Adenosine derivatives and pharmaceutical compositions containing the same

Abstract

Disclosed herein are adenosine derivative prodrugs and compositions thereof that can be used to treat HIV infection or RNA virus infection.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and the benefit of priority to U.S. Provisional Application Serial No. 63 / 141,450, filed January 25, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to adenosine derivative prodrugs capable of inhibiting reverse transcriptase. The present disclosure also relates to pharmaceutical compositions comprising the adenosine derivative prodrugs that can be used to treat acquired immune deficiency syndrome (AIDS), HIV-1, HIV-2, multidrug resistant HIV, or a combination thereof. [Background technology]

[0003] Retroviruses, such as the human immunodeficiency virus (HIV), are associated with the immunosuppressive disease known as acquired immune deficiency syndrome (AIDS). Multiple retroviral strains, such as HIV type 1 (HIV-1) and HIV type 2 (HIV-2), are known to be associated with the disease. Individuals infected with the HIV retrovirus may be asymptomatic initially, but subsequently develop an AIDS-related complex (ARC) and subsequently AIDS. Replication of HIV by a host cell requires the integration of the viral genome into the host cell's DNA. A critical step in this process involves the transcription of the viral RNA genome into DNA via an enzyme known as reverse transcriptase (RT).

[0004] Reverse transcriptase typically can have multiple enzymatic functions, acting as (1) an RNA-dependent DNA polymerase that transcribes a single-stranded DNA copy (first DNA) of the viral RNA, (2) as a ribonuclease that destroys the original viral RNA and liberates the newly produced DNA from the original RNA, and (3) as a DNA-dependent DNA polymerase that uses the first DNA strand as a template to produce a second, complementary DNA strand. The two DNA strands then form double-stranded DNA, which is integrated into the host cell's genome by the integrase enzyme.

[0005] Many compounds are capable of inhibiting reverse transcriptase (RT) activity. These compounds may be useful in treating HIV infection in humans by inhibiting HIV replication in infected cells or individuals. Examples of compounds approved for use in treating 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, among others. 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.).

[0006] The adenosine derivative EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine, also known as MK-8591, islatravir) is an NRTI that has demonstrated anti-HIV activity through inhibition of reverse transcriptase by preventing translocation (U.S. Patent Nos. 7,339,053, 7,625,877, 8,039,614; Singh et al., Pharmaceuticals, 12, 62, 2019, DOI: 10.3390 / ph12020062, each of which is incorporated herein by reference in its entirety). The compound has broad inhibitory activity and potency against various subtypes and mutations, including HIV-1, HIV-2, multidrug-resistant (MDR) and wild-type (WT) strains, and reverse transcriptase inhibitor (RTI)-resistant viruses. Several modified EFdAs and prodrugs are described in U.S. Patent Application Publication No. 2018 / 0002366, which is incorporated by reference in its entirety.

[0007] A common problem arising from the treatment of HIV infection with antiretroviral inhibitor compounds is viral resistance to the inhibitors. Such resistance is typically the result of mutations occurring in the reverse transcriptase segment of the pol gene. The continued use of antiviral compounds such as inhibitor compounds to prevent HIV infection will inevitably result in the emergence of new resistant strains of HIV. Thus, there is a continuing need for new RT inhibitors that are effective against HIV strains, including mutant HIV and multidrug-resistant HIV strains.

[0008] Another common problem is medication adherence. Medication adherence is essential for HIV-infected individuals to successfully complete treatment throughout their life. Adherence to a daily regimen can be difficult, which also negatively impacts patients' quality of life due to daily reminders of their HIV status. Therefore, there is a need to identify long-acting compounds or regimens (e.g., weekly, monthly, or bimonthly treatments) to help patients overcome these challenges associated with taking daily oral medications. Summary of the Invention

[0009] The present disclosure relates to adenosine derivatives and compositions thereof that can be used to treat retroviral diseases such as HIV and AIDS.

[0010] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (I), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 1 and R 2can form, together with the atoms to which they are attached, a 3- to 25-membered heterocyclic ring; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0011] In some embodiments, the disclosure provides an adenosine derivative having the structure of Formula (Ia), (Ib), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0012] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ic), (Id), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0013] In some embodiments, the disclosure provides an adenosine derivative having the structure of Formula (Ie), (If), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0014] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ig) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, E is a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0015] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ih), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0016] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ii), (Ij), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0017] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ik), (Il), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0018] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Im), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0019] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (In), (Io), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0020] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ip), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0021] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Iq), (Ir), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0022] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] and a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0023] The present disclosure further relates to pharmaceutical compositions comprising one or more adenosine derivatives, pharma- ceutically acceptable salts, stereoisomers, tautomers, or solvates, or combinations thereof, disclosed herein, and one or more pharma- ceutically acceptable carriers.

[0024] The present disclosure also relates to methods of making compounds having formula (I). In one embodiment, the process of making compounds having formula (I) is as described in the examples provided herein.

[0025] The present disclosure also includes a method for treating a disease (e.g., acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV)) by administering to a subject in need thereof an effective dosage of a pharmaceutical composition comprising one or more of the adenosine derivatives disclosed herein.

[0026] The present disclosure also relates to a method for the prevention of infection, comprising administering to a subject in need thereof an effective dosage of a pharmaceutical composition comprising one or more of the adenosine derivatives disclosed herein. [Brief description of the drawings]

[0027] [Figure 1] FIG. 1 shows the plasma concentration-time profiles of Compound 2 and EFdA following a single IM injection of Compound 2 (10 mg / kg) in cynomolgus monkeys. [Diagram 2] FIG. 1 shows the plasma concentration-time profiles of Compound 7 and EFdA following a single IM injection of Compound 7 (10 mg / kg) in cynomolgus monkeys. [Diagram 3] FIG. 1 shows the plasma concentration-time profiles of Compound 10 and EFdA following a single IM injection of Compound 10 (10 mg / kg) in cynomolgus monkeys. [Figure 4] FIG. 1 shows the plasma concentration-time profiles of Compound 12 and EFdA following a single IM injection of Compound 12 (10 mg / kg) in cynomolgus monkeys.

[0028] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The following is a more detailed description of various concepts related to the methods and apparatus according to the present disclosure, and embodiments thereof. It should be understood that the various aspects of the subject matter introduced above and discussed in more detail below can be implemented in any of a number of ways, as the subject matter is not limited to a particular implementation. Specific examples and applications are provided primarily for illustrative purposes.

[0030] As used herein, "alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the remainder of the molecule by a single bond. Alkyl containing any number of carbon atoms from 1 to 20 is included. Alkyl containing up to 12 carbon atoms is any of the groups C1-C 12 Alkyl, an alkyl group containing up to 10 carbon atoms, is C1-C 10 An alkyl group having up to 6 carbon atoms is a C1-C6 alkyl group, and an alkyl group having up to 5 carbon atoms is a C1-C5 alkyl group. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes all of the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9, and C 10 Also includes alkyl. Similarly, C1-C 20 Alkyl includes all of the above moieties, except that C 11 Alkyl and C 20 Includes alkyl. C1~C 20Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specified in the specification, an alkyl group may be optionally substituted.

[0031] As used herein, "alkylene" or "alkylene chain" refers to a fully saturated, straight or branched, divalent hydrocarbon chain radical having 1 to 20 carbon atoms. 20 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specified in the specification, an alkylene chain can be optionally substituted.

[0032] As used herein, the term "alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain radical containing at least one carbon-carbon double bond, having a number of carbon atoms in the specified range, and attached to the remainder of the molecule by a single bond. For example, "C2-C20 alkenyl" (or "C2-C 20 "Alkenyl") refers to an alkenyl having 2 to 20 carbon atoms, either straight or branched, or an isomer. In another example, C2-C6 alkenyl can have 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl). Unless otherwise specified in the specification, an alkenyl group can be optionally substituted.

[0033] As used herein, "alkenylene" or "alkenylene chain" refers to an unsaturated, straight or branched divalent hydrocarbon chain radical having one or more carbon-carbon double bonds and having 2 to 20 carbon atoms. 20 Non-limiting examples of alkenylene include ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., those described herein) through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specified in the specification, an alkenylene chain can be optionally substituted.

[0034] As used herein, the term "alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain radical containing at least one carbon-carbon triple bond, having a number of carbon atoms in the specified range, and attached to the remainder of the molecule by a single bond. For example, "C2-C20 alkynyl" (or "C2-C 20 "Alkynyl") refers to either a straight or branched chain alkynyl or isomer having 2 to 20 carbon atoms. In another example, C2-C6 alkynyl can have 1-butynyl, 2-butynyl, 3-butynyl, isobutynyl, 1-propynyl, 2-propynyl, and ethynyl. Unless otherwise specified in the specification, the alkynyl group chain can be optionally substituted.

[0035] As used herein, "alkynylene" or "alkynylene chain" refers to an unsaturated, straight or branched divalent hydrocarbon chain radical having one or more carbon-carbon triple bonds and having 2 to 20 carbon atoms. 20Non-limiting examples of alkynylene include ethynylene, propynylene, n-butynylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specified in the specification, the alkynylene chain can be optionally substituted.

[0036] As used herein, "cycloalkyl" refers to a stable non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from 3 to 25 carbon atoms, attached to the atoms by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. In some embodiments, "cycloalkyl" refers to any single ring of an alkane having a particular number of carbon atoms in the specified range. For example, "C3-C25 cycloalkyl" (or "C3-C25 cycloalkyl"). 25 "Cycloalkyl" refers to a single ring of an alkane having 3 to 25 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified in the specification, a cycloalkyl group may be optionally substituted.

[0037] As used herein, the terms "heterocycloalkyl," "heterocycle," or "heterocycle" refer to a saturated or partially saturated, 3- to 25-membered ring consisting of 2 to 24 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, a heterocycloalkyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in a heterocycloalkyl can be optionally oxidized, for example, to form an N-oxide, sulfoxide, or sulfone, and / or the nitrogen atom can be optionally quaternized, for example, to form a quaternary ammonium cation. Examples of such heterocycloalkyls include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. In some embodiments, "3-10 membered heterocycloalkyl" refers to a cycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S. In some embodiments, "heterocycloalkyl," "heterocycle," or "heterocycle" refers to a 3- to 10-membered ring structure having, as members of the ring structure, carbon atoms and one or more heteroatoms selected from N, O, S, or combinations thereof. Unless otherwise specified in the specification, heterocycloalkyl groups can be optionally substituted and can include saturated and / or unsaturated rings.

[0038] As used herein, the term "aryl" refers to a hydrocarbon ring system containing hydrogen, 6-18 carbon atoms, and at least one aromatic ring, attached to the remainder of the molecule by a single bond. For purposes of this disclosure, aryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems. Aryl includes, but is not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, preadene, pyrene, and triphenylene. In some embodiments, "aryl" refers to phenyl, or one or more fused ring hydrocarbon ring systems in which at least one ring is aromatic. Unless otherwise specified herein, "aryl" may be optionally substituted.

[0039] As used herein, the term "heteroaryl" refers to a 5-20 membered ring system containing a hydrogen atom, 1-19 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, at least one aromatic ring, and attached to the remainder of the molecule by a single bond. For purposes of this disclosure, a heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in a heteroaryl can be optionally oxidized, for example, to form an N-oxide, sulfoxide, or sulfone, and / or the nitrogen atom can be optionally quaternized, for example, to form a quaternary ammonium cation. Non-limiting examples of heteroaryls can include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, 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-(furazanyl), or 1,3,4-isomers), oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-membered heterobicyclic fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromanyl, isochromanyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, and 2,3-dihydrobenzo-1,4-dioxinyl. Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0040] Unless expressly stated to the contrary in the particular context, it will be understood that any of the various cyclic 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), or may be bonded to the remainder of the compound at any two ring atoms, provided that such bonding is chemically possible.

[0041] The term "halogen" (or "halo") as used herein refers to fluorine, chlorine, bromine, and iodine (or alternatively, fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I)).

[0042] The term "substituted," as used herein, means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom has been replaced with a bond to a non-hydrogen atom, such as, but not limited to, a halogen atom, such as F, Cl, Br, and I; an oxygen atom, such as in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom, such as in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom, such as in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom, such as in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups, as well as other heteroatoms in various other groups. "Substituted" also means that one or more hydrogen atoms have been replaced with a higher order bond (such as a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" means that one or more hydrogen atoms have been replaced with -NR g Rh , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h "Substituted" also refers to any of the above groups replaced with one or more hydrogen atoms. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R also means any of the above groups substituted with g and R hare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms have been replaced with amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. In addition, each of the foregoing substituents may be optionally substituted with one or more of the substituents described above.

[0043] As used herein, the term "isomer" refers to structural isomers, such as groups or atoms located at different positions of a molecule; stereoisomers, such as chiral isomers, enantiomers, diastereomers, and cis / trans isomers; tautomers, such as amino isomers, imino isomers, or combinations thereof. In a non-limiting example, the adenosine derivatives of the present disclosure can have amino isomers, imino isomers, or combinations thereof. In another non-limiting example, it is understood that when an -OH substituent is permitted on an aromatic heterocycle and keto-enol tautomerism is possible, the substituent may actually exist in whole or in part in the oxo (=O) form. Mixtures of isomers may also be suitable. A mixture of isomers may include each isomer in any ratio. Salts of isomers may also be suitable. The adenosine derivatives of the present disclosure may include an isomer thereof, one or more salts thereof, one or more solvates, including hydrates thereof, solvated salts thereof, or mixtures thereof. The absolute stereochemistry or isomeric configuration may be determined by X-ray crystallography, vibrational circular dichroism (VCD) spectroscopy, or a combination thereof.

[0044] Adenosine derivatives may be identified by their names based on the nomenclature recommended by the International Union of Pure and Applied Chemistry (IUPAC) or by their nucleoside-based names (nucleoside-based nomenclature). Adenosine derivatives may also be identified by their chemical structure diagrams. Names and structures may be used interchangeably, unless expressly stated to the contrary in a particular context.

[0045] Any of the atoms in the compounds disclosed herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure is meant to include all suitable isotopic variations of the compounds disclosed herein.

[0046] The compound may be administered in the form of a pharma- ceutically acceptable salt or solvate. The term "pharma-ceutically acceptable salt" refers to a salt or solvate that is not biologically or otherwise undesirable (e.g., not toxic or harmful to the recipient or subject). Mixtures of the compounds disclosed herein with one or more salts or solvates thereof are also contemplated herein. Illustrative examples of pharma-ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-diate, hexyne-1, These include, but are not limited to, 6-diacid salts, benzoates, chlorobenzoates, methyl benzoate, dinitrobenzoate, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, y-hydroxybutyrate, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0047] Additionally, the compounds disclosed herein may exist in amorphous form and / or one or more crystalline forms, or a combination thereof.

[0048] The term "RNA viral infection" refers to diseases caused by RNA viruses, such as the common cold, influenza, SARS, COVID-19, Hepatitis C, Hepatitis E, West Nile, Ebola, rabies, polio, and measles.

[0049] The term "HIV infection" refers to disease caused by human immunodeficiency viruses (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 multi-drug resistant HIV. The term "AIDS" refers to acquired immune deficiency syndrome, which is caused by HIV infection and advanced forms of the disease.

[0050] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound as described herein. Thus, the term "prodrug" refers to a pharma- ceutically acceptable precursor of a biologically active compound. A prodrug can be a biologically inactive or substantially inactive compound that can be metabolized in the body, i.e., in vivo, to produce a drug having the desired activity. The term "substantially inactive" means that a prodrug can have about 1% to about 10% of the activity of the corresponding drug, or as a percentage based on the weight of the prodrug after metabolism in vivo. In some embodiments, the term "substantially inactive" means that a prodrug has less than about 5% of the activity of the corresponding drug, or as a percentage based on the weight of the prodrug after metabolism in vivo. Doses of a prodrug and its biologically active compound are considered to be dose equivalents if they are the same molar amount.

[0051] The terms "anti-HIV agent", "antiviral agent" or grammatical variations refer to a compound, a mixture of one or more compounds, a preparation, a chemical agent, or a biological agent such as an antibody, a protein, a peptide, a nucleotide, another biological compound, or a combination thereof, that may be directly or indirectly effective in inhibiting HIV, treating or preventing HIV infection, or treating, preventing, or delaying the onset or progression of AIDS, and / or a disease or condition resulting therefrom or related thereto, an RNA viral infection, or a combination thereof. Anti-HIV agents can include HIV antiviral agents, immunomodulators, anti-infective agents, vaccines, or combinations thereof that are useful in treating HIV infection or AIDS. Examples of antiviral agents for treating HIV infection or AIDS include atazanavir (Reyataz®), darunavir (Prezista®), dolutegravir (Tivicay®), dolutegravir (MK-1439), efavirenz (EFV, Sustiva®, Stocrine®), cabotegravir, bictegravir, emtricitabine (FTC, Emtricitabine), cyclosporine (cyclospor ... These include, but are not limited to, Riva®), rilpivirine, etravirine (TMC-125), maraviroc (Selzentry®), rilpivirine (Edurant®), tenofovir DF (DF=disoproxil fumarate, TDF, Viread®), tenofovir hexadecyloxypropyl (CMX-157), tenofovir alafenamide fumarate (GS-7340), lenacapavir (GS-6207), MK-8507. Some of the above anti-HIV agents can be used in the form of a salt, for example, atazanavir sulfate, tenofovir alafenamide fumarate, or other salts. The anti-HIV agent can have one or more activities such as an entry inhibitor (EI), a fusion inhibitor (FI), an integrase inhibitor (InI), a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (nRTI or NRTI) or a non-nucleoside reverse transcriptase inhibitor (nnRTI or NNRTI), a capsid inhibitor, etc. The anti-HIV agent can include two or more agents disclosed herein.The adenosine derivatives of the present disclosure may be in combination with an anti-HIV agent or agents, or with other anti-HIV agents or agents.

