which addresses these and other problems, relates to adenosine derivatives and compositions thereof, which can be used to treat retroviral diseases such as HIV and AIDS and RNA virus infections.

[0009] In some embodiments, the present invention provides a composition comprising the following effective doses: (a) a capsid (CA) inhibitor; and (b) an adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the adenosine derivative is a compound having the structure of formula (1): (1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1, R1', and R2 are each independently H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, or -Z-L4-R5, provided that at least one of R1 and R2 is not H; R3, R3', and R4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl, or heteroaryl; R5 is: R6 series: H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl or heteroaryl; -L1-R5 series: -(C1-C10 alkylene)-N(R7)-R5, -(C1-C10 alkylene)-O-R5, -(C1-C10 alkylene)-S-R5, -(C2-C10 alkenylene)-N(R7)-R5, -(C2-C10 alkenylene)-O-R5, -(C2-C10 alkenylene)-S-R5, -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2- O-R5, -C(O)O-L2-S-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)O-L2-C(O)N(R7) -L3-N(R7)-R5, -C(O)O-L2-C(O)N(R7)-L3-O-R5, -C(O)O-L2-C(O)N(R7)-L3-S-R5, -C(O)N(R7)-R5 , -C(O)N(R7)-L2-N(R7)-R5, -C(O)N(R7)-L2-O-R5, -C(O)N(R7)-L2-S-R5, -C(O)N(R7)-L2-C(O)O -R5, -C(O)N(R7)-L2-C(O)N(R8)-R5-, -C(O)N(R7)-L2-C(O)N(R8)-L3-N(R7)-R5, -C(O)O-L2-N(R 7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2- N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)N(R8)-L3-O-R5 or -C(O)N(R7)-L2-C(O)N(R8)-L3-S-R5;-Z-series -C(O)-, -C(O)O- or -C(O)N(R7)-; -L4-R5-series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5 or -(C2-C10 alkenyl)-S-R5; R7 and R8 are each independently H, C1-C10 alkyl or C2-C10 alkenyl; R9 is independently H, -F, C1-C10 alkyl or C2-C10 alkenyl; L2 and L3 are each -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and X-series halogen atoms. ;

[0010] In some embodiments, the compositions further comprise a pharmaceutically acceptable carrier.

[0011] In some embodiments, the present invention provides a method for treating or preventing HIV infection, comprising administering to a subject in need an effective amount of: (a) a capsid (CA) inhibitor; and (b) an adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the adenosine derivative is a compound of formula (1) having the following structure: (1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1, R1', and R2 are each independently H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, or -Z-L4-R5, provided that at least one of R1 and R2 is not H; R3, R3', and R4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl, or heteroaryl; R5 is: R6 series H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl or heteroaryl;-L1-R5 series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5, -(C2-C10 alkenyl)-S-R5, -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2- O-R5, -C(O)O-L2-S-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)O-L2-C(O)N(R7) -L3-N(R7)-R5, -C(O)O-L2-C(O)N(R7)-L3-O-R5, -C(O)O-L2-C(O)N(R7)-L3-S-R5, -C(O)N(R7)-R5 , -C(O)N(R7)-L2-N(R7)-R5, -C(O)N(R7)-L2-O-R5, -C(O)N(R7)-L2-S-R5, -C(O)N(R7)-L2-C(O)O -R5, -C(O)N(R7)-L2-C(O)N(R8)-R5-, -C(O)N(R7)-L2-C(O)N(R8)-L3-N(R7)-R5, -C(O)O-L2-N(R 7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2- N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)N(R8)-L3-O-R5 or -C(O)N(R7)-L2-C(O)N(R8)-L3-S-R5; -Z-series -C(O)-, -C(O)O- or -C(O)N(R7)-; -L4-R5-series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5 or -(C2-C10 alkenyl)-S-R5; R7 and R8 are each independently H, C1-C10 alkyl or C2-C10 alkenyl; R9 is independently H, -F, C1-C10 alkyl or C2-C10 alkenyl; L2 and L3 are each -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and X-series halogen atoms. ;

[0012] In some embodiments of formula (1), R1, R1' and R2 are each independently:

[0013] In some embodiments, the adenosine derivative is selected from the group consisting of: formula (2-A):, formula (3-A):, formula (4-A):, formula (5-A):, formula (6-A):, formula (7-A):, formula (8-A):, formula (4-C):, or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0014] In some embodiments, the adenosine derivative is a compound having the following structure: (4-A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0015] In some embodiments, the CA inhibitor is a compound having the following structure: or a pharmaceutically acceptable salt, tautomer or solvate thereof.

Implementation Method

[0017] Cross-reference to related applications

[0018] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 141,445, filed on January 25, 2021, which is incorporated herein by reference in its entirety.

[0019] The following is a more detailed description of various concepts and embodiments of the method and apparatus according to the present invention. It should be understood that the various forms of the object described above and discussed in more detail below can be implemented in any of many ways, as the object is not limited to any particular implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes.

[0020] Definition

[0021] As used herein, the term "alkyl (alkyl or alkyl group)" means a fully saturated, straight-chain or branched hydrocarbon chain having one to twelve carbon atoms, and which is bonded by single bonds to the remainder of the molecule. This includes alkyl groups containing any number of carbon atoms from 1 to 12. Alkyl groups comprising up to 12 carbon atoms (C1-C12 alkyl), alkyl groups comprising up to 10 carbon atoms (C1-C10 alkyl), alkyl groups comprising up to 6 carbon atoms (C1-C6 alkyl), and alkyl groups comprising up to 5 carbon atoms (C1-C5 alkyl). C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all portions described above for C1-C5 alkyl but also includes C6 alkyl. C1-C10 alkyl includes all portions described above for C1-C5 and C1-C6 alkyl but also includes C7, C8, C9, and C10 alkyl. Similarly, C1-C12 alkyl groups include all the foregoing portions, but also include C11 and C12 alkyl groups. Non-limiting examples of C1-C12 alkyl groups include methyl, ethyl, n-propyl, isopropyl, secondary propyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, tertiary pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise stated in this specification, alkyl groups may be substituted as needed.

[0022] As used herein, the term "alkylene" or "alkylene chain" refers to a fully saturated, straight-chain or branched divalent hydrocarbon chain group having one to twelve carbon atoms. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is bonded to the remainder of the molecule and to free radicals (e.g., those described herein) by single bonds. The bonding sites of the alkylene chain to the remainder of the molecule and to free radicals can be one or any two carbons within the chain. Unless otherwise stated in this specification, the alkylene chain may be substituted as desired.

[0023] 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 number of carbon atoms within a specified range. For example, "C2-C10 alkenyl" (or "C2-C10 alkenyl") refers to any alkenyl group having 2 to 10 carbon atoms, which is straight-chain, branched, or isomer. In another example, C2-C6 alkenyl groups may have 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl). The alkyl chain may bind to the remainder of the molecule and to free radicals via one or any two carbons within the chain. Unless otherwise stated in this specification, the alkyl chain may be substituted as required.

[0024] As used herein, the term "alkenyl" or "alkenyl chain" refers to an unsaturated, straight-chain or branched divalent hydrocarbon chain group having one or more olefins and two to twelve carbon atoms. Non-limiting examples of C2-C12 alkenyl groups include vinyl, propenyl, n-butenyl, and the like. The alkenyl chain is bonded to the remainder of the molecule and to free radicals (e.g., those described herein) by single bonds. The alkenyl chain may bind to the remainder of the molecule and to free radicals via one or any two carbons within the chain. Unless otherwise stated in this specification, the alkenyl chain may be substituted as desired.

[0025] 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 may include fused or bridged ring systems having three to twenty carbon atoms (e.g., three to ten carbon atoms) and all of them being bonded by single bonds to the remainder of the molecule. Monocyclic cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl includes, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. In some embodiments, "cycloalkyl" refers to any monocyclic alkane having a number of carbon atoms within a specified range. For example, "C3-C10 cycloalkyl" (or "C3-C10 cycloalkyl") refers to a monocyclic alkane having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise expressly stated in this specification, cycloalkyl groups may be substituted as required.

[0026] 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 two to nineteen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur, and which are bonded by single bonds to the remainder of the molecule. Unless otherwise stated in this specification, the heterocyclic alkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl may be oxidized as needed, for example, to form an N-oxide, arsenide, or arsenide, and / or the nitrogen atom may be quaternized as needed, for example, to form a quaternary ammonium cation. Examples of such heterocyclic alkyl groups include (but are not limited to) dioxolane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-sideoxypiperazinyl, 2-sideoxypiperidinyl, 2-sideoxypyrrolidinyl, oxazolinyl, piperidinyl, piperazine, 4-piperidinoneyl, pyrrolidinyl, pyrazolidinyl, quininecycloyl, thiazodinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiomorpholinyl, 1-sideoxy-thiomorpholinyl, and 1,1-disideoxy-thiomorpholinyl. In some embodiments, "3 to 10 heterocyclic alkyl groups" 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 ring structure members. Unless otherwise stated in this specification, heterocyclic alkyl may be substituted as needed and may include saturated and / or unsaturated rings.

[0027] As used herein, the term "halogen" (or "halogen group") refers to fluorine, chlorine, bromine and iodine (or fluorine group (-F), chlorine group (-Cl), bromine group (-Br) and iodine group (-I)).

[0028] 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 bonded to the remainder of the molecule by a single bond. For the purposes of this invention, the aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused or bridged ring systems. Aryl groups include (but are not limited to) aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azurite, benzene, benzo[a], fluoranthene, fen, as-indacene, s-indacene, indane, indene, naphthalene, benzo[a]naphthalene, phenanthrene, heptamethrin, pyrene, and terphenyl. In some embodiments, "aryl" refers to a phenyl or one or more fused cyclic hydrocarbon ring systems, wherein at least one ring is an aromatic ring. Unless otherwise stated in this specification, the "aryl" may be substituted as required.

[0029] As used herein, the term "heteroaryl" refers to a 5- to 20-membered ring system comprising a hydrogen atom, 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 bonded to the remainder of the molecule by a single bond. For the purposes of this invention, the heteroaryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl may be oxidized as needed, for example, to form an N-oxide, arsenide, or arsenide, and / or the nitrogen atom may be quaternized as needed, for example, to form a quaternary ammonium cation. Non-limiting examples of heteroaryl groups may include pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, triazolyltriazolyl (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-(furazolyl) or 1,3,4-isomers), oxtriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-member heterobicyclic and fused ring systems include, for example, benzofuranyl, indolyl, indazole, naphthidyl, isobenzofuranyl, benzopiperidinyl, benzoisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, flakingyl, quinazolinyl, tetrahydroquinolinyl. (uinolinyl), tetrahydroisoquinolinyl, isoindolyl, benzodioxacyclopentenyl, benzopiperidinyl, benzoisooxazolyl, benzoxazolyl, benzodihydropiperanyl (chromanyl), isobenzodihydropiperanyl, benzothiophenyl, benzofuranyl, imidazo[1,2-a]pyridyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazole, indololinyl, isoindololinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl and 2,3-dihydrobenzo-1,4-dioxinyl. Unless otherwise stated in this specification, heteroaryl groups may be substituted as needed.

[0030] It should be understood that unless otherwise expressly contradicted in the specific text, any of the various rings and ring systems described herein may be bonded to the remainder of the compound at any ring atom (i.e., any carbon atom or any heteroatom), provided that such bonding is chemically permissible.

[0031] As used herein, the term "substituted" means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclic and / or heteroaryl) in which at least one hydrogen atom is substituted by a non-hydrogen atom, such as (but not limited to): halogen atoms, such as F, Cl, Br and I; hydroxyl, ... Oxygen atoms in alkoxy and ester groups; sulfur atoms in groups such as mercapto, thioalkyl, ternary, sulfonylurea, and ternidine; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, amides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., double or triple bond) of a heteroatom, such as oxygen in oxy, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile groups. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are substituted with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. "Substituted" also means any of the above groups in which one or more hydrogen atoms are substituted with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, and -CH2SO2NRgRh. In the foregoing, Rg and Rh are the same or different and independently derived from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are substituted by an amino, cyano, hydroxyl, imino, nitro, oxy, thionyl, halogen, alkyl, alkenyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl bonds. In addition, each of the aforementioned substituents may be replaced by one or more of the substituents mentioned above, as needed.

[0032] As used herein, the term "isomer" means a structural isomer, such as a group or atom located at different positions in a molecule; a stereoisomer, such as angiomeric, enantiomer, non-mirror image isomer, and cis / trans isomer; or a tautomer, such as an amino isomer, an imino isomer, or a combination thereof. In a non-limiting example, the adenosine derivatives of the present invention may have an amino isomer, an imino isomer, or a combination thereof. In another non-limiting example, where a -OH substituent is permitted on the heteroaromatic ring and keto-enol tautomerism is possible, it should be understood that the substituent may be present virtually entirely or partially as a side oxygen group (=O). Mixtures of isomers may also be suitable. Mixtures of isomers may contain individual isomers in all proportions. Salts of isomers may also be suitable. The adenosine derivatives of the present invention may contain isomers thereof, one or more salts thereof, one or more solvates thereof (including hydrates), solvated salts thereof, or mixtures thereof. Absolute stereochemistry or isomer configuration can be determined by X-ray crystallography, vibrational circular dichroism (VCD) spectroscopy, or a combination thereof.

[0033] Adenosine derivatives can be identified by nomenclature based on the nomenclature recommended by the International Union of Pure and Applied Chemistry (IUPAC) or by nucleoside nomenclature. These adenosine derivatives can also be identified by their chemical structural diagrams. Unless otherwise expressly contradictory in the specific text, names and structures are used interchangeably.

[0034] Any of the atoms in the compounds disclosed herein may exhibit their equivalent natural isotopic abundance, or one or more of these atoms may be artificially enriched with a specific isotope having the same number of atoms but a different atomic mass or mass number than that of the predominantly occurring atomic mass or mass number in nature. This invention is intended to include all suitable isotopic variations of the compounds disclosed herein.

[0035] The compound may be administered in the form of a pharmaceutically acceptable salt or solvate. The term "pharmaceutically acceptable salt" means a salt or solvate that is not biologically or otherwise undesirable (e.g., non-toxic and otherwise harmless to the recipient or subject). The present invention also takes into consideration the compounds disclosed herein and mixtures of one or more of their salts or solvates. 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, propionates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, and solvates. Benzoate, butyn-1,4-diate, hexyn-1,6-diate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0036] Furthermore, the compounds disclosed herein may exist in amorphous form and / or one or more crystalline forms, or combinations thereof.

[0037] The term "retrovirus" or "retroviral infection" refers to a virus that uses RNA as its genetic material. When a retrovirus infects a cell, it produces a copy of its genome DNA, which is inserted into the DNA of the host cell.

[0038] The term "RNA virus infection" refers to diseases caused by RNA viruses, such as the common cold, influenza, SARS, COVID-19, hepatitis C, hepatitis E, West Nile fever, Ebola virus disease, rabies, poliomyelitis and measles.

[0039] The term "HIV infection" refers to the disease caused by 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 the late forms of the disease.

[0040] 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 pharmaceutically acceptable precursor of a bioactive compound. A prodrug may be a biologically inactive or substantially inactive compound that can be metabolized in vivo (i.e., in vivo) to produce a drug having the desired activity. The term "substantially inactive" means that the prodrug may have about 1% to about 10% of the activity of the corresponding drug, or a percentage of the prodrug's weight after metabolism in vivo. In some embodiments, the term "substantially inactive" means that the prodrug has less than about 5% of the activity of the corresponding drug, or a percentage of the prodrug's weight after metabolism in vivo. The doses of the prodrug and its bioactive compound are considered dose-equivalent when they are all in the same molar amount.

[0041] 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, which can directly or indirectly effectively inhibit HIV, treat or prevent HIV infection, and / or treat, prevent, or delay the onset or progression of AIDS and / or diseases or conditions arising from or associated with it, RNA virus infection, or combinations thereof. Such anti-HIV agents may include HIV antiviral agents, immunomodulators, anti-infective agents, vaccines, or combinations thereof suitable for treating HIV infection or AIDS. Examples of antiviral agents used to treat HIV infection or AIDS include (but are not limited to) abacavir (ABC, Ziagen®), abacavir + lamivudine (Epzicom®), abacavir + lamivudine + zidovudine (Trizivir®), amprenavir (Agenerase®), atazanavir (Reyataz®), AZT (zidovudine, zidovudine, or Retrovir®), capravirine, darunavir (Prezista®), ddC (zalcitabine, dideoxycytidine, or Hivid®), ddI (desoxyinosine, dideoxyinosine, or Videox®), ddI (enteric-coated, Videox EC®), and delavirdine. (DLV or Rescriptor®), dolutegravir (Tivicay®), doravirine (MK-1439), efavirenz (EFV, Sustiva®, Stocrin®), efavirenz + emtricitabine + tenofovir DF (Atripla®), EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine), elvitegravir, cabotegravir, dolutegravir, bictegravir, emtricitabine (FTC, Emtriva®), emtricitabine + tenofovir DF (Truvada®), emvirine (Coactinon®), enfuvirtide (Fuzeon®), enteric-coated norhydroxyinosine (Videx EC®), etravirine (TMC-125), Fosamprenavir (calcium fosanavir)calcium (Lexiva®), indinavir (Crixivan®), lamivudine (3TC, Epivir®), lamivudine + zidovudine (Combivir®), lopinavir, lopinavir + ritonavir (Kaletra®), maraviroc (Selzentry®), nelfinavir (Viracept®), nevirapine (NVP, Viramune®), PPL-100 (also known as PL-462) (Ambrilia), raltegravir (MK-0518 or Isentress™), rilpivirine (Edurant®), ritonavir (Norvir®), saquinavir (Invirase® or Fortovase®), stavudine (d4T, didehydrodeoxythymidine or Zerit®), tenofovir DF (DF = dipyridyl fumarate, TDF, Viread®), tenofovir (hexadecyloxypropyl (CMX-157), tenofovir alafenamide fumarate (GS-7340), titranavir) (Aptivus®) and vicriviroc. Some of the anti-HIV agents shown above can be used in salt form; for example, abacavir sulfate, deraviridine mesylate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate, saquinavir mesylate, or other salts. Anti-HIV agents may have one or more activities such as entry inhibitors (EI), fusion inhibitors (FI); integrase inhibitors (InI); protease inhibitors (PI); nucleoside reverse transcriptase inhibitors (nRTI or NRTI) or non-nucleoside reverse transcriptase inhibitors (nnRTI or NNRTI). Anti-HIV agents may comprise two or more of the agents disclosed herein. The adenosine derivatives of the present invention may be anti-HIV agents together or in combination with other anti-HIV agents or agents.

