Adenosine derivatives and pharmaceutical compositions containing the same

Abstract

The examples of this specification disclose an adenosine derivative prodrug having in vivo reverse transcriptase inhibitor activity. The examples of this specification also relate to a pharmaceutical composition comprising an adenosine derivative, which can be used to treat HIV infection or RNA virus infection.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 879,414, filed July 27, 2019, under Title 35, Section 119(e) of the United States Code, which is incorporated herein by reference in its entirety for all purposes. Technical Field

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

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

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

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

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

[0008] A common problem arising from the use of antiretroviral inhibitory compounds to treat HIV infection is viral resistance to the inhibitors. This resistance is usually the result of mutations occurring in the reverse transcriptase region of the pol gene. Continued use of antiviral compounds, such as inhibitory compounds, to prevent HIV infection will inevitably lead to the emergence of new drug-resistant HIV strains. Therefore, there is a persistent need for novel RT inhibitors that are effective against HIV strains, including mutant HIV and multidrug-resistant HIV strains. Summary of the Invention

[0009] This 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, this disclosure provides adenosine derivatives or stereoisomers having formula (1), pharmaceutically acceptable salts, tautomers, or solvates:

[0011]

[0012] in,

[0013] R 1 R1' and R 2 Each is independently -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 or -ZL 4 -

[0014] R 5 , where R 1 and R 2 At least one of them is not -H;

[0015] R 3 R 3' and R 4 Each of them is independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0016] R 5 yes:

[0017]

[0018] R 6 It is -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3-to-10-membered heterocyclic alkyl, aryl or heteroaryl;

[0019] -L1 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkylene)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5 -(C2-C10 imenoyl)-SR 5 -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL 2 -OR 5 -C(O)OL 2 -SR 5 -C(O)OL 2 -C(O)OR 5 -C(O)OL 2 -C(O)N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -OR 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -SR 5 -C(O)N(R) 7 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )-R 5 -C(O)N(R) 7 )-L 2 -OR 5 -C(O)N(R) 7 )-L 2 -SR 5 -C(O)N(R) 7 )-L 2-C(O)OR 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-R 5 -、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -OR 5 or -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -SR 5 ;

[0020] -Z- represents divalent -C(O)-, -C(O)O-, or -C(O)N(R). 7 )-;

[0021] -L 4 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkyl)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5or -(C2-C10 imidene)-SR 5 ;

[0022] R 7 R 8 and R 9 Each is independently -H, C1-C10 alkyl, or C2-C10 alkenyl;

[0023] L 2 and L 3 Each is -(C1-C10 alkylene)- or -(C2-C10 alkenylene)-; and

[0024] X is a halogen atom.

[0025] In some implementations, the adenosine derivative is selected from the group consisting of:

[0026] Equation (2-A):

[0027]

[0028] Equation (3-A):

[0029]

[0030] Equation (4-A):

[0031]

[0032] Equation (5-A):

[0033]

[0034] Equation (6-A):

[0035]

[0036] Equation (7-A):

[0037]

[0038] Equation (8-A):

[0039]

[0040] Equation (4-C):

[0041]

[0042] Or its stereoisomers, pharmaceutically acceptable salts, tautomers or solvates.

[0043] In some embodiments of formula (1), the adenosine derivative comprises R 1 R1' R 2 Alternatively, the structure can be selected from Equation 9-24:

[0044]

[0045]

[0046] This disclosure further relates to a pharmaceutical composition comprising one or more of the adenosine derivatives disclosed herein, pharmaceutically acceptable salts, stereoisomers, or combinations thereof, and one or more pharmaceutically acceptable carriers.

[0047] This disclosure also relates to a method for treating a disease (e.g., acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV)), the method comprising administering to a subject in need an effective dose of a pharmaceutical composition comprising one or more adenosine derivatives disclosed herein.

[0048] This disclosure also relates to a method for preventing infection, the method comprising administering to a subject in need an effective dose of a pharmaceutical composition comprising one or more adenosine derivatives disclosed herein.

[0049] By incorporating via reference

[0050] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference. Attached Figure Description

[0051] Figures 1A-1I Exemplary chemical structures of adenosine derivatives having halogen atoms and having formulas (1)-(8) and 4-B are shown.

[0052] Figures 2A-2I An exemplary chemical structure of an adenosine derivative having fluorine atoms and having the formula (1-A)-(8-A) and 4-C is shown.