[0052] Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaryl ring described as containing a range of "1 to 4 heteroatoms" means that the ring may contain 1, 2, 3, or 4 heteroatoms. Any range cited herein should also be understood to include within its scope all of the subranges within that range. Thus, for example, a heterocycle described as containing "1 to 4 heteroatoms" is intended to include, in its embodiments, heterocycles 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 another example, C1-C10 alkyl means alkyl containing 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms, including all subranges. Thus, C1-C10 alkyl can be linear or branched methyl, ethyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, and C10 alkyl. Divalent C1-C10 alkyl can be linear or branched -CH2-, -C2H4-, -C3H6-, -C4H8-, -C5H 10 -, -C6H 12 -, -C7H 17 -, -C8H 18 -, -C9H 18 - or -C 10 H 20 -. Similarly, C2-C10 alkenyl means linear or branched alkenyl containing 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms, including all subranges. Linear or branched alkenyl may be suitable. C3-C10 cycloalkyl means linear or branched cycloalkyl containing 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms.

[0053] Unless otherwise indicated, open terms such as "contain," "containing," "include," and "including" mean comprising.

[0054] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this application are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

[0055] The term "about" and its grammatical equivalents in connection with a reference numerical value, and its grammatical equivalents as used herein, can include a range of values ​​±10%, e.g., a range of values ​​that is plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from the value. For example, the amount "about 10" includes the amount from 9 to 11.

[0056] The pharmaceutical composition may be suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active ingredient may be coated with a material to protect it from the action of acids and other natural conditions that may inactivate the active ingredient. As used herein, the phrase "parenteral administration" refers to a method of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. In some embodiments, the pharmaceutical composition of the present disclosure is formulated for intramuscular and / or subcutaneous injection. Alternatively, the pharmaceutical composition may be administered via a topical, epidermal, or mucosal route of administration, such as a parenteral route, e.g., intranasal, oral, vaginal, rectal, sublingual, or topical. The pharmaceutical composition may be in the form of a sterile aqueous solution or dispersion. Pharmaceutical compositions can also be formulated in microemulsions, liposomes, or other ordered structures suitable to high drug concentration.

[0057] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (I), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 1 and R 2 can form, together with the atoms to which they are attached, a 3- to 25-membered heterocyclic ring; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0058] In some embodiments, A is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, A is selected from the group consisting of -(CO)-G- or -(CO)-G-(C 1-5 In some embodiments, A is (CO)-G-(C 1-5 In some embodiments, A is a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, A is selected from the group consisting of -(CO)-O- or -(CO)-O-(C 1-5 In some embodiments, A is (CO)-O-(C 1-5 In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0059] In some embodiments, E is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, E is a bond. In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0060] In some embodiments, R 1 , H, C 1-20 Alkyl, or C 3-20 In some embodiments, R 1 , H, C 1-5 Alkyl, or C 3-15 In some embodiments, R 1 is H or C 3-20 In some embodiments, R 1 , H, C 1-5alkyl, or adamantyl. In some embodiments, R 1 is H or adamantyl. In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C 3-20 The cycloalkyl is adamantyl.

[0061] In some embodiments, R 2 , H, C 1-20 Alkyl, or C 3-20 In some embodiments, R 2 , H, C 1-10 Alkyl, or C 3-20 In some embodiments, R 2 , H, C 1-10 Alkyl, or C 5-15 In some embodiments, R 2 , H, C 1-5 Alkyl, or C 5-15 In some embodiments, R 2 is C 5-15 In some embodiments, R 2 , H, C 1-5 alkyl, or adamantyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C 3-20 The cycloalkyl is adamantyl.

[0062] In some embodiments, R 1 and R 2 can be taken together with the atoms to which they are attached to form a 6- to 25-membered heterocycle. 1 and R 2 can be taken together with the atoms to which they are attached to form a 6-15 membered heterocycle. In some embodiments, R 1 and R 2can be taken together with the atoms to which they are attached to form a 10-15 membered heterocyclic ring. 1 and R 2 At least one of R is not H. In some embodiments, R 1 , H, C 1-5 Alkyl, or C 3-20 cycloalkyl, R 2 , H, C 1-5 Alkyl, or C 3-20 In some embodiments, R 1 , H, C 1-5 alkyl, or adamantyl; R 2 , H, C -s5 alkyl, or adamantyl. In some embodiments, R 1 is H, C 1-5 alkyl, or adamantyl; R 2 is H. In some embodiments, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C 3-20 The cycloalkyl is adamantyl.

[0063] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0064] In some embodiments, R 1 and R 2are each as defined herein, and R 3 is H.

[0065] In some embodiments, the disclosure provides an adenosine derivative having the structure of Formula (Ia), (Ib), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0066] In some embodiments, R 1 , H, C 1-20 Alkyl, or C 3-20In some embodiments, R 1 , H, C 1-5 Alkyl, or C 3-15 In some embodiments, R 1 is H or C 3-20 In some embodiments, R 1 , H, C 1-5 alkyl, or adamantyl. In some embodiments, R 1 is H or adamantyl. In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C 3-20 The cycloalkyl is adamantyl.

[0067] In some embodiments, R 2 , H, C 1-20 Alkyl, or C 3-20 In some embodiments, R 2 , H, C 1-10 Alkyl, or C 3-20 In some embodiments, R 2 , H, C 1-10 Alkyl, or C 5-15 In some embodiments, R 2 , H, C 1-5 Alkyl, or C 5-15 In some embodiments, R 2 is C 5-15 In some embodiments, R 2 , H, C 1-5 alkyl, or adamantyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C 3-20 The cycloalkyl is adamantyl.

[0068] In some embodiments, R 1 and R 2can be taken together with the atoms to which they are attached to form a 6- to 25-membered heterocycle. 1 and R 2 can be taken together with the atoms to which they are attached to form a 6-15 membered heterocycle. In some embodiments, R 1 and R 2 can be taken together with the atoms to which they are attached to form a 10-15 membered heterocyclic ring. 1 and R 2 At least one of R is not H. In some embodiments, R 1 , H, C 1-5 Alkyl, or C 3-20 cycloalkyl, R 2 , H, C 1-5 Alkyl, or C 3-20 In some embodiments, R 1 , H, C 1-5 alkyl, or adamantyl; R 2 , H, C -s5 alkyl, or adamantyl. In some embodiments, R 1 is H, C 1-5 alkyl, or adamantyl; R 2 is H. In some embodiments, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C 3-20 The cycloalkyl is adamantyl.

[0069] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0070] In some embodiments, R 1 and R 2 are each as defined herein, and R 3 is H.

[0071] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ic), (Id), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0072] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0073] In some embodiments, R 4 , H, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl. 4 , H, C 1-5 Alkyl, C 1-5 Haloalkyl and C 1-5 In some embodiments, R 4 , H, C 1-3 Alkyl, C 1-2 Haloalkyl and C 1-3 In some embodiments, R 4 is H.

[0074] In some embodiments, R 5 , H, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl. 5, H, C 1-5 Alkyl, C 1-5 Haloalkyl and C 1-5 In some embodiments, R 5 , H, C 1-3 Alkyl, C 1-2 Haloalkyl and C 1-3 In some embodiments, R 5 is H.

[0075] In some embodiments, the disclosure provides an adenosine derivative having the structure of Formula (Ie), (If), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0076] In some embodiments, A is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, A is selected from the group consisting of -(CO)-G- or -(CO)-G-(C 1-5 In some embodiments, A is (CO)-G-(C 1-5 In some embodiments, A is a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5In some embodiments, A is selected from the group consisting of -(CO)-O- or -(CO)-O-(C 1-5 In some embodiments, A is (CO)-O-(C 1-5 In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0077] In some embodiments, E is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, E is a bond. In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0078] In some embodiments, R 1 , H, C 1-20 Alkyl, or C 3-20 In some embodiments, R 1 , H, C 1-5 Alkyl, or C 3-15 In some embodiments, R 1 is H or C 3-20 In some embodiments, R 1 , H, C 1-5 alkyl, or adamantyl. In some embodiments, R 1 is H or adamantyl. In one embodiment, C 1-5Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C 3-20 The cycloalkyl is adamantyl.

[0079] In some embodiments, R 2 , H, C 1-20 Alkyl, or C 3-20 In some embodiments, R 2 , H, C 1-10 Alkyl, or C 3-20 In some embodiments, R 2 , H, C 1-10 Alkyl, or C 5-15 In some embodiments, R 2 , H, C 1-5 Alkyl, or C 5-15 In some embodiments, R 2 is C 5-15 In some embodiments, R 2 , H, C 1-5 alkyl, or adamantyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C 3-20 The cycloalkyl is adamantyl.

[0080] In some embodiments, E is a bond and R 1 is H.

[0081] In some embodiments, A is a bond and R 2 is H.

[0082] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0083] In some embodiments, R 4 , H, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl. 4 , H, C 1-5 Alkyl, C 1-5 Haloalkyl and C 1-5 In some embodiments, R 4 , H, C 1-3 Alkyl, C 1-2 Haloalkyl and C 1-3 In some embodiments, R 4 is H.

[0084] In some embodiments, R 5 , H, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl. 5 , H, C 1-5 Alkyl, C 1-5 Haloalkyl and C 1-5 In some embodiments, R 5, H, C 1-3 Alkyl, C 1-2 Haloalkyl and C 1-3 In some embodiments, R 5 is H.

[0085] In some embodiments, the adenosine derivative of Formula (Ie) has the structure: [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, 1 , R 3 , and R 4 is as defined above.

[0086] In some embodiments, the adenosine derivative of Formula (Ie) has the structure: [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, 1 , and R 3 is as defined above.

[0087] In some embodiments, the adenosine derivative of Formula (Ie) has the structure: [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, 1 , and R 3 is as defined above.

[0088] In some embodiments, the adenosine derivative of Formula (Ie) has the structure: [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, 1 is as defined above.

[0089] In some embodiments, the adenosine derivative of Formula (Ie) has the structure: [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, 1 is as defined above.

[0090] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ig) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, E is a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0091] In some embodiments, E is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, E is a bond. In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0092] In some embodiments, R 1 , H, C 1-20 Alkyl, or C 3-20 In some embodiments, R 1 , H, C 1-5 Alkyl, or C 3-15 In some embodiments, R 1 is H or C 3-20 In some embodiments, R 1 , H, C 1-5 alkyl, or adamantyl. In some embodiments, R 1 is H or adamantyl. In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, C3-20 The cycloalkyl is adamantyl.

[0093] In some embodiments, E is a bond and R 1 is H.

[0094] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0095] In some embodiments, R 4 , H, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl. 4 , H, C 1-5 Alkyl, C 1-5 Haloalkyl and C 1-5 In some embodiments, R 4 , H, C 1-3 Alkyl, C 1-2 Haloalkyl and C 1-3 In some embodiments, R 4 is H.

[0096] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ih), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E are independently a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 It is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0097] In some embodiments, A is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5In some embodiments, A is selected from the group consisting of -(CO)-G- or -(CO)-G-(C 1-5 In some embodiments, A is (CO)-G-(C 1-5 In some embodiments, A is a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, A is selected from the group consisting of -(CO)-O- or -(CO)-O-(C 1-5 In some embodiments, A is (CO)-O-(C 1-5 In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0098] In some embodiments, D is C 1-20 In some embodiments, D is C 1-10 In some embodiments, D is C 3-10 In some embodiments, D is C 3-6 It is alkylene.

[0099] In some embodiments, E is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5In some embodiments, E is a bond. In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0100] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0101] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ii), (Ij), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0102] In some embodiments, D is C 1-20 In some embodiments, D is C 1-10 In some embodiments, D is C 3-10 In some embodiments, D is C 3-6 It is alkylene.

[0103] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0104] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ik), (Il), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0105] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0106] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Im), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0107] In some embodiments, A is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, A is selected from the group consisting of -(CO)-G- or -(CO)-G-(C 1-5 In some embodiments, A is (CO)-G-(C 1-5 In some embodiments, A is a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, A is selected from the group consisting of -(CO)-O- or -(CO)-O-(C 1-5 In some embodiments, A is (CO)-O-(C 1-5In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0108] In some embodiments, E is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, E is a bond. In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0109] In some embodiments, Q 1 , Q 2 , Q 3 , Q4, and Q 5 forms a cyclic ring, said ring being selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. 1 , Q 2 , Q 3 , Q4, and Q 5 forms a cyclic ring, said ring being selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl, or pyridinyl. 1 , Q 2 , Q 3 , Q4, and Q 5forms a cyclic ring, said ring being selected from the group consisting of cyclohexyl, piperidinyl, morpholinyl, phenyl, or pyridinyl. 1 , Q 2 , Q 3 , Q4, and Q 5 forms a cyclic ring, said ring being selected from the group consisting of cyclohexyl, piperidinyl, or morpholinyl. 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, said ring being cyclohexyl.

[0110] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0111] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (In), (Io), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0112] In some embodiments, Q 1 , Q 2 , Q 3 , Q4, and Q 5 forms a cyclic ring, said ring being selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. 1 , Q 2 , Q 3 , Q4, and Q 5 forms a cyclic ring, said ring being selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl, or pyridinyl. 1 , Q 2 , Q 3 , Q4, and Q 5 forms a cyclic ring, said ring being selected from the group consisting of cyclohexyl, piperidinyl, morpholinyl, phenyl, or pyridinyl. 1 , Q 2 , Q 3 , Q4, and Q 5forms a cyclic ring, said ring being selected from the group consisting of cyclohexyl, piperidinyl, or morpholinyl. 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, said ring being cyclohexyl.

[0113] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0114] In some embodiments, R 6 is C 1-5 Alkyl, C 1-3 Haloalkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl. 6 is C 1-5 Alkyl, C 1-3 Haloalkyl and C 1-5 In some embodiments, R 6 is C 1-3 Alkyl, C 1-2 Haloalkyl and C 1-3 In some embodiments, R 6is methyl, ethyl, isopropyl, methoxy, isopropyl, CF3, CH2CF3, methoxy, ethoxy, or isopropoxy.

[0115] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Ip), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0116] In some embodiments, A is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, A is selected from the group consisting of -(CO)-G- or -(CO)-G-(C 1-5 In some embodiments, A is (CO)-G-(C 1-5 In some embodiments, A is a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, A is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, A is selected from the group consisting of -(CO)-O- or -(CO)-O-(C 1-5 In some embodiments, A is (CO)-O-(C 1-5 In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0117] In some embodiments, E is a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-G-, and -(CO)-G-(C 1-5 In some embodiments, E is selected from the group consisting of a bond, -(CO)-, -(CO)-O-, and -(CO)-O-(C 1-5 In some embodiments, E is a bond. In some embodiments, G is a bond or O. In some embodiments, G is O. In some embodiments, J is a bond or O. In some embodiments, J is a bond.

[0118] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0119] In some embodiments, R 6 is C 1-5 Alkyl, C 1-3 Haloalkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl. 6 is C 1-5 Alkyl, C 1-3 Haloalkyl and C 1-5 In some embodiments, R 6 is C 1-3 Alkyl, C 1-2 Haloalkyl and C 1-3 In some embodiments, R 6 is methyl, ethyl, isopropyl, methoxy, isopropyl, CF3, CH2CF3, methoxy, ethoxy, or isopropoxy.

[0120] In some embodiments, the disclosure provides an adenosine derivative having the structure of formula (Iq), (Ir), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0121] In some embodiments, R 3 H, -(CO)-GC 1-10 Alkyl, or C 1-10 In some embodiments, R 3 is H, -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 In one embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. In some embodiments, R 3 is H, -(CO)-CH, -(CO)-O-CH, or CH. In some embodiments, R 3 is H.

[0122] In some embodiments, R 6 is C 1-5 Alkyl, C 1-3 Haloalkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5Alkynyl, C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl. 6 is C 1-5 Alkyl, C 1-3 Haloalkyl and C 1-5 In some embodiments, R 6 is C 1-3 Alkyl, C 1-2 Haloalkyl and C 1-3 In some embodiments, R 6 is methyl, ethyl, isopropyl, methoxy, isopropyl, CF3, CH2CF3, methoxy, ethoxy, or isopropoxy.