[0042] Unless otherwise expressly stated to the contrary, all scopes referenced herein are inclusive. It should be understood that any scope referenced herein includes all subscopes within that scope. For example, a dose in the range of "100 to 2000 mg" means a dose of 100 mg, 101 mg, 101.1 mg, 101.01 mg, etc., and 2000 mg, including all doses within that range. In another non-limiting example, a time range of "1 to 8 days" means 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, and 8 days, including all time subscopes within that range or each one or more individual time points. In yet another non-limiting example, a description of a heteroaryl ring contained in the range of "1 to 4 heteroatoms" means that the ring may contain 1, 2, 3, or 4 heteroatoms. It should also be understood that any scope referenced herein includes all subscopes within that range. Therefore, for example, the description of a heterocyclic ring containing "1 to 4 heteroatoms" is intended to include 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 instances, C1-C10 alkyl means alkyl groups containing 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms (inclusive of all subranges). Thus, C1-C10 alkyl groups can be methyl, ethyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, and C10 alkyl, straight-chain or branched-chain. C1-C10 alkyl groups can be -CH2-, -C2H4-, -C3H6-, -C4H8-, -C5H10-, -C6H12-, -C7H17-, -C8H18-, -C9H18-, or -C10H20-, and can be straight-chain or branched. Similarly, C2-C10 alkenyl groups mean alkenyl groups containing 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms, and can be straight-chain or branched (including all subranges). Straight-chain or branched alkenyl groups can be suitable. C3-C10 cycloalkyl groups mean cycloalkyl groups containing 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms, and can be straight-chain or branched.

[0043] Unless otherwise indicated, open terms (e.g., "contain / containing"), "include / including") and similar terms mean "comprising".

[0044] Unless otherwise expressly stated herein, the singular forms “a,” “an,” and “the” are used to include a plurality of references. Therefore, unless otherwise indicated, the numerical parameters listed in this application are approximate values ​​and may vary depending on the desired properties obtainable by the present invention.

[0045] The term “about” and its syntactic equivalents as used herein may include a range of values ​​plus or minus 10% of that value, such as values ​​plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of that value. For example, the quantity of “about 10” includes quantities from 9 to 11.

[0046] The term "injection" refers to intravenous, intramuscular, subcutaneous, non-enteric, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active ingredient may be encapsulated in a material to protect it from acids and other natural conditions that may deactivate it. As used herein, the phrase "non-enteric administration" means a mode of administration other than enteric and local administration, typically by injection, and includes (but is not limited to) intravenous, intramuscular, intra-arterial, intrasheath, intracapsular, intra-capsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions. Other non-parenteral routes may include, for example, local, epidermal, or mucosal administration routes, such as intranasal, oral, vaginal, rectal, sublingual, or local administration. Pharmaceutical compositions may be in the form of sterile aqueous solutions or dispersions. This pharmaceutical composition can also be formulated into microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The compounds of this invention...

[0047] In some embodiments, the present invention provides an adenosine derivative having the structure of formula (1): , or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: R1, R1' and R2 are each independently H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5 or -Z-L4-R5, provided that at least one of R1 and R2 is not H; R3, R3' and R4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10-membered heterocycloalkyl, aryl or heteroaryl; R5 is: ; R6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10-membered heterocycloalkyl, aryl or heteroaryl; -L1-R5 series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5, -(C2-C10 alkenyl)-S-R5, -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2- O-R5, -C(O)O-L2-S-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)O-L2-C(O)N(R7) -L3-N(R7)-R5, -C(O)O-L2-C(O)N(R7)-L3-O-R5, -C(O)O-L2-C(O)N(R7)-L3-S-R5, -C(O)N(R7)-R5 , -C(O)N(R7)-L2-N(R7)-R5, -C(O)N(R7)-L2-O-R5, -C(O)N(R7)-L2-S-R5, -C(O)N(R7)-L2-C(O)O -R5, -C(O)N(R7)-L2-C(O)N(R8)-R5-, -C(O)N(R7)-L2-C(O)N(R8)-L3-N(R7)-R5, -C(O)O-L2-N(R 7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2- N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)N(R8)-L3-O-R5 or -C(O)N(R7)-L2-C(O)N(R8)-L3-S-R5; -Z- is -C(O)-, -C(O)O- or -C(O)N(R7)-;-L4-R5 series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5 or -(C2-C10 alkenyl)-S-R5; R7 and R8 are each independently H, C1-C10 alkyl or C2-C10 alkenyl; R9 is independently H, -F, C1-C10 alkyl or C2-C10 alkenyl; L2 and L3 are each divalent -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and X series halogen atoms.

[0048] The adenosine derivatives of the present invention may be free of monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof. In some embodiments, the R1, R1', or R2 groups of the adenosine derivatives of the present invention are free of monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof. Non-limiting examples of adenosine derivatives having halogen atoms are shown in formulas (1) to (8) and (4-B).

[0049] In some embodiments of formula (1), the C1-C10 alkyl and C2-C10 alkenyl groups are straight-chain or branched chains. In some embodiments, the compound of formula (1) comprises a combination of C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl and heteroaryl groups.

[0050] In some embodiments, R1 and R1' are each independently selected from one of formulas 9 to 24. In some embodiments, R2 is H, -COO (C1-C3 alkyl), or H. In some embodiments, R2 is H.

[0051] In some embodiments, R2 is selected from one of formulas 9 to 24. In some embodiments, R1 and R1' are each independently H, -COO (C1-C3 alkyl), or H. In some embodiments, R1 is H, -COO (C1-C3 alkyl), or R1' is H. In some embodiments, R1' is H, -COO (C1-C3 alkyl), or R1 is H.

[0052] In some embodiments, R3 and R3' 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, R3 and R3' 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, R3 and R3' are each independently H or C1-C5 alkyl. In some embodiments, R3 and R3' are each independently H or C1-C3 alkyl. In some embodiments, R3 and R3' are each independently H, methyl, ethyl, or isopropyl.

[0053] In some embodiments, R4-based 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, R4-based H, C1-C5 alkyl, C3-C6 cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, or 5 to 6-membered heteroaryl. In some embodiments, R4-based H or C1-C5 alkyl. In some embodiments, R4-based H or C1-C3 alkyl. In some embodiments, R4-based H, methyl, ethyl, or isopropyl.

[0054] In some embodiments of formula (1), R1 is H and R2 is -C(O)N(R3)(R3'). In some embodiments, R1 is -C(O)N(R3)(R3') and R2 is H. In some embodiments, R3 is C1-C5 alkyl or C3-C6 cycloalkyl and R3' is H. In some embodiments, R3 is methyl, ethyl or isopropyl and R3' is H. In some embodiments, R3 is methyl and R3' is H.

[0055] In some embodiments of formula (1), R1 is H and R2 is -R5 or -L1-R5. In some embodiments, R1 is -L1-R5 and R2 is H. In some embodiments, -L1-R5 is -C(O)N(R7)-L2-N(R7)-R5, -C(O)O-L2-OR5, -C(O)N(R7)-L2-N(R7)-C(O)O-R5, -C(O)O-L2-N(R7)-C(O)O-R5, -C(O)N(R7)-L2-N(R8)-C(O)N(R8)-R5 or -C(O)O-L2-N(R8)-C(O)N(R8)-R5. In some embodiments, R5 is a C1-C5 alkyl group. In some embodiments, R6 is methyl, ethyl or isopropyl. In some embodiments, R6 is methyl. In some embodiments, R7 is H or Me. In some embodiments, R9 is H, F, or C1-C5 alkyl. In some embodiments, R9 is H, F, or Me. In some embodiments, R9 is H. In some embodiments, L2 is C2-C5 alkylene. In some embodiments, L2 is ethylene or propylene. In some embodiments, L2 is ethylene.

[0056] In some embodiments of formula (1), R1 is -C(O)O-R5 or -R5 and R2 is H. In some embodiments, R1 is H and R2 is -C(O)O-R5 or -R5. In some embodiments, R5 is H. In some embodiments, R6 is C1-C5 alkyl. In some embodiments, R6 is methyl, ethyl or isopropyl. In some embodiments, R6 is methyl. In some embodiments, R9 is H, F or Me. In some embodiments, R9 is H.

[0057] In some embodiments of formula (1), R1 is -L1-R5. In some embodiments, R1' is H or -L1-R5. In some embodiments, R1' is H. In some embodiments, R1' is -L1-R5. In some embodiments, R1 is -L1-R5 and R1' is H. In some embodiments, R1 is -L1-R5 and R1' is -L1-R5. In some embodiments, R1 is -L1-R5, R1' is H, and R2 is H. In some embodiments, R1 is -L1-R5, R1' is -L1-R5, and R2 is H. In some embodiments, -L1-R5 is selected from the group consisting of: -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2-O-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)N(R7)-R5, -C (O)N(R7)-L2-O-R5, -C(O)O-L2-N(R7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N( R8)-R5, -C(O)N(R7)-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)O-R5 and -C(O)N(R7)-L2-C(O)N(R8)-R5-. In some embodiments, -L1-R5 is selected from the group consisting of: -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2-N(R7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-N(R7)-R5, and -C(O)N(R7)-L2-C(O)N(R8)-R5-. In some embodiments, -L1-R5 is -C(O)O-R5. In some embodiments, R2 is H.

[0058] The divalent linker L1 may also contain one or more repeats of the same group or a combination of different groups. In some embodiments, L1 contains -C(O)O- and C1-C10 alkyl groups. In some embodiments, L1 contains two or more repeats of -C(O)O-. In some embodiments, L1 contains two or more repeats of -C(O)O(CH2)n-. In some embodiments, L1 contains two or more repeats of -C(O)N(R7)-. In some embodiments, L1 contains two or more repeats of -C(O)N(R7)(CH2)n-. In some embodiments, L1 contains a combination of -C(O)O-, C1-C10 alkyl groups, and -C(O)N(R7)-. In some embodiments, L1 contains a combination of -C(O)O-, -(CH2)n-, and -C(O)N(R7)-. In some embodiments, L1 contains a combination of -C(O)N(R7)- and C1-C10 alkyl groups. In some embodiments, L1 comprises two or more repetitions of -C(O)O(CH2)nC(O)N(R7)-. In some embodiments, L1 is -C(O)O-. In some embodiments, L1 is -C(O)N(R7)-. 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 this art, the above combinations are limiting examples, and other possible chemical combinations of L1 have also been carefully considered by the present invention.

[0059] In some embodiments, R6 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, R6 is H, C1-C10 alkyl, C2-C10 alkenyl, or C3-C10 cycloalkyl. In some embodiments, R6 is H, C1-C5 alkyl, C2-C5 alkenyl, or C3-C6 cycloalkyl. In some embodiments, R6 is H, C1-C3 alkyl, or C2-C4 alkenyl. In some embodiments, R6 is 1-C10 alkyl. In some embodiments, R6 is C1-C5 alkyl. In some embodiments, R6 is C1-C3 alkyl. In some embodiments, R6 is selected from the group consisting of: H, methyl, ethyl, isopropyl, and cyclopropyl. In some embodiments, R6 is methyl, ethyl, or isopropyl. In some embodiments, R6 is methyl. In some embodiments, R6 is isopropyl.

[0060] In some embodiments, R7 and R8 are each independently H, C1-C10 alkyl, or C3-C6 cycloalkyl. In some embodiments, R7 and R8 are each independently H, C1-C5 alkyl, or C3-C6 cycloalkyl. In some embodiments, R7 and R8 are each independently H or C1-C5 alkyl. In some embodiments, the C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R7 and R8 are each independently H, methyl, ethyl, isopropyl, or cyclopropyl.

[0061] In some embodiments, R7 is H or C1-C10 alkyl. In some embodiments, R7 is H or C1-C5 alkyl. In some embodiments, the C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, R7 is H or Me. In some embodiments, R7 is H.

[0062] In some embodiments, R8-based H or C1-C10 alkyl. In some embodiments, R8-based H or C1-C5 alkyl. In some embodiments, R8-based H or Me. In some embodiments, R8-based H.

[0063] In some embodiments, R9 is H, F, C1-C10 alkyl, or C2-C10 alkenyl. In some embodiments, R9 is H, F, C1-C5 alkyl, or C2-C5 alkenyl. In some embodiments, R9 is H, F, or C1-C5 alkyl. In some embodiments, R9 is H, F, or C1-C3 alkyl. In some embodiments, R9 is H or C1-C3 alkyl. In some embodiments, R9 is C1-C3 alkyl. In some embodiments, R9 is H, F, or Me. In some embodiments, R9 is H, F, Me, or isopropyl. In some embodiments, R9 is H or Me. In some embodiments, R9 is H or F. In some embodiments, R9 is H.

[0064] The adenosine derivative of the present invention may comprise one or more of its isomers. Isomers may include steric isomers comprising one or more steric centers, tautomers that are interconvertible via the repositioning of hydrogen atoms and double bonds (such as amino isomers, imine isomers), or combinations thereof. In non-limiting examples, the adenosine derivative may have amino isomers, imine isomers, or combinations thereof. In other non-limiting examples, the adenosine derivative may comprise enantiomers, non-mirror image isomers, and cis / trans isomers, tautomers, or combinations thereof. It also includes isomers that may have in vivo reverse transcriptase inhibitor (RTI) activity.

[0065] In some embodiments of formula (1), X is selected from the group consisting of halogen atoms of the following composition: fluorine, chlorine, bromine, and iodine (or fluorinyl (F), chlorinyl (Cl), bromine (Br), and iodine (I)). In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is Br.

[0066] In some embodiments, the adenosine derivative of the present invention comprises R1, R1', and R2, each independently comprising one or more 5- to 10-membered heterocyclic rings. In some embodiments, R1, R1', or R2 each independently comprises a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, or a 6- to 10-membered heterocyclic ring. In some embodiments, R1, R1', and R2 each independently comprises a 6- to 10-membered heterocyclic ring. In some embodiments, R1, R1', and R2 each independently comprises a 5-membered heterocyclic ring. In some embodiments, R1, R1', and R2 each independently comprises a 6-membered heterocyclic ring. The heterocyclic ring of the present invention 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 other embodiments, R1, R1', and R2 each independently comprise a 5-membered heterocyclic ring of formulas 9 to 24 disclosed herein. In even other embodiments, the adenosine derivatives of the present invention comprise R1, R1', and R2, each of which independently comprises the aforementioned -R5, -L1-R5, and -Z-L4-R5 groups. In some embodiments, the -R5, -L1-R5, and -Z-L4-R5 are selected from formulas 9 to 24:

[0067] In some embodiments, -R5, -L1-R5, and -Z-L4-R5 are selected from the group consisting of:

[0068] In some embodiments, the adenosine derivative of the present invention comprises R1 and R1', each of which is independently H, -C(O)N(R3)(R3') or -C(O)OR4, and R2, which is -C(O)N(R3)(R3'), -C(O)OR4 or one of formulas 9 to 24.

[0069] In some embodiments, the adenosine derivative of the present invention comprises R1 and R1', each of which is independently -C(O)N(R3)(R3') or -C(O)OR4, and R2, which is one of H, -C(O)N(R3)(R3'), -C(O)OR4 or formulas 9 to 24.

[0070] In some embodiments, the adenosine derivative of the present invention comprises R2, which is H, -C(O)N(R3)(R3') or -C(O)OR4, and R1, which is -C(O)N(R3)(R3') or -C(O)OR4 or one of formulas 9 to 24.

[0071] In some embodiments, the adenosine derivative of the present invention comprises R2, which is -C(O)N(R3)(R3') or -C(O)OR4, and R1, which is H, -C(O)N(R3)(R3'), -C(O)OR4 or one of formulas 9 to 24.

[0072] In some embodiments, the adenosine derivative of the present invention comprises R1 and R1', each of which is H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, -Z-L4-R5 or one of formulas 9 to 24, and R2, which is -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, -Z-L4-R5 or one of formulas 9 to 24.

[0073] In some embodiments, the adenosine derivative of the present invention comprises R1, which is one of -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, -Z-L4-R5 or formula 9 to 24, and R2, which is one of H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, -Z-L4-R5 or formula 9 to 24.

[0074] In some embodiments, each of R1, R1' and R2 is independently selected from one of Formulas 9 to 24.

[0075] In some embodiments, the present invention relates to an adenosine derivative having the structure of formula (1a): (1a), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R1 and X are as defined above with respect to formula (1).

[0076] In some embodiments, the present invention relates to an adenosine derivative having the structure of formula (1b): (1b), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R2 and X are as defined above with respect to formula (1).

[0077] In some embodiments, the adenosine derivatives of the present invention are selected from the group consisting of: Formula (2):, Formula (3):, Formula (4):, Formula (5):, Formula (6):, Formula (7):, Formula (8):, Formula (4-B):, or pharmaceutically acceptable salts, tautomers or solvates thereof, wherein X is as described herein.

[0078] In some embodiments, the X-series Cl, F, or Br. In some embodiments, the X-series F.

[0079] In other embodiments, the adenosine derivative of the present invention is selected from the group consisting of: formula (2-A):, formula (3-A):, formula (4-A):, formula (5-A):, formula (6-A):, formula (7-A):, formula (8-A):, formula (4-C):, or pharmaceutically acceptable salts, tautomers or solvates thereof.

[0080] In some embodiments, the adenosine derivative of the present invention is a compound selected from the group consisting of: isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin- 6-yl)carbamate isopropyl ester, ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester, methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran) -2-yl)methyl ester, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-dioxacyclopenten-2-one, (2-(methyl((5-methyl-2-sideoxy-1,3-dioxacyclopenten-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-sideoxy-1,3-dioxacyclopenten-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl] methyl ester, and their pharmaceutically acceptable salts.

[0081] In some embodiments, the adenosine compounds of the present invention are isomers of formulas (1) to (8), (1a), (1b), or (1-A) to (8-A). In some embodiments, the isomers are stereoisomers, for example, enantiomers or non-mirror image isomers. In some embodiments, the isomers are inhibitors of reverse transcriptases having in vivo activity.