[0053] Figures 3A-3J Exemplary chemical structures of adenosine derivatives having -R5, -L1-R5 or -Z-L4-R5 groups are shown.

[0054] Figure 4A – Figure 4F Exemplary chemical structures of adenosine derivatives having -L1-R5 or -Z-L4-R5 groups of formula (19)-(24) are shown.

[0055] Figures 5A-5B It shows 4'-ethynyl-2-halogen-2'-deoxyadenosine ( Figure 5AFormula (T-1) and 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) Figure 5B The exemplary chemical structure of formula (T-1A) is shown. Detailed Implementation

[0056] The following is a more detailed description of various concepts and implementation schemes of the methods and apparatus according to this disclosure. It should be understood that the various aspects of the subject matter described above and discussed in more detail below can be implemented in any of a variety of ways, as the subject matter is not limited to any particular implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes.

[0057] As used herein, the term "alkyl" or "alkyl group" refers to a fully saturated straight-chain or branched hydrocarbon chain having one to twelve carbon atoms and connected to the remainder of the molecule by single bonds. This includes alkyl groups containing any number of carbon atoms from 1 to 12. Alkyl groups containing a maximum of 12 carbon atoms are C1-C1. 12 Alkyl groups, those containing a maximum of 10 carbon atoms, are C1-C6. 10 Alkyl groups, specifically C1-C6 alkyl groups containing up to six carbon atoms, and C1-C5 alkyl groups containing up to five carbon atoms, are defined as alkyl groups. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include all the portions described above for C1-C5 alkyl groups, but also include C6 alkyl groups. C1-C 10 Alkyl groups include all the portions described above for C1-C5 and C1-C6 alkyl groups, but also include C7, C8, C9, and C6 alkyl groups. 10 Alkyl groups. Similarly, C1-C 12 Alkyl groups include all the foregoing portions, but also include C. 11 and C 12 Alkyl group. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in the specification, the alkyl group may optionally be substituted.

[0058] As used herein, the term "alkylene" or "alkylene chain" refers to a fully saturated straight-chain or branched divalent hydrocarbon chain group having one to twelve carbon atoms. C1-C 12Non-limiting examples of alkylenes include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by single bonds and to free radicals (such as those described herein) by single bonds. The connection points between the alkylene chain and the rest of the molecule, as well as with free radicals, can be one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkylene chain may optionally be substituted.

[0059] As used herein, the term "alkenyl" or "alkenyl group" refers to a straight-chain or branched aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having a number of carbon atoms within a specific range. For example, "C2-C10 alkenyl" (or "C2-C...)" 10 "Alkenyl" refers to a straight-chain or branched alkenyl group, or any of its isomers, having 2 to 10 carbon atoms. In another example, the C2-C6 alkenyl group may be 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and vinyl (or vinyl). The alkylene chain may be attached to the rest of the molecule and to a free radical via one or any two carbons within the chain. Unless otherwise specified in the specification, the alkylene chain may optionally be substituted.

[0060] As used herein, the term "alkenyl" or "alkenyl chain" refers to an unsaturated straight-chain or branched divalent hydrocarbon chain group having one or more olefins and two to twelve carbon atoms. (C2-C) 12 Non-limiting examples of alkenyl groups include vinylene, propyleneene, n-butene, etc. The alkenyl chain is connected to the rest of the molecule by single bonds and to free radicals (such as those described herein) by single bonds. The connection points of the alkenyl chain to the rest of the molecule and to the free radicals can be one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkenyl chain may optionally be substituted.

[0061] As used herein, the term "cycloalkyl" refers to a stable, non-aromatic, fully saturated monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, which may include fused or bridged ring systems having three to twenty carbon atoms (e.g., three to ten carbon atoms) and being linked to the rest of the molecule by single bonds. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. In some embodiments, "cycloalkyl" refers to any monocyclic alkane having a number of carbon atoms within a specified range. For example, "C3-C10 cycloalkyl" (or "C3-C... 10"Cycloalkyl" refers to a monocyclic alkyl group of an alkane having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specifically stated in the specification, the cycloalkyl group may optionally be substituted.