[0123] In some embodiments, the adenosine derivative is a compound in Table 1, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0124] In some embodiments, the adenosine derivative is: [ka] and a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0125] In some embodiments, the adenosine derivative of formula (I) is:

[0126] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)acetate,

[0127] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 1-adamantyl methyl carbonate,

[0128] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl adamantane-1-carboxylate,

[0129] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 1-adamantyl carbonate,

[0130] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)1-adamantyl carbonate,

[0131] (((2R,3S,5R)-3-((((1-adamantyl)oxy)carbonyl)oxy)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-2-yl)methyl)1-adamantyl carbonate,

[0132] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)ethyl carbonate,

[0133] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)2-(1-adamantyl)ethyl carbonate,

[0134] ((2R,3S,5R)-2-((((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)2-(1-adamantyl)ethyl carbonate,

[0135] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propyl carbonate,

[0136] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl) 3-(1-adamantyl)propyl carbonate,

[0137] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 4-(1-adamantyl)butyl carbonate,

[0138] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)4-(1-adamantyl)butyl carbonate,

[0139] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propanoate,

[0140] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 4-(1-adamantyl)butanoate,

[0141] (10aR,12R,13aS)-12-(6-amino-2-fluoro-9H-purin-9-yl)-10a-ethynylhexahydro-4H,10H-furo[3,2-d][1,3,7,9]tetraoxacyclododecine-2,8-dione,

[0142] (11aR,13R,14aS)-13-(6-amino-2-fluoro-9H-purin-9-yl)-11a-ethynyloctahydro-11H-furo[3,2-d][1,3,7]trioxacyclotridecine-2,9(4H)-dione,

[0143] ((2R,3S,5R)-2-((((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)ethyl carbonate,

[0144] ((2R,3S,5R)-2-((((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)isobutyrate,

[0145] ((2R,3S,5R)-2-(((((1-adamantyl)methoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)isobutyrate,

[0146] ((2R,3S,5R)-2-((((3-(1-adamantyl)propoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)isobutyrate,

[0147] ((2R,3S,5R)-3-[3-(1-adamantyl)propoxycarbonyloxy]-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propyl carbonate,

[0148] ((2R,3S,5R)-3-(1-adamantylmethoxycarbonyloxy)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-2-yl)methyl 1-adamantyl methyl carbonate,

[0149] ((2R,3S,5R)-2-(1-adamantylmethoxycarbonyloxymethyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-3-yl)ethyl carbonate,

[0150] ((2R,3S,5R)-2-[4-(1-adamantyl)butoxycarbonyloxymethyl]-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-3-yl)ethyl carbonate,

[0151] ((2R,3S,5R)-2-[3-(1-adamantyl)propoxycarbonyloxymethyl]-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-3-yl)ethyl carbonate,

[0152] 1-adamantyl((2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-3-ethoxycarbonyloxy-2-ethynyl-tetrahydrofuran-2-yl)methyl carbonate,

[0153] ((2R,3S,5R)-2-(1-adamantyloxycarbonyloxymethyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-3-yl) 2-methylpropanoate,

[0154] (1R,13R,15R)-15-(6-amino-2-fluoro-9H-purin-9-yl)-13-ethynyl-2,9,11,14-tetraoxabicyclo[11.3.0]hexadecane-3,10-dione, and

[0155] (6R,8R,10R)-8-(6-amino-2-fluoro-9H-purin-9-yl)-10-ethynyl-3,5,9,12,14-pentaoxatricyclo[14.4.0.06,10]icosane-4,13-dione.

[0156] The adenosine derivatives of the present disclosure can be converted into targeted drugs that may include reverse transcriptase inhibitor activity in vivo, reverse transcriptase chain terminator activity in vivo, DNA translocation inhibitor activity in vivo, or a combination thereof.Accordingly, the adenosine derivatives of the present disclosure can be used to treat HIV, AIDS, RNA infection, or other diseases disclosed herein.

[0157] The adenosine derivatives of the present disclosure may be prodrugs that have no activity or limited activity in the original (i.e., parent) form as described herein, and can be metabolized in vivo to exhibit the desired activity of the target drug, including reverse transcriptase inhibitor activity, reverse transcriptase chain terminator activity, DNA translocation inhibitor activity, or a combination thereof.

[0158] While not wishing to be bound by a particular mechanism or theory, Applicants have discovered that the adenosine derivatives of the present disclosure can be metabolized in vivo to produce a compound or mixture of compounds similar or identical to the targeted drug 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has reverse transcriptase inhibitor activity and other antiviral activity.

[0159] The adenosine derivatives of the present disclosure can include one or more isomers thereof. In some embodiments, the adenosine derivatives of the present disclosure are isomers of formula (I)-(Ir), or compounds (1)-(30). In some embodiments, the isomers are stereoisomers, such as enantiomers or diastereomers. In some embodiments, the isomers are inhibitors of reverse transcriptase with in vivo activity.

[0160] The present disclosure is further directed to a pharmaceutical composition comprising an adenosine derivative disclosed herein (e.g., compounds of Formulas (I)-(Ir) or compounds (1)-(30)) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, and a pharma- ceutically acceptable carrier.

[0161] In some embodiments, the pharmaceutical composition comprises an adenosine derivative having the structure of Formula (I), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1, H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 1 and R 2 can form, together with the atoms to which they are attached, a 3- to 25-membered heterocyclic ring; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0162] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of Formula (Ia), (Ib), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0163] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of Formula (Ic), (Id), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, and C 1-10 selected from the group consisting of alkyl; R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0164] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of Formula (Ie), (If), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 selected from the group consisting of alkyl; R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0165] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of formula (Ig), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, E is a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 selected from the group consisting of alkyl; R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0166] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of formula (Ih), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; D is -C 1-20Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0167] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of Formula (Ii), (Ij), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0168] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of Formula (Ik), (Il), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0169] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of formula (Im), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0170] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of Formula (In), (Io), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0171] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of formula (Ip), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0172] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative having the structure of Formula (Iq), (Ir), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0173] In some embodiments, the pharmaceutical compositions of the present disclosure comprise an adenosine derivative selected from the group consisting of the compounds disclosed in Table 1 and pharma- ceutically acceptable salts, tautomers, or solvates thereof.

[0174] The adenosine derivatives of the present disclosure can include one or more isomers thereof. In some embodiments, the adenosine derivatives of the present disclosure are isomers of formula (I)-(Ir), or compounds (1)-(30). In some embodiments, the isomers are stereoisomers, such as enantiomers or diastereomers. In some embodiments, the isomers are inhibitors of reverse transcriptase with in vivo activity.

[0175] As disclosed above, the pharmaceutical compositions of the present disclosure include adenosine derivatives that may not include a monophosphate group, a diphosphate group, a triphosphate group, or a combination thereof. In some embodiments, the R of the adenosine derivatives disclosed herein is 1 and / or R 2 The group does not include a monophosphate group, a diphosphate group, a triphosphate group, or combinations thereof.

[0176] In some embodiments, a pharmaceutical composition of the present disclosure comprises a pharma- ceutically acceptable carrier.

[0177] Non-limiting examples of pharmaceutically acceptable carriers may include pharmaceutical excipients, surfactants, emulsifiers, fillers, carriers, isotonicity agents, dispersants, viscosity adjusting agents, resuspending agents, buffers, or combinations thereof. Pharmaceutical excipients typically do not have the properties of medicinal or drug active ingredients, also known as active pharmaceutical ingredients (API), and are typically used to streamline the manufacturing process or packaging of active ingredients, or to deliver APIs to patients or other subjects. Pharmaceutically acceptable carriers, excipients, or inactive ingredients from the inactive ingredients database available from the US FDA (https: / / www.fda.gov / drugs / drug-approvals-and-database / inactive-ingredients-database-download) may be suitable. Some of the generally recognized as safe (GRAS) food substances 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 suitable.

[0178] In some embodiments of the present disclosure, the pharma- ceutically acceptable carrier is polyethylene glycol (PEG), sulfobutyl ether b-cyclodextrin (SRBCD), acacia, animal oil, benzyl alcohol, benzyl benzoate, calcium stearate, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, cyclodextrin, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, glycerol stearate, glyceryl monooleate, glyceryl monostearate, water, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin. (HPBCD), Hypromellose (Hydroxypropyl methylcellulose (HPMC)), Lanolin, Lanolin alcohol, Lecithin, Medium chain triglycerides, Metal soaps, Methylcellulose, Mineral oil, Sodium dihydrogen phosphate, Monoethanolamine, Oleic acid, Polyethylene glycol (PEG3350, PEG4000, PEG6000), Polyoxyethylene-polyoxypropylene copolymer (Poloxamer), Polyoxyethylene alkyl ether, Polyoxyethylene castor oil, Polyoxyethylene castor oil derivatives, Polyoxyethylene sorbitan fatty acid esters, Polyoxyethylene stearate, Polysorbate, Polyoxyethylene (20) sorbitan monolaurate (Tween Polysorbate 20), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium dihydrogen phosphate, sodium phosphate dibasic, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth, triethanolamine, vegetable oil, water, xanthan gum, or combinations thereof.

[0179] In further embodiments, the pharma- ceutically acceptable carrier comprises dextrose, glycerin, histidine, hydrochloric acid, hydroxypropylcellulose, hydroxypropyl-β-cyclodextrin (HPBCD), hypromellose (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, sodium phosphate dibasic, or combinations thereof.

[0180] The pharmaceutical compositions of the present disclosure may further comprise an effective dosage of one or more additional anti-HIV agents (also referred to as antiviral agents) selected from the group consisting of lenacapavir, atazanavir, atazanavir sulfate, bictagrevir, cabotegravir, darunavir, dolutegravir, doravirine, efavirenz, tenofovir disoproxil fumarate, tenofovir alafenamide, etravirine, a combination of darunavir and cobicistat, rilpivirine, or a combination thereof. In some embodiments, the one or more additional anti-HIV agents are selected from the group consisting of lenacapavir, bictegravir, and cabotegravir. In some embodiments, the pharmaceutical compositions of the present disclosure further comprise an effective dosage of one additional anti-HIV agent. In some embodiments, the pharmaceutical compositions of the present disclosure further comprise effective dosages of two additional anti-HIV agents.

[0181] In some embodiments, the pharmaceutical compositions of the present disclosure include an adenosine derivative, e.g., a compound of Formula (I)-(Ir), or compounds (1)-(30), and one or more additional anti-HIV agents in a single formulation that can be administered to a subject together.

[0182] Thus, in some embodiments, the pharmaceutical compositions of the present disclosure comprise (1) (a) an adenosine derivative or a pharma- ceutically acceptable salt, tautomer, or solvate thereof (e.g., of Formulas (I)-(Ir), or compounds (1)-(30)), and (b) an effective dose of one or more additional anti-HIV agents disclosed herein; and (2) a pharma- ceutically acceptable carrier disclosed herein.

[0183] The pharmaceutical compositions of the present disclosure can include an adenosine derivative and one or more additional anti-HIV agents in separate formulations that can be administered simultaneously or sequentially to a subject. The pharmaceutical compositions of the present disclosure can also be mixed together with one or more additional disclosed anti-HIV agents in separate formulations that can be administered simultaneously to a subject.

[0184] The present disclosure further relates to a method of treating a disease, the method comprising administering to a subject in need thereof an effective amount of an adenosine derivative (e.g., a compound of Formula (I)-(Ir) or compounds (1)-(30)), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof disclosed herein.

[0185] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (I), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 1 and R 2 can form, together with the atoms to which they are attached, a 3- to 25-membered heterocyclic ring; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0186] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Ia), (Ib), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0187] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Ic), (Id), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, and C 1-10 selected from the group consisting of alkyl; R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0188] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Ie), (If), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 selected from the group consisting of alkyl; R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0189] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Ig), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, E is a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 selected from the group consisting of alkyl; R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0190] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Ih), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; D is -C 1-20 Alkylene-, -C2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0191] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Ii), (Ij), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0192] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Ik), (Il), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0193] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Im), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0194] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (In), (Io), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0195] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Ip), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0196] In some embodiments of the methods of the present invention, the adenosine derivative is a compound of formula (Iq), (Ir), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0197] In some embodiments of the methods of the present invention, the adenosine derivative is selected from the group consisting of the compounds disclosed in Table 1 and pharma- ceutically acceptable salts, tautomers, or solvates thereof.

[0198] The adenosine derivatives of the present disclosure can include one or more isomers thereof. In some embodiments, the adenosine derivatives of the present disclosure are isomers of formula (I)-(Ir), or compounds (1)-(30). In some embodiments, the isomers are stereoisomers, such as enantiomers or diastereomers. In some embodiments, the isomers are inhibitors of reverse transcriptase with in vivo activity.

[0199] In some embodiments of the present disclosure, the pharmaceutical composition is administered to a subject via intramuscular (IM) injection, subcutaneous (SC) injection, intravenous (IV) injection, oral administration, topical application, implant application, or a combination thereof. In some embodiments, the pharmaceutical composition of the present disclosure is formulated for intramuscular and / or subcutaneous injection. Implant application may include implantable devices or films that include the pharmaceutical composition disclosed herein. Implant application may include vaginal rings, films, membranes, patches, other devices, or a combination thereof.

[0200] The methods of the present disclosure can further include measuring a sample from the subject to determine a measured level of a target drug in the sample, the target drug having a formula (T-1): [ka] In some embodiments, X is a halogen selected from the group consisting of F, Cl, Br, and I. In some embodiments, X is I.

[0201] In some embodiments, the targeted agent is a compound having the structure of formula (T-1A): [ka] or a pharma- ceutically acceptable salt, stereoisomer, tautomer thereof. Formula (T-1A) is also referred to herein as EFdA.

[0202] In some embodiments, the targeted drug is (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (also known as 4'-ethynyl-2-fluoro-2'-deoxyadenosine, EFdA), or a pharma- ceutically acceptable salt thereof.

[0203] In some embodiments, the targeted drug is a degradation product or metabolic product of compound (T-1), (T-1A), or EFdA.

[0204] The specimen can be a blood sample, a urine sample, a bodily fluid sample, a tissue sample, or a combination thereof from a subject, such as a patient.

[0205] The measured levels of the target drug can be determined by analytical methods known to those of skill in the art, including, but not limited to, HPLC, GC, MS, GC-MS, or combinations thereof.

[0206] The methods of the present disclosure can further include adjusting the effective dose to produce a modified effective dose when the measured level of the target drug differs from a predetermined target level of the target drug, and administering the modified effective dose to the subject.

[0207] In some embodiments of the method, the disease is HIV, acquired immune deficiency syndrome (AIDS), or an RNA virus infection. In some embodiments, the disease is AIDS, wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, multi-drug resistant HIV, or an RNA virus infection. In some embodiments, the disease is wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, or multi-drug resistant HIV.

[0208] In some embodiments, the methods of the present disclosure further comprise administering to the subject an effective dosage of one or more additional anti-HIV agents selected from lenacapavir, atazanavir, atazanavir sulfate, bictegravir, cabotegravir, darunavir, dolutegravir, doravirine, efavirenz, tenofovir disoproxil fumarate, tenofovir alafenamide, etravirine, a combination of darunavir and cobicistat, rilpivirine, MK-8507, or combinations thereof. In some embodiments, the one or more additional anti-HIV agents are selected from the group consisting of lenacapavir, bictegravir, and cabotegravir. Other anti-HIV agents identified or developed, or combinations thereof, may also be suitable.

[0209] Combinations of the adenosine derivatives of the present disclosure (e.g., Formulae (I)-(Ir) or compounds (1)-(30)) with one or more additional anti-HIV agents described herein may be useful in treating or preventing AIDS or other HIV-related conditions. The additional anti-HIV agents may be used in these combinations in conventional dosage ranges and regimens reported in the art, including, for example, dosages described in the Physicians' Desk Reference, Thomson PDR, Thomson PDR, 57th edition (2003), the 58th edition (2004), or the 59th edition (2005), and the current Physicians' Desk Reference (68th ed.). (2014), Montvale, NJ: PDR Network.

[0210] The adenosine derivatives of the present disclosure and one or more additional anti-HIV agents described herein can be administered to a subject together or separately via oral administration, parenteral administration, or a combination thereof. In some embodiments, parenteral administration includes SC and / or IM injection. The adenosine derivatives and one or more additional anti-HIV agents can be administered to a subject on a daily, weekly, biweekly, or monthly dosing schedule.

[0211] The present disclosure further relates to the use of the pharmaceutical composition for the treatment of a disease in a subject in need thereof, the disease being acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, multi-drug resistant HIV, or an RNA virus infection. Any of the aforementioned pharmaceutical compositions may be suitable. The pharmaceutical composition may be used together with one or more additional anti-HIV drugs for the treatment of the diseases described herein. The adenosine derivative and the one or more additional anti-HIV drugs may be administered to the subject together or separately via oral administration, parenteral administration, or a combination thereof. The adenosine derivative and the one or more additional anti-HIV drugs may be administered to the subject on a daily, weekly, biweekly, or monthly administration schedule.

[0212] The present disclosure further relates to the use of the adenosine derivative disclosed herein, optionally one or more pharmacologic acceptable carriers, in the manufacture of a medicament for treating a disease, wherein the disease is acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, multidrug-resistant HIV, or RNA virus infection.The above-mentioned adenosine derivatives may be suitable.The above-mentioned pharmacologic acceptable carriers may be suitable.

[0213] The present disclosure relates to a method for the prevention of an infection in a subject in need thereof, the method comprising administering to the subject an effective dose of the pharmaceutical composition of the method disclosed herein, and the subject being free of detectable symptoms of the infection. In some embodiments, the infection comprises a disease selected from acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, multi-drug resistant HIV infection, RNA virus infection, or a combination thereof.

[0214] Detectable symptoms include, but are not limited to, symptoms of acquired immune deficiency syndrome (AIDS), symptoms of infection with HIV virus, including wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, multi-drug resistant HIV, or combinations thereof. Detection of HIV virus can be performed by PCR, reverse PCR, immunodetection of antigens or antibodies associated with AIDS or HIV.

[0215] In some embodiments, the pharmaceutical compositions of the methods of the present invention are administered to a subject on a daily, weekly, biweekly, or monthly dosing schedule.

[0216] In some embodiments, the methods of the disclosure further comprise administering to the subject an effective dose of one or more additional anti-HIV agents selected from lenacapavir, atazanavir, atazanavir sulfate, bictegravir, cabotegravir, darunavir, dolutegravir, doravirine, efavirenz, tenofovir disoproxil fumarate, tenofovir alafenamide, etravirine, a combination of darunavir and cobicistat, rilpivirine, MK-8507, or combinations thereof. In some embodiments, the one or more additional anti-HIV agents are selected from the group consisting of lenacapavir, bictegravir, and cabotegravir.