[0082] The adenosine derivative of the present invention can be converted into a targeted drug and may contain in vivo reverse transcriptase inhibitor activity, in vivo reverse transcriptase chain terminator activity, in vivo DNA translocation inhibitor activity, or a combination thereof.

[0083] The adenosine derivative of the present invention may be a prodrug in its initial (i.e., parent) form as shown herein, having little or limited activity and capable of being metabolized in vivo to exhibit the desired activity of a targeted drug (including reverse transcriptase inhibitor activity, reverse transcriptase chain terminator activity, DNA translocation inhibitor activity, or a combination thereof).

[0084] Not wanting to be bound by a specific mechanism or theory, the applicant has discovered that the adenosine derivative of the present invention can be metabolized in vivo to produce compounds or mixtures of compounds similar to or the same as 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), a targeted drug with reverse transcriptase inhibitor and other antiviral activities.

[0085] As disclosed herein, the adenosine derivatives of the present invention may comprise isomers thereof (e.g., enantiomers, non-mirror image isomers and / or tautomers), one or more pharmaceutically acceptable salts thereof, one or more solvates thereof (including hydrates), solvated salts thereof, or mixtures thereof.

[0086] Adenosine derivatives are also described in WO 2021 / 021717, which is incorporated herein by reference in its entirety. Compositions of the present invention

[0087] The present invention provides pharmaceutical compositions comprising adenosine derivatives disclosed herein or pharmaceutically acceptable salts, tautomers, or solvates thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0088] In some embodiments, the present invention 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.

[0089] In some embodiments, the present invention 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.

[0090] In some embodiments, the CA inhibitor is lenapavir. As used herein, lenapavir refers to a compound having the following structure: a pharmaceutically acceptable salt, tautomer, or solvate thereof, or a combination thereof. Suitable commercially available lenapavir is the composition disclosed herein.

[0091] In some embodiments, the pharmaceutical composition of the present invention 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.

[0092] In some embodiments, the anti-HIV agent is selected from the group consisting of: abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bictagrevir, cabotevir, derunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate, and tenofovir alafenamide. The anti-HIV agent comprises alafenamide, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, aviravir, etravirine, fosanavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, combinations of lopinavir and ritonavir, derunavir, combinations of derunavir and cobicistat, maravirovir, nelfinavivir, nelfinavivir mesylate, nevirapine, PPL-100, retegvir, rilpivirine, stavudine, telanavir, vicriviroc, one or more capsid (CA) inhibitors, GS-6207 (lenakapavir), and combinations thereof. In some embodiments, the anti-HIV agent is a capsid (CA) inhibitor. In some embodiments, the anti-HIV agent is lenakapavir.

[0093] 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 (ddl), 2',3'-dideoxycytidine (ddC), d4T, 3TC, abacavir, emtricitabine, tenofovir disoproxil fumarate, nevirapine, deraviridine, efavirenz, rilpivirine, and doravirine.

[0094] The compositions of the present invention can be used to treat diseases including (but not limited to) acquired immunodeficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multidrug-resistant HIV, or RNA virus infection. In some embodiments, the disease is human immunodeficiency virus 1 (HIV-1). In some embodiments, the HIV-1 is multidrug-resistant.

[0095] In some embodiments, the compositions of the present invention comprise adenosine derivative of formula (1): (1), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: R1, R1' and R2 are each independently H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5 or -Z-L4-R5, wherein at least one of R1 and R2 is not H; R3, R3' and R4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10-membered heterocycloalkyl, aryl or heteroaryl; R5 is:; R6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10-membered heterocycloalkyl, aryl or heteroaryl; -L1-R5 series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5, -(C2-C10 alkenyl)-S-R5, -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2-O -R5, -C(O)O-L2-S-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)O-L2-C(O)N(R7)- L3-N(R7)-R5, -C(O)O-L2-C(O)N(R7)-L3-O-R5, -C(O)O-L2-C(O)N(R7)-L3-S-R5, -C(O)N(R7)-R5 , -C(O)N(R7)-L2-N(R7)-R5, -C(O)N(R7)-L2-O-R5, -C(O)N(R7)-L2-S-R5, -C(O)N(R7)-L2-C(O)O -R5, -C(O)N(R7)-L2-C(O)N(R8)-R5-, -C(O)N(R7)-L2-C(O)N(R8)-L3-N(R7)-R5, -C(O)O-L2-N(R 7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2- N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)N(R8)-L3-O-R5 or -C(O)N(R7)-L2-C(O)N(R8)-L3-S-R5; -Z- is -C(O)-, -C(O)O- or -C(O)N(R7)-;-L4-R5 series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5 or -(C2-C10 alkenyl)-S-R5; R7 and R8 are each independently H, C1-C10 alkyl or C2-C10 alkenyl; R9 is independently H, -F, C1-C10 alkyl or C2-C10 alkenyl; L2 and L3 are each divalent -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and X series halogen atoms.

[0096] In some embodiments of formula (1), the C1-C10 alkyl and C2-C10 alkenyl groups are straight-chain or branched chains. 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 heterocycloalkyl, aryl and heteroaryl groups.

[0097] In some embodiments, the adenosine derivatives disclosed herein include the divalent linker L1 disclosed herein, which comprises one or more repeating or different groups of the same group. Non-limiting examples of linker L1 and other possible chemical combinations include those described above (e.g.) in formula (1).

[0098] In some embodiments, R1, R1', and R2 are each independently R5, -L1-R5, or -Z-L4-R5. In some embodiments, the structures of R5, -L1-R5, and -Z-L4-R5 are:

[0099] In some embodiments, the pharmaceutical composition of the present invention comprises the adenosine derivative disclosed herein, wherein R1 and R1' are H, -C(O)N(R3)(R3') or -C(O)OR4 and R2 is -C(O)N(R3)(R3'), -C(O)OR4 or one of formulas 9 to 24.

[0100] In some embodiments, the pharmaceutical composition of the present invention comprises the adenosine derivative disclosed herein, wherein R1 is -C(O)N(R3)(R3') or -C(O)OR4, and R2 is H, -C(O)N(R3)(R3'), -C(O)OR4 or one of formulas 9 to 24.

[0101] In some embodiments, the pharmaceutical composition of the present invention comprises the adenosine derivative disclosed herein, wherein R2 is H, -C(O)N(R3)(R3') or -C(O)OR4, and R1 is -C(O)N(R3)(R3') or -C(O)OR4 or one of formulas 9 to 24.

[0102] In some embodiments, the pharmaceutical composition of the present invention comprises the adenosine derivative disclosed herein, wherein R2 is -C(O)N(R3)(R3') or -C(O)OR4, and R1 and R1' are each independently one of H, -C(O)N(R3)(R3'), -C(O)OR4 or formulas 9 to 24.

[0103] In some embodiments, the pharmaceutical composition of the present invention comprises the adenosine derivative disclosed herein, wherein R1 and R1' are each independently one of H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, -Z-L4-R5 or formula 9 to 24, and R2 is one of -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, -Z-L4-R5 or formula 9 to 24.

[0104] In some embodiments, the pharmaceutical composition of the present invention comprises the adenosine derivative disclosed herein, wherein R1 is one of -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, -Z-L4-R5 or formula 9 to 24, and R2 is one of H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, -Z-L4-R5 or formula 9 to 24.

[0105] In some embodiments, the pharmaceutical composition of the present invention comprises an adenosine derivative disclosed herein, wherein R1, R1' and R2 are each independently selected from one of formulas 9 to 24.

[0106] In some embodiments, R3, R3', and R4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, or C3-C10 cycloalkyl. In some embodiments, R3, R3', and R4 are each independently H, C1-C5 alkyl, C2-C5 alkenyl, or C3-C6 cycloalkyl. In some embodiments, R3, R3', and R4 are each independently H or C1-C5 alkyl. In some embodiments, the C1-C5 alkyl group is methyl, ethyl, or isopropyl. In some embodiments, R3, R3', and R4 are each independently H, methyl, or isopropyl.

[0107] In some embodiments, R6 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, R6 is H, C1-C10 alkyl, C2-C10 alkenyl, or C3-C10 cycloalkyl. In some embodiments, R6 is H, C1-C5 alkyl, C2-C5 alkenyl, or C3-C6 cycloalkyl. In some embodiments, R6 is H, C1-C3 alkyl, or C2-C4 alkenyl. In some embodiments, R6 is C1-C10 alkyl. In some embodiments, R6 is C1-C5 alkyl. In some embodiments, R6 is C1-C3 alkyl. In some embodiments, R6 is selected from the group consisting of: H, methyl, ethyl, isopropyl, and cyclopropyl. In some embodiments, R6 is methyl, ethyl, or isopropyl. In some embodiments, R6 is methyl. In some embodiments, R6 is isopropyl.

[0108] In some embodiments, R7 and R8 are each independently H, C1-C10 alkyl, or C3-C6 cycloalkyl. In some embodiments, R7 and R8 are each independently H, C1-C5 alkyl, or C3-C6 cycloalkyl. In some embodiments, R7 and R8 are each independently H or C1-C5 alkyl. In some embodiments, the C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R7 and R8 are each independently H, methyl, ethyl, isopropyl, or cyclopropyl.

[0109] In some embodiments, R7 is H or C1-C10 alkyl. In some embodiments, R7 is H or C1-C5 alkyl. In some embodiments, the C1-C5 alkyl is methyl, ethyl, or isopropyl. In some embodiments, R7 is H or Me. In some embodiments, R7 is H.

[0110] In some embodiments, R8-based H or C1-C10 alkyl. In some embodiments, R8-based H or C1-C5 alkyl. In some embodiments, R8-based H or Me. In some embodiments, R8-based H.

[0111] In some embodiments, R9 is H, F, C1-C10 alkyl, or C2-C10 alkenyl. In some embodiments, R9 is H, F, C1-C5 alkyl, or C2-C5 alkenyl. In some embodiments, R9 is H, F, or C1-C5 alkyl. In some embodiments, R9 is H, F, or C1-C3 alkyl. In some embodiments, R9 is H or C1-C3 alkyl. In some embodiments, R9 is C1-C3 alkyl. In some embodiments, R9 is H, F, or Me. In some embodiments, R9 is H, F, Me, or isopropyl. In some embodiments, R9 is H or Me. In some embodiments, R9 is H or F. In some embodiments, R9 is H.

[0112] In some embodiments, X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine (or 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. This document provides non-limiting examples of adenosine derivatives of the present invention.

[0113] In some embodiments, the compositions of the present invention comprise an adenosine derivative of formula (1a): (1a), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R1 and X are as defined above with respect to formula (1).

[0114] In some embodiments, the compositions of the present invention comprise an adenosine derivative of formula (1b): (1b), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R2 and X are as defined above for formula (1).

[0115] In some embodiments, the pharmaceutical composition of the present invention comprises an adenosine derivative having a formula selected from the group consisting of: formula (2):, formula (3):, formula (4):, formula (5):, formula (6):, formula (7):, and formula (8):, formula (4-B):, or a pharmaceutically acceptable salt, tautomer, solvate, or combination thereof.

[0116] In some embodiments, the X-series Cl, F, or Br. In some embodiments, the X-series F.

[0117] In some embodiments, the pharmaceutical composition of the present invention comprises an adenosine derivative having a formula selected from the group consisting of: formula (2-A):, formula (3-A):, formula (4-A):, formula (5-A):, formula (6-A):, formula (7-A):, formula (8-A):, formula (4-C):, its stereoisomer, its pharmaceutically acceptable salt, or a combination thereof.

[0118] In some embodiments, the adenosine derivative of the pharmaceutical composition is a compound of formula (1) to (8), formula (1a), formula (1b), formula (1-A) to (8-A), formula (4-B) or formula (4-C).

[0119] In some embodiments, the adenosine compound of the pharmaceutical composition is an isomer of formula (1) to (8), formula (1a), formula (1b), formula (1-A) to (8-A), formula (4-B), or formula (4-C). The isomers described above (such as tautomers, enantiomers, non-mirror image isomers, cis / trans isomers, or combinations thereof) may be suitable. In some embodiments, the isomer is a stereoisomer, for example, an enantiomer or a non-mirror image isomer. In some embodiments, the isomer is an inhibitor of a reverse transcriptase having in vivo activity.

[0120] As disclosed herein, the pharmaceutical compositions of the present invention may comprise an adenosine derivative selected from the group consisting of: isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purinyl) Isopropyl methyl methacrylate ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl methacrylate, methyl methacrylate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl methacrylate (2-yl)methyl ester, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-dioxacyclopenten-2-one, (2-(methyl((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)amino)ethyl)carbamic acid((2R,3S,5R) 5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, 4-[methyl-[(5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl] methyl ester and their pharmaceutically acceptable salts.

[0121] As disclosed above, the pharmaceutical compositions of the present invention comprising adenosine derivatives may be free of monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof. In some embodiments, the R1 and / or R2 groups of the adenosine derivatives disclosed herein are free of monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof.

[0122] In some embodiments, the pharmaceutical composition of the present invention comprises 10 mg to 2000 mg, for example, 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 the adenosine derivative disclosed herein or its pharmaceutically acceptable salts, tautomers, or solvates, including all ranges and values ​​between these. In some embodiments, the pharmaceutical composition of the present invention comprises 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, 600 mg to 1000 mg, 1 ... 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 mg, 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 mg This article discloses adenosine derivatives or their pharmaceutically acceptable salts, tautomers or solvates.In some embodiments, the pharmaceutical composition comprises 700 mg to 2000 mg of the adenosine derivative disclosed herein or a pharmaceutically acceptable salt, tautomer, or solvation thereof. In some embodiments, the pharmaceutical composition comprises 700 mg to 1200 mg of the adenosine derivative disclosed herein or a pharmaceutically acceptable salt, tautomer, or solvation thereof.

[0123] In some embodiments, the pharmaceutical composition of the present invention comprises 10 mg to 2000 mg, for example, 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 anti-HIV agent, including all ranges and values ​​between them. 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, 100 mg to 2000 mg, 100 mg to 12 ... 1000 mg to 1200 mg, 1000 mg to 1200 mg, 1000 mg to 2000 mg of anti-HIV agent. In some embodiments, the pharmaceutical composition comprises 700 mg to 1000 mg of anti-HIV agent.

[0124] In some embodiments, the pharmaceutical composition of the present invention comprises 10 mg to 2000 mg, for example, 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 CA inhibitors, such as lenakapavir. 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, 100 mg to 2000 mg, 100 mg to 12 ... 1000 mg to 1200 mg, 1000 mg to 1200 mg, 1000 mg to 2000 mg CA inhibitors, such as lenakapavir. In some embodiments, the pharmaceutical composition comprises 700 mg to 1000 mg of a CA inhibitor.

[0125] The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.

[0126] Non-limiting examples of pharmaceutically acceptable carriers include pharmaceutical excipients, surfactants, emulsifiers, fillers, carriers, isotonic agents, dispersants, viscosity modifiers, resuspending agents, buffers, or combinations thereof. Pharmaceutical excipients generally do not possess the properties of a pharmaceutical or active pharmaceutical ingredient (also known as an active pharmaceutical ingredient (API)) and are typically used to streamline the manufacturing process or packaging of such active ingredients, or to deliver APIs to patients or other subjects. Pharmaceutically acceptable carriers, excipients, or inactive ingredients may be appropriate from the inactive ingredient database available from the US FDA (https: / / www.fda.gov / drugs / drug-approvals-and-databases / inactive-ingredients-database-download). Some of the generally recognized safe (GRAS) food substances that are available from the US FDA's GRAS Substances (SCOGS) database (https: / / www.fda.gov / food / generally-recognized-safe-gras / gras-substances-scogs-database) may also be appropriate.

[0127] In some embodiments of the present invention, pharmaceutically acceptable carriers include gum arabic, animal oil, benzyl alcohol, methyl benzoate, calcium stearate, carbomer, cetearyl alcohol, cetyl alcohol, cholesterol, cyclodextrin, dextran, diethanolamine, emulsifying wax, ethylene glycol palmitate, glycerin, glyceryl monostearate, glyceryl stearate, glyceryl monooleate, glyceryl monostearate, hydration, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin (HPBCD), hydroxypropyl methylcellulose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohol, lecithin, medium-chain triglycerides, metallic soaps, methylcellulose, mineral oil, sodium dihydrogen phosphate, monoethanolamine, oleic acid, polyethylene glycol (PEG 3350, PEG 4000, PEG...). 6000), polyoxyethylene-polyoxypropylene copolymer (poloxam), polyoxyethylene alkyl ester, polyoxyethylene castor oil, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polysorbate, polyoxyethylene (20) sorbitan monolaurate (Tween 20, polysorbate 20), polyoxyethylene (20) sorbitan monooleate (Tween 80, polysorbate 80), povidone, propylene glycol alginate, brine, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sorbitan ester, stearic acid, stearyl alcohol, sunflower seed oil, tragacanth gum, triethanolamine, vegetable oil, water, senna gum, or combinations thereof.

[0128] In other embodiments, pharmaceutically acceptable carriers include dextran, glycerol, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-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 dihydrogen phosphate, disodium hydrogen phosphate, or combinations thereof.

[0129] In some embodiments, the adenosine derivative, such as compounds of formulas (1) to (8), (1a), (1b), or (1-A)-(8-A), and the anti-HIV agent, such as a CA inhibitor, are provided as a single formulation for administration to a subject. In some embodiments, the adenosine derivative and the anti-HIV agent, such as a CA inhibitor, are provided as separate formulations for administration to a subject simultaneously or sequentially. The pharmaceutical compositions of the present invention may also be administered to a subject simultaneously with one or more other anti-HIV agents as separate formulations.

[0130] In some embodiments, the adenosine derivative of the present invention is administered to the subject simultaneously, before, or after the CA inhibitor. In some embodiments, the adenosine derivative and the CA inhibitor are each administered to the subject periodically.