[0062] As used herein, the terms "heterocyclic alkyl", "heterocyclic ring" or "heterocycle" refer to a saturated or partially saturated 3- to 20-membered ring consisting of 2 to 19 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, connected by single bonds to the remainder of the molecule. Unless otherwise specifically stated in the specification, heterocyclic alkyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl group may optionally be oxidized, for example to form an N-oxide, sulfoxide, or sulfone, and / or the nitrogen atom may optionally be quaternized, for example to form a quaternary ammonium cation. Examples of such heterocyclic alkyl groups include, but are not limited to, dioxolane, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, etc. Isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidyl, oxazolyl, piperidinyl, piperazine, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, trithiazolyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In some embodiments, "3- to 10-membered heterocyclic alkyl" refers to a cycloalkyl group containing one or more heteroatoms selected from the group consisting of N, O, and S. In some embodiments, "heterocyclic alkyl," "heterocyclic ring," or "heterocycle" refers to a 3- to 10-membered ring structure having a carbon atom and one or more heteroatoms selected from N, O, S, or combinations thereof as members of the ring structure. Unless otherwise specifically stated in the specification, heterocyclic alkyl groups may optionally be substituted and include saturated and / or unsaturated rings.

[0063] As used herein, the term “halogen” (or “halogenated group”) refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I)).

[0064] As used herein, the term "aryl" refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, which is connected to the remainder of the molecule by a single bond. For the purposes of this disclosure, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, those derived from anthracene, acenaphthene, phenanthrene, anthracene, azulene, benzene, etc. Aryl groups of fluoranthene, fluorene, asymmetric indole, symmetric indole, indene, indene, naphthalene, phenanthene, pleiadene, pyrene, and triphenylene. In some embodiments, "aryl" refers to a phenyl group or one or more fused cyclic hydrocarbon ring systems in which at least one ring is aromatic. Unless otherwise specified in the specification, "aryl" may optionally be substituted.

[0065] As used herein, the term "heteroaryl" refers to a 5- to 20-membered ring system comprising a hydrogen atom, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring connected to the remainder of the molecule by a single bond. For the purposes of this disclosure, a heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl may optionally be oxidized, for example to form an N-oxide, sulfoxide, or sulfone, and / or the nitrogen atom may optionally be quaternized, for example to form a quaternary ammonium cation. Non-limiting examples of heteroaryl groups include pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, triazolyltriazolyl (i.e., 1,2,3-triazolyl or 1,2,4-triazolyl), tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl (i.e., 1,2,3-, 1,2,4-, 1,2,5-(furazanyl) or 1,3,4-isomer), oxtriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-membered heterobicyclic fused ring systems include, for example, benzofuranyl, indolyl, indazole, naphridinyl, isobenzofuranyl, benzopiperidinyl, benzoisooxazolyl, benzooxazolyl, chromenyl, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxazolyl, benzopiperidinyl, benzoisooxazolyl, benzooxazolyl, chromanyl, isochromyl, benzothiophenyl, benzofuranyl, imidazo[1,2-a]pyridyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazole, indololinyl, isoindololinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, and 2,3-dihydrobenzo-1,4-dioxinyl. Unless otherwise specified in the specification, heteroaryl groups may be optionally substituted.

[0066] It should be understood that, unless explicitly stated to the contrary in a particular context, any of the various cyclic rings and ring systems described herein may be attached to the remainder of the compound at any ring atom (i.e., any carbon atom or any heteroatom), provided that such attachment is chemically permissible.

[0067] As used herein, the term “substituted” means any group described herein (e.g., alkyl, alkenyl, alkoxy, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclic and / or heteroaryl) in which at least one hydrogen atom is replaced by a bond with a non-hydrogen atom, the non-hydrogen atom being such as, but not limited to, halogen atoms such as F, Cl, Br and I; oxygen atoms in groups such as hydroxyl groups, alkoxy groups and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides and enamines; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the aforementioned groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double or triple bond) with a heteroatom, wherein the heteroatom is oxygen in groups such as oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile groups. For example, "substituted" includes any of the aforementioned groups in which one or more hydrogen atoms are replaced by a group with the following group: -NR g R h -NR g C(=O)R h -NR g C(=O)NR g R h -NR g C(=O)OR h -NR g SO2R h -OC(=O)NR g R h -OR g -SR g -SOR g -SO2R g ,、-OSO2R g -SO2OR g =NSO2R g and -SO2NR g R h "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by the following group: -C(=O)R g -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NR g R hIn the foregoing, R g and R h They are the same or different, and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond with the following groups: amino, cyano, hydroxyl, imino, nitro, oxo, thio, halo, alkyl, alkenyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl groups. Furthermore, each of the above substituents may optionally be replaced by one or more of the above substituents.