[0217] The one or more additional anti-HIV agents may be administered to a subject together with the pharmaceutical composition of the present disclosure, or separately.

[0218] Without being bound by any particular theory, an advantage of the adenosine derivatives disclosed herein (e.g., Formulas (I)-(Ir), or Compounds (1)-(30)) is their rapid conversion to the target drug. In some embodiments, the rapid conversion is in a period of less than about 1 hour, e.g., in a period of about 30 minutes to about 45 minutes. As described below, more than about 60% of the adenosine derivatives disclosed herein can be surprisingly and unexpectedly converted to the target drug within about 30 minutes of contact with human plasma. In some embodiments, more than about 60%, more than about 65%, more than about 70%, more than about 75%, more than about 80%, more than about 85%, more than about 90%, or more than about 95% of the adenosine derivatives disclosed herein are converted to the target drug within about 30 minutes of contact with human plasma. In some embodiments, the conversion occurs in vitro. In some embodiments, the conversion occurs in vivo. In some embodiments, the conversion occurs after parenteral (e.g., SC and / or IM) administration. In some embodiments, the conversion occurs following oral administration.

[0219] Numbered Embodiments of the Disclosure Other subject matter contemplated by this disclosure is described in the following numbered embodiments. 1. An adenosine derivative having the structure of formula (I), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-20 Alkyl, C1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 1 and R 2 can form, together with the atoms to which they are attached, a 3- to 25-membered heterocyclic ring; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0220] 1a. A is a bond, -(CO)-, -(CO)-G-, or -(CO)-G-(C 1-5 The adenosine derivative according to embodiment 1, wherein the adenosine derivative is selected from the group consisting of:

[0221] 1b. A is -(CO)-G- or -(CO)-G-(C 1-5 The adenosine derivative according to embodiment 1 or 1a, wherein R is an alkylene)-J-.

[0222] 1c. E is a bond, -(CO)-G-, and -(CO)-G-(C1-5 The adenosine derivative according to any one of embodiments 1 to 1b, wherein R is 0, 1 or 2; R is 1 or 2; and R is 2 or 3.

[0223] 1d. The adenosine derivative according to any one of embodiments 1-1c, wherein E is a bond.

[0224] 1e. The adenosine derivative according to any one of embodiments 1 to 1d, wherein G is a bond or O.

[0225] 1f. The adenosine derivative according to any one of embodiments 1 to 1e, wherein J is a bond or O.

[0226] 1g. The adenosine derivative according to any one of embodiments 1-1f, wherein G is O and J is a bond.

[0227] 1h. R 1 But, H, C 1-5 Alkyl, or adamantyl ( [ka] ) is adenosine derivative according to any one of embodiments 1 to 1g.

[0228] 1i.R 1 The adenosine derivative according to any one of embodiments 1 to 1h, wherein

[0229] 1j.R 2 But, H, C 1-5 The adenosine derivative according to any one of embodiments 1 to 1i, which is alkyl, or adamantyl.

[0230] 1k.R 2 Adamantil ( [ka] ) is a 2-aminopropyl group; and

[0231] 1l. R 1 and R 2 together with the atoms to which they are attached form a 6- to 15-membered heterocycle.

[0232] 1m.R 3 -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 The adenosine derivative according to any one of embodiments 1 to 1l, which is alkyl.

[0233] 1n.R 3 The adenosine derivative according to any one of embodiments 1 to 1m, wherein

[0234] 2. The adenosine derivative according to embodiment 1, wherein the adenosine derivative is a compound of formula (Ia), (Ib), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 Cycloalkyl, C 3-20 selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 Cycloalkyl, C 3-20 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl, where R1 and R 2 At least one of them is not H, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl.

[0235] 3. The adenosine derivative according to embodiment 1, wherein the adenosine derivative is a compound of formula (Ic), (Id), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl.

[0236] 4. The adenosine derivative according to embodiment 1, wherein the adenosine derivative is a compound of formula (Ie), (If), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0237] 5. The adenosine derivative of embodiment 1, wherein the adenosine derivative is a compound of formula (Ig) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, E is a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 Cycloalkyl, C 3-20 selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl.

[0238] 6. The adenosine derivative of embodiment 1, wherein the adenosine derivative is a compound of formula (Ih) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 Cycloalkyl, C 3-20 selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 ) is selected from the group consisting of alkyl.

[0239] 7. The adenosine derivative according to embodiment 1, wherein the adenosine derivative is a compound of formula (Ii), (Ij), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 Cycloalkyl, C 3-20 selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 ) is selected from the group consisting of alkyl.

[0240] 8. The adenosine derivative according to embodiment 1, wherein the adenosine derivative is a compound of formula (Ik), (Il), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl.

[0241] 9. The adenosine derivative according to embodiment 1, wherein the adenosine derivative is a compound of formula (Im) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl.

[0242] 10. The adenosine derivative according to embodiment 1, wherein the adenosine derivative is a compound of formula (In), (Io), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl.

[0243] 11. The adenosine derivative according to embodiment 1, wherein the adenosine derivative is a compound of formula (Ip) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl.

[0244] 12. The adenosine derivative of embodiment 1, wherein the adenosine derivative is a compound of formula (Iq), (Ir), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 is selected from the group consisting of heterocycloalkyl, aryl, and heteroaryl.

[0245] 13. The adenosine derivative, [ka] [ka] and a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0246] 13a. The adenosine derivative is [ka] 14. The adenosine derivative according to embodiment 1 or 13, selected from the group consisting of:

[0247] 14. The adenosine derivative of any one of embodiments 1 to 13, wherein the adenosine derivative comprises reverse transcriptase inhibitor activity in vivo, reverse transcriptase chain terminator activity in vivo, DNA translocation inhibitor activity in vivo, or a combination thereof.

[0248] 15. A pharmaceutical composition comprising an adenosine derivative having the structure of formula (I): [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 1 and R 2 can form, together with the atoms to which they are attached, a 3- to 25-membered heterocyclic ring; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0249] 15a. A is a bond, -(CO)-, -(CO)-G-, or -(CO)-G-(C 1-5 The adenosine derivative according to embodiment 15, selected from the group consisting of:

[0250] 15b. A is -(CO)-G- or -(CO)-G-(C 1-5 The adenosine derivative according to embodiment 15 or 15a, wherein R is H, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29,

[0251] 15c. E is a bond, -(CO)-G-, and -(CO)-G-(C 1-5 The adenosine derivative according to any one of embodiments 15 to 15b, wherein R is 0, 1 or 2; R is 1 or 2; and R is 2 or 3.

[0252] 15d. The adenosine derivative according to any one of embodiments 15-15c, wherein E is a bond.

[0253] 15e. The adenosine derivative according to any one of embodiments 15 to 15d, wherein G is a bond or O.

[0254] 15f. The adenosine derivative according to any one of embodiments 15-15e, wherein J is a bond or O.

[0255] 15g. The adenosine derivative according to any one of embodiments 15-15f, wherein G is O and J is a bond.

[0256] 15h.R 1 But, H, C 1-5 Alkyl, or adamantyl ( [ka] ) is adenosine derivative according to any one of embodiments 15 to 15g.

[0257] 15i.R 1 The adenosine derivative according to any one of embodiments 15 to 15h, wherein

[0258] 15j.R 2 But, H, C 1-5 The adenosine derivative according to any one of embodiments 15 to 15i, which is alkyl, or adamantyl.

[0259] 15k.R 2 Adamantil ( [ka] ) is adenosine derivative according to any one of embodiments 15 to 15j.

[0260] 15l.R 1 and R 2 together with the atoms to which they are attached form a 6- to 15-membered heterocycle.

[0261] 15m.R 3 -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 The adenosine derivative according to any one of embodiments 15 to 15l, which is alkyl.

[0262] 15n.R 3 The adenosine derivative according to any one of embodiments 15 to 15m, wherein

[0263] 16. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Ia), (Ib), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl;

[0264] 17. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Ic), (Id), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0265] 18. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Ie), (If), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0266] 19. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Ig) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, E is a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl;

[0267] 20. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Ih) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; D is -C 1-20 Alkylene-, -C2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 ) is selected from the group consisting of alkyl.

[0268] 21. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Ii), (Ij), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 ) is selected from the group consisting of alkyl.

[0269] 22. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Ik), (Il), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-OC1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0270] 23. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Im) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0271] 24. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (In), (Io), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0272] 25. The pharmaceutical composition according to embodiment 15, wherein the adenosine derivative is a compound of formula (Ip) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0273] 26. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is a compound of formula (Iq), (Ir), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0274] 27. The pharmaceutical composition of embodiment 15, wherein the adenosine derivative is selected from the group consisting of the compounds disclosed in Table 1 of embodiment 13 and pharma- ceutically acceptable salts, tautomers, or solvates thereof.

[0275] 28. A pharmaceutical composition described in any one of embodiments 15 to 27, further comprising a pharma- ceutically acceptable carrier.

[0276] 29. The pharmaceutical composition of any one of embodiments 14-27, further comprising an effective dose of one or more additional antiviral agents selected from lenacapavir, bictegravir, cabotegravir, atazanavir, atazanavir sulfate, darunavir, dolutegravir, doravirine, efavirenz, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, etravirine, a combination of darunavir and cobicistat, maraviroc, rilpivirine, MK-8507, or a combination thereof.

[0277] 30. A method of treating a disease, the method comprising administering to a subject in need thereof an effective dosage of a pharmaceutical composition comprising an adenosine derivative having a structure of formula (I), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 1 and R 2 can form, together with the atoms to which they are attached, a 3- to 25-membered heterocyclic ring; R 3H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0278] 30a. A is a bond, -(CO)-, -(CO)-G-, or -(CO)-G-(C 1-5 The adenosine derivative according to embodiment 30, wherein the adenosine derivative is selected from the group consisting of:

[0279] 30b. A is -(CO)-G- or -(CO)-G-(C 1-5 The adenosine derivative according to embodiment 30 or 30a, wherein R is an alkylene)-J-.

[0280] 30c. E is a bond, -(CO)-G-, and -(CO)-G-(C 1-5 The adenosine derivative according to any one of embodiments 30 to 30b, wherein R is 0, 1 or 2; R is 0, 1 or 2;

[0281] 30d. The adenosine derivative according to any one of embodiments 30-30c, wherein E is a bond.

[0282] 30e. The adenosine derivative of any one of embodiments 30-30d, wherein G is a bond or O.

[0283] 30f. The adenosine derivative of any one of embodiments 30-30e, wherein J is a bond or O.

[0284] 30g. The adenosine derivative of any one of embodiments 30-30f, wherein G is O and J is a bond.

[0285] 30h.R 1 But, H, C 1-5 Alkyl, or adamantyl ( [ka] ) is adenosine derivative according to any one of embodiments 30 to 30g.

[0286] 30i.R 1 The adenosine derivative according to any one of embodiments 30 to 30h, wherein

[0287] 30j.R 2 But, H, C 1-5 The adenosine derivative according to any one of embodiments 30 to 30i, which is alkyl, or adamantyl.

[0288] 30k.R 2 Adamantil ( [ka] ) is adenosine derivative according to any one of embodiments 30 to 30j.

[0289] 30l.R 1 and R 2 together with the atom to which they are attached form a 6- to 15-membered heterocycle.

[0290] 30m.R 3 -(CO)-C 1-5 Alkyl, -(CO)-OC 1-5 Alkyl, or C 1-5 The adenosine derivative according to any one of embodiments 30 to 30l, which is alkyl.

[0291] 30n.R 3 The adenosine derivative according to any one of embodiments 30 to 30l, wherein

[0292] 31. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Ia), (Ib), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 1 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-20 is selected from the group consisting of cycloalkyl, 3-20 membered heterocycloalkyl, aryl, and heteroaryl, where R 1 and R 2 At least one of them is not H, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl;

[0293] 32. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Ic), (Id), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0294] 33. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Ie), (If), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 2 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 5 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0295] 34. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Ig), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, E is a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 1 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 is selected from the group consisting of alkyl, R 4 , H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0296] 35. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Ih), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 ) is selected from the group consisting of alkyl.

[0297] 36. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Ii), (Ij), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, D is -C 1-20 Alkylene-, -C 2-20 Alkenylene-, -C 2-20 Alkynylene-, -C 1-20 Haloalkylene-, -C 1-20 Alkoxyalkylene-, C 3-20 selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R 3 H, -(CO)-OC 1-10 Alkyl, and C 1-10 ) is selected from the group consisting of alkyl.

[0298] 37. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Ik), (Il), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-OC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0299] 38. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Im), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0300] 39. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (In), (Io), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; Q 1 , Q 2 , Q 3 , Q4, and Q 5 form a cyclic ring, wherein said ring is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0301] 40. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Ip), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C 1-10 alkylene)-J-, -(CO)-G-(C 2-10 alkenylene)-J-, and -(CO)-G-(C 2-10 alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, -(CO)-G-; R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0302] 41. The method of embodiment 30, wherein the adenosine derivative is a compound of formula (Iq), (Ir), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: [ka] (In the formula, R 3 H, -(CO)-GC 1-10 Alkyl, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R 6 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

[0303] 42. The method of embodiment 30, wherein the adenosine derivative is selected from the group consisting of the compounds disclosed in Table 1 of embodiment 13 and pharma- ceutically acceptable salts, tautomers, or solvates thereof.

[0304] 43. The method of any one of embodiments 30 to 42, wherein the pharmaceutical composition is administered to the subject via intramuscular (IM) injection, subcutaneous (SC) injection, intravenous (IV) injection, oral administration, topical application, implant application, or a combination thereof.

[0305] 44. The method of any one of embodiments 30-43, further comprising measuring the control sample to determine a measured level of the target drug in the sample, wherein the target drug has the formula (T-1) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X is a halogen selected from the group consisting of F, Cl, Br, and I: [ka]

[0306] 45. The method of embodiment 44, wherein the targeted drug has the formula (T-1A) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof: [ka]

[0307] 46. ​​The method of embodiment 44, wherein the targeted drug is (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol, or a pharma- ceutically acceptable salt thereof.

[0308] 47. The method of any one of embodiments 44 to 46, further comprising adjusting the effective dose to produce a revised effective dose if the measured level of the targeted drug differs from a predetermined target level of the targeted drug, and administering the revised effective dose to the subject.

[0309] 48. The method of any one of embodiments 30 to 47, wherein the disease is acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0310] 49. The method of any one of embodiments 30-48, further comprising administering to the subject an effective dose of one or more additional anti-HIV agents selected from lenacapavir, bictegravir, cabotegravir, atazanavir, atazanavir sulfate, darunavir, dolutegravir, doravirine, efavirenz, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, etravirine, a combination of darunavir and cobicistat, maraviroc, rilpivirine, MK-8507, or a combination thereof.

[0311] 50. The method of embodiment 49, wherein the adenosine derivative and the one or more additional anti-HIV agents are administered to the subject together or separately via oral administration, parenteral administration, or a combination thereof.

[0312] 51. The method of embodiment 50, wherein the adenosine derivative and the one or more additional anti-HIV agents are administered to the subject on a daily, weekly, biweekly, monthly, bimonthly, or semi-annual dosing schedule.

[0313] 52. Use of an adenosine derivative according to any one of embodiments 1 to 14 for treating a disease, wherein the disease is acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0314] 53. Use of a pharmaceutical composition according to any one of embodiments 15 to 29 for the treatment of a disease in a subject in need thereof, wherein the disease is acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0315] 54. Use of the method according to any one of embodiments 30 to 51 for the treatment of a disease in a subject in need thereof, wherein the disease is acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0316] 55. A method for the prevention of an infection in a subject in need thereof, said method comprising administering to the subject an effective dose of the pharmaceutical composition of any one of embodiments 15 to 29, wherein the subject has no detectable symptoms of the infection.

[0317] 56. The method of embodiment 55, wherein the infectious disease comprises a disease selected from infection with acquired immune deficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with an M184V mutation, HIV with K65R, multidrug-resistant HIV, or a combination thereof.

[0318] 57. The method of embodiment 55, wherein the detectable symptoms include symptoms of acquired immune deficiency syndrome (AIDS), symptoms of infection with an HIV virus, including wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with an M184V mutation, HIV with K65R, multidrug-resistant HIV, or a combination thereof.

[0319] 58. The method of embodiment 55, wherein the pharmaceutical composition is administered to the subject on a daily, weekly, biweekly, monthly, bimonthly, or semi-annual dosing schedule.

[0320] 59. The method of embodiment 58, further comprising administering to the subject an effective dose of one or more additional anti-HIV agents selected from lenacapavir, atazanavir, atazanavir sulfate, bictegravir, cabotegravir, darunavir, dolutegravir, doravirine, efavirenz, tenofovir disoproxil fumarate, tenofovir alafenamide, etravirine, a combination of darunavir and cobicistat, maraviroc, rilpivirine, or a combination thereof.

[0321] 60. The method of embodiment 59, wherein the one or more additional anti-HIV agents are administered to the subject together with or separately from the pharmaceutical composition.

[0322] 61. A method for treating HIV infection, comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition of any one of embodiments 1 to 29.

[0323] 62. A method for preventing HIV infection, comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition of any one of embodiments 1 to 29.