[0131] The pharmaceutical compositions of the present invention are suitable for oral, intravenous, intramuscular, subcutaneous, non-enteric, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active ingredient may be encapsulated in a material to protect it from acids and other natural conditions that may deactivate it. As used herein, the phrase "non-enteric administration" means administration methods other than enteric and local administration, typically by injection, and includes (but is not limited to) intravenous, intramuscular, intra-articular, intrasheath, intracapsular, intra-capsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions. Alternatively, the pharmaceutical composition may be administered via an enteric route, such as a local, epidermal, or mucosal administration route, for example, intranasal, oral, vaginal, rectal, sublingual, or local administration. These pharmaceutical compositions may be in the form of sterile aqueous solutions or dispersions. These pharmaceutical compositions can also be formulated into microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The method of this invention...

[0132] In some embodiments, the present invention provides a method for treating or preventing HIV infection, comprising administering to a subject in need 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.

[0133] In some embodiments, the present invention provides a method for treating HIV infection, comprising administering to a subject in need 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.

[0134] In some embodiments of the methods disclosed herein, the anti-HIV agent is selected from the group consisting of: abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bicretiravir, cabotevir, derunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, 4'-ethynyl-2-fluoro- 2'-Deoxyadenosine, Aviravir, Etravirine, Forsanavir calcium, Indinavir, Indinavir sulfate, Lamivudine, Lopinavir, a combination of Lopinavir and Ritonavir, Derunavir, a combination of Derunavir and Cobicistat, Maravirox, Neferunavir, Neferunavir mesylate, Nevirapine, PPL-100, Rettagvir, Rilpivirine, Stavudine, Tiranavir, Veviroc, one or more capsid (CA) inhibitors and GS-6207 (Lenacapapavir), 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 herein by reference 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 lenakapavir. In some embodiments, the anti-HIV agent is lenakapavir.

[0135] As used herein, lenapavir refers to a compound having the following structure: , or a pharmaceutically acceptable salt, tautomer, or solvate thereof. Commercially available lenapavir may be used in the methods disclosed herein.

[0136] In some embodiments, the present invention provides a method for treating or preventing HIV infection, comprising administering to a subject in need 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 lenakapavir.

[0137] In some embodiments, the present invention provides a method for treating HIV infection, comprising administering to a subject in need 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 lenakapavir.

[0138] In some embodiments, the capsid (CA) inhibitor, such as lenapavir mentioned above, is administered in doses 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 12 ...1200 mg. The CA inhibitor is administered to the subject at doses ranging from 700 mg to 1200 mg, 800 mg to 1200 mg, 900 mg to 1200 mg, 1000 mg to 1200 mg, and 1000 mg to 2000 mg (effective dose). In some embodiments, the CA inhibitor is administered to the subject at an effective dose in the range of 700 mg to 1000 mg using one of the dosing schedules described above and below. In some embodiments, the CA inhibitor is administered to the subject at a single dose in the range of 100 mg to 2000 mg every 6 months. The CA inhibitor may be administered to the subject via one or more injections.

[0139] In some embodiments, an effective dose of a capsid (CA) inhibitor, such as lenakapavir mentioned above, is administered to the subject at a rate ranging from 100 mg to 2000 mg every 1 to 7 days to about every 8 weeks. In some embodiments, the effective dose of the CA inhibitor is 300 mg daily, every two days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, 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 effective dose of the CA inhibitor is 400 mg daily, every two days, every three days, every four days, every five days, every six days, every seven 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 the CA inhibitor is 500 mg daily, every two days, every three days, every four days, every five days, every six days, every seven 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 the CA inhibitor is 600 mg daily, every two days, every three days, every four days, every five days, every six days, every seven 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 the CA inhibitor is 800 mg daily, every two days, every three days, every four days, every five days, every six days, every seven 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 the CA inhibitor is 900 mg once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once weekly (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 the CA inhibitor is 1000 mg daily, every two days, every three days, every four days, every five days, every six days, every seven 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 the CA inhibitor varies from 700 mg to 2000 mg once a month (QM). The CA inhibitor can be administered orally to the subject with or without food. The CA inhibitor can also be administered to the subject by injection (such as subcutaneous injection into the abdomen).

[0140] In some embodiments, lenakapavir is administered orally to the subject. In some embodiments, lenakapavir is administered orally to the subject at a dose of 100 mg to 1000 mg per day. In some embodiments, lenakapavir is administered orally at a dose of 300 mg to 600 mg per day. In some embodiments, lenakapavir is administered orally at a dose of 300 mg or 600 mg per day.

[0141] In some embodiments, lenakapavir is administered by subcutaneous injection. In some embodiments, the lenakapavir is administered subcutaneously. In some embodiments, the lenakapavir is administered subcutaneously at a dose of 500 mg to 1500 mg per day. In some embodiments, the lenakapavir is administered subcutaneously at a dose of 800 mg to 100 mg per day. In some embodiments, the lenakapavir is administered subcutaneously at a dose of 927 mg per day.

[0142] The adenosine derivative used in the method disclosed in this invention may be any adenosine derivative disclosed herein, its pharmaceutically acceptable salt, tautomer or solvate.

[0143] In some embodiments, the adenosine derivatives applicable to the method disclosed in this invention are compounds of formula (1): (1), or pharmaceutically acceptable salts, tautomers or solvates thereof, wherein: R1, R1' and R2 are each independently of H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5 or -Z-L4-R5, wherein at least one of R1 and R2 is not H; R3, R3' and R4 are each independently of H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10-membered heterocycloalkyl, aryl or heteroaryl; R5 is:; R6 is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10-membered heterocycloalkyl, aryl or heteroaryl; -L1-R5 series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5, -(C2-C10 alkenyl)-S-R5, -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2-O -R5, -C(O)O-L2-S-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)O-L2-C(O)N(R7)- L3-N(R7)-R5, -C(O)O-L2-C(O)N(R7)-L3-O-R5, -C(O)O-L2-C(O)N(R7)-L3-S-R5, -C(O)N(R7)-R5 , -C(O)N(R7)-L2-N(R7)-R5, -C(O)N(R7)-L2-O-R5, -C(O)N(R7)-L2-S-R5, -C(O)N(R7)-L2-C(O)O -R5, -C(O)N(R7)-L2-C(O)N(R8)-R5-, -C(O)N(R7)-L2-C(O)N(R8)-L3-N(R7)-R5, -C(O)O-L2-N(R 7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2- N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)N(R8)-L3-O-R5 or -C(O)N(R7)-L2-C(O)N(R8)-L3-S-R5; -Z- is -C(O)-, -C(O)O- or -C(O)N(R7)-;-L4-R5 series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5 or -(C2-C10 alkenyl)-S-R5; R7 and R8 are each independently H, C1-C10 alkyl or C2-C10 alkenyl; R9 is independently H, -F, C1-C10 alkyl or C2-C10 alkenyl; L2 and L3 are each divalent -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and X series halogen atoms.

[0144] In some embodiments, the adenosine derivatives applicable to the methods disclosed in this invention are compounds of formulas (1) to (8), (1a), (1b), (1-A) to (8-A), (4-B), or (4-C). In some embodiments, the adenosine derivatives applicable to the methods disclosed in this invention are compounds of formula (4-A) or (4-C). In some embodiments, the adenosine derivatives applicable to the methods disclosed in this invention are compounds of formula (4-A) having the following structure: , or pharmaceutically acceptable salts, tautomers, or solvates thereof.

[0145] In some embodiments of the method of the present invention, the adenosine derivative is an isomer of formula (1) to (8), formula (1a), formula (1b), formula (1-A) to (8-A), formula (4-B), or formula (4-C). The isomers described above, such as tautomers, stereoisomers, cis / trans isomers, or combinations thereof, may be suitable. In some embodiments, the stereoisomers of the adenosine derivatives disclosed herein are enantiomers and / or non-mirror image isomers. In some embodiments, the isomer is an inhibitor of a reverse transcriptase having in vivo activity.

[0146] In some embodiments of the method of the present invention, the adenosine derivative of formula (1) comprises a straight-chain or branched-chain C1-C10 alkyl and / or C2-C10 alkenyl groups. In some embodiments, the adenosine derivative comprises a combination of C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl and heteroaryl groups.

[0147] In some embodiments of the method of the present invention, the adenosine derivative includes a linker L1, which comprises one or more repeating or different groups of the same group as disclosed herein. Non-limiting examples of linker L1 and other possible chemical combinations include those described above (for example) in formula (1).

[0148] In some embodiments, X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine (or 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. This document provides non-limiting examples of adenosine derivatives of the present invention.

[0149] In some embodiments, the adenosine derivatives used in the methods disclosed in this invention are compounds of formula (1a): (1a), or pharmaceutically acceptable salts, tautomers or solvates thereof, wherein R1 and X are as defined above for formula (1).

[0150] In some embodiments, the adenosine derivatives used in the methods disclosed in this invention are compounds of formula (1b): (1b), or pharmaceutically acceptable salts, tautomers or solvates thereof, wherein R2 and X are as defined above for formula (1).

[0151] In some embodiments, the methods disclosed herein include adenosine derivatives having a group of the following compositions: formula (2):, formula (3):, formula (4):, formula (5):, formula (6):, formula (7):, and formula (8):, formula (4-B):, or pharmaceutically acceptable salts, tautomers or solvates thereof.

[0152] In some embodiments, the X-series Cl, F, or Br. In some embodiments, the X-series F.

[0153] In some embodiments, the methods disclosed herein include adenosine derivatives having a composition selected from the group consisting of: formula (2-A):, formula (3-A):, formula (4-A):, formula (5-A):, formula (6-A):, formula (7-A):, formula (8-A):, formula (4-C):, or pharmaceutically acceptable salts, tautomers or solvates thereof.

[0154] In some embodiments, the method of the present invention includes an adenosine derivative selected from the group consisting of: isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin- 6-yl)carbamate isopropyl ester, ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester, methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran) -2-yl)methyl ester, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-dioxacyclopenten-2-one, (2-(methyl((5-methyl-2-sideoxy-1,3-dioxacyclopenten-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-sideoxy-1,3-dioxacyclopenten-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl] methyl ester and their pharmaceutically acceptable salts.

[0155] As discussed above, the adenosine derivatives applicable to the methods disclosed in this invention may not contain monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof. In some embodiments, the R1 and / or R2 groups of the adenosine derivatives disclosed herein do not contain monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof.

[0156] 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, for example, 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 ​​between these values.In some embodiments, the adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof is used in concentrations 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 5 ... 100 mg to 400 mg, or 100 mg to 300 mg, 200 mg to 1000 mg, 300 mg to 1000 mg, 400 mg to 500 mg, 100 mg to 1000 mg, 400 mg to 500 mg, 100 mg to 1000 mg, 400 mg to 50 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 mg, 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, 9 ... The adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof was administered to the subject at a dose (effective dose) ranging from 700 mg to 2000 mg. In some embodiments, the adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof was administered to the subject at a dose (effective dose) ranging from 700 mg to 1200 mg.

[0157] In some embodiments, the adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof is administered to the subject via intramuscular (IM), subcutaneous (SC), intravenous (IV), oral administration, implant application, or a combination thereof. In some embodiments, the adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof is administered to the subject via IM and / or SC. Implant applications may include implantable devices or films containing the pharmaceutical compositions disclosed herein. The implant application may include vaginal rings, films, membranes, patches, other devices, or combinations thereof.

[0158] In some embodiments, the methods disclosed herein include administering an effective dose orally and / or by injection. In some embodiments, the methods disclosed herein include administering such effective doses orally. In some embodiments, the methods disclosed herein include administering such effective doses orally to a subject, such as by taking one or more tablets once a week (QW) to once every eight weeks (Q8W). In some embodiments, the methods disclosed herein include administering such effective doses to the subject by injection, such as by one or more injections per 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, such effective doses are administered by subcutaneous and / or intramuscular injection.

[0159] In some embodiments, a capsid (CA) inhibitor or a composition thereof and an adenosine derivative or a composition thereof are administered to a subject simultaneously or sequentially. In some embodiments, the CA inhibitor or composition and the adenosine derivative or a composition thereof are administered to the subject simultaneously. The term "simultaneously" means that the CA inhibitor or composition and the adenosine derivative or a composition thereof are administered to the subject simultaneously or over a period of several seconds (e.g., 0 to 60 seconds to several minutes, e.g., 1 to 5 minutes). In some embodiments, the CA inhibitor or composition and the adenosine derivative or a composition thereof are administered sequentially to the subject over a period of time 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 used in tablet form, one or more tablets containing the CA inhibitor and one or more tablets containing the adenosine derivative are administered to the subject by a single oral ingestion or within the time period described above. Any of the time ranges disclosed herein refers to administration before or after this period. In some embodiments, the CA inhibitor or its composition is administered before administration of the adenosine derivative or its composition. In some embodiments, the CA inhibitor or its composition is administered after administration of the adenosine derivative or its composition.

[0160] In some embodiments, a capsid (CA) inhibitor or a combination thereof and an adenosine derivative or a combination thereof are administered to the subject once daily to once every 12 months. In some embodiments, the CA inhibitor or a combination thereof and the adenosine derivative or a combination 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 a combination thereof and the adenosine derivative or a combination thereof are administered to the subject once every 6 months. The CA inhibitor or a combination thereof and the adenosine derivative or a combination thereof are administered to the subject simultaneously or sequentially as described above and below. In some embodiments, the CA inhibitor or a combination thereof and the adenosine derivative or a combination thereof are administered to the subject once every 1 to 8 weeks. In some embodiments, the CA inhibitor or a composition thereof and the adenosine derivative or a composition thereof are administered to the subject once weekly (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 CA inhibitor or a composition thereof and the adenosine derivative or a composition thereof are administered to the subject once monthly (QM). In some embodiments, the CA inhibitor or a composition thereof and the adenosine derivative or a composition thereof are administered orally to the subject in one or more tablets. In some embodiments, the CA inhibitor or a composition thereof and the adenosine derivative or a composition thereof are administered orally to the subject once weekly (QW) in one or more tablets. The administration times and frequencies described above and below are collectively referred to herein in the plural or singular form as "administration schedule" or "dosing schedule".

[0161] In some embodiments, a capsid (CA) inhibitor or a combination thereof and an adenosine derivative or a combination thereof are administered to a subject simultaneously or sequentially, using oral and injectable administration as described above and below. In some embodiments, the CA inhibitor or a combination thereof is administered to the subject by injection every 6 months, and the adenosine derivative or a combination thereof is administered to the subject orally once weekly (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 CA inhibitor or a combination thereof is administered to the subject monthly (QM) by injection or oral administration, and the adenosine derivative or a combination thereof is administered to the subject orally once monthly (QM).

[0162] In some embodiments, the effective dose of the capsid (CA) inhibitor is in the range of 300 mg to 2000 mg once weekly (QW) to once every 8 weeks (Q8W), and the effective dose of the adenosine derivative or combination thereof is in the range of 100 mg to 2000 mg of the adenosine derivative once weekly (QW) to once every 8 weeks (Q8W). In some embodiments, the effective dose of the CA inhibitor is in the range of 300 mg to 2000 mg once monthly (QM), and the effective dose of the adenosine derivative or combination thereof is in the range of 100 mg to 2000 mg of the adenosine derivative once monthly (QM). In some embodiments, the effective dose of the CA inhibitor is in the range of 300 mg to 1200 mg once monthly (QM), and the effective dose of the adenosine derivative is in the range of 100 mg to 1200 mg of the adenosine derivative once monthly (QM).

[0163] In some embodiments, effective doses of the anti-HIV agents disclosed herein and adenosine derivatives, or pharmaceutically acceptable salts, tautomers, or solvates thereof, provide 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, multidrug-resistant HIV, or RNA virus infection. In some embodiments, effective doses of the CA inhibitors disclosed herein and adenosine derivatives, or pharmaceutically acceptable salts, tautomers, or solvates thereof, provide 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, multidrug-resistant HIV, or RNA virus infection. In some embodiments, the disease is HIV-1. In some embodiments, the CA inhibitor is lenakapavir and the adenosine derivative is a compound having the structure of formula (4-A).

[0164] This document discloses that an effective dose of a capsid (CA) inhibitor and an effective dose of an adenosine derivative, individually or in combination, is suitable. For example, the effective dose of the CA inhibitor is administered once weekly (QW) and the effective dose of the adenosine derivative is administered once weekly (QW) to once every 8 weeks (Q8W). In another example, the effective dose of the adenosine derivative is administered once weekly (QW) and the effective dose of the CA inhibitor is administered once weekly (QW) to once every 8 weeks (Q8W). The combination of once weekly (QW) is preferred. In some embodiments, the effective dose of the CA inhibitor is in the range of 300 mg to 600 mg once weekly (QW) and the effective dose of the adenosine derivative is in the range of 600 mg to 900 mg once weekly (QW). In some embodiments, the effective dose of the CA inhibitor is in the range of 300 mg to 600 mg once weekly (QW) via one or more oral tablets, and the effective dose of the adenosine derivative is in the range of 600 mg to 900 mg once weekly (QW) via one or more oral tablets. In some embodiments, the effective dose of the CA inhibitor is in the range of 600 mg to 2000 mg once monthly (QM), the effective dose of the adenosine derivative is in the range of 600 mg to 2000 mg once monthly (QM), or a combination thereof. In some embodiments, the effective dose of the CA inhibitor is in the range of 300 mg to 600 mg once weekly (QW) of lenakapavir, and the effective dose of the adenosine derivative is in the range of 100 mg to 2000 mg once weekly (QW) to once every 8 weeks (Q8W). In some embodiments, the effective dose of the CA inhibitor is in the range of 900 mg to 2000 mg once a month (QM) of lenakapavir and the effective dose of the adenosine derivative is in the range of 100 mg to 1200 mg once a week (QW) to 100 mg to 2000 mg once every 8 weeks (Q8W) of the adenosine derivative.

[0165] In some embodiments, at least one of a capsid (CA) inhibitor or a composition thereof and an adenosine derivative or a composition thereof is administered to the subject once monthly (QM). In some embodiments, as described above and below, the CA inhibitor or a composition thereof is administered to the subject once monthly (QM) and the adenosine derivative or a composition thereof is administered to the subject once weekly (QW) to once every 12 months. In some embodiments, as described above and below, the adenosine derivative or a composition thereof is administered to the subject once monthly (QM) and the CA inhibitor or a composition thereof is administered to the subject once weekly (QW) to once every 12 months. 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 monthly (QM).

[0166] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose of 900 mg once weekly (QW) together with 900 mg of a CA inhibitor (such as GS-6207 (lenapavir)) every 6 months.