[0068] As used herein, the term "isomer" refers to structural isomers, such as groups or atoms located at different positions in a molecule; stereoisomers, such as chiral isomers, enantiomers, diastereomers, and cis / trans isomers; and tautomers, such as amino isomers, imino isomers, or combinations thereof. In a non-limiting example, the adenosine derivatives of this disclosure may have amino isomers, imino isomers, or combinations thereof. In another non-limiting example, where a -OH substituent is permitted on a heteroaromatic ring and keto-enol tautomerism may be present, it should be understood that the substituent may actually be present entirely or partially as an oxo group (=O). Mixtures of isomers may also be suitable. Mixtures of isomers may contain all proportions of the corresponding isomers. Salts of isomers may also be suitable. The adenosine derivatives of this disclosure may include their isomers, one or more of their salts, one or more of their solvates (including hydrates), their solvated salts, or mixtures thereof. Absolute stereochemistry or isomer configuration can be determined by X-ray crystallography, vibrational circular dichroism (VCD) spectroscopy, or a combination thereof.

[0069] Adenosine derivatives can be identified by names based on the nomenclature recommended by the International Union of Pure and Applied Chemistry (IUPAC) or by nucleoside-based names. Adenosine derivatives can also be identified by their chemical structure diagrams. Unless explicitly stated otherwise in a specific context, names and structures are used interchangeably.

[0070] Any atom in the compounds disclosed herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope that has the same atomic number but a different atomic mass or mass number than that which is predominantly found in nature. This disclosure is intended to include all suitable isotopic variants of the compounds disclosed herein.

[0071] The compounds may be administered in the form of pharmaceutically acceptable salts or solvates. The term "pharmaceutically acceptable salt" refers to a salt or solvate that is not biologically or otherwise undesirable (e.g., neither toxic nor harmful to the recipient or subject). Mixtures of the disclosed compounds with one or more of their salts or solvates are also considered herein. Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propynates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0072] Furthermore, the compounds disclosed herein may exist in amorphous form and / or one or more crystalline forms or combinations thereof.

[0073] The term "RNA virus infection" refers to diseases caused by RNA viruses, such as the common cold, influenza, SARS, COVID-19, hepatitis C, hepatitis E, West Nile fever, Ebola virus disease, rabies, polio, and measles.

[0074] The term "HIV infection" refers to the illness caused by the human immunodeficiency virus (HIV), such as HIV-1 and HIV-2. In some cases, HIV infection can be caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with the K65R mutation, or multidrug-resistant HIV. The term "AIDS" refers to Acquired Immunodeficiency Syndrome, which is caused by HIV infection and is a later form of the disease.

[0075] The term "prodrug" refers to a compound that can be converted into the bioactive compound described herein under physiological conditions or by solvent degradation. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. A prodrug can be a biologically inactive or substantially inactive compound that can be metabolized in the body (i.e., in vivo) to produce a drug with desired activity. The term "substantially inactive" means that, based on a percentage by weight of the prodrug, the prodrug may have about 1% to about 10% of the activity of the corresponding drug or its activity after metabolism in vivo. In some embodiments, the term "substantially inactive" means that, based on a percentage by weight of the prodrug, the prodrug has less than about 5% of the activity of the corresponding drug or its activity after metabolism in vivo. When the molar amounts of the prodrug and its bioactive compound are equal, their doses are considered equivalent doses.