[0324] 63. The method of embodiment 61 or 62, wherein the HIV infection is caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with an M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0325] 64. The method of any one of embodiments 61 to 63, wherein the administration is by oral administration.

[0326] 65. The method of any one of embodiments 61 to 63, wherein the administration is by parenteral administration.

[0327] 66. The method of embodiment 65, wherein the parenteral administration is by intramuscular or subcutaneous injection.

[0328] 67. A method according to any one of embodiments 61 to 66, wherein administration of the pharmaceutical composition results in a higher plasma concentration of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

[0329] 68. The method of embodiment 67, wherein administration of the pharmaceutical composition results in a plasma concentration of EFdA that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% higher when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

[0330] 69. The method of embodiment 67, wherein administration of the pharmaceutical composition results in a plasma concentration of EFdA that is 50% to 80%, 50% to 100%, or 50% to 200% higher when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

[0331] 70. A method according to any one of embodiments 61 to 69, wherein administration of the pharmaceutical composition results in a more prolonged release of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

[0332] 71. A method according to any one of embodiments 61 to 70, wherein administration of the pharmaceutical composition results in a higher AUC of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

[0333] 72. The method of embodiment 71, wherein administration of the pharmaceutical composition results in an AUC of EFdA that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than administration of a dose-equivalent amount of EFdA under the same conditions.

[0334] 73. The method of embodiment 71, wherein administration of the pharmaceutical composition results in an AUC of EFdA that is 50% to 200%, 50% to 150%, or 80% to 120% higher than administration of a dose-equivalent amount of EFdA under the same conditions.

[0335] The present disclosure will now be illustrated by the following non-limiting examples. EXAMPLES

[0336] The present invention is further defined in the following examples. It should be understood that these examples, although showing preferred embodiments of the invention, are provided only as examples. From the above discussion and these examples, those skilled in the art can ascertain the essential features of the present invention without departing from the spirit and scope thereof, and can make various changes and modifications of the present invention to adapt to various uses and conditions.

[0337] Example 1: ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)acetate (Compound 1) [ka]

[0338] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)acetate

[0339] To a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (50 mg, 0.17 mmol, 1 equiv.) in pyridine (2 mL) was added 2-(1-adamantyl)acetyl chloride (39.9 mg, 0.19 mmol, 1.1 equiv.) slowly at 0° C. The resulting mixture was stirred at 20° C. for 5 h. The reaction mixture was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluting with 0-5% MeOH / DCM at 30 mL / min) to give ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)acetate (17.9 mg, 22.4% yield) as a white solid. LCMS (ESI) m / z, C 24 H 28 FN5O4: Calculated 469.21, Found (M+H) + : 470.1. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.97 (s, 1H), 6.36 (br s, 2H), 6.26-6.23 (m, 1H), 4.76 (q, J = 7.2 Hz, 1H), 4.27 (q, J = 12 Hz, 2H), 3.72 (d, J = 6.4 Hz, 1H), 2.98 (s, 1H), 2.91-2.89 (m, 1H), 2.59-2.55 (m, 1H), 2.22 (s, 1H), 1.84 (br s, 3H), 1.69-1.52 (m, 7H), 1.52-1.42 (m, 6H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.74 (s, 1F).

[0340] Example 2: ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 1-adamantyl methyl carbonate (compound 2) [ka]

[0341] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 1-adamantyl methyl carbonate

[0342] To a solution of [(2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl(4-nitrophenyl)carbonate (330 mg, 0.72 mmol, 1 equiv.) in THF (15 mL) was added DMAP (8.80 mg, 0.072 mol, 0.1 equiv.) and 1-adamantylmethanol (299 mg, 1.80 mmol, 2.5 equiv.). The resulting mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×30 mm×3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 40%-70%, 9 min) to give ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 1-adamantyl methyl carbonate (11.1 mg, 3.2% yield) as a white solid. LCMS (ESI) m / z, C 24 H 28 FN5O5: Calculated 485.21, Found (M+H) + : 486.2. 1H NMR (400 MHz, CD3OD) δ (ppm) 8.15 (s, 1H), 6.35-6.32 (m, 1H), 4.86-4.83 (m, 1H), 4.61 (br s, 1H), 4.42 (q, J = 12 Hz, 2H), 3.73-3.66 (m, 1H), 3.64-3.56 (m, 1H), 3.20 (s, 1H), 2.87-2.85 (m, 1H), 2.70-2.65 (m, 1H), 1.95 (s, 3H), 1.79-1.72 (m, 3H), 1.71-1.64 (m, 3H), 1.52 (s, 6H). 19 F NMR (376 MHz, CD3OD) δ (ppm) -52.90 (s, 1F).

[0343] Example 3: ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl adamantane-1-carboxylate (compound 3) [ka]

[0344] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl adamantane-1-carboxylate

[0345] To a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (500 mg, 1.71 mmol, 1 equiv.) in pyridine (5 mL) was added adamantane-1-carbonyl chloride (4.51 g, 22.7 mmol, 13.3 equiv.) in THF (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with H2O (60 mL) and extracted with DCM (70 mL). The organic layer was washed with H2O (60 mL), brine (60 mL), dried over Na2SO4, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluting with a 0-8% methanol / dichloromethane gradient at 40 mL / min) to give ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl adamantane-1-carboxylate (172 mg, 21.7% yield) as a white solid. LCMS (ESI) m / z, C 23 H 26 FN5O4: Calculated 455.20, Found (M+H) + : 456.2. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.98 (s, 1H), 6.32 (br s, 2H), 6.25-6.22 (m, 1H), 4.75-4.69 (m, 1H), 4.27 (q, J = 12 Hz, 2H), 3.71-3.70 (m, 1H), 2.97 (s, 1H), 2.97-2.90 (m, 1H), 2.62-2.56 (m, 1H), 1.75-1.54 (m, 15H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.72 (s, 1F).

[0346] Example 4, Example 5, and Example 6: ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 1-adamantyl carbonate (compound 4), ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)1-adamantyl carbonate (compound 5), and (((2R,3S,5R)-3-((((1-adamantyl)oxy)carbonyl)oxy)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-2-yl)methyl)1-adamantyl carbonate (compound 6). [ka]

[0347] Preparation of 1-adamantyl(4-nitrophenyl) carbonate [ka]

[0348] To a solution of (4-nitrophenyl)carbonochloridate (992 mg, 4.92 mmol, 1.5 equiv) in MeCN (15 mL) was added pyridine (10.6 mL, 131 mmol, 40 equiv) and adamantan-1-ol (500 mg, 3.28 mmol, 1 equiv). The resulting mixture was stirred at 20° C. for 4 h and then concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluting with 0-10% ethyl acetate / petroleum ether gradient at 30 mL / min) to give 1-adamantyl(4-nitrophenyl)carbonate (868 mg, 83.4% yield) as a white solid.

[0349] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 1-adamantyl carbonate, ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)1-adamantyl carbonate, and (((2R,3S,5R)-3-((((1-adamantyl)oxy)carbonyl)oxy)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-2-yl)methyl)1-adamantyl carbonate [ka]

[0350] To a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (100 mg, 0.34 mol, 1 equiv.) in THF (20 mL) was added DMAP (8.32 mg, 0.068 mol, 0.2 equiv.) and 1-adamantyl(4-nitrophenyl)carbonate (162 mg, 0.51 mol, 1.5 equiv.). The resulting mixture was stirred at 20° C. for 32 h and then concentrated. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×30 mm×3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 49%-79%, 9 min) to give three products.

[0351] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 1-adamantyl carbonate (16.5 mg, 10.3% yield, white solid): LCMS (ESI) m / z, C 23 H 26 FN5O5: Calculated 471.19, Found (M+H) + : 472.2. 1H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (s, 1H), 6.32 (br s, 2H), 6.24-6.23 (m, 1H), 4.75 (q, J = 7.2 Hz, 1H), 4.44 (d, J = 12 Hz, 1H), 4.14 (d, J = 12 Hz, 1H), 3.70 (d, J = 6.4 Hz, 1H), 2.98 (s, 1H), 2.85-2.84 (m, 1H), 2.60-2.50 (m, 1H), 2.14-2.07 (m, 5H), 1.92-1.85 (m, 4H), 1.63 (s, 6H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.78 (s, 1F).

[0352] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl) 1-adamantyl carbonate (7.8 mg, 4.87% yield, white solid). LCMS (ESI) m / z, C 23 H 26 FN5O5: Calculated 471.19, Found (M+H) + : 472.1. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.98 (s, 1H), 6.44 (br s, 2H), 6.37-6.33 (m, 1H), 5.49-5.47 (m, 1H), 5.09-5.05 (m, 1H), 3.90-3.75 (m, 2H), 3.05-3.01 (m, 1H), 2.99 (s, 1H), 2.59-2.57 (m, 1H), 2.15 (s, 8H), 1.71 (s, 6H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -53.38 (s, 1F).

[0353] (((2R,3S,5R)-3-((((1-adamantyl)oxy)carbonyl)oxy)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-2-yl)methyl)1-adamantyl carbonate (4.2 mg, 1.90% yield, white solid). LCMS (ESI) m / z, C 34 H 40 FN5O7: Calculated 649.29, Found (M+H) + : 650.2. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.96 (s, 1H), 6.35 (br s, 2H), 6.31-6.28 (m, 1H), 5.58 (t, J = 6.4 Hz, 1H), 4.35 (q, J = 11.6 Hz, 2H), 3.14-3.12 (m, 1H), 3.04 (s, 1H), 2.77-2.68 (m, 1H), 2.19 (s, 3H), 2.13 (s, 9H), 2.02-1.95 (m, 5H), 1.91 (s, 1H), 1.72-1.59 (m, 12H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.46 (s, 1F).

[0354] Example 7, Example 8, and Example 9 ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)ethyl carbonate (Compound 7), ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)2-(1-adamantyl)ethyl carbonate (Compound 8) and ((2R,3S,5R)-2-((((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)2-(1-adamantyl)ethyl carbonate (compound 9). [ka]

[0355] The title compound was prepared by following the procedures of Examples 4, 5, and 6, substituting 2-(1-adamantyl)ethyl(4-nitrophenyl)carbonate for 1-adamantyl(4-nitrophenyl)carbonate. 2-(1-adamantyl)ethyl(4-nitrophenyl)carbonate was prepared similarly to 1-adamantyl(4-nitrophenyl)carbonate, except that adamantan-1-ol was replaced with 2-(1-adamantyl)ethan-1-ol.

[0356] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)ethyl carbonate (12.7 mg, 14.9% yield, white solid). LCMS (ESI) m / z, C 25 H 30 FN5O5: Calculated 499.22, Found (M+H) + : 500.2. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (s, 1H), 6.29 (br s, 2H), 6.27-6.24 (m, 1H), 4.76-4.71 (m, 1H), 4.36 (q, J = 12 Hz, 2H), 4.13-4.02 (m, 2H), 3.69 (d, J = 6.4 Hz, 1H), 2.99 (s, 1H), 2.87-2.81 (m, 1H), 2.63-2.50 (m, 1H), 1.91 (s, 3H), 1.75-1.58 (m, 6H), 1.49 (s, 6H), 1.35-1.31 (m, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.84 (s, 1F).

[0357] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)2-(1-adamantyl)ethyl carbonate (5.9 mg, 6.93% yield, white solid). LCMS (ESI) m / z, C 25 H 30 FN5O5: Calculated 499.22, Found (M+H) + : 500.2. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (s, 1H), 6.42 (br s, 2H), 6.38-6.31 (m, 1H), 5.51-5.49 (m, 1H), 5.01-4.97 (m, 1H), 4.27-4.21 (m, 2H), 3.86-3.74 (m, 2H), 3.04-3.02 (m, 1H), 2.95 (s, 1H), 2.59-2.54 (m, 1H), 1.77-1.61 (m, 8H), 1.56 (m, 6H), 1.49-1.46 (m, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -53.33 (s, 1F).

[0358] ((2R,3S,5R)-2-((((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)2-(1-adamantyl)ethyl carbonate (4.2 mg, 3.49% yield, white solid). LCMS (ESI) m / z, C 38 H 48 FN5O7: Calculated 705.35, Found (M+H) + : 706.3. 1H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (s, 1H), 6.32-6.29 (m, 3H), 5.66-5.63 (m, 1H), 4.42 (q, J = 11.6 Hz, 2H), 4.28-4.22 (m, 2H), 4.16-4.03 (m, 2H), 3.19-3.08 (m, 1H), 3.03 (s, 1H), 2.76-2.65 (m, 1H), 1.91 (s, 4H), 1.76-1.60 (m, 13H), 1.59-1.44 (m, 15H), 1.35 (t, J = 7.2 Hz, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.54 (s, 1F).

[0359] Example 10 and Example 11: ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propyl carbonate (compound 10) and ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl) 3-(1-adamantyl)propyl carbonate (compound 11). [ka]

[0360] Preparation of 3-(1-adamantyl)propyl(4-nitrophenyl)carbonate [ka]

[0361] 3-(1-adamantyl)propan-1-ol was prepared from 1-adamantylmethanol according to literature procedures (WO2011 / 058582A1).

[0362] To a solution of 3-(1-adamantyl)propan-1-ol (100 mg, 0.51 mmol, 1 equiv.) in MeCN (2 mL) was added pyridine (1.63 g, 20.6 mmol, 40 equiv.) and (4-nitrophenyl)carbonochloridate (207 mg, 1.03 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 4 h and then concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluting with 0-30% ethyl acetate / petroleum ether gradient at 15 mL / min) to give 3-(1-adamantyl)propyl(4-nitrophenyl)carbonate (130 mg, 70.9% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ (ppm) 8.31-8.27 (m, 2H), 7.41-7.37 (m, 2H), 4.28- 4.25 (m, 2H), 2.00-1.94 (m, 3H), 1.77-1.69 (m, 5H), 1.65-1.61 (m, 3H), 1.52-1.47 (m, 6H), 1.18-1.14 (m, 2H).

[0363] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propyl carbonate and ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)3-(1-adamantyl)propyl carbonate [ka]

[0364] To a solution of 3-(1-adamantyl)propyl(4-nitrophenyl)carbonate (91.6 mg, 0.255 mmol, 1.5 equiv.) and (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (50 mg, 0.17 mmol, 1 equiv.) in THF (2 mL) was added DMAP (4.15 mg, 0.034 mmol, 0.2 equiv.). The resulting mixture was stirred at room temperature for 32 h and then concentrated. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×30 mm×3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 60%-90%, 9 min) to give two products.

[0365] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propyl carbonate (4.5 mg, 5.2% yield) was obtained as a white solid. LCMS (ESI) m / z, C 26 H 32 FN5O5: Calculated value 513.24, Found value (M+H) + : 514.3. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.95 (s, 1H), 6.43-6.40 (m, 1H), 6.08-6.01 (m, 2H), 4.77-4.74 (m, 1H), 4.54-4.46 (m, 2H), 4.15-4.11 (m, 2H), 2.95-2.89 (m, 1H), 2.83-2.75 (m, 1H), 2.72-2.66 (m, 1H), 2.50-2.45 (m, 1H), 1.99-1.90 (m, 3H), 1.72-1.69 (m, 3H), 1.65-1.60 (m, 3H), 1.46-1.43 (m, 6H), 1.30-1.26 (m, 1H), 1.12-1.06 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ (ppm) -49.39 (s, 1F).

[0366] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl) 3-(1-adamantyl)propyl carbonate (3.6 mg, 4.1% yield) was obtained as a white solid. LCMS (ESI) m / z, C 26 H 32 FN5O5: Calculated value 513.24, Found value (M+H) + : 514.2. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.95 (s, 1H), 6.40-6.37 (m, 1H), 6.13-6.08 (m, 2H), 5.65-5.64 (m, 1H), 4.23-4.15 (m, 2H), 4.10-4.07 (m, 1H), 3.99-3.96 (m, 1H), 3.28-3.20 (m, 1H), 2.70-2.65 (m, 1H), 2.62-2.57 (m, 1H), 2.01-1.95 (m, 3H), 1.75-1.72 (m, 3H), 1.70-1.68 (m, 1H), 1.65-1.62 (m, 3H), 1.50-1.45 (m, 7H), 1.17-1.13 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ (ppm) -49.66 (s, 1F).

[0367] Example 12 and Example 13 ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 4-(1-adamantyl)butyl carbonate (Compound 12) and ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl) 4-(1-adamantyl) butyl carbonate (compound 13). [ka]

[0368] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 4-(1-adamantyl)butyl carbonate and ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)4-(1-adamantyl)butyl carbonate are the 4-(1-adamantyl derivatives of 3-(1-adamantyl)propan-1-ol. )butan-1-ol was substituted with ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propyl carbonate and ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)3-(1-adamantyl)propyl carbonate, using the same procedure as for the preparation of propyl carbonate. 4-(1-adamantyl)butan-1-ol was prepared from 2-(1-adamantyl)ethan-1-ol according to literature procedures (WO2011 / 058582A1).

[0369] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 4-(1-adamantyl)butyl carbonate (4.6 mg, 5.1% yield, white solid). LCMS (ESI) m / z, C 27 H 34 FN5O5: Calculated value 527.25, Measured value (M+H) + : 528.2. 1H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (s, 1H), 6.28-6.25 (m, 3H), 4.75-4.70 (m, 1H), 4.47-4.44 (m, 1H), 4.29-4.26 (m, 1H), 4.07-4.00 (m, 2H), 3.70-3.68 (m, 1H), 3.01-2.96 (m, 1H), 2.86-2.80 (m, 1H), 2.60-2.53 (m, 1H), 1.95-1.90 (m, 3H), 1.72-1.69 (m, 3H), 1.64-1.61 (m, 3H), 1.53-1.48 (m, 2H), 1.45-1.44 (m, 6H), 1.28-1.20 (m, 2H), 1.05-1.00 (m, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.85 (s, 1F).