[0167] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose of 900 mg once weekly (QW) together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose ranging from 100 mg to 900 mg every 3 months.

[0168] In some embodiments, the adenosine derivative or a combination thereof is administered to the subject at a dose of 900 mg once weekly (QW) together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose ranging from 100 mg to 900 mg once monthly.

[0169] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose of 900 mg once weekly (QW) together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose ranging from 100 mg to 900 mg every two weeks.

[0170] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose of 900 mg once weekly (QW) together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose in the range of 100 mg to 900 mg once weekly (QW).

[0171] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose of 600 mg to 2000 mg every 6 months together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose of 900 mg to 2000 mg every 6 months.

[0172] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose ranging from 600 mg to 1200 mg every 6 months together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose ranging from 900 mg to 1200 mg every 6 months.

[0173] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose ranging from 600 mg to 2000 mg every 3 months together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose ranging from 900 mg to 2000 mg every 6 months.

[0174] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose ranging from 600 mg to 2000 mg once a month together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose ranging from 900 mg to 2000 mg once every 6 months.

[0175] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose ranging from 600 mg to 1200 mg every two weeks together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose ranging from 900 mg to 2000 mg every 6 months.

[0176] In some embodiments, the adenosine derivative of the present invention is administered to the subject at a dose ranging from 600 mg to 1200 mg once weekly, together with a CA inhibitor (such as GS-6207 (lenapavir)) at a dose ranging from 900 mg to 2000 mg once every 6 months.

[0177] In some embodiments, the adenosine derivative of the present invention is administered orally in tablet form, and an injectable CA inhibitor (such as GS-6207 (lenapavir)) is administered. In some embodiments, the CA inhibitor (such as GS-6207 (lenapavir)) is administered orally in tablet form.

[0178] In some embodiments, HIV infection is caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0179] In some embodiments, the subjects are HIV patients who have undergone high-level treatment, HIV patients who have undergone heavy treatment and are multidrug resistant to HIV, HIV positive patients, patients undergoing pre-exposure prophylaxis (PrEP) by taking one or more anti-HIV drugs, women at HIV risk, or men at HIV risk.

[0180] In some embodiments, the capsid inhibitor and the adenosine derivative disclosed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, when administered to a subject according to the methods disclosed herein, provide synergistic antiviral activity in the treatment of HIV, AIDS, or RNA viruses. In some embodiments, this synergistic antiviral activity is measured by a synergistic volume. In some embodiments, a synergistic volume of 50 to 100 indicates synergistic antiviral activity. In some embodiments, a synergistic volume >100 indicates highly synergistic antiviral activity. As used herein, a synergistic effect is achieved when the combined effect of the adenosine derivative and the capsid inhibitor is greater than the additive effect of the individual drugs.

[0181] In some embodiments, the method of the present invention further includes measuring a sample of a subject to determine a measured concentration of a targeted drug in the sample, wherein the targeted drug may have formula (T-1): , its isomer 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.

[0182] In some embodiments, the targeted drug has the formula (T-1A):, its isomer or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the targeted drug is (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-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.

[0184] In some embodiments, the targeted drug is a degradation or metabolite of compound (T-1), (T-1A) or EFdA.

[0185] The sample is a blood sample, urine sample, body fluid sample, tissue sample or a combination thereof from the subject (such as a patient).

[0186] The concentration of the targeted drug is determined using analytical methods known to those skilled in the art, such as (but not limited to) HPLC, GC, MS, GC-MS, or combinations thereof.

[0187] The method of the present invention further includes adjusting the effective dose to produce a modified effective dose and administering the modified effective dose to the subject if the measured concentration of the targeted drug is different from the predetermined target concentration of the targeted drug.

[0188] In some embodiments, the targeted drug formula (T-1A) compound:, its isomer or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the targeted drug is (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-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.

[0190] In some embodiments, the targeted drug is a degradation or metabolite of compound (T-1), (T-1A) or EFdA.

[0191] The sample may be a blood sample, urine sample, body fluid sample, tissue sample or a combination thereof from the subject (such as a patient).

[0192] The concentration of targeted drugs can be determined using analytical methods known to those skilled in the art, such as (but not limited to) HPLC, GC, MS, GC-MS, or combinations thereof.

[0193] The method of the present invention may further include adjusting the effective dose to produce a modified effective dose and administering the modified effective dose to the subject if the measured concentration of the targeted drug is different from the predetermined target concentration of the targeted drug.

[0194] In some embodiments, the method of the present invention further includes administering to a subject an effective dose of one or more additional anti-HIV agents selected from the group consisting of: abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bicitiravir, cabotevir, derunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate, etc. Norfovir alafenamide, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, aviravir, etravirine, forsanavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, combinations of lopinavir and ritonavir, derunavir, combinations of derunavir and cobicistat, maravirocin, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, retegvir, rilpivirine, stavudine, telanavir, and vevirocin or combinations thereof. Other identified or developed anti-HIV agents or combinations thereof may also be suitable.

[0195] This invention further relates to the use of the adenosine derivatives and capsid (CA) inhibitors disclosed herein, as needed, in the manufacture of medicaments for treating diseases, 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 the K65R mutation, multidrug-resistant HIV, or RNA virus infection. Any of the aforementioned adenosine derivatives may be suitable. Any of the aforementioned pharmaceutically acceptable carriers may be suitable.

[0196] The present invention further relates to a method for preventing infection in a subject in need, the method comprising administering to the subject an effective dose of any of the pharmaceutical or therapeutic compositions disclosed herein, wherein the subject is free of detectable symptoms of the infection. In some embodiments, the infection comprises a disease selected from: Acquired immunodeficiency syndrome (AIDS), wild-type HIV-1 infection, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with the K65R mutation, multidrug-resistant HIV, RNA virus infection, or a combination thereof.

[0197] Detectable symptoms may include (but are not limited to) symptoms of Acquired Immunodeficiency Syndrome (AIDS), symptoms of HIV infection (including wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multidrug-resistant HIV, or combinations thereof). Detection of these HIV viruses can be performed by PCR, reverse PCR, or immunodetection of antigens or antibodies associated with AIDS or HIV.

[0198] Not wishing to be bound by any particular theory, the advantage of the compositions and methods of the present invention is that the adenosine derivatives disclosed herein can be rapidly converted into targeted drugs. As described in the examples below, more than about 60% of the adenosine derivatives of the present invention can unexpectedly and unsurprisingly be converted into the targeted drug within about 30 minutes of contact with human plasma.

[0199] One advantage of the combination of adenosine derivatives and capsid (CA) inhibitors (such as GS-6207 (lenakapavir)) is the potential benefit of HIV infection prevention via pre-exposure prophylaxis (PrEP), a method of preventing HIV infection in individuals who are not HIV-positive but at very high risk of HIV infection through regular medication. Currently, medications available under the brand name Truvada contain two drugs (tenofovir and emtricitabine), which are used in combination with other drugs to treat HIV. These drugs work to prevent permanent infection when someone is exposed to HIV. The combination of adenosine derivatives and capsid (CA) inhibitors (such as GS-6207 (lenakapavir)) disclosed herein provides additional PrEP for HIV prevention, preferably on a once-weekly (QW) schedule. PrEP is known to be highly effective in preventing HIV when taken consistently. Without consistent use, the efficacy of PrEP is much lower. The weekly (QW) schedule for combinations of adenosine derivatives and capsid (CA) inhibitors (such as GS-6207 (lenapavir)) disclosed herein can provide convenience and assistance in maintaining continuous drug intake and thus contribute to HIV prevention. (Numbered Examples of the Invention)

[0200] The following numbered examples illustrate other objects that are carefully considered by the present invention: 1. A method of treating or preventing HIV infection, comprising administering to a subject in need an effective amount of: (a) a capsid inhibitor; and (b) an adenosine derivative, wherein the adenosine derivative is a compound of formula (1): (1), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1, R1' and R2 are each independently H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5 or -Z-L4-R5, provided that at least one of R1 and R2 is not H; R3, R3' and R4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl or heteroaryl; R5 is: R6 series: H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl or heteroaryl; -L1-R5 series: -(C1-C10 alkylene)-N(R7)-R5, -(C1-C10 alkylene)-O-R5, -(C1-C10 alkylene)-S-R5, -(C2-C10 alkenylene)-N(R7)-R5, -(C2-C10 alkenylene)-O-R5, -(C2-C10 alkenylene)-S-R5, -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2- O-R5, -C(O)O-L2-S-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)O-L2-C(O)N(R7) -L3-N(R7)-R5, -C(O)O-L2-C(O)N(R7)-L3-O-R5, -C(O)O-L2-C(O)N(R7)-L3-S-R5, -C(O)N(R7)-R5 , -C(O)N(R7)-L2-N(R7)-R5, -C(O)N(R7)-L2-O-R5, -C(O)N(R7)-L2-S-R5, -C(O)N(R7)-L2-C(O)O -R5, -C(O)N(R7)-L2-C(O)N(R8)-R5-, -C(O)N(R7)-L2-C(O)N(R8)-L3-N(R7)-R5, -C(O)O-L2-N(R 7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2- N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)N(R8)-L3-O-R5 or -C(O)N(R7)-L2-C(O)N(R8)-L3-S-R5;-Z-series -C(O)-, -C(O)O-, or -C(O)N(R7)-; -L4-R5-series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5, or -(C2-C10 alkenyl)-S-R5; R7 and R8 are each independently H, C1-C10 alkyl, or C2-C10 alkenyl; R9 is independently H, -F, C1-C10 alkyl, or C2-C10 alkenyl; L2 and L3 are each divalent -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and X is a halogen atom. 2. The method of Example 1, wherein R1 and R2 are each independently H, -R5, -L1-R5, or -Z-L4-R5. 3. The method of Example 1 or 2, wherein R1 and R2 are each independently H, -R5, or -L1-R5. 4. The method of any one of Examples 1 to 3, wherein R1 is -L1-R5. 5. The method of any one of Examples 1 to 4, wherein R1' is -L1-R5. 6. The method of any one of Examples 1 to 4, wherein R1' is H. 7. As in any of Examples 1 to 6, -L1-R5 is selected from the group consisting of: -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2-O-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)N(R7)-R5, -C(O)N(R7)-L2-N(R7)- R5, -C(O)N(R7)-L2-O-R5, -C(O)O-L2-N(R7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O )N(R8)-R5, -C(O)N(R7)-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)O-R5 and -C(O)N(R7)-L2-C(O)N(R8)-R5-. 8.As in any of the methods in Examples 1 to 7, -L1-R5 is selected from the group consisting of: -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2-N(R7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-N(R7)-R5 and -C(O)N(R7)-L2-C(O)N(R8)-R5-. 9. The method of any one of Examples 1 to 7, wherein -L1-R5 is -C(O)O-R5. 10. The method of any one of Examples 1 to 9, wherein R2 is H. 11. The method of any one of Examples 1 to 10, wherein R3 and R3' are each independently H, C1-C10 alkyl, or C3-C6 cycloalkyl. 12. The method of any one of Examples 1 to 10, wherein R3 and R3' are each independently H or C1-C3 alkyl. 13. The method of Example 1, wherein R4 is C1-C10 alkyl or C3-C6 cycloalkyl. 14. The method of Example 1 or 2, wherein -Z-L4-R5 is Z-(C1-C10 alkyl)-N(R7)-R5 or Z-(C1-C10 alkyl)-O-R5. 15. The method of any one of Examples 1, 2, and 14, wherein -Z- is -C(O)N(R7)-. 16. The method of any one of Examples 1 to 15, wherein R6 is a C1-C5 alkyl group. 17. The method of Example 16, wherein R6 is a methyl group. 18. The method of any one of Examples 1 to 17, wherein R7 is H or a C1-C5 alkyl group. 19. The method of Example 18, wherein R7 is H or a methyl group. 20. The method of any one of Examples 1 to 19, wherein R8 is H or a C1-C5 alkyl group. 21. The method of Example 20, wherein R8 is H or a methyl group. 22. The method of any one of Examples 1 to 21, wherein R9 is H or Me. 22a. The method of Example 22, wherein R9 is H. 23. The method of any one of Examples 1 to 22a, wherein X is F. 24. The method of Example 1, wherein the adenosine derivative has the structure: , formula (4-C): , formula (6-A): , or a pharmaceutically acceptable salt, tautomer, or solvate thereof. 25. The method of Example 1, wherein the adenosine derivative is: ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester,4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-dioxacyclopenten-2-one, or ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-((((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxy)carbonyl)oxy)tetrahydrofuran-2-yl)methyl ester, or a pharmaceutically acceptable salt or solvation thereof. 26. The method of any one of Examples 1 to 25, wherein the adenosine derivative has in vivo reverse transcriptase inhibitor activity, in vivo reverse transcriptase chain terminator activity, in vivo DNA translocation inhibitor activity, or a combination thereof. 27. The method of any one of Examples 1 to 26, wherein the adenosine derivative or a pharmaceutically acceptable salt or solvate thereof is administered orally. 28. The method of any one of Examples 1 to 27, wherein the capsid (CA) inhibitor and the adenosine derivative or a pharmaceutically acceptable salt or solvate thereof are administered to an individual simultaneously or sequentially. 29. The method of Example 28, wherein the CA inhibitor and the adenosine derivative or a pharmaceutically acceptable salt or solvate thereof are administered to an individual sequentially over a period ranging from 0.1 minutes to 72 hours. 30. The method of any one of Examples 1 to 29, wherein the CA inhibitor and the adenosine derivative or a pharmaceutically acceptable salt or solvate thereof are administered to an individual once daily to once every 12 months. 31. The method of Example 30, wherein the CA inhibitor and the adenosine derivative or a pharmaceutically acceptable salt or solvation thereof are administered to an individual once every 6 months. 32. The method of Example 30, wherein the CA inhibitor and the adenosine derivative or a pharmaceutically acceptable salt or solvation thereof are administered to an individual once every 1 to 8 weeks. 33. The method of Example 30, wherein at least one of the CA inhibitor and the adenosine derivative or a pharmaceutically acceptable salt or solvation thereof is administered to an individual once a month. 34. The method of any one of Examples 1 to 33, wherein the CA inhibitor is a compound having the following structure: [structure not specified], or a pharmaceutically acceptable salt, tautomer, or solvation thereof. 35. The method of Example 34, wherein the effective dose of the CA inhibitor is a single dose in the range of 100 mg to 2000 mg administered every 6 months. 36. The method of Example 34, wherein the effective dose of the CA inhibitor is administered every 1 to 7 days in the range of 200 mg to 1200 mg. 37. The method of Example 34, wherein the effective dose of the CA inhibitor is administered once weekly (QW) in the range of 300 mg to 1200 mg.The effective dose of the adenosine derivative or its pharmaceutically acceptable salt or solvate is administered once weekly (QW) to once every 8 weeks (Q8W) in the range of 100 mg to 2000 mg. 38. The method of Example 34, wherein the effective dose of the CA inhibitor is administered once monthly (QM) in the range of 900 mg to 2000 mg, and the effective dose of the adenosine derivative or its pharmaceutically acceptable salt or solvate is administered once weekly (QW) to once every 8 weeks (Q8W) in the range of 100 mg to 2000 mg. 39. The method of any one of Examples 1 to 38, 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 multidrug-resistant HIV. 40. The method of any one of Examples 1 to 39, wherein the subject is an HIV patient who has undergone high-level treatment, a heavily treated and multidrug resistant HIV patient, an HIV-positive patient, a person undergoing pre-exposure prophylaxis (PrEP) with one or more anti-HIV drugs, a woman at HIV risk, or a man at HIV risk. 40a. The method of any one of Examples 1 to 40, wherein the capsid inhibitor is administered orally. 40b. The method of any one of Examples 1 to 40, wherein the capsid inhibitor is administered non-enterically. 40c. The method of Example 40b, wherein the non-enteric administration is by intramuscular and / or subcutaneous injection. 40d. The method of any one of Examples 1 to 40, wherein the adenosine derivative or a pharmaceutically acceptable salt or solvate thereof is administered orally. 40e. The method of any one of Examples 1 to 40, wherein the adenosine derivative or a pharmaceutically acceptable salt or solvate thereof is administered non-enterically. 40f. The method of Example 40e, wherein the non-enteric administration is by intramuscular and / or subcutaneous injection. 41. A pharmaceutical composition comprising an effective amount of: (a) a capsid (CA) inhibitor; and (b) an adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the adenosine derivative is a compound having the structure of formula (1): (1), wherein R1, R1', and R2 are each independently H, -C(O)N(R3)(R3'), -C(O)OR4, -R5, -L1-R5, or -Z-L4-R5, provided that at least one of R1 and R2 is not H; R3, R3', and R4 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl, or heteroaryl; R5 is: R6 series H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3 to 10 heterocycloalkyl, aryl or heteroaryl;-L1-R5 series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5, -(C2-C10 alkenyl)-S-R5, -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2- O-R5, -C(O)O-L2-S-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)O-L2-C(O)N(R7) -L3-N(R7)-R5, -C(O)O-L2-C(O)N(R7)-L3-O-R5, -C(O)O-L2-C(O)N(R7)-L3-S-R5, -C(O)N(R7)-R5 , -C(O)N(R7)-L2-N(R7)-R5, -C(O)N(R7)-L2-O-R5, -C(O)N(R7)-L2-S-R5, -C(O)N(R7)-L2-C(O)O -R5, -C(O)N(R7)-L2-C(O)N(R8)-R5-, -C(O)N(R7)-L2-C(O)N(R8)-L3-N(R7)-R5, -C(O)O-L2-N(R 7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2- N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)N(R8)-L3-O-R5 or -C(O)N(R7)-L2-C(O)N(R8)-L3-S-R5; -Z-series -C(O)-, -C(O)O- or -C(O)N(R7)-; -L4-R5-series -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -(C1-C10 alkyl)-S-R5, -(C2-C10 alkenyl)-N(R7)-R5, -(C2-C10 alkenyl)-O-R5 or -(C2-C10 alkenyl)-S-R5; R7 and R8 are each independently H, C1-C10 alkyl or C2-C10 alkenyl; R9 is independently H, -F, C1-C10 alkyl or C2-C10 alkenyl; L2 and L3 are each -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and X-series halogen atoms. 42. The composition of Example 41, wherein R1 and R2 are each independently H, -R5, -L1-R5, or -Z-L4-R5. 43.44. A composition as described in Examples 41 or 42, wherein R1 and R2 are each independently H, -R5, or -L1-R5. 45. A composition as described in any one of Examples 41 to 43, wherein R1 is -L1-R5. 46. A composition as described in any one of Examples 41 to 44, wherein R1' is -L1-R5. 47. A composition as described in any one of Examples 41 to 44, wherein R1' is H. The composition of any one of Examples 41 to 46, wherein -L1-R5 is selected from the group consisting of: -(C1-C10 alkyl)-N(R7)-R5, -(C1-C10 alkyl)-O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2-O-R5, -C(O)O-L2-C(O)O-R5, -C(O)O-L2-C(O)N(R7)-R5, -C(O)N(R7)-R5, -C(O)N(R7)-L2-N(R7) -R5, -C(O)N(R7)-L2-O-R5, -C(O)O-L2-N(R7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O )N(R8)-R5, -C(O)N(R7)-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-C(O)O-R5 and -C(O)N(R7)-L2-C(O)N(R8)-R5-. 48. The composition of any one of Examples 41 to 47, wherein -L1-R5 is selected from the group consisting of: -C(O)O-R5, -C(O)O-L2-N(R7)-R5, -C(O)O-L2-N(R7)C(O)O-R5, -C(O)N(R8)-L2-N(R7)C(O)O-R5, -C(O)O-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-N(R7)C(O)N(R8)-R5, -C(O)N(R7)-L2-N(R7)-R5 and -C(O)N(R7)-L2-C(O)N(R8)-R5-. 49. A composition of any one of Examples 41 to 47, wherein -L1-R5 is -C(O)O-R5. 50. A composition of any one of Examples 41 to 49, wherein R2 is H. 51. A composition of any one of Examples 41 to 50, wherein R3 and R3' are each independently H, C1-C10 alkyl, or C3-C6 cycloalkyl. 52. A composition of any one of Examples 41 to 50, wherein R3 and R3' are each independently H or C1-C3 alkyl. 53. A composition of Example 41, wherein R4 is C1-C10 alkyl or C3-C6 cycloalkyl. 54.55. The composition of Example 41 or 42, wherein -Z-L4-R5 is Z-(C1-C10 alkyl)-N(R7)-R5 or Z-(C1-C10 alkyl)-O-R5. 56. The composition of any one of Examples 41 to 55, wherein R6 is C1-C5 alkyl. 57. The composition of Example 56, wherein R6 is methyl. 58. The composition of any one of Examples 41 to 57, wherein R7 is H or C1-C5 alkyl. 59. The composition of Example 58, wherein R7 is H or methyl. 60. The composition of any one of Examples 41 to 59, wherein R8 is H or C1-C5 alkyl. 61. The composition of Example 60, wherein R8 is H or methyl. 62. A composition of any one of Examples 41 to 61, wherein R9 is H or Me. 62a. A composition of Example 62, wherein R9 is H. 63. A composition of any one of Examples 41 to 62a, wherein X is F. 64. A composition of Example 41, wherein the adenosine derivative is a compound having the following structures: Formula (2):, Formula (3):, Formula (4):, Formula (5):, Formula (6):, Formula (7):, Formula (8):, Formula (4-B):, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. 65. The composition of Example 41, wherein the adenosine derivative is a compound having the following structures: formula (2-A):, formula (3-A):, formula (4-A):, formula (5-A):, formula (6-A):, formula (7-A):, formula (8-A):, formula (4-C):, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. 66. The composition of any one of Examples 41 to 65, wherein the adenosine derivative is ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester, 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-dioxacyclopenten-2-one, ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-((((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxy)carbonyl)oxy)tetrahydrofuran-2-yl)methyl ester, or combinations thereof. 67.The composition of Example 41, wherein R5, -L1-R5, or -Z-L4-R5 is: 68. The composition of any one of Examples 41 to 67, wherein the CA inhibitor is a compound having the following structure: , or a pharmaceutically acceptable salt or solvate thereof. 69. The composition of any one of Examples 41 to 68, further comprising a pharmaceutically acceptable carrier. 70. The composition of any one of Examples 41 to 69, wherein the effective dose of the adenosine derivative is 200 mg to 2000 mg and the effective dose of the capsid inhibitor is 300 mg to 2000 mg. 71. The composition of any one of Examples 41 to 70, wherein the pharmaceutical composition is suitable for oral administration. 72. The composition of any one of Examples 41 to 70, wherein the pharmaceutical composition is suitable for non-enteral administration. 73. The composition of Example 72, wherein the non-enteral administration is by intramuscular and / or subcutaneous injection. Examples