[0076] The terms "anti-HIV agent," "antiviral agent," or grammatical variations refer to compounds, mixtures of one or more compounds, formulations, chemical agents, or biological agents (such as antibodies, proteins, peptides, nucleotides, other biological compounds, or combinations thereof) that can directly or indirectly and effectively inhibit, treat, or prevent HIV infection, and / or treat, prevent, or delay the onset or progression of AIDS and / or diseases or disorders arising from or associated with it, RNA virus infection, or combinations thereof. Anti-HIV agents may include HIV antiviral agents, immunomodulators, anti-infective agents, vaccines, or combinations thereof that can be used to treat HIV infection or AIDS. Examples of antiviral agents for the treatment of HIV infection or AIDS include, but are not limited to, abacavir (ABC), under their respective trademarks or registered trademarks of their respective owners. Abacavir + Lamivudine Abacavir + Lamivudine + Zidovudine Amponavir Azanavir AZT (zidovudine, azidothymidine or) ), kalavirine, darunavir ddC (zacitabine, dideoxycytidine or) ), ddI (desoxyinosine, dideoxyinosine or ), ddI (enteric-coated, Videox) ), deraviridine (DLV or Dolutegravir Doravirine (MK-1439), Efavirenz (EFV, ), Efavirenz + Emtricitabine + Tenofovir DF EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine), erteiravir, cabozantinvir, dolutegravir, bicretiravir, emtricitabine (FTC), ), Emtricitabine + Tenofovir DF Estimivirine Enfuwedi Enteric-coated hydroxyinosine (Videx) ), Etravirine (TMC-125), Fosanavir Calcium Indinavir ( Lamivudine (3TC, Lamivudine + Zidovudine Lopinavir, Lopinavir + Ritonavir Maravero Nefernavir NVP, PPL-100 (also known as PL-462) (Ambrilia), raltirapvir (MK-0518 or Isentress) TM Rilpivirine Litonavir Saquinavir or Stavudine (d4T, didehydrodeoxythymidine or) Tenofovir DF (DF = dipyridoxine fumarate, TDF, Tenofovir (CMX-157), Tenofovir Alaminamide Fumarate (GS-7340), Tenofovir Disoproxil Fumarate (CMX-157), Tenofovir Alaminamide Fumarate (GS-7340), Tenonavir And velivirox. Some of the anti-HIV agents shown above can be used in salt form; for example, abacavir sulfate, deraviridine mesylate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate, saquinavir mesylate, or other salts. Anti-HIV agents can have one or more activities, such as entry inhibitors (EI), fusion inhibitors (FI); integrase inhibitors (InI); protease inhibitors (PI); nucleoside reverse transcriptase inhibitors (nRTI or NRTI) or non-nucleoside reverse transcriptase inhibitors (nnRTI or NNRTI). Anti-HIV agents may comprise two or more agents disclosed herein. The adenosine derivatives disclosed herein can be anti-HIV agents together with or in combination with one or more other anti-HIV agents.

[0077] Unless explicitly stated to the contrary, all ranges cited herein include end values. For example, a heterocyclic ring described as containing “1 to 4 heteroatoms” means that the ring may contain 1, 2, 3, or 4 heteroatoms. It should also be understood that any range cited herein includes all subranges within that range. Thus, for example, a heterocyclic ring described as containing “1 to 4 heteroatoms” is intended to include, as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, or 4 heteroatoms. In other instances, C1-C10 alkyl means alkyl groups containing 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms (inclusive of all subranges). Therefore, C1-C10 alkyl groups can be straight-chain or branched methyl, ethyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, and C10 alkyl groups. Divalent C1-C10 alkyl groups can be straight-chain or branched -CH2-, -C2H4-, -C3H6-, -C4H8-, and -C5H-. 10 -、-C6H 12 -、-C7H 17 -、-C8H 18 -、-C9H 18 -or-C 10 H 20 Similarly, C2-C10 alkenyl refers to a straight-chain or branched alkenyl group containing 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms (inclusive of all subranges). Straight-chain or branched alkenyl groups may be suitable. C3-C10 cycloalkyl refers to a straight-chain or branched cycloalkyl group containing 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms.

[0078] Unless otherwise stated, open terms such as “contain,” “containing,” “include,” and “including” mean “including.”

[0079] The singular forms “a,” “an,” and “the” are used herein to include a plural of indicators unless the context explicitly indicates otherwise. Therefore, unless otherwise indicated, the numerical parameters set forth in this application are approximations, which may vary depending on the desired properties sought to be obtained by this disclosure.

[0080] As used herein, the term “about” and its grammatical equivalents in relation to reference values ​​and their grammatical equivalents can include a range of values ​​plus or minus 10%, such as a range of values ​​plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. For example, the quantity “about 10” includes quantities from 9 to 11.

[0081] Pharmaceutical compositions 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 encapsulated in a material to protect it from acids and other natural conditions that could inactivate it. As used herein, the phrase "parenteral administration" refers to administration methods normally administered by injection, other than enteral and local administration, and includes, but is not limited to, intravenous, intramuscular, intra-articular, intrathecal, intracapsular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions. Alternatively, pharmaceutical compositions may be administered via non-parenteral routes, such as local, epidermal, or mucosal administration routes, such as intranasal, oral, vaginal, rectal, sublingual, or local administration. Pharmaceutical compositions may be in the form of sterile aqueous solutions or suspensions. Pharmaceutical compositions may be formulated as microemulsions, liposomes, or other ordered structures suitable for high drug concentrations.