[0370] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl)4-(1-adamantyl)butyl carbonate (6.4 mg, 7.1% yield, white solid). LCMS (ESI) m / z, C 27 H 34 FN5O5: Calculated value 527.25, Measured value (M+H) + : 528.2. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (m, 1H), 6.40-6.32 (m, 3H), 5.52-5.49 (m, 1H), 4.99-4.96 (m, 1H), 4.20-4.13 (m, 2H), 3.88-3.84 (m, 1H), 3.80-3.74 (m, 1H), 3.08-3.00 (m, 1H), 2.97-2.92 (m, 1H), 2.60-2.55 (m, 1H), 1.95-1.90 (m, 3H), 1.77-1.71 (m, 3H), 1.66-1.59 (m, 5H), 1.50-1.43 (m,6H), 1.37-1.29 (m, 2H), 1.11-1.06 (m, 2H).19 F NMR (376 MHz, CD3CN) δ (ppm) -53.34 (s, 1F).

[0371] Example 14: ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propanoate (compound 14) [ka]

[0372] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propanoate was prepared using the same procedure as for the preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)acetate, substituting 3-(1-adamantyl)propanoyl chloride for 2-(1-adamantyl)acetyl chloride (65.1 mg, 53.9% yield, white solid). 3-(1-Adamantyl)propanoyl chloride was synthesized from methyl 3-(1-adamantyl)propanoate according to literature procedures (WO2011 / 058582A1).

[0373] LCMS (ESI) m / z, C 25 H 30 FN5O4: Calculated value 483.23, Measured value ((M+H) + : 484.2. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.10 (s, 1H), 6.36-6.25 (m, 3H), 4.79-4.75 (m, 1H), 4.50-4.42(m, 2H), 3.00-2.94 (m, 1H), 2.84-2.79 (m, 1H), 2.76-2.68 (m, 1H), 2.33-2.28 (m, 2H), 1.97-1.93 (m, 3H), 1.71-1.68 (m, 3H), 1.62-1.59 (m, 3H), 1.44-1.43 (m, 6H), 1.40-1.38 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ (ppm) -48.80 (s, 1F).

[0374] Example 15: ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 4-(1-adamantyl)butanoate (compound 15) [ka]

[0375] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 4-(1-adamantyl)butanoate was prepared using the same procedure as for the preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propanoate, substituting 4-(1-adamantyl)butanoyl chloride for 3-(1-adamantyl)propanoyl chloride (61.4 mg, 51.7% yield, white solid). 4-(1-Adamantyl)butanoyl chloride was prepared from methyl 4-(1-adamantyl)butanoate according to literature procedures (WO2011 / 058582Al).

[0376] LCMS (ESI) m / z, C26 H 32 FN5O4: Calculated 497.24, Found (M+H) + : 498.3. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.96 (s, 1H), 6.30 (br s, 2H), 6.26-6.23 (m, 1H), 4.78-4.73 (m, 1H), 4.41 (d, J = 12.0 Hz, 1H), 4.20 (d, J = 11.6 Hz, 1H), 3.64 (d, J = 6.4 Hz, 1H), 2.98 (s, 1H), 2.83-2.81 (m, 1H), 2.61-2.57 (m, 1H), 2.23-2.19 (m, 1H), 1.93-1.85 (m, 3H), 1.71-1.68 (m, 3H), 1.63-1.60 (m, 3H), 1.46-1.38 (m, 8H), 0.95-0.90 (m, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.81 (s, 1F).

[0377] Example 16: (10aR,12R,13aS)-12-(6-amino-2-fluoro-9H-purin-9-yl)-10a-ethynylhexahydro-4H,10H-furo[3,2-d][1,3,7,9]tetraoxacyclododecine-2,8-dione (compound 16) [ka]

[0378] Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((((4-nitrophenoxy)carbonyl)oxy)methyl)tetrahydrofuran-3-yl(4-nitrophenyl)carbonate [ka]

[0379] To (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (150 mg, 0.512 mmol, 1 equiv.) in MeCN (15 mL) was added pyridine (1.62 g, 20.4 mmol, 1.65 mL, 40 equiv.) and (4-nitrophenyl)carbonochloridate (619 mg, 3.07 mmol, 6 equiv.). The resulting mixture was stirred at 15° C. for 41 h. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluting with a 0-5% methanol / DCM gradient at 50 mL / min) to give (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((((4-nitrophenoxy)carbonyl)oxy)methyl)tetrahydrofuran-3-yl(4-nitrophenyl)carbonate (250 mg, 78.3% yield) as a white solid.

[0380] Preparation of (10aR,12R,13aS)-12-(6-amino-2-fluoro-9H-purin-9-yl)-10a-ethynylhexahydro-4H,10H-furo[3,2-d][1,3,7,9]tetraoxacyclododecine-2,8-dione [ka]

[0381] To a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((((4-nitrophenoxy)carbonyl)oxy)methyl)tetrahydrofuran-3-yl(4-nitrophenyl)carbonate (300 mg, 0.481 mmol, 1 equiv.) in MEK (30 mL) was added DMAP (58.8 mg, 0.481 mmol, 1 equiv.) and propane-1,3-diol (32.9 mg, 0.433 mmol, 0.9 equiv.). The resulting mixture was stirred at 20° C. for 18 h. The reaction mixture was concentrated and purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 17%-47%, 9 min) to give (10aR,12R,13aS)-12-(6-amino-2-fluoro-9H-purin-9-yl)-10a-ethynylhexahydro-4H,10H-furo[3,2-d][1,3,7,9]tetraoxacyclododecine-2,8-dione (5.2 mg, 2.56% yield, white solid). LCMS (ESI) m / z, C 17 H 16 FN5O7: Calculated value 421.10, Found value (M+H) + : 422.2. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.96 (s, 1H), 6.34 (br s, 2H), 6.32-6.29 (m, 1H), 6.05-6.01 (m, 1H), 4.57-4.53 (m, 2H), 4.41-4.37 (m, 4H), 3.11 (s, 1H), 2.97-2.94 (m, 1H), 2.85-2.80 (m, 1H), 2.21-2.19 (m, 1H), 2.13-1.94 (m, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.39 (s, 1F).

[0382] Example 17: (11aR,13R,14aS)-13-(6-amino-2-fluoro-9H-purin-9-yl)-11a-ethynyloctahydro-11H-furo[3,2-d][1,3,7]trioxacyclotridecine-2,9(4H)-dione (compound 17) [ka]

[0383] Preparation of tert-butyl 6-[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-yl]oxycarbonyloxyhexanoate [ka]

[0384] tert-Butyl 6-(4-nitrophenoxy)carbonyloxyhexanoate was prepared using the same procedure as for the preparation of 3-(1-adamantyl)propyl(4-nitrophenyl)carbonate, replacing 3-(1-adamantyl)propan-1-ol with tert-butyl 6-hydroxyhexanoate. tert-Butyl 6-hydroxyhexanoate was synthesized from oxepan-2-one according to literature procedures (WO2015187596A2).

[0385] To a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-ol (200 mg, 0.49 mmol, 1 equiv.) in MeCN (20 mL), DMAP (60.0 mg, 0.49 mmol, 1 equiv.), Et3N (149 mg, 1.47 mmol, 3 equiv.), and tert-butyl 6-(4-nitrophenoxy)carbonyloxyhexanoate (346 mg, 0.98 mmol, 2 equiv.) were added. The resulting mixture was stirred at 15° C. for 16 h. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluting with 0-3% MeOH / DCM at 30 mL / min) to give tert-butyl 6-[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-yl]oxycarbonyloxyhexanoate (250 mg, 81.9% yield) as a yellow solid. 1 H NMR (400 MHz, CD3CN) δ (ppm) 8.22 (s, 1H), 6.52-6.48 (m, 1H), 6.08 (br s, 2H), 5.50-5.48 (m, 1H), 4.25-4.17 (m, 2H), 4.00 (q, J = 12 Hz, 2H), 2.82-2.79 (m, 2H), 2.70 (s, 1H), 2.26-2.22 (m, 2H), 1.75-1.71 (m, 2H), 1.65-1.61 (m, 2H), 1.47-1.43 (m, 11H), 0.93 (s, 9H), 0.14 (s, 6H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -49.79 (s, 1F).

[0386] Preparation of 6-[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxycarbonyloxyhexanoic acid [ka]

[0387] To a solution of tert-butyl 6-[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-yl]oxycarbonyloxyhexanoate (100 mg, 0.16 mmol, 1 equiv.) in THF (5 mL) was added TBAF (1 M in THF, 0.25 mL, 1.5 equiv.). The resulting mixture was stirred at 15° C. for 1 h. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluting with 0-4% ethyl acetate / petroleum ether gradient at 25 mL / min) to give tert-butyl 6-[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxycarbonyloxyhexanoate (80 mg, 98.0% yield) as a pale yellow gum. To a solution of tert-butyl 6-[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxycarbonyloxyhexanoate (80 mg, 0.16 mmol, 1 equiv) in DCM (20 mL) was added TFA (1 mL). The resulting mixture was stirred for 16 hours at 15° C. The reaction mixture was concentrated and purified by preparative TLC (silica gel, DCM / MeOH=10 / 1) to give 6-[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9)-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxycarbonyloxyhexanoic acid (60 mg, 84.3% yield) as a yellow gum.

[0388] Preparation of (11aR,13R,14aS)-13-(6-amino-2-fluoro-9H-purin-9-yl)-11a-ethynyloctahydro-11H-furo[3,2-d][1,3,7]trioxacyclotridecine-2,9(4H)-dione [ka]

[0389] To a solution of 6-[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxycarbonyloxyhexanoic acid (60 mg, 0.13 mmol, 1 equiv.) in DCM (6 mL) and ACN (6 mL) was added TCFH (104 mg, 0.37 mmol, 2.8 equiv.) and NMI (36.0 mg, 0.44 mmol, 3.3 equiv.). The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated and purified by preparative HPLC (NH4HCO3 condition; column: Welch Xtimate C18 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 32%-62%, 9 min) to give (11aR,13R,14aS)-13-(6-amino-2-fluoro-9H-purin-9-yl)-11a-ethynyloctahydro-11H-furo[3,2-d][1,3,7]trioxacyclotridecine-2,9(4H)-dione (3.4 mg, 6.03% yield, white solid). LCMS (ESI) m / z, C 19 H 20 FN5O6: Calculated 433.14, Found (M+H) + : 434.1. 1H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (s, 1H), 6.37-6.34 (m, 3H), 5.86-5.83 (m, 1H), 4.47-4.41 (m, 2H), 4.33 (d, J = 10.8 Hz, 1H), 4.17-4.11 (m, 1H), 3.25-3.19 (m, 1H), 3.01 (s, 1H), 2.75-2.68 (m, 1H), 2.43-2.40 (m, 2H), 1.75-1.71 (m, 2H), 1.63-1.55 (m, 2H), 1.37-1.34 (m, 1H), 0.98-0.95 (m, 1H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.52 (s, 1F).

[0390] Example 18: ((2R,3S,5R)-2-((((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)ethyl carbonate (compound 18) [ka]

[0391] ((2R,3S,5R)-2-(((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)ethyl carbonate was prepared using the same procedure as for the preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)acetate, substituting ethyl carbonochloridate for 2-(1-adamantyl)acetyl chloride (11.2 mg, 19.6% yield, white solid). LCMS (ESI) m / z, C 28 H 34 FN5O7: Calculated 571.24, Found (M+H) + : 572.3.1 H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (s, 1H), 6.34-6.30 (m, 3H), 5.65-5.62 (m, 1H), 4.43 (q, J = 11.6 Hz, 2H), 4.24-4.20 (m, 2H), 4.12-4.06 (m, 2H), 3.18-3.11 (m, 1H), 3.04 (s, 1H), 2.74-2.70 (m, 1H), 1.93-1.84 (m, 3H), 1.74-1.61 (m, 6H), 1.54-1.65 (m, 6H), 1.36-1.28 (m, 5H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.54 (s, 1F).

[0392] Example 19: ((2R,3S,5R)-2-((((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)isobutyrate (compound 19) [ka]

[0393] ((2R,3S,5R)-2-((((2-(1-adamantyl)ethoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)isobutyrate was prepared using the same procedure as for the preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl)methyl 2-(1-adamantyl)acetate, substituting isobutyryl chloride for 2-(1-adamantyl)acetyl chloride (12.8 mg, 22.5% yield, white solid). LCMS (ESI) m / z, C 29 H 36 FN5O6: Calculated value 569.26, Found value (M+H) + : 570.3. 1H NMR (400 MHz, CD3CN) δ (ppm) 7.98 (s, 1H), 6.38 (br s, 2H), 6.35-6.32 (m, 1H), 5.73-5.70 (m, 1H), 4.41 (q, J = 12 Hz, 2H), 4.13-4.06 (m, 2H), 3.12-3.08 (m, 1H), 3.06 (s, 1H), 2.69-2.64 (m, 2H), 1.95-1.90 (m, 3H), 1.74-1.58 (m, 6H), 1.50 (s, 6H), 1.40-1.32 (m, 2H), 1.24-1.16 (m, 6H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.63 (s, 1F).

[0394] Example 20: ((2R,3S,5R)-2-(((((1-adamantyl)methoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)isobutyrate (compound 20) [ka]

[0395] Preparation of 1-adamantylmethyl(2,3,4,5,6-pentafluorophenyl) carbonate [ka]

[0396] To a solution of 1-adamantylmethanol (1.00 g, 6.01 mmol, 1 equiv.) in pyridine (5 mL) and MeCN (5 mL) was added bis(2,3,4,5,6-pentafluorophenyl)carbonate (3.08 g, 7.82 mmol, 1.3 equiv.). The reaction mixture was stirred at 15° C. for 16 h and then concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, elution with 0-1% ethyl acetate / petroleum ether gradient at 25 mL / min) to give 1-adamantylmethyl(2,3,4,5,6-pentafluorophenyl)carbonate (2.20 g, 98% yield) as a white solid.

[0397] Preparation of 1-adamantylmethyl [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate [ka]

[0398] To a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (200 mg, 0.68 mmol, 1 equiv) in pyridine (2 mL) and DCM (0.5 mL) was added DMAP (8.33 mg, 0.068 mmol, 0.1 equiv) and 1-adamantylmethyl(2,3,4,5,6-pentafluorophenyl)carbonate (898 mg, 2.39 mmol, 3.5 equiv) at 0° C. The reaction mixture was stirred at 15° C. for 20 h. The resulting mixture was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, elution with 0–1.5% MeOH / DCM at 35 mL / min) to afford 1-adamantylmethyl [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (150 mg, 45% yield) as a white solid.

[0399] Preparation of ((2R,3S,5R)-2-((((1-adamantyl)methoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)isobutyrate [ka]

[0400] To a solution of 1-adamantylmethyl[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (150 mg, 0.309 mmol, 1 equiv.) in pyridine (5 mL) was added 2-methylpropanoyl chloride (98.8 mg, 0.927 mmol, 3 equiv.) at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h. The reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with H2O (30 mL), brine (30 mL), dried over Na2SO4, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0-1% MeOH / DCM at 25 mL / min) to give the crude product. The crude product was further purified by preparative TLC (SiO2, DCM:MeOH=10:1) to give the title compound (100 mg, 58% yield) as a white solid. LCMS (ESI) m / z, C 28 H 34 FN5O6: Calculated value 555.25, Found value (M+H) + : 556.2. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.99 (s, 1H), 6.36-6.33 (m, 3H), 5.73-5.69 (m, 1H), 4.42 (AB q, J = 11.2 Hz, 2H), 3.72-3.64 (m, 2H), 3.08-3.06 (m, 1H), 3.01 (s, 1H), 2.66-2.62 (m, 2H), 1.95-1.93 (m, 3H), 1.79-1.71 (m, 3H), 1.71-1.59 (m, 3H), 1.50-1.49 (m, 6H), 1.22-1.18 (m, 6H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.62 (s, 1F).

[0401] Example 21: ((2R,3S,5R)-2-((((3-(1-adamantyl)propoxy)carbonyl)oxy)methyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyltetrahydrofuran-3-yl)isobutyrate (compound 21) [ka]

[0402] To a solution of 3-(1-adamantyl)propyl[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (24 mg, 0.047 mmol, 1 equiv.) in pyridine (1 mL) was added 2-methylpropanoyl chloride (0.1 mL, 0.94 mmol, 20 equiv.) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (40 mL). The organic layer was washed with H2O (40 mL×3) and brine (40 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×30 mm×3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 73%-100%, 9 min) to give the title compound (5.6 mg, 20.4% yield) as a white solid. LCMS (ESI) m / z, C 30 H 38 FN5O6: Calculated value 583.28, Found value (M+H) + : 584.3. 1H NMR (400 MHz, CD3CN) δ (ppm) 7.98 (s, 1H), 6.37-6.32 (m, 3H), 5.72-5.69 (m, 1H), 4.49 (d, J = 11.6 Hz, 1H), 4.33 (d, J = 11.6 Hz, 1H), 4.04-3.96 (m, 2H), 3.11-3.05 (m, 1H), 3.01 (s, 1H), 2.68-2.60 (m, 2H), 1.91 (br s, 3H), 1.72-1.61 (m, 6H), 1.57-1.51 (m, 2H), 1.45 (d, J = 2.4 Hz, 6H), 1.22-1.18 (m, 6H), 1.06-1.02 (m, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.62 (s, 1F).