[0201] The present invention is further described in the following non-limiting examples. It should be understood that these examples, while indicating preferred embodiments of the invention, are given only by way of illustration. From the above discussion and these examples, those skilled in the art will recognize the essential characteristics of the invention, and various changes and modifications can be made to adapt it to various uses and conditions without departing from its spirit and scope. Properties of the adenosine derivatives of the present invention

[0202] The properties of adenosine derivatives are listed in Table 1. Table 1: Nomenclature and properties. Formula ID IUPAC naming molecular weight T-1A (EFdA) (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol 293.25 2-A Isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester 378.36 3-A (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate isopropyl ester 379.34 4-A ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester 449.35 5-A Methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester 350.31 6-A 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-dioxacyclopenten-2-one 405.34 7-A (2-(methyl((5-methyl-2-sideoxy-1,3-dioxacyclopenten-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) 505.46 8-A 4-(methyl(((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)butyric acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester 662.51 4-C ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-((((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxy)carbonyl)oxy)tetrahydrofuran-2-yl)methyl ester) 605.44 Example 1: Preparation of isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester; (4-nitrophenyl)carbonate [(2R,3S,5R)-5-[6-(tributoxycarbonylamino)-2-fluoro-purin-9-yl]-2-ethynyl-3-hydroxytetrahydrofuran-2-yl] methyl ester

[0203] A solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tributyl ester (80 mg, 0.203 mmol, 1 equivalent) in pyridine (0.8 mL) was added to (4-nitrophenyl)carbon chloride (41 mg, 0.203 mmol, 1 equivalent). The mixture was stirred at 10 °C for 16 hours, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL). The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to produce a crude product, (4-nitrophenyl)carbonate [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (114 mg, crude), which was a yellow oil and could be used in the next reaction without further purification. LCMS (ESI) m / z, C24H23FN6O9: calculated value 558.2, measured value (M+H)+: 559.1. Preparation of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(isopropylaminomethoxymethyl)tetrahydrofuran-2-yl]-2-fluoropurine-6-yl]carbamate tert-butyl ester

[0204] A mixture of (4-nitrophenyl)carbonate [(2R,3S,5R)-5-[6-(tributoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (10 mg, 0.018 mmol, 1 equivalent) and triethylamine (3.6 mg, 0.035 mmol, 2 equivalent) in THF (0.5 mL) was supplemented with propan-2-amine (1.3 mg, 0.021 mmol, 1.2 equivalent). The mixture was stirred at 15 °C for 2.5 h, water (5 mL) was added, and the mixture was extracted with EtOAc (2 x 10 mL). The organic layer was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15% to 45%, 11 min) to produce a white solid, N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(isopropylaminomethoxymethyl)tetrahydrofuran-2-yl]-2-fluoropurine-6-yl]carbamate tributyl ester (3.6 mg, 45.0% yield). LCMS (ESI) m / z, C21H27FN6O6: calculated value 478.2, measured values ​​(M+H)+: 479.3; (M+Na)+: 501.2. Preparation of isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester

[0205] TFA (77 mg, 0.68 mmol, 0.05 mL, 89.8 equivalents) was added to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(isopropylaminomethoxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate (3.6 mg, 0.0075 mmol, 1 equivalent) in DCM (0.5 mL) at 10 °C. The mixture was stirred at 10 °C for 40 hours. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Agela DuraShell 150 mm x 25 mm x 5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 10% to 40%, 8 min) to produce isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester (1.2 mg, 40.0% yield) as a white solid. LCMS (ESI) m / z, C16H19FN6O4: calculated value 378.2, measured values ​​(M+H)+: 379.3; (M+Na)+: 401.2. 1H 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 (376 MHz, DMSO-d6) δ (ppm) -51.79 (s). Example 2: Preparation of methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl methyl carbamate.

[0206] Methyl methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) is prepared using the same procedure as that for isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) except that propyl-2-amine is replaced with methylamine. LCMS (ESI) m / z, C14H15FN6O4: calculated value 350.1, measured value (M+H)+: 351.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.26 (s, 1H), 7.87 (br s, 2H), 7.13 (br d, J =4.4 Hz, 1H), 6.24 (dd, J =7.6, 5.0 Hz, 1H), 5.76 (br d, J =4.4 Hz, 1H), 4.55 (br d, J =5.2 Hz, 1H), 4.35 (d, J =11.6 Hz, 1H), 4.03 (d, J =11.6 Hz, 1H), 3.60 (s, 1H). 2.70–2.79 (m, 1H), 2.54 (s, 3H), 2.40–2.45 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ (ppm) -51.75 (s). Example 3: Preparation of isopropyl 4-methylbenzoic acid (2R,3S,5R)-5-[6-[bis(isopropoxycarbonyl)amino]-2-fluoro-9H-purin-9-yl]-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)-tetrahydrofuran-3-yl ester

[0207] Isopropyl carbon chloride (23 mg, 0.19 mmol, 2 equivalents) was added to a mixture of methyl 4-methylbenzoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (50 mg, 0.094 mmol, 1 equivalent) and Et3N (10 mg, 0.094 mmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 15 °C for 16 hours. The mixture was concentrated under reduced pressure and 2 mL of water was added, followed by extraction with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure to produce crude 4-methylbenzoic acid (2R,3S,5R)-5-(6-(bis(isopropoxycarbonyl)amino)-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl ester, which could be used in the next reaction without further purification. LCMS (ESI) m / z, C36H36FN5O9: calculated value 701.3, measured value (M+H)+: 702.1. Preparation of isopropyl 9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate.

[0208] NaOMe (34 mg, 0.19 mmol, 30%, 2 equivalents) was added to a solution of 4-methylbenzoic acid (2R,3S,5R)-5-[6-[bis(isopropoxycarbonyl)amino]-2-fluoro-9H-purin-9-yl]-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl] ester (66 mg, 0.094 mmol) in THF (1 mL) at -20 °C, and the mixture was stirred at -20 °C for 16 hours. An additional NaOMe (17 mg, 0.095 mmol, 30%, 1 equivalent) was added, and the mixture was stirred again at -20 °C for 40 hours. The mixture was neutralized with AcOH (0.1 mL), concentrated under reduced pressure, and purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica blister column, 0–8% MeOH / DCM gradient at 20 mL / min) and further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 x 30 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5% to 30%, 7 min) to produce 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, C16H18FN5O9: calculated value 379.1 (measured value (M+Na)+: 402.1). 1H NMR (400 MHz, CDCl3) δ (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). 19F NMR (376 MHz, CDCl3) δ (ppm) -46.89 (s).Example 4 (Method 1): Preparation of ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate S-ethylO-((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl) ester.

[0209] A mixture of ethanethiol (16 g, 257.5 mmol, 19.1 mL, 1 equivalent) and triethylamine (26.1 g, 257.5 mmol, 35.8 mL, 1 equivalent) in THF (1 L) was added to bis(trichloromethyl) carbonate (76.4 g, 257.5 mmol, 1 equivalent) in THF (50 mL). The mixture was heated to 18 °C and stirred at 18 °C for 2 h. The mixture was filtered, and the filtrate was concentrated under vacuum to produce chloromethanesulfonate S-ethyl ester (13 g, crude), which was a yellow oil and could be used directly in the next reaction without further purification.

[0210] A mixture of 4-(hydroxymethyl)-5-methyl-1,3-dioxanepenten-2-one (13 g, 99.9 mmol, 1 equivalent) in Et2O (800 mL) was added to Et2O (200 mL) containing pyridine (7.90 g, 99.9 mmol, 8.1 mL, 1 equivalent) and chloromethane sulfate S-ethyl ester (12.45 g, 99.9 mmol, 1.0 equivalent). The mixture was stirred at 0 °C for 1 h, then heated to 18 °C and stirred at 18 °C for 16 h. The mixture was filtered and concentrated under vacuum, then dissolved in DCM (150 mL) and washed with saturated NaHCO3 aqueous solution (150 mL x 2) and water (150 mL x 2). The mixture was concentrated under reduced pressure and purified by rapid silica gel chromatography (ISCO®; 120 g SepaFlash® silica blister converter, 0–15% ethyl acetate / petroleum ether gradient at 70 mL / min) to produce methyl ethyl thioalkylformate (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl) as a pale yellow oil (9.2 g, 42.2% yield). ¹H NMR (400 MHz, CDCl₃) 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). Preparation of (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methylcarbide.

[0211] Thiocyanate (618.5 mg, 4.58 mmol, 0.46 mL, 2 equivalents) was added to a mixture of methyl 5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl) ethyl thiocarboxylic acid (500 mg, 2.29 mmol, 1 equivalent) in DCM (50 mL). The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was washed with water (50 mL x 2), 5% Na2CO3 aqueous solution (50 mL x 2), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methylcarbon chloride (350 mg, crude) as a yellow oil. The product was dissolved in 10 mL of DCM and stored in a refrigerator. Preparation of tert-butyl (9-(((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(((((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxy)carbonyl)oxy)methyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)carbamate

[0212] A mixture of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tributyl ester (100 mg, 0.25 nmol, 1 equivalent) in pyridine (2 mL) was added to (140 mg, 0.73 mmol, 4 mL, 2.86 equivalent, 35 mg / mL in DCM), and the mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure and purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica blister converter, 0–5% MeOH / DCM gradient elution at 25 mL / min) to produce a yellow solid (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl carbonate [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (45 mg, 32.2% yield). LCMS (ESI) m / z, C23H24FN5O10: calculated value 549.2, measured value (M+H)+: 550.1. Preparation of ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0213] TFA (154 mg, 1.35 mmol, 0.1 mL, 16.5 equivalents) was added to a mixture of (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl carbonate [(2R,3S,5R)-5-[6-(tributoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (45 mg, 0.082 mmol, 1 equivalent) in toluene (1 mL) at 20 °C. The mixture was stirred at 20 °C for 16 hours and then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Boston Green ODS 150 x 30 mm x 5 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 13% to 43%, 8 min) to produce a white solid ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester (11 mg, 25.4% yield). LCMS (ESI) m / z, C18H16FN5O6: calculated 449.1, measured (M+H)+: 450.1. 19F NMR (376 MHz, CD3OD) δ (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). Example 4 (Method 2): Preparation of ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester; (4-nitrophenyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0214] (4-Nitrophenyl)carbon chloride (82 mg, 0.41 mmol, 1.2 equivalent) was added to a mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (100 mg, 0.34 mmol, 1 equivalent) in pyridine (5 mL), and the mixture was stirred at 26 °C for 16 h. (4-Nitrophenyl)carbon chloride (82 mg, 0.41 mmol, 1.2 equivalent) was added, and the mixture was stirred at 26 °C for 24 h. The reaction solution was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica blister converter, 0–5% DCM / MeOH gradient elution at 25 mL / min) to produce a white solid (4-nitrophenyl)carbonate [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (80 mg, 51.2% yield). LCMS (ESI) m / z, C19H15FN6O7: calculated 458.4, found (M+H)+: 459.1. Preparation of ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0215] DMAP (3.6 mg, 0.023 mmol, 0.1 equivalent) was added to a mixture of (4-nitrophenyl)carbonate [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (150 mg, 0.298 mmol, 1 equivalent) and 4-(hydroxymethyl)-5-methyl-1,3-dioxanepenten-2-one (96 mg, 0.745 mmol, 2.5 equivalent) in THF (3 mL), and the mixture was stirred at 25 °C for 2 h. The reaction solution was purified by rapid silica gel chromatography (ISCO®; 24 g SepaFlash® silica blister converter, 0–2.5% DCM / MeOH gradient elution at 25 mL / min) to produce a white solid (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl carbonate [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (85 mg, 63.5% yield). LCMS (ESI) m / z, C18H16FN5O8 calculated value 449.4, found value 450.1 (M+H)+. 1H NMR (400 MHz, CD3CN) δ (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). 19F NMR (376 MHz, CD3CN) δ (ppm) -52.87 (s, 1F). Example 4 (Method 3): Preparation of ((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester and (4-nitrophenyl)carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0216] A mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (5 g, 17.05 mmol, 1 equivalent) in pyridine (50 mL) was added dropwise to (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methylcarbon chloride (16.42 g, 85.25 mmol, 5 equivalent) in DCM (16 mL), and then the mixture was stirred at 16 °C for 10 min. The mixture was diluted with DCM (200 mL) and washed with water (150 mL) and brine (150 mL x 2), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by rapid silica gel chromatography (ISCO®; 80 g SepaFlash® silica blister column, 0-5% MeOH / DCM gradient elution at 65 mL / min) to produce (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl carbonate [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (5.10 g, 11.35 mmol, 66.6% yield), which was a pale yellow solid. LCMS (ESI) m / z, C18H16FN5O8: calculated 449.4, measured (M+H)+: 450.1. 1H NMR (400 MHz, CD3CN) δ (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). 19F NMR (376 MHz, CD3CN) δ (ppm) -52.84 (s, 1F). Recrystallization of methyl ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)carbonate.