[0082] In some embodiments, this disclosure provides an adenosine derivative or a pharmaceutically acceptable salt, tautomer, or solvate thereof having formula (1):

[0083]

[0084] in,

[0085] R 1 R1' and R 2 Each is independently -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 or -ZL 4 -R 5 , where R 1 and R 2 At least one of them is not -H;

[0086] R 3 R 3' and R 4 Each of them is independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0087] R 5 yes:

[0088]

[0089] R 6It is -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3-to-10-membered heterocyclic alkyl, aryl or heteroaryl;

[0090] -L 1 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkylene)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5 -(C2-C10 imenoyl)-SR 5 -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL 2 -OR 5 -C(O)OL 2 -SR 5 -C(O)OL 2 -C(O)OR 5 -C(O)OL 2 -C(O)N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -OR 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -SR 5 -C(O)N(R) 7 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )-R 5 -C(O)N(R) 7 )-L 2 -OR 5 -C(O)N(R)7 )-L 2 -SR 5 -C(O)N(R) 7 )-L 2 -C(O)OR 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-R 5 -、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -OR 5 or -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -SR 5 ;

[0091] -Z- represents divalent -C(O)-, -C(O)O-, or -C(O)N(R). 7 )-;

[0092] -L 4 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkylene)-SR5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5 or -(C2-C10 imidene)-SR 5 ;

[0093] R 7 R 8 and R 9 Each is independently -H, C1-C10 alkyl, or C2-C10 alkenyl;

[0094] L 2 and L 3 Each is expected to be -(C1-C10 alkylene)- or -(C2-C10 alkenylene)-; and

[0095] X is a halogen atom.

[0096] The adenosine derivatives disclosed herein may be free of monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof. In some embodiments, the R of the adenosine derivatives disclosed herein... 1 R 1' Or R 2 The group does not contain monophosphate, diphosphate, triphosphate, or combinations thereof. Non-limiting examples of adenosine derivatives having halogen atoms are shown in formulas (1)-(8) and (4-B). Figures 1A-1I )middle.

[0097] In some embodiments, the C1-C10 alkyl and C2-C10 alkenyl groups of formula (1) are straight-chain or branched. In some embodiments, the compound of formula (1) comprises a combination of C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl and heteroaryl groups.

[0098] In some implementations of equation (1), R 1 It is H and R 2 It is -C(O)N(R) 3 (R) 3' In some implementations, R 1 It is -C(O)N(R) 3 (R) 3' And R 2 It is H. In some implementations, R 3 It is a C1-C5 alkyl or C3-C6 cycloalkyl and R 3' It is H. In some implementations, R 3 It is methyl, ethyl, or isopropyl and R 3' It is H.

[0099] In some implementations of equation (1), R 1 It is H and R 2 Yes -R 5 or -L 1 -R 5 In some implementations, R 1 Yes -L 1 -R 5 And R 2 It is H. In some implementations, -L 1 -R 5 It is -C(O)N(R) 7 )-L 2 -N(R 7 )-R 5 -C(O)OL 2 -OR 5 -C(O)N(R) 7 )-L 2 -N(R 7 )-C(O)OR 5 -C(O)OL 2 -N(R 7 )-C(O)OR 5、 -C(O)N(R 7 )-L 2 -N(R 8 )-C(O)N(R 8 )-R 5 or -C(O)OL 2 -N(R 8 )-C(O)N(R 8 )-R 5 In some implementations, R 5 yes In some implementation schemes, R 6 It is a C1-C5 alkyl group. In some embodiments, R 6 It is methyl, ethyl, or isopropyl. In some embodiments, R 6 It is methyl. In some embodiments, R 7 Each is independently either H or Me. In some implementations, R 9 It is H, F, or Me. In some implementations, R 9 It is H. In some implementations, L 2 It is a C2-C5 alkylene group. In some embodiments, L 2 It is ethylene or propylene. In some embodiments, L 2 It is ethylene.

[0100] In some implementations of equation (1), R 1It is -C(O)OR 5 or -R 5 And R 2 It is H. In some implementations, R 1 It is H and R 2 It is -C(O)OR 5 or -R 5 In some implementations, R 5 yes In some implementation schemes, R 6 It is a C1-C5 alkyl group. In some embodiments, R 6 It is methyl, ethyl, or isopropyl. In some embodiments, R 6 It is methyl. In some embodiments, R 9 It is H, F, or Me. In some implementations, R 9 It is H.