[0403] Example 22: ((2R,3S,5R)-3-[3-(1-adamantyl)propoxycarbonyloxy]-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-2-yl)methyl 3-(1-adamantyl)propyl carbonate (compound 22) [ka]

[0404] To a solution of 3-(1-adamantyl)propan-1-ol (28.0 mg, 0.144 mmol, 3 equiv.) and [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-[(4-nitrophenoxy)carbonyloxymethyl]tetrahydrofuran-3-yl](4-nitrophenyl)carbonate (30 mg, 0.048 mmol, 1 equiv.) in THF (2 mL) was added DMAP (5.88 mg, 0.048 mmol, 1 equiv.). The reaction mixture was stirred at 15° C. for 32 h and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×30 mm×3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 82%-100%, 9 min) to give the title compound (10.1 mg, 28.7% yield) as a white solid. LCMS (ESI) m / z, C 40 H 52 FN5O7: Calculated 733.39, Found (M+H) + : 734.4. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.71 (s, 1H), 6.28-6.05 (m, 3H), 5.37 (t, J = 7.2 Hz, 1H), 4.27 (d, J = 11.6 Hz, 1H), 4.07 (d, J = 11.6 Hz, 1H), 3.91-3.86 (m, 2H), 3.75-3.73 (m, 2H), 2.88-2.86 (m, 1H), 2.78 (s, 1H), 2.48-2.46 (m, 1H), 1.69-1.67 (m, 6H),1.44-1.38 (m, 12H), 1.24-1.19 (m, 16H), 0.87-0.80 (m, 4H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.49 (s, 1F).

[0405] Example 23: ((2R,3S,5R)-3-(1-adamantylmethoxycarbonyloxy)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-2-yl)methyl 1-adamantyl methyl carbonate (compound 23) [ka]

[0406] To a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (35 mg, 0.119 mmol, 1 equiv.) in THF (5 mL) was added DMAP (29.2 mg, 0.239 mmol, 2 equiv.) and 1-adamantylmethyl(2,3,4,5,6-pentafluorophenyl)carbonate (404 mg, 1.07 mmol, 9 equiv.). The mixture was stirred at 15° C. for 40 h and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, elution of 0-4% i-PrOH / DCM at 25 mL / min) to give the title compound (72.8 mg, 90% yield) as a white solid. LCMS (ESI) m / z, C 36 H 44 FN5O7: Calculated 677.32, Found (M+H) + : 678.3. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.98 (s, 1H), 6.38-6.32 (m, 3H), 5.63 (t, J = 5.6 Hz, 1H), 4.44 (d, J = 11.6 Hz, 2H), 3.81 (d, J = 11.6 Hz, 2H), 3.71-3.63 (m, 2H), 3.18-3.11 (m, 1H), 3.05 (s, 1H), 2.77-2.70 (m, 1H), 2.15-2.10 (m, 2H), 2.11-1.96 (m, 4H), 1.77-1.63 (m, 12H), 1.58-1.57 (m, 6H), 1.50-1.49 (m, 6H).19 F NMR (376 MHz, CD3CN) δ (ppm) -52.49 (s, 1F).

[0407] Example 24: ((2R,3S,5R)-2-(1-adamantylmethoxycarbonyloxymethyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-3-yl)ethyl carbonate (compound 24) [ka]

[0408] To a solution of 1-adamantylmethyl[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (15 mg, 0.031 mmol, 1 equiv.) in pyridine (2 mL) was added ethyl carbonochloridate (0.07 mL, 0.74 mmol, 24 equiv.). The mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (15 ml×3), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 67%-97%, 9 min) to give the title compound (2.5 mg, 11% yield) as a white solid. LCMS (ESI) m / z, C 27 H 32 FN5O7: Calculated 557.23, Found (M+H) + : 558.2. 1H NMR (400 MHz, CD3CN) δ (ppm) 7.72 (s, 1H), 6.13-6.07 (m, 3H), 5.40-5.37 (m, 1H), 4.28 (d, J = 11.6 Hz, 1H), 4.10 (d, J = 11.6 Hz, 1H), 4.00-3.96 (m, 2H), 3.46-3.38 (m, 2H), 2.90-2.88 (m, 1H), 2.80 (s, 1H), 2.50-2.48 (m, 1H), 1.69-1.68 (m, 3H), 1.46-1.41 (m, 3H), 1.38-1.24 (m, 3H), 1.26-1.21 (m, 6H), 1.05 (t, J = 7.2 Hz, 3H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.51 (s, 1F).

[0409] Example 25: ((2R,3S,5R)-2-(1-adamantylmethoxycarbonyloxymethyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-3-yl)ethyl carbonate (compound 25) [ka]

[0410] To a solution of 4-(1-adamantyl)butyl[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (20 mg, 0.038 mmol, 1 equiv.) in pyridine (2 mL) was added ethyl carbonochloridate (0.20 mL, 2.09 mmol, 55 equiv.). The mixture was stirred at 0° C. for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (30 ml), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 70%-100%, 9 min) to give the title compound (4.8 mg, 21% yield) as a white solid. LCMS (ESI) m / z, C 30 H 38 FN5O7: Calculated 599.28, Found (M+H) + : 600.3. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.73 (s, 1H), 6.12 (br s, 1H), 6.11-6.07 (m, 2H), 5.41-5.38 (m, 1H), 4.30 (d, J = 11.6 Hz, 1H), 4.10 (d, J = 11.6 Hz, 1H), 4.09-3.98 (m, 2H), 3.82-3.78 (m, 2H), 2.92-2.89(m, 1H), 2.81(s, 1H), 2.50-2.46 (m, 1H), 1.72 (s, 3H), 1.48-1.45 (m, 3H), 1.40-1.37 (m, 3H), 1.32-1.25 (m, 2H), 1.22-1.21 (d, J = 2.4 Hz, 6H), 1.8-1.04 (m, 3H), 1.03-0.97(m, 2H), 0.81-0.77(m, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.55 (s, 1F).

[0411] Example 26: ((2R,3S,5R)-2-[3-(1-adamantyl)propoxycarbonyloxymethyl]-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-3-yl)ethyl carbonate (compound 26) [ka]

[0412] To a solution of 3-(1-adamantyl)propyl[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (20 mg, 0.039 mmol, 1 equiv.) in pyridine (2 mL) was added ethyl carbonochloridate (0.07 mL, 0.74 mmol, 19 equiv.). The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (15 ml), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 67%-97%, 9 min) to give the title compound (1.3 mg, 5.7% yield) as a white solid. LCMS (ESI) m / z, C 29 H 36 FN5O7: Calculated 585.26, Found (M+H) + : 586.3. 1H NMR (400 MHz, CD3CN) δ (ppm) 7.74 (s, 1H), 6.10 (t, J = 6.4 Hz, 3H), 5.40 (t, J = 7.2 Hz, 1H), 4.31(d, J = 11.2 Hz, 1H), 4.15-4.07(d, J = 11.2 Hz, 1H), 4.05-3.95 (m, 2H), 3.85-3.70 (m, 2H), 2.94-2.90 (m, 1H), 2.82 (s, 1H), 2.53-2.45 (m, 1H), 1.70-1.68 (m, 3H), 1.53-1.45 (m, 3H), 1.44-1.37 (m, 3H), 1.36-1.26 (m, 2H), 1.27-1.20 (m, 6H), 1.07 (t, J = 7.2 Hz, 3H), 0.84-0.79 (m, 2H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.54 (s, 1F).

[0413] Example 27: 1-Adamantyl ((2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-3-ethoxycarbonyloxy-2-ethynyl-tetrahydrofuran-2-yl) methyl carbonate (compound 27) [ka]

[0414] To a solution of 1-adamantyl[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (15 mg, 0.032 mmol, 1 equiv.) in pyridine (1 mL) was added ethyl carbonochloridate (0.175 mL, 1.86 mmol, 58 equiv.). The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with water (5 mL) at 0° C., then diluted with DCM (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 57%-87%, 9 min) to give the title compound (5.0 mg, 28.67% yield) as a white solid. LCMS (ESI) m / z, C 26 H 30 FN5O7: Calculated 543.21, Found (M+H) + : 544.0. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.96 (s, 1H), 6.36-6.29 (m, 3H), 5.67-5.63 (m, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.26-4.20 (m, 3H), 3.19-3.12 (m, 1H), 3.03 (s, 1H), 2.75-2.68 (m, 1H), 2.14-2.11 (m, 5H), 1.95-1.93 (m, 2H), 1.90-1.88 (m, 2H), 1.64 (s, 6H), 1.32-1.27 (m, 3H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.48 (s, 1F).

[0415] Example 28: ((2R,3S,5R)-2-(1-adamantyloxycarbonyloxymethyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-tetrahydrofuran-3-yl) 2-methylpropanate (compound 28) [ka]

[0416] To a solution of 1-adamantyl[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (15 mg, 0.032 mmol, 1 equiv.) in pyridine (1 mL), 2-methylpropanoyl chloride (0.2 mL, 1.92 mmol, 60 equiv.) was added. The mixture was stirred at 0° C. for 1 h. The resulting mixture was diluted with EtOAc (30 mL), then washed with H2O (20 mL×2), brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 66%-99%, 9 min) to give the title compound (2.6 mg, 15.0% yield) as a white solid. LCMS (ESI) m / z, C 27 H 32 FN5O6: Calculated value 541.23, Found value (M+H) + : 542.0. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.98 (s, 1H), 6.37-6.29 (m, 3H), 5.74-5.71 (m, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.21 (d, J = 11.6 Hz, 1H), 3.13-3.06 (m, 1H), 3.01 (s, 1H), 2.68-2.60 (m, 2H), 2.13-2.09 (m, 6H), 2.01-1.96 (m, 3H), 1.64 (br s, 6H), 1.22-1.18 (m, 6H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.58 (s, 1F).

[0417] Example 29: (1R,13R,15R)-15-(6-amino-2-fluoro-9H-purin-9-yl)-13-ethynyl-2,9,11,14-tetraoxabicyclo[11.3.0]hexadecane-3,10-dione (compound 29) [ka]

[0418] Preparation of tert-butyl 6-[[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]hexanoate [ka]

[0419] To a solution of [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl(4-nitrophenyl)carbonate (150 mg, 0.327 mmol, 1 equiv.) in THF (10 mL) was added DMAP (4.03 mg, 0.033 mmol, 0.1 equiv.) and tert-butyl 6-hydroxyhexanoate (185 mg, 0.982 mmol, 3 equiv.). The mixture was stirred at 15° C. for 16 h and then concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, elution with 0-3% MeOH / DCM at 22 mL / min) to afford tert-butyl 6-[[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]hexanoate (60 mg, 36% yield) as a pale yellow gum.

[0420] Preparation of 6-[[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]hexanoic acid [ka]

[0421] To a solution of tert-butyl 6-[[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]hexanoate (90 mg, 0.177 mmol, 1 equiv.) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 15° C. for 16 h and then concentrated. The resulting residue was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to give 6-[[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]hexanoic acid (40 mg, 50% yield) as a yellow gum.

[0422] Preparation of (1R,13R,15R)-15-(6-amino-2-fluoro-purin-9-yl)-13-ethynyl-2,9,11,14-tetraoxabicyclo[11.3.0]hexadecane-3,10-dione [ka]

[0423] To a solution of 6-[[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]hexanoic acid (40 mg, 0.089 mmol, 1 equiv.) in MeCN (3 mL) and DCM (3 mL) was added TCFH (69.9 mg, 0.248 mmol, 2.8 equiv.) and 1-methylimidazole (24.1 mg, 0.292 mmol, 3.3 equiv.). The mixture was stirred at 15° C. for 40 h and then concentrated. The resulting residue was purified by preparative HPLC (NH4HCO3 condition; column: Phenomenex Gemini-NX 80×30 mm×3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 31%-61%, 9 min) to give the title compound (2.3 mg, 6.0% yield) as a white solid. LCMS (ESI) m / z, C 19 H 20 FN5O6: Calculated 433.14, Found (M+H) + : 434.1. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (s, 1H), 6.33-6.31 (m, 3H), 5.83-5.79 (m, 1H), 4.76 (d, J = 10.8 Hz, 1H), 4.58-4.57 (m, 1H), 4.16 (d, J = 11.2 Hz, 1H), 4.07-4.05 (m, 1H), 3.08-3.04 (m, 2H), 2.61-2.51 (m, 1H), 2.50-2.35 (m, 1H), 2.24-2.19 (m, 1H), 1.75-1.65 (m, 4H), 1.68-1.52 (m, 1H), 1.47-1.29 (m, 1H). 19 F NMR (376 MHz, CD3CN) δ (ppm) -52.44 (s, 1F).

[0424] Example 30: (6R,8R,10R)-8-(6-amino-2-fluoro-9H-purin-9-yl)-10-ethynyl-3,5,9,12,14-pentaoxatricyclo[14.4.0.06,10]icosane-4,13-dione (compound 30) [ka]

[0425] Preparation of [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-[(2,3,4,5,6-pentafluorophenoxy)carbonyloxymethyl]tetrahydrofuran-3-yl](2,3,4,5,6-pentafluorophenyl)carbonate [ka]

[0426] To a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (100 mg, 0.341 mmol, 1 equiv.) in THF (10 mL) was added DMAP (8.3 mg, 0.068 mmol, 0.2 equiv.) and bis(2,3,4,5,6-pentafluorophenyl)carbonate (282 mg, 0.716 mmol, 2.1 equiv.). The mixture was stirred at 10° C. for 6 h and then concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, elution with 0-5% MeOH / DCM gradient at 50 mL / min) to give [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-[(2,3,4,5,6-pentafluorophenoxy)carbonyloxymethyl]tetrahydrofuran-3-yl](2,3,4,5,6-pentafluorophenyl)carbonate (80 mg, 32.9% yield) as a white solid.

[0427] Preparation of (6R,8R,10R)-8-(6-amino-2-fluoro-purin-9-yl)-10-ethynyl-3,5,9,12,14-pentaoxatricyclo[14.4.0.06,10]icosane-4,13-dione [ka]

[0428] To a solution of [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-2-[(2,3,4,5,6-pentafluorophenoxy)carbonyloxymethyl]tetrahydrofuran-3-yl](2,3,4,5,6-pentafluorophenyl)carbonate (80 mg, 0.112 mmol, 1 equiv.) in THF (12 mL) was added DMAP (13.7 mg, 0.112 mmol, 1 equiv.) and [(1R,2S)-2-(hydroxymethyl)cyclohexyl]methanol (16.2 mg, 0.112 mmol, 1 equiv.). The mixture was stirred at 10° C. for 44 h and then concentrated. The residue was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to give (6R,8R,10R)-8-(6-amino-2-fluoro-purin-9-yl)-10-ethynyl-3,5,9,12,14-pentaoxatricyclo[14.4.0.06,10]icosane-4,13-dione (2.8 mg, 5.1% yield) as a white solid. LCMS (ESI) m / z, C 22 H 24 FN5O7: Calculated 489.17, Found (M+H) + : 490.2. 1 H NMR (400 MHz, CD3CN) δ (ppm) 7.95 (d, J = 9.6 Hz, 1H), 6.36-6.31 (m, 2H), 6.14-6.10 (m, 0.5H), 5.63-5.61 (m, 0.5H), 4.78 (d, J = 11.2 Hz, 0.5H), 4.57-4.37 (m, 2.5H), 4.22-4.15 (m, 2H), 4.01-3.91 (m, 1H), 3.25-3.17 (m, 0.5H), 3.03 (d, J = 3.2 Hz, 1H), 2.98-2.91 (m, 0.5H), 2.82-2.74 (m, 0.5H), 2.67-2.61 (m, 0.5H), 2.47 (br s, 0.5H), 2.21 (br s, 0.5H), 1.78-1.57 (m, 2.5H), 1.54-1.23 (m, 7.5H). 19F NMR (376 MHz, CD3CN) δ (ppm) -52.45 (s, 1F).

[0429] Example 31: Conversion and stability of adenosine derivative prodrugs

[0430] The stability of the prodrug and the conversion of the prodrug to the parent EFdA (formula T-1A) were measured in both plasma and liver S9 assays and the data are shown in Table 2.

[0431] plasma stability Pooled frozen plasma was thawed in a 37°C water bath prior to the experiment. Plasma was centrifuged at 4000 rpm for 5 min to remove any clots. pH was adjusted to 7.4 ± 0.1 if necessary.

[0432] Preparation of test compounds and positive control (propantheline bromide): 1 mM intermediate solutions were prepared by diluting 10 μL of stock solution with 90 μL of MeOH. Positive control 1 mM intermediate propantheline was prepared by diluting 10 μL of stock solution with 90 μL of ultrapure water. 100 μM dosing solutions were prepared by diluting 20 μL of intermediate solution (1 mM) with 180 μL of MeOH. 98 μL of blank plasma was spiked with 2 μL of dosing solution (100 μM) to achieve a final concentration of 2 μM in duplicate, and samples were incubated at 37° C. in a water bath. 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 precipitate proteins and mixed thoroughly. The sample plate was centrifuged at 4,000 rpm for 10 minutes. An aliquot (100 μL) of the supernatant was transferred from each well to a separate plate. Data Analysis: The % remaining of the test compound after incubation in plasma was calculated using the following formula: % remaining = 100 x (PAR at a given incubation 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. The designated incubation time points are T0 (0 min), Tn (n = 0, 10, 30, 60, 120 min).