[0217] A mixture of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl-(5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl carbonate (9.5 g, 21.14 mmol, 1 equivalent) in MeCN (50 mL) and EtOAc (50 mL) was heated at 80 °C for 30 min, and solid dissolution was observed. 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 produce methyl 5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl carbonate [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl] ester (8.0 g, 17.80 mmol, 84.2% yield), which was a white solid. LCMS (ESI) m / z, C18H16FN5O8: calculated 449.4, measured (M+H)+: 450.1. 1H NMR (400 MHz, CD3CN) δ (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). 19F NMR (376 MHz, CD3CN) δ (ppm) -52.84 (s, 1F). Example 5 (Method 1): Preparation of tert-butyl 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-dioxacyclopenten-2-one(9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)((5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl)carbamate

[0218] K₂CO₃ (70 mg, 0.51 mmol, 2 equivalents) and 4-(bromomethyl)-5-methyl-1,3-dioxane-2-one (147 mg, 0.76 mmol, 3 equivalents) were added to a mixture of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate (100 mg, 0.25 nmol, 1 equivalent) in DMF (5 mL). The reaction mixture was then heated at 60 °C for 12 hours, concentrated, and diluted with H₂O (30 mL). The resulting mixture was extracted with EtOAc (30 x 3 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica blister column, 0-10% methanol / dichloromethane gradient at 30 mL / min) to produce N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl]carbamate tributyl ester (45 mg, 35.0% yield), which was a pale yellow oil. 1H NMR (400 MHz, CDCl3) 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). Preparation of 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-dioxacyclopenten-2-one

[0219] TFA (0.5 mL) was added to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl]carbamate (40 mg, 0.079 mmol, 1 equivalent) in dichloromethane (DCM) (3 mL) at 25 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated and purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 15% to 45%, 8 min) to produce a white solid 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-dioxane-2-one (1.7 mg, 5% yield). LCMS (ESI) m / z, C17H16FN5O6: calculated value 405.1, measured value (M+H)+: 406.1. (M+Na)+: 428.1. 1H NMR (400 MHz, CD3OD) δ (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). 19F NMR (376 MHz, CD3OD) δ (ppm) -53.00. Example 5 (Method 2): Preparation of tert-butyl 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-dioxacyclopenten-2-one N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl]carbamate

[0220] NaHCO3 (128 mg, 1.52 mmol, 2 equivalents) was added to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tributyl ester (300 mg, 0.76 mmol, 1 equivalent) in DMF (5 mL), followed by the addition of 4-(bromomethyl)-5-methyl-1,3-dioxacyclopenten-2-one (294 mg, 1.52 mmol, 2 equivalents). The mixture was stirred at 25 °C for 48 h. The mixture was then concentrated. The resulting residue was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica blister converter, eluting with a gradient of 0–100% ethyl acetate / petroleum ether at 20 mL / min) to produce a white solid, N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl]carbamate tributyl ester (200 mg, 52% yield). 1H NMR (400 MHz, CDCl3) 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). Preparation of 4-[[[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]amino]methyl]-5-methyl-1,3-dioxacyclopenten-2-one

[0221] ZnBr2 (45 mg, 0.20 mmol, 2 equivalents) was added to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl]carbamate tributyl ester (50 mg, 0.10 mmol, 1 equivalent) in CH3CN (5 mL). The mixture was stirred at 25 °C for 48 h. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative HPLC (FA conditions; column: 3-Phenomenex Luna C18 75 x 30 mm x 3 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 22% to 52%, 6 min) to produce a white solid 4-[[[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]amino]methyl]-5-methyl-1,3-dioxacyclopenten-2-one (19.8 mg, 48.8% yield). LCMS (ESI) m / z, C17H16FN5O6: calculated value 405.34, measured value (M+H)+: 406.1. 1H NMR (400 MHz, CD3OD) δ (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). 19F NMR (376 MHz, CD3OD) δ (ppm) -52.33. Example 6: Transformation and stability of adenosine derivative prodrugs.

[0222] The stability of the prodrug and its conversion to the targeted drug adenosine derivative (EFdA) (formula T-1A) were measured in both plasma and liver S9 analysis, and the data are shown in Table 2. Plasma stability

[0223] Before the experiment, the combined frozen plasma was frozen in a water bath at 37°C. The plasma was centrifuged at 4000 rpm for 5 min, and any clots were removed. The pH was adjusted to 7.4 ± 0.1 as needed.

[0224] Preparation of test compounds and positive control (propamine bromide): 1 mM intermediate solution was prepared by diluting 10 µL of stock solution with 90 µL MeOH; 1 mM positive control propamine bromide intermediate was prepared by diluting 10 µL of stock solution with 90 µL ultrapure water. 100 µM dosing solution was prepared by diluting 20 µL of intermediate solution (1 mM) with 180 µL MeOH. 2 µL of dosing solution (100 µM) was added to 98 µL of blank plasma in duplicate to achieve a final concentration of 2 µM, and the samples were cultured in a water bath at 37°C. At each time point (0, 10, 30, 60, and 120 min), 400 μL of stop solution (0.1% FA in MeOH containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) was added to the precipitated protein and thoroughly mixed. The sample trays were centrifuged at 4,000 rpm for 10 min. The supernatant (100 μL) of the aliquots was transferred from each well to the other trays.

[0225] Data Analysis: The residual % of the tested compound after culture in plasma was calculated using the following equation: Residual % = 100 x (PAR at the specified culture time / PAR at T0 time) where PAR is the peak area ratio of the analyte to the internal standard (IS). (LC / MS / MS mobile phase conditions: 0.1% formic acid in water / 0.1% formic acid in acetonitrile. Specified culture time points are T0 (0 min), Tn (n = 0, 10, 30, 60, 120 min). Liver S9 stability

[0226] Intermediate solution: Dilute 5 μL of the compound or control (7-ethoxycoumarin) with 495 μL MeOH (concentration: 100 μM, 1% DMSO, 99% MeOH) from the stock solution (10 mM). Stop solution: Cold ACN (containing 100 ng / mL tolbutamide and labetalol as internal standards). Except for the matrix blank, add 2 μL of the test compound or control working solution / well to all pans (T0, T5, T10, T20, T30, T60, NCF60). Add 600 μL / well of stop solution (cooled at 4°C, containing 100 ng / mL tolbutamide / 100 ng / mL labetalol) to terminate pan T0, then place it on ice. Dispense 840 μL / well S9 solution to the 96-well pan as a reservoir according to the pan plot. Then add 100 μL / well to each Apricot pan. Except for NCF60 and T0, the S9 solution and compounds were incubated at 37°C for approximately 10 min. After adding the S9 solution and 98 μL of PB buffer to the NCF60, the mixture was incubated at 37°C without preheating, and timer 1 was started. After 60 min, 600 μL / well stop solution was added to terminate the reaction. After preheating, 760 μL / well of cofactor solution was dispensed into 96-well pans as a reservoir according to the pan plot. Then, 98 μL / well was added to each Apricot pan to start the reaction. The mixture was incubated at 37°C, timer 2 was started, and 600 μL / well stop solution (cooled at 4°C, containing 100 ng / mL tolbutamide and labetalol) was added to terminate the reaction. The samples were centrifuged at 4000 rpm for 20 min. Simultaneously with centrifugation, 300 μL of HPLC water was loaded into eight new 96-well plates, followed by the transfer of 100 μL of supernatant, which was then mixed with water for LC / MS / MS analysis. The samples were then transferred to the Bioanalytical Services department for LC-MS / MS analysis. t1 / 2 and CL were calculated using a first-order kinetic equation: First-order kinetic equation:

[0227] The stability results of the exemplary compounds in human plasma and human liver S9 are listed in Table 2 below. Table 2: Transformation and half-life data. Mode Stability in human blood plasma Stability in human liver S9 half life Formation of EFdA half life Formation of EFdA 2-A A no B no 3-A A no B no 4-A C yes C yes 5-A A no B no 6-A C no C yes 7-A B no C no 4-C C yes C yes Half-life range: A: >200 minutes; B: 50 to 200 minutes; C: <50 minutes.

[0228] Data show that adenosine derivatives 4-A and 4-C can be efficiently converted into the targeted drug in human plasma and liver S9 analysis, and 6-A can be efficiently converted into the targeted drug in liver S9 analysis. Example 7: Antiviral activity of the prodrug in a two-drug combination study using lenakapavir (GS-6207) against the HIV-1 laboratory strain HIV-1 NL4-3 in MT-4 cells.

[0229] Methods: Compound preparation: Stock solutions of prodrug formula 4-A and lenakapavir (10 mM in DMSO) were prepared and aliquoted. These stock solutions were stored at -20°C until the day of analysis. The stock solutions were used to generate fresh working drug diluents each day of the analytical setup. Each aliquot of the stock solution was for single use only and discarded after the experiment. Fresh working diluents were prepared from previously unused stock solution aliquots for each experimental analysis to avoid compound degradation. Five diluent combinations of formula 4-A diluents were tested with the second anti-HIV drug, the capsid inhibitor lenakapavir. In all cases, the final DMSO concentration was < 0.25%, which had previously been shown to have no effect on the analyses described herein.

[0230] Viral strains and cell lines: The viruses and cell lines used for these assessments were obtained from the NIH AIDS Research and Reference Reagents Program (Germantown, Maryland). Evaluation was performed using cell protection (CPE) assays.

[0231] For each antiviral assay, the pre-titrated aliquots of virus were removed from the freezer (-80°C) and rapidly thawed. The virus was resuspended and diluted in tissue culture medium so that the amount of virus added to each well was determined to be the amount that would result in a loss of 85% to 95% of cell viability due to virus-induced cytopathic effects (CPE assay).

[0232] Analysis of antiviral efficacy in MT4 T ​​cells: MT4 cells were passaged in T-75 flasks prior to the antiviral assay. The cells were divided 1:2 the day before the assay to ensure they were in the exponential growth phase at the time of infection. Total cell count and viability were quantified using a hematology counter and trypan blue exclusion assay. Cell viability was greater than 95% for use in this assay. The cells were resuspended in tissue culture medium and added to a microtiter containing the drug at a seeding density of 110 µl / well and 5.0 x 10³ cells / well.

[0233] For each analysis, aliquots of pre-titrated HIV-1 NL4-3 virus were removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biosafety cabinet. The virus was resuspended and diluted in tissue culture medium such that the amount of virus added to each well, in a volume of 50 µL, was determined to result in 85 to 95% cell killing on day 6 post-infection. The TCID50 calculated by endpoint titration in MT4 cells indicated an infection multiplicity of approximately 0.01 for these analyses.

[0234] A checkerboard pattern was used to test five concentrations of lenakapavir in all possible combinations with eight concentrations of Formula 4-A. Combination antiviral efficacy was assessed on three identical analytical plates (i.e., triplicate measurements) including cell control wells (cells only) and virus control wells (cells plus virus). Combination cytotoxicity was assessed in parallel on two identical analytical plates (i.e., replicate measurements) including cell control wells. When color was observed at the compound concentration used in the experiment, a compound color control plate was used for background subtraction. Antiviral efficacy and cytotoxicity were monitored at the experimental endpoint by MTS staining.

[0235] MTS staining for cell viability: At the end of the analysis, the analytical discs were stained with a soluble tetrazolium-based dye, MTS reagent (CellTiter® 96 reagent, or Promega under the respective registered trademarks), to determine cell viability and quantify compound toxicity. MTS is metabolized by mitochondrial enzymes of metabolically active cells to produce soluble formazan, allowing for rapid quantitative analysis of cell viability and compound cytotoxicity. At the end of the analysis, 20 µL of MTS reagent was added to each well, and the microtiter discs were then incubated at 37°C and 5% CO2 for 4 to 6 hours for HIV cell protection analysis; the incubation interval was selected based on empirically determined optimal dye reduction time. Using adhesive disc sealant instead of lids, the sealed discs were inverted several times to mix the soluble formazan product and read using a Molecular Devices SpectraMax i3 plate reader at 490 / 650 nm spectrophotometry.

[0236] Data Analysis: Combination antiviral assays were performed in MT4 cells using HIV-1 NL4-3 as described above. For each combination assay, five concentrations of lenakapavir were tested in all possible combinations with eight concentrations of Formula 4-A. In uninfected MT4 cells, triple replicates were used to determine combination antiviral efficacy, and double replicates were used to determine combination cytotoxicity. Unless otherwise stated, each combination assay was performed twice.

[0237] The drug combination analysis data were then analyzed using the MacSynergy II program for data analysis and statistical evaluation. In short, the MacSynergy II program calculates the theoretical cumulative interaction of these drugs based on the mathematical definition of Bliss independence of the expected effects of drug-drug interactions. This Bliss independence model is based on statistical probability and assumes that the drugs act independently to affect viral replication; this independent effect model is also known as the two-site (DS) model and was used in all combination analyses reported in this paper.

[0238] Theoretical cumulative interactions are calculated from the dose-response curves of each drug used individually. This calculated cumulative surface (representing the predicted or cumulative interaction) is then subtracted from the experimentally determined dose-response surface to reveal regions of non-cumulative activity. If the interactions are only cumulative, the resulting surface is displayed on the graph as a plane with a level above the calculated 0% inhibition. Any peak above this cumulative plane indicates a synergistic effect. Similarly, any depression below this cumulative plane indicates an antagonistic effect. Data are statistically evaluated using a 95% confidence interval around the experimental dose-response surface, and the volumes of these peaks / depressions are calculated to quantify the volume of the synergistic / antagonistic effect. The peak volume observed in the synergistic effect graph (in units of concentration multiplied by concentration multiplied by percentage; e.g., µM2%, nM2%, nMµM%, etc.) is calculated using this formula. This peak volume is a three-dimensional counterpart of the area under the 3D dose-response surface and is a quantitative measurement of the synergistic or antagonistic effect. For these studies, synergistic effect is defined as a combination of drugs producing a synergistic volume greater than 50. Mild synergistic activity and high synergistic activity are operationally defined as producing synergistic volumes of 50 to 100 and > 100, respectively. Additive drug interactions have synergistic volumes in the range of -50 to 50, while those between -50 and -100 are considered mildly antagonistic, and those < -100 are considered highly antagonistic.

[0239] Results: In the study of two-drug combination therapy against HIV-1 NL4-3 virus in MT4 cells, Formula 4-A showed synergistic antiviral activity when combined with lenakapavir (Table 3). Table 3: Summary of antiviral efficacy results of Formula 4-A combined with lenakapavir in MT4 T ​​cells. compound Average synergistic / antagonistic volume (nM 2 % n=2) Explanation of antiviral combination 1 (Synergy / Antagonism) Formula 4-A + Lenapavir 162 / -5.03 Highly collaborative Stavudine + Ribavirin 0 / -572 High antagonism 1. Synergistic effect is defined as a combination of drugs that produces a synergistic volume greater than 50. Mild synergistic activity and high synergistic activity are defined as producing synergistic volumes of 50 to 100 and > 100, respectively. Cumulative drug interactions have synergistic volumes in the range of -50 to 50, while those between -50 and -100 are considered mildly antagonistic and those < -100 are considered highly antagonistic.

[0240] A representative example of the mean 3D surface plot of the interaction between Formula 4-A and the antiviral drug lenakapavir in MT4 cells with HIV-1 NL-43 is shown in Figure 1. Example 8: Plasma exposure after oral administration of the prodrug in contrast dogs.

[0241] The pharmacokinetics of EFdA and prodrug formula 4-A were studied in dogs after oral administration of a dose of 5 mg equivalent / kg EFdA.

[0242] Preparation: Prepare a solution of 1.65 mg / mL by dissolving the prodrug in a 20% PEG400 aqueous solution within 0.5 hours before administration.

[0243] Dosing and Sample Collection: The lifecycle phases of this study were conducted at the Charles River Laboratory (CRL) in Worcester, Massachusetts, in accordance with the CRL Institutional Animal Care and Use Committee (IACUC) standard animal procedures, in accordance with the Animal Welfare Act and the IACUC guidelines for laboratory animal care and use, and approved by the IACUC Committee. Fasted male beagle dogs (10 + / - 2 kg) were used for these studies. Each drug was administered as a single dose via oral tube feeding (5 ml / kg). The prodrug formula 4-A dose (8.25 mg / kg) was equivalent to 5 mg / kg of EFdA. Plasma samples were collected at 0 (before administration), 30 min after administration, and at 1, 2, 4, 6, 8, 12, and 24 h. Blood (approximately 0.1 to 0.2 mL) was immediately processed against plasma after collection by centrifugation at 3,500 rpm at 5°C for 10 min. Plasma samples were frozen and maintained at -70°C until analysis. To stabilize the prodrug during sample collection and subsequent analysis, the following stabilizing reagents were added to the blood collection K2EDTA tubes on wet ice prior to sample collection: For each 100 mL of blood, 15 mL of a pre-prepared inhibitor mixture consisting of 1 mM DFP, 100 mM diclofenac, 100 mM 2-hydroxyquinoline, 100 mM PCMB, 1 mM paraoxon, 100 mM PMSF, 100 mM NaF, 30.0 mM EDTA, 15 mM citrate, 10 mL of 0.2 M physostigmine, and 10 mL of 0.2 M BNPP solution.

[0244] Determination of EFdA and prodrug in plasma: Briefly, plasma (20 μL) was mixed with 100 μL acetonitrile to precipitate proteins. The same mixing protocol was followed as in the sample collection procedure to stabilize the prodrug in the standard and QC samples.

[0245] Bioanalysis: Quantitative analysis of plasma samples was performed using a Sciex API-6500 triple quadrupole mass spectrometer coupled to a Shimadzu HPLC system (Framingham, MA 01701). Waters HSS T3 columns (2.1 x 50 mm, 1.8 mm) were used. The mobile phases used were: 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 min. The HPLC gradient started at 98% A / 2% B for 0.20 min, followed by a linear gradient increasing to 25% over the next 1.40 min; this gradient was then increased to 100% mobile phase B over the next 1.0 min and held for 0.2 min, followed by a decrease to 2% mobile phase B over the next 0.2 min. The detection of the prodrug and EFdA was achieved using positive ion electrospray mass spectrometry in unit resolution mode. Multiple reaction monitoring (MRM) mode was used to quantify both the prodrug and EFdA; for example, the MRM conversion coefficient for EFdA was 294.0 to 153.90 Da, and for prodrug 4-A, it was 450.0 to 153.9 Da. Peak areas were determined using Sciex Analyst® program version 1.6.3 running on a Windows 7 computer, where concentration was determined by a weighted (1 / x2) linear regression of the peak area ratio (peak area of ​​EFdA / corresponding peak area of ​​IS) compared to the nominal concentration of the plasma calibration standard. Unrounded figures were calculated. Overall, Analyst® determined the precision and accuracy of the calibration standard and QC samples.

[0246] Pharmacokinetic calculations: Non-compartmental (NCA) analysis of EFdA and individual prodrug plasma concentration-time data was performed using the WinNonlin module (version 8.3.0.5005, Certara Inc., Princeton, NJ 08540) in the Phoenix PK / PD platform. Calculations were performed before rounding and the nominal sampling time was used in the pharmacokinetic analysis. Exposure is expressed as the area under the concentration curve from 0 to 24 hours in plasma (AUC0-24h). AUC values ​​were calculated using the linear trapezoidal rule.