[0101] In some implementations of equation (1), R 1 Yes -L 1 -R 5 In some implementations, R 1’ Is it –H or -L 1 -R 5 In some implementations, R 1’ Yes -H. In some implementations, R 1’ Yes -L 1 -R 5 In some implementations, R 1 Yes -L 1 -R 5 And R 1’ It is H. In some implementations, R 1 Yes -L 1 -R 5 And R 1’ Yes -L 1 -R 5 In some implementations, R 1 Yes -L 1 -R 5 R 1’ It is H and R 2 It is H. In some implementations, R 1 Yes -L 1 -R 5 R 1’ Yes -L 1 -R 5 And R 2 It is H. In some implementations, L 1 -R 5 Choose from the following groups: -(C1-C10 alkylene)-N(R)7 )-R 5 -(C1-C10 alkylene)-OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL 2 -OR 5 -C(O)OL 2 -C(O)OR 5 -C(O)OL 2 -C(O)N(R 7 )-R 5 -C(O)N(R) 7 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )-R 5 -C(O)N(R) 7 )-L 2 -OR 5 -C(O)OL 2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -C(O)OR 5 and -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-R 5 -. In some implementations, -L 1 -R 5 Choose from the following groups: -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )-R 5 and -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-R 5 -. In some implementations, -L 1 -R 5 It is -C(O)OR 5 In some implementations, R 2 It is H.

[0102] Divalent connector L 1 It may also contain one or more repetitions of the same group or combinations of different groups. In some embodiments, L 1 It contains -C(O)O- and C1-C10 alkyl groups. In some embodiments, L 1 Two or more repetitions of -C(O)O-. In some implementations, L 1 Contains C(O)O(CH2) n - repeated two or more times. In some implementations, L 1 Includes -C(O)N(R) 7 The repetition of )- two or more times. In some implementations, L 1 Includes -C(O)N(R) 7 (CH2) n - repeated two or more times. In some implementations, L 1 Includes -C(O)O-, C1-C10 alkyl groups and -C(O)N(R) 7 The combination of )-. In some implementations, L 1 Includes -C(O)O- and -(CH2) n- and -C(O)N(R) 7 The combination of )-. In some implementations, L 1 Includes -C(O)N(R) 7 Combinations of α- and C1-C10 alkyl groups. In some embodiments, L 1 Contains -C(O)O(CH2) n -C(O)N(R 7 The number is repeated two or more times. In some embodiments, n is an integer from 0 to 10. In some embodiments, n is an integer from 1 to 3. As understood in the art, the above combinations are non-limiting examples, and this disclosure also considers L. 1 Other possible chemical combinations.

[0103] The adenosine derivatives disclosed herein may include one or more isomers thereof. Isomers may include chiral isomers (also called stereoisomers) containing one or more chiral centers, tautomers that can interconvert via the repositioning of protons or other atoms, such as amino isomers, imino isomers, or combinations thereof. In examples, the adenosine derivative may have amino isomers, imino isomers, or combinations thereof. In further examples, the adenosine derivative may include enantiomers, diastereomers, and cis / trans isomers, tautomers, or combinations thereof. Isomers that can have reverse transcriptase inhibitor (RTI) activity in vivo are particularly preferred.

[0104] In some embodiments of formula (1), X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine (alternatively referred to as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I)). In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is Br.

[0105] In some embodiments, this disclosure relates to adenosine derivatives or pharmaceutically acceptable salts, tautomers or solvates thereof having formula (1a):

[0106]

[0107] Where R 1 X is defined as in equation (1) above.

[0108] In some embodiments, this disclosure relates to adenosine derivatives or pharmaceutically acceptable salts, tautomers or solvates thereof having formula (1b):

[0109]

[0110] Where R 2 X is defined as in equation (1) above.

[0111] In some embodiments, the adenosine derivatives of this disclosure are selected from the group consisting of:

[0112] Equation (2):

[0113]

[0114] Equation (3):

[0115]

[0116] Equation (4):

[0117]

[0118] Equation (5):

[0119]

[0120] Equation (6):

[0121]

[0122] Equation (7):

[0123]

[0124] Equation (8):

[0125]

[0126] Equation (4-B):

[0127]

[0128] Or its pharmaceutically acceptable salts, tautomers or solvates.

[0129] In some implementations, X is Cl, F, or Br. In some implementations, X is F.