[0433] Liver S9 Stability Intermediate solution: 5 μL of compound or control (7-ethoxycoumarin) from stock solution (10 mM) diluted with 495 μL of MeOH (concentration: 100 μM, 1% DMSO, 99% MeOH). Stop solution: cold ACN (containing 100 ng / mL tolbutamide and labetalol as internal standards). Add 2 μL per well of working solution of test compound or control to all plates (T0, T5, T10, T20, T30, T60, NCF60) except matrix blank. Terminate T0 plate by adding 600 μL / well of stop solution (cooled at 4 °C, containing 100 ng / mL tolbutamide / 100 ng / mL labetalol) and place it on ice. Dispense S9 solution at 840 μL / well into 96 plates as reservoirs according to the plate map. Then add 100 μL / well to all plates by Apricot. Incubate S9 solution and compounds at 37°C for about 10 min, except for NCF60 and T0. After adding S9 solution and 98μL LPB buffer to NCF60, incubate at 37°C without preheating and start timer 1. After 60 min, add 600μL / well of stop solution to terminate the reaction. After preheating, dispense cofactors at 760μL / well according to the plate map into the 96 plates as reservoirs. Then add 98μL / well to all plates by Apricot to start the reaction. Incubate at 37°C, start timer 2, and add 600μL / well of stop solution (cooled at 4°C, containing 100ng / mL tolbutamide and labetalol) to terminate the reaction. Centrifuge the samples at 4000rpm for 20 min. While centrifuging, 300 μL of HPLC water was loaded onto eight new 96-well plates, and then 100 μL of the supernatant was transferred, mixed with LC / MS / MS water, and transported to Bioanalytical Services for LC-MS / MS analysis. Using the first-order kinetic equation, t 1 / 2 and calculate CL: First order kinetic equation:

number

[0434] The stability results of exemplary compounds in human plasma and human liver S9 are listed in Table 2 below. [Table 3]

[0435] Example 32: Plasma exposure following intramuscular administration of prodrugs to cynomolgus monkeys The pharmacokinetics of EFdA and compounds 2, 7, 10, and 12 were studied in cynomolgus monkeys following a single intramuscular (IM) dose of 10 mg / kg.

[0436] Formulation: The prodrug was formulated as a homogeneous, opaque suspension at 100 mg / mL in 20% PEG400, 10% Solutol, and 88% water within 0.5 hours prior to administration.

[0437] Dose Administration and Sample Collection: The in-life phase of this study was conducted at WuXi Apptec(Suzhou) Co., Ltd, Suzhou, China, following standard animal procedures of the WuXi Institutional Animal Care and Use Committee (IACUC), in accordance with the Animal Welfare Act, Guide for the Care and Use of Laboratory Animals, and in line with IACUC guidelines approved by the IACUA Committee. Non-naive male cynomolgus monkeys (3 + / - 1 kg) were used in the study. Each drug was administered as a single dose of 10 mg / kg by intramuscular injection (0.1 ml / kg). Plasma samples were collected at 0 (pre-dose), 15 and 30 min, 1, 2, 4, 7, 12, 24, 48, 72, 96, 120, 144, and 168 h after dosing. Blood (approximately 0.9 mL) was immediately processed for plasma immediately after collection using commercially available ice-cold K2EDTA tubes pre-aliquoted with concentrated cocktail blood stabilizer (1:9 ratio) by centrifugation at 3,500 rpm for 10 min at 5° C. Plasma samples were frozen and kept at −70° C. until analysis.

[0438] Measurement of EFdA and prodrugs in plasma: Briefly, plasma (20 μL) was mixed with 200 μl of acetonitrile containing the internal standard to precipitate proteins. Consistent with the sample collection procedure, the same cocktail protocol was also added to stabilize the prodrugs in standard and QC samples.

[0439] Bioanalysis: A Sciex API-6500 plus triple quadrupole mass spectrometer coupled with a Waters ACQUITY UPLC system (Milford, MA) was used for quantitative analysis of plasma samples. The column was a Waters HSS T3 column (2.1 × 50 mm, 1.8 mm). The mobile phases used were: A, 0.1% formic acid in water; B, 0.1% formic acid in acetonitrile. The flow rate was 0.6 mL / min with a total run time of 2.0 min. The UPLC gradient started at 95% A / 5% B followed by a linear gradient increasing to 30% B in 0.7 min, after which the gradient was increased to 98% mobile phase B in the next 0.5 min, then held for 0.6 min before decreasing to 5% mobile phase B within the next 0.2 min. Detection of the prodrugs and EFdA was achieved using positive ion electrospray mass spectrometry mode using unit resolution mode. Both prodrug and EFdA were quantified using multiple reaction monitoring (MRM) mode. Peak areas were integrated by the Sciex program Analyst®, version 1.6.3. Concentrations were determined by weighted (1 / x2) linear regression of peak area ratios (peak area of ​​EFdA / peak area of ​​corresponding IS) to normal concentrations of plasma calibration standards. Calculations were performed on unrounded numbers. Overall, Analyst® determined the precision and accuracy of the calibration standards and QC samples.

[0440] Pharmacokinetic calculations: Noncompartmental (NCA) analysis of individual plasma concentration-time data of EFdA and prodrug was performed using the WinNonlin module of the Phoenix PK / PD platform (Certara Inc., Princeton, NJ 08540). Calculations were performed before rounding, and nominal sampling times were used for pharmacokinetic analysis. Exposure was measured as the area under the plasma concentration curve from 0 to 168 hours (AUC 0-168h ) AUC values ​​were calculated using the linear trapezoidal rule.

[0441] Plasma Concentrations: The results of the PK studies are shown in Table 3 and Figures 1-4. These data demonstrate in vivo that compounds 2, 7, 10, and 12 can be readily delivered into muscle and efficiently release EFdA in vivo with minimal to low levels of prodrug detected in the systemic circulation. [Table 4]

Claims

1. An adenosine derivative having the structure of formula (I), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: 【Chemistry 1】 (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C １－１０ alkylene)-J-, -(CO)-G-(C ２－１０ alkenylene)-J-, and -(CO)-G-(C ２－１０ alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, and -(CO)-G-; R １ is H, C １－２０ Alkyl, C １－２０ Haloalkyl, C １－２０ Alkoxy, C ２－２０ Alkenyl, C ２－２０ Alkynyl, C ３－２０ selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R ２ is H, C １－２０ Alkyl, C １－２０ Haloalkyl, C １－２０ Alkoxy, C ２－２０ Alkenyl, C ２－２０ Alkynyl, C ３－２０ is selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl, where R １ and R ２ At least one of is not H, R １ and R ２ together with the atoms to which they are attached form a 3- to 25-membered heterocyclic ring, R ３ is H, -(CO)-GC １－１０ Alkyl, C １－１０ Alkyl, C １－１０ Haloalkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

2. A is a bond, -(CO)-, -(CO)-G-, or -(CO)-G-(C １－５ 2. The adenosine derivative of claim 1, selected from the group consisting of: alkylene)-J-.

3. A is -(CO)-G- or -(CO)-G-(C １－５ 3. The adenosine derivative according to claim 1, wherein the adenosine derivative is a substituted or unsubstituted alkylene)-J-.

4. E is a bond, -(CO)-G-, or -(CO)-G-(C １－５ The adenosine derivative according to any one of claims 1 to 3, wherein the adenosine derivative is a substituted or unsubstituted alkylene)-J-.

5. The adenosine derivative according to any one of claims 1 to 4, wherein E is a bond.

6. The adenosine derivative according to any one of claims 1 to 5, wherein G is a bond or O.

7. The adenosine derivative according to any one of claims 1 to 6, wherein J is a bond or O.

8. The adenosine derivative according to any one of claims 1 to 7, wherein G is O and J is a bond.

9. R １ But, H, C １－５ The adenosine derivative according to any one of claims 1 to 8, which is alkyl or adamantyl.

10. R １ The adenosine derivative according to any one of claims 1 to 9, wherein is H.

11. R ２ But, H, C １－５ The adenosine derivative according to any one of claims 1 to 10, which is alkyl or adamantyl.

12. R ２ but 【Chemistry 2】 and R 4 is H, C 1-5 alkyl, C 1-5 haloalkyl, or C 1-5 alkoxy; The adenosine derivative according to any one of claims 1 to 11.

13. R １ and R ２ The adenosine derivative according to any one of claims 1 to 8, wherein, together with the atoms to which they are attached, form a 6- to 15-membered heterocycle.

14. R ３ is H, -(CO)-C １－５ Alkyl, -(CO)-O-C １－５ Alkyl, or C １－５ The adenosine derivative according to any one of claims 1 to 13, which is alkyl.

15. R ３ The adenosine derivative according to any one of claims 1 to 14, wherein is H.

16. 2. The adenosine derivative of claim 1, wherein the adenosine derivative is a compound of formula (Ie), (If), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof: 【Chemistry 3】 (In the formula, A and E each independently represent a bond, -(CO)-, -(CO)-G-, -(CO)-G-(C １－１０ alkylene)-J-, -(CO)-G-(C ２－１０ alkenylene)-J-, and -(CO)-G-(C ２－１０ alkynylene)-J-; G is selected from the group consisting of a bond, O, NH, and S; J is selected from the group consisting of a bond, O, NH, S, and -(CO)-G-; R １ is H, C １－１０ Alkyl, C １－１０ Haloalkyl, C １－１０ Alkoxy, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－２０ selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R ２ is H, C １－１０ Alkyl, C １－１０ Haloalkyl, C １－１０ Alkoxy, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－２０ selected from the group consisting of cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, and heteroaryl; R ３ is H, -(CO)-OC １－１０ Alkyl, and C １－１０ is selected from the group consisting of alkyl, R ４ is H, C １－１０ Alkyl, C １－１０ Haloalkyl, C １－１０ Alkoxy, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl; R ５ is H, C １－１０ Alkyl, C １－１０ Haloalkyl, C １－１０ Alkoxy, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ is selected from the group consisting of cycloalkyl, 3- to 12-membered heterocycloalkyl, aryl, and heteroaryl.

17. A and E are each independently a bond, -(CO)-, -(CO)-G-, or -(CO)-G-(C １－５ 2. The adenosine derivative of claim 1, selected from the group consisting of: alkylene)-J-.

18. A is -(CO)-G- or -(CO)-G-(C １－５ 18. The adenosine derivative according to claim 17, wherein the adenosine derivative is a substituted or unsubstituted alkylene)-J-.

19. 19. The adenosine derivative of claim 17 or 18, wherein E is a bond.

20. 20. The adenosine derivative according to any one of claims 17 to 19, wherein G is a bond or O.

21. The adenosine derivative according to any one of claims 17 to 20, wherein J is a bond or O.

22. 22. The adenosine derivative according to any one of claims 17 to 21, wherein G is O and J is a bond.

23. R １ and R ２ are each independently H, C １－５ The adenosine derivative according to any one of claims 17 to 22, which is alkyl or adamantyl.

24. R １ The adenosine derivative according to any one of claims 17 to 23, wherein is H.

25. R ２ But, H, C １－５ The adenosine derivative according to any one of claims 17 to 24, which is alkyl or adamantyl.

26. R ２ but 【Chemistry 4】 and R 4 is H, C 1-5 alkyl, C 1-5 haloalkyl, or C 1-5 alkoxy; The adenosine derivative according to any one of claims 17 to 25.

27. R ３ The adenosine derivative according to any one of claims 17 to 26, wherein is H.

28. The adenosine derivative is 【Chemistry 5-1】 【Chemistry 5-2】 2. The adenosine derivative of claim 1, selected from the group consisting of: and pharma- ceutically acceptable salts, tautomers, or solvates thereof.

29. The adenosine derivative, 【Chemistry 6】 2. The adenosine derivative of claim 1, selected from the group consisting of: and pharma- ceutically acceptable salts, tautomers, or solvates thereof.

30. 30. The adenosine derivative of any one of claims 1 to 29, wherein the adenosine derivative comprises in vivo reverse transcriptase inhibitor activity, in vivo reverse transcriptase chain terminator activity, in vivo DNA translocation inhibitor activity, or a combination thereof.

31. A pharmaceutical composition comprising the adenosine derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 30, and a pharma- ceutically acceptable carrier.

32. 32. The pharmaceutical composition of claim 31, wherein the pharmaceutical composition is suitable for oral administration.

33. 32. The pharmaceutical composition of claim 31, wherein the pharmaceutical composition is suitable for parenteral administration.

34. 34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition is a long-acting injectable composition.

35. 35. The pharmaceutical composition of claim 33 or 34, wherein the pharmaceutical composition is suitable for intramuscular or subcutaneous injection.

36. The pharmaceutical composition according to any one of claims 31 to 35, wherein the pharmaceutical composition is in a liquid dosage form.

37. 37. The pharmaceutical composition of claim 36, wherein the liquid dosage form is a solution, emulsion, or liquid suspension.

38. The pharmaceutical composition according to any one of claims 31 to 35, wherein the pharmaceutical composition is in a solid dosage form.

39. 39. The pharmaceutical composition of claim 38, wherein the solid dosage form is a tablet, capsule, granule, powder, sachet, reconstitutable powder, inhalable dry powder, or chewable.

40. The pharma- ceutically acceptable carrier may be polyethylene glycol (PEG), sulfobutyl ether b-cyclodextrin (SRBCD), acacia, animal oil, benzyl alcohol, benzyl benzoate, calcium stearate, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, cyclodextrin, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glycerol stearate, glyceryl monooleate, glyceryl monostearate, water, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin, glyceryl stearate, glyceryl monooleate, glyceryl monostearate, water, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin, glyceryl monostearate ... stearin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohol, lecithin, medium chain triglycerides, metal soaps, methylcellulose, mineral oil, sodium dihydrogen phosphate hydrate, monoethanolamine, oleic acid, polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer (poloxamer), polyoxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, polysorbate, polyoxyethylene (20) sorbitan monolaurate (Tween 40. The pharmaceutical composition of any one of claims 31 to 39, comprising an aqueous solution of at least one of: polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium dihydrogen phosphate, sodium phosphate dibasic, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth, triethanolamine, vegetable oil, water, xanthan gum, or any combination thereof.

41. 41. The pharmaceutical composition of claim 40, wherein the pharma- ceutically acceptable carrier comprises polyethylene glycol 400.

42. 42. The pharmaceutical composition of any one of claims 31-41, further comprising one or more additional antiviral agents selected from lenacapavir, atazanavir, atazanavir sulfate, bictegravir, cabotegravir, darunavir, dolutegravir, doravirine, efavirenz, tenofovir disoproxil fumarate, tenofovir alafenamide, etravirine, a combination of darunavir and cobicistat, maraviroc, rilpivirine, MK-8507, or combinations thereof.

43. 43. The pharmaceutical composition of claim 42, wherein the one or more additional antiviral agents is lenacapavir, cabotegravir, or a prodrug thereof.

44. A pharmaceutical composition of any one of claims 31 to 43 for use in the treatment of HIV infection.

45. A pharmaceutical composition according to any one of claims 31 to 43 for use in the prevention of HIV infection.

46. The pharmaceutical composition of claim 44 or 45, wherein the HIV infection is caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with an M184V mutation, HIV with K65R, or multidrug-resistant HIV.

47. The pharmaceutical composition of any one of claims 44 to 46, wherein the pharmaceutical composition is administered orally.

48. The pharmaceutical composition of any one of claims 44 to 46, wherein the pharmaceutical composition is administered parenterally.

49. 49. The pharmaceutical composition of claim 48, wherein said parenteral administration is by intramuscular or subcutaneous injection.

50. 50. The pharmaceutical composition of any one of claims 44 to 49, wherein administration of the pharmaceutical composition results in a more sustained plasma concentration of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

51. 50. The pharmaceutical composition of any one of claims 44 to 49, wherein administration of said pharmaceutical composition results in higher plasma concentrations of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

52. 52. The pharmaceutical composition of claim 51, wherein administration of the pharmaceutical composition results in a plasma concentration of EFdA that is at least about 10%, 20%, 30%, 40%, or 50% higher when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

53. 50. The pharmaceutical composition of any one of claims 44 to 49, wherein administration of said pharmaceutical composition results in a more prolonged release of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

54. 54. The pharmaceutical composition of any one of claims 44 to 53, wherein administration of said pharmaceutical composition results in a higher AUC of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

55. 55. The pharmaceutical composition of claim 54, wherein administration of the pharmaceutical composition results in at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher AUC of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions.

56. Administration of the pharmaceutical composition results in a higher C of EFdA when compared to administration of a dose-equivalent amount of EFdA under the same conditions. ｍａｘ The pharmaceutical composition according to any one of claims 44 to 49,

57. Administration of the pharmaceutical composition results in at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher C of EFdA compared to administration of a dose equivalent of EFdA under the same conditions. ｍａｘ 57. The pharmaceutical composition of claim 56, 58. The pharmaceutical composition of any one of claims 44 to 57, further comprising an effective dose of one or more additional antiviral agents selected from lenacapavir, atazanavir, atazanavir sulfate, bictegravir, cabotegravir, darunavir, dolutegravir, doravirine, efavirenz, tenofovir disoproxil fumarate, tenofovir alafenamide, etravirine, a combination of darunavir and cobicistat, rilpivirine, and MK-8507, or combinations thereof.

59. The pharmaceutical composition of claim 58, wherein the one or more additional antiviral agents are lenacapavir, cabotegravir, or a prodrug thereof.

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