[0247] Plasma Concentrations: Results of the PK study are shown in Tables 3 and 4. These data confirm in vivo that prodrug formulation 4-A can be readily delivered orally and releases EFdA efficiently in vivo with minimal prodrug detection in systemic circulation. For example, prodrug formulation 4-A releases significantly more EFdA in vivo than dose-equivalent EFdA, i.e., 91%, 102%, 55%, 79%, and 200% more at time points of 0.25, 0.5, 1, 2, and 4 hours, respectively (see Table 4). Furthermore, prodrug formulation 4-A produces higher AUC and Cmax than dose-equivalent EFdA (see Table 4). Table 4: Plasma concentrations of EFdA and prodrug formulation 4-A after a single oral dose in male beagle dogs. EFdA concentration in canine plasma (ng / mL) Prodrug Formula 4-A PO (8.25 mg / kg) Animal ID Time point (hour) 2001 2002 2003 average value SD %CV 0.250 463 533 1040 679 315 46.4% 0.500 593 621 749 654 83.2 12.7% 1.00 585 555 538 559 23.8 4.3% 2.00 369 410 239 339 89.3 26.3% 4.00 33.4 45.4 31.9 36.9 7.40 20.1% 6.00 4.93 5.39 2.45 4.26 1.58 37.1% 8.00 1.30 1.84 1.76 1.63 0.291 17.9% 12.0 BQL BQL BQL NA NA NA 24.0 BQL BQL BQL NA NA NA Concentration of preform 4-A in canine plasma (ng / mL) Prodrug Formula 4-A PO (8.25 mg / kg) Animal ID Time point (hour) 2001 2002 2003 average value SD %CV 0.250 1.13 1.63 1.09 1.28 0.301 23.5% 0.500 BQL 1.68 BQL 1.68 NA NA 1.00 BQL BQL 1.43 1.43 NA NA<00°0696>2.00 BQL BQL BQL NA NA NA 4.00 BQL BQL BQL NA NA NA 6.00 BQL BQL BQL NA NA NA 8.00 BQL BQL BQL NA NA NA<°000724>12.0 BQL BQL BQL NA NA NA 24.0 BQL BQL BQL NA NA NA Concentration of EFdA in dog plasma (ng / mL) EFdA PO (5 mg / kg) Animal ID Time point (hours) 4001 4002 4003 Average SD %CV 0.250 456 333 276 355 It should be noted that there is a "<°°000724>" in the original text which seems to be an incorrect format. I translated it as "<°000724>" as best as possible. If this is a specific symbol that has a correct meaning, it may need to be adjusted according to the actual situation. 92.0 25.9% 0.500 391 299 280 323 59.4 18.4% 1.00 369 353 361 361 8.00 2.2% 2.00 211 212 143 189 39.6 21.0% 4.00 12.6 17.9 6.30 12.3 5.81 47.2% 6.00 BQL BQL BQL NA NA NA 8.00 BQL BQL BQL NA NA NA 12.0 BQL BQL BQL NA NA NA 24.0 BQL BQL BQL NA NA NA BQL = Below Quantitative Level; NA = Not Applicable. Table 5: Plasma EFdA Exposure in Dogs After Oral Administration of EFdA and Prodrug Formula 4-A. compound Dosage (mg / kg) AUC (ng*hr / mL) C max (ng / mL) EFdA 5 792 392 Prodrug Formula 4-A 8.25 (~5 mg equivalent EFdA) 1432 753 Example 9: Plasma exposure in Sprague-Dowley rats following administration of Example 4-A and lenakapavir via intravenous infusion

[0248] The pharmacokinetics of EFdA, prodrug formula 4-A, and lenakapavir were studied in rats after intravenous infusion at doses of 1.0 mg / kg, either alone or in combination.

[0249] Preparation: 0.5 hours before administration, prepare a solution of 1.0 mg / mL by dissolving the prodrug and lenakapavir alone or in combination in 20% PEG400 and 10% Solotol aqueous solution.

[0250] Dosing and Sample Collection: The lifecycle phase of this study was conducted in Shanghai, China, at WuXi AppTec (Wuxi) in accordance with the Institutional Animal Care and Use Committee (IACUC) standard animal procedures, in compliance with the Animal Welfare Act and the Guidelines for Laboratory Animal Care and Use, and was approved by the IACUC Committee. Male Sprague-Dawley rats (0.262 + / - 0.019 kg) were used in these studies. Drugs were administered as single doses via 30-minute IV infusions (1 ml / kg) alone or in combination. Plasma samples were collected at 0 (before administration), and at 5, 10, 15, and 30 min, 1, 2, 4, 7, 12, and 24 h post-administration. Blood (approximately 0.1 mL) was immediately processed against plasma within half an hour of collection by centrifugation at 3,200 g at 4°C for 10 min. Plasma samples were frozen and maintained at -70°C until analysis. To stabilize the prodrug during sample collection and subsequent analysis, the following stabilizing agents were added to the blood collection K2EDTA tubes on wet ice prior to sample collection: for each 100 mL of blood, 10 mL of a pre-prepared inhibitor mixture consisting of 600 mM citric acid, 400 mM PMSF, 400 mM NaF, and 400 mM diclofenac.

[0251] Determination of EFdA and prodrug in plasma: Briefly, plasma (20 μL) was mixed with 100 μL acetonitrile to precipitate proteins. The same mixing protocol was followed as in the sample collection procedure to stabilize the prodrug in the standard and QC samples.

[0252] Bioanalysis: Quantitative analysis of plasma samples was performed using a Sciex API-6500 Plus triple quadrupole mass spectrometer coupled to a Waters Acquity UPLC system (Framingham, MA 01701). Waters HSS T3 columns (2.1 x 50 mm, 1.8 micrometer) were used. The mobile phases used were: A, 0.1% formic acid in water; B, 0.1% formic acid in acetonitrile. For the analysis of EFdA and prodrugs in plasma, the flow rate was 0.6 mL / min and the total run time was 2.0 min. The HPLC gradient started at 100% A for 0.30 min, followed by a linear gradient increasing to 40% B over the next 0.7 min; this gradient was then increased to 100% mobile phase B over the next 0.7 min, held for 0.2 min, and then decreased to 100% mobile phase A over the next 0.1 min. The detection of the prodrug and EFdA was achieved using positive ion electrospray mass spectrometry in unit resolution mode. Multiple reaction monitoring (MRM) mode was used to quantify both the prodrug and EFdA; for example, the MRM conversion range for EFdA was 294.0 to 154.2 Da, and the conversion range for prodrug 4-A was 449.3 to 164.9 Da. For the analysis of lenapavir in plasma, the flow rate was 0.7 mL / min and the total run time was 1.5 min. The HPLC gradient started at 95% A / 5% B for 0.50 min, followed by a linear gradient increase to 10% B over the next 0.2 min; this gradient was then maintained at 100% mobile phase B for the next 0.7 min, and then decreased to 95% mobile phase A over the next 0.1 min. The detection of lenapavir was achieved using positive ion electrospray mass spectrometry in unit resolution mode. Lenacapapravir was quantified using multiple reaction monitoring (MRM) mode, with the MRM conversion coefficient for lenacapapravir ranging from 968.1 to 869.4 Da. Peak area was determined using Sciex Analyst® program version 1.6.3 running on a Windows 7 computer, where concentration was determined by a weighted (1 / x2) linear regression of the peak area ratio (peak area of ​​EFdA / peak area of ​​the corresponding IS) compared to the nominal concentration of the plasma calibration standard. Unrounded figures were calculated. Overall, Analyst® determines the precision and accuracy of calibration standards and QC samples.

[0253] Pharmacokinetic calculations: Non-compartmental (NCA) analysis of EFdA and individual prodrug plasma concentration-time data was performed using the WinNonlin module (version 8.3.0.5005, Certara Inc., Princeton, NJ 08540) in the Phoenix PK / PD platform. Calculations were performed before rounding and the nominal sampling time was used in the pharmacokinetic analysis. Exposure is expressed as the area under the curve (AUC0-24h) of plasma concentration from 0 to 24 hours. AUC values ​​were calculated using the linear trapezoidal rule.

[0254] Plasma Concentrations: Results of the PK studies are shown in Tables 6 to 13. These data demonstrate in vivo that the prodrug formula 4-A can be readily delivered orally, and releases EFdA efficiently in vivo, with minimal prodrug detection in systemic circulation in both absence and presence of lenakapavir. Furthermore, the pharmacokinetic profile of lenakapavir is unaffected by co-administration with the prodrug (e.g., formula 4-A). Table 6: Plasma concentrations of EFdA and prodrug formula 4-A after a single IV infusion in male Sprague-Dowley rats when administered alone. EFdA concentration in rat plasma (ng / mL) when administered alone Prodrug Formula 4-A IV (1.0 mg / kg) Animal ID Time point (hour) R01 R02 R03 R04 average value SD %CV 0.0830 106 95.3 107 84.4 98.2 ± 10.6 0.167 122 124 150 129 131 ± 12.8 0.250 148 170 170 158 162 ± 10.6 0.500 122 189 162 208 170 ± 37.3 1.00 43.4 49.4 57.2 48.0 49.5 ± 5.74 2.00 9.05 7.76 10.6 9.02 9.11 ± 1.16 4.00 BQL BQL 1.30 1.58 1.44 ± ND 7.00 BQL BQL BQL BQL ND ± ND 12.0 BQL BQL BQL BQL ND ± ND 24.0 BQL BQL BQL BQL ND ± ND Table 7: Plasma concentrations of EFdA and prodrug 4-A in male Sprague-Dowley rats after a single IV infusion when co-administered with lenakapavir. EFdA concentration (ng / mL) in rat plasma when administered co-administered with lenakapvir Prodrug Formula 4-A IV (1.0 mg / kg) Animal ID Time point (hour) R09 R10 R11 R12 average value SD %CV 0.0830 105 91.2 82.1 95.7 93.5 ± 9.53 0.167 154 115 116 119 126 ± 18.7 0.250 191 157 161 134 161 ± 23.4 0.500 170 178 164 175 172 ± 6.13 1.00 41.1 51.7 50.3 40.6 45.9 ± 5.89 2.00 9.00 11.6 10.0 9.96 10.1 ± 1.08 4.00 1.89 1.70 1.43 1.36 1.60 ± 0.245 7.00 BQL BQL BQL BQL ND ± ND 12.0 BQL BQL BQL BQL ND ± ND 24.0 BQL BQL BQL BQL ND ± ND 48.0 BQL BQL BQL BQL ND ± ND 72.0 BQL BQL BQL BQL ND ± ND Table 8: Plasma prodrug form 4A concentration (ng / mL) in rat plasma when administered alone. Concentration (ng / mL) of prodrug 4A in rat plasma when administered alone. Prodrug Formula 4-A IV (1.0 mg / kg) Animal ID Time point (hour) R01 R02 R03 R04 average value SD %CV 0.0830 BQL BQL BQL BQL ND ± ND 0.167 BQL BQL BQL BQL ND ± ND 0.250 BQL 2.27 BQL BQL ND ± ND 0.500 BQL BQL BQL BQL ND ± ND 1.00 BQL BQL BQL BQL ND ± ND 2.00 BQL BQL BQL BQL ND ± ND 4.00 BQL BQL BQL BQL ND ± ND 7.00 BQL BQL BQL BQL ND ± ND 12.0 BQL BQL BQL BQL ND ± ND 24.0 BQL BQL BQL BQL ND ± ND Table 9: Plasma concentrations (ng / mL) of prodrug form 4A in rats when co-administered with lenakapavir. The concentration of prodrug formula 4A in rat plasma (ng / mL) when administered co-administered with lenapavir. Prodrug Formula 4-A IV (1.0 mg / kg) Animal ID Time point (hour) R09 R10 R11 R12 average value SD %CV 0.0830 1.37 5.19 1.54 2.80 2.73 ± 1.76 0.167 BQL BQL BQL BQL ND ± ND 0.250 1.13 BQL 2.38 BQL 1.76 ± ND 0.500 1.13 BQL BQL BQL ND ± ND 1.00 1.06 BQL BQL BQL ND ± ND 2.00 BQL BQL BQL BQL ND ± ND 4.00 BQL BQL BQL BQL ND ± ND 7.00 BQL BQL BQL BQL ND ± ND 12.0 BQL BQL BQL BQL ND ± ND 24.0 BQL BQL BQL BQL ND ± ND 48.0 BQL BQL BQL BQL ND ± ND 72.0 BQL BQL BQL BQL ND ± ND Table 10: Plasma concentrations of lenakapavir in rats when administered alone. The concentration of lenakapavir in rat plasma when administered alone (ng / mL) Lenakapavir IV (1.0 mg / kg) Animal ID Time point (hour) R05 R06 R07 R08 average value SD %CV 0.0830 692 485 603 667 612 ± 92.4 0.167 694 845 682 734 739 ± 74.2 0.250 796 810 801 894 825 ± 46.2 0.500 980 612 580 984 789 ± 223 1.00 261 166 222 240 222 ± 40.7 2.00 181 104 149 164 150 ± 33.0 4.00 171 102 157 195 156 ± 39.4 7.00 185 84.6 141 142 138 ± 41.2 12.0 145 79.4 106 139 117 ± 30.6 24.0 141 123 141 139 136 ± 8.72 48.0 107 69.4 68.7 79.7 81.2 ± 17.9 72.0 51.3 59.7 57.2 110 69.6 ± 27.2 Table 11: Plasma concentrations of lenakapavir in rats when administered in combination with prodrug formula 4-A. The concentration of lenakapavir in rat plasma (ng / mL) when administered co-administered with prodrug formula 4-A. Lenakapavir IV (1.0 mg / kg) Animal ID Time point (hour) R09 R10 R11 R12 average value SD %CV 0.0830 488 460 391 314 413 ± 77.7 0.167 546 479 589 415 507 ± 76.4 0.250 696 623 664 375 590 ± 146 0.500 774 643 714 448 645 ± 142 1.00 201 170 170 107 162 ± 39.5 2.00 174 135 105 94.7 127 ± 35.6 4.00 98.9 93.1 101 80.9 93.5 ± 9.02 7.00 140 101 72.3 58.8 93.0 ± 35.9 12.0 139 137 158 78.6 128 ± 34.4 24.0 129 164 176 62.5 133 ± 51.0 48.0 66.2 64.1 113 59.5 75.7 ± 25.0 72.0 40.1 97.8 97.2 98.0 83.3 ± 28.8 BQL = Below Quantitative Level; ND = Undetermined. Table 12: EFdA Exposure in Plasma of Prodrug Formula 4-A, Alone or in Combination with Lenapamil, in Rats Method of drug administration Dosage (mg / kg) AUC (ng*hr / mL) C max (ng / mL) alone 1 147 179 Combined with Lenapaveri 1 149 177 Table 13: Plasma exposure to lenapavir in rats, alone or in combination with prodrug 4-A via IV administration. Administration method Dosage (mg / kg) AUC (ng*hr / mL) C max (ng / mL) alone 1 7976 903 Combination with prodrug formula 4-A 1 7483 645 By reference and integration

[0255] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent or patent application were expressly and individually incorporated herein by reference. [Simplified Explanation of the Diagram]

[0016] Figure 1: A representative non-limiting example of the average 3-D surface plot of Formula 4-A and the interaction between the antiviral drug lenacapavir and the drug.

Claims

1. Use of an adenosine derivative of formula (4-A) or a pharmaceutically acceptable salt or hydrate thereof for the preparation of a medicament for the treatment or prevention of HIV infection in an individual in need, wherein the treatment or prevention comprises administering to the individual an effective amount of the adenosine derivative of formula (4-A) or a pharmaceutically acceptable salt or hydrate thereof and an effective amount of a capsid inhibitor or a pharmaceutically acceptable salt thereof, wherein the adenosine derivative of formula (4-A) has the following structure: (4-A), and the capsid inhibitor has the following structure: .

2. As claimed in claim 1, wherein the treatment or prevention comprises the simultaneous administration to the individual of the capsid inhibitor or a pharmaceutically acceptable salt thereof and the adenosine derivative or a pharmaceutically acceptable salt or hydrate thereof.

3. The use as claimed in claim 1, wherein the treatment or prevention comprises sequential administration to the individual of the capsid inhibitor or a pharmaceutically acceptable salt thereof and the adenosine derivative or a pharmaceutically acceptable salt or hydrate thereof.

4. As claimed in claim 3, wherein the treatment or prevention comprises sequentially administering the capsid inhibitor or a pharmaceutically acceptable salt thereof and the adenosine derivative or a pharmaceutically acceptable salt or hydrate thereof to the individual over a period ranging from 0.1 minutes to 72 hours.

5. The use of any of claims 1 to 4, wherein the treatment or prevention comprises administering to the individual once daily to once every 12 months the capsid inhibitor or a pharmaceutically acceptable salt thereof and the adenosine derivative or a pharmaceutically acceptable salt or hydrate thereof.

6. For any of the uses in claims 1 to 4, 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 multidrug-resistant HIV.

7. The use of any of claims 1 to 4, wherein the treatment or prevention includes oral administration of the capsid inhibitor or a pharmaceutically acceptable salt thereof to the individual.

8. The use of any of claims 1 to 4, wherein the treatment or prevention includes non-enteral administration of the capsid inhibitor or a pharmaceutically acceptable salt thereof to the individual.

9. As claimed in item 8, wherein the non-enteral administration is performed by intramuscular and / or subcutaneous injection.

10. The use of any of claims 1 to 4, wherein the treatment or prevention comprises oral administration to the individual of the adenosine derivative or a pharmaceutically acceptable salt or hydrate thereof.

11. A pharmaceutical combination for treating or preventing HIV comprising: (a) a capsid inhibitor or a pharmaceutically acceptable salt thereof; and (b) an adenosine derivative of formula (4-A) or a pharmaceutically acceptable salt or hydrate thereof, wherein the adenosine derivative of formula (4-A) has the following structure: (4-A), and the capsid inhibitor has the following structure: .

12. The pharmaceutical combination of claim 11 further includes a pharmaceutically acceptable carrier.

13. The pharmaceutical combination as requested in item 11 or 12, wherein the combination is suitable for oral administration.

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