[0130] In a further embodiment, the adenosine derivative of this disclosure is selected from the group consisting of:

[0131] Equation (2-A):

[0132]

[0133] Equation (3-A):

[0134]

[0135] Equation (4-A):

[0136]

[0137] Equation (5-A):

[0138]

[0139] Equation (6-A):

[0140]

[0141] Equation (7-A):

[0142]

[0143] Equation (8-A):

[0144]

[0145] Equation (4-C):

[0146]

[0147] Or its stereoisomers, pharmaceutically acceptable salts, tautomers or solvates ( Figures 2A-2I ).

[0148] In some embodiments, the adenosine compound of this disclosure is an isomer of formula (1)-(8), formula (1a), formula (1b), or formula (1-A)-(8-A). In some embodiments, the isomer is a stereoisomer, such as an enantiomer or a diastereomer. In some embodiments, the isomer is an inhibitor of a reverse transcriptase with in vivo activity.

[0149] As disclosed herein, the adenosine derivatives of the present disclosure include isopropylcarbamic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate, ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl carbonate ((5-methyl-2-oxo-1,3-dioxolanyl-4-yl)methyl) ester, methyl ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)carbamate, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-1,3-dioxolanyl-2-one, (2-(methyl((5-methyl-2-oxo-1,3-dioxolanyl-4-yl)methyl)amino)ethyl) ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methylcarbamate, 4-[methyl-[(5-methyl-2-oxo-1,3-dioxolanyl-4-yl)methoxycarbonyl]amino]butanoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl] methyl ester, or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the adenosine derivatives of the present disclosure comprise R 1 、R 1’ or R 2 , each of which independently comprises one or more 5- to 10-membered heterocycles. R 1 、R 1’ or R 2 may each independently comprise a 5-membered heterocycle in one embodiment, a 6-membered heterocycle in another embodiment, or a 6- to 10-membered heterocycle in yet another embodiment. The heterocycles of the present disclosure may have one or more substituents. In some embodiments, the 5-membered heterocycle comprises carbon atoms and heteroatoms selected from the group consisting of N, O, and S in the range of 1 to 4. In some embodiments, the 5-membered heterocycle comprises 1 to 3 O atoms. In a further embodiment, R 1 、R 1’ or R 2Each of the components independently comprises a 5-membered heterocycle of formulas 9-24. In even further embodiments, the adenosine derivatives of this disclosure comprise R. 1 R 1’ Or R 2 Each of them independently contains the previously mentioned -R 5 -L 1 -R 5 -ZL 4 -R 5 Group. In some embodiments, -R 5 -L 1 -R 5 -ZL 4 -R 5 Selected from formula 9-24 ( Figures 3A-3J and Figures 4A-4F ):

[0151]

[0152]

[0153] In some implementations, -R 5 -L 1 -R 5 -ZL 4 -R 5 Choose from the following groups:

[0154]

[0155] In some embodiments, the adenosine derivative of this disclosure comprises R 1 and R 1’ Their respective values ​​are -H and -C(O)N(R). 3 (R) 3’ ) or -C(O)OR 4 ; and R 2 It is -C(O)N(R) 3 (R) 3’ -C(O)OR 4 , or one of formulas 9–24.

[0156] In another embodiment, the adenosine derivative of this disclosure comprises R 1 and R 1’ Each of them is -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 ; and R 2 It is -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4, or one of formulas 9–24.

[0157] In yet another embodiment, the adenosine derivative of this disclosure comprises R 2 It is -H, -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 ; and R 1 It is -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 , or one of formulas 9–24.

[0158] In yet another embodiment, the adenosine derivative of this disclosure comprises R 2 It is -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 ; and R 1 It is -H, -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 , or one of formulas 9–24.

[0159] In yet another embodiment, the adenosine derivative of this disclosure comprises R 1 and R 1’ Their respective values ​​are -H and -C(O)N(R). 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 -ZL 4 -R 5 , or one of formulas 9–24; and R 2 It is -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 -ZL 4 -R 5 , or one of formulas 9–24.

[0160] In yet another embodiment, the adenosine derivative of this disclosure comprises R 1 It is -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R5 -ZL 4 -R 5 , or one of formulas 9–24; and R 2 It is -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 -ZL 4 -R 5 , or one of formulas 9–24.

[0161] In a further implementation plan, R 1 R 1’ and R 2 Each of them is independently selected from one of Equations 9-24.

[0162] The adenosine derivative disclosed herein can undergo conversion to a target drug and may include in vivo reverse transcriptase inhibitor activity, in vivo reverse transcriptase chain terminator activity, in vivo DNA translocation inhibitor activity, or a combination thereof.

[0163] The adenosine derivatives disclosed herein may be prodrugs that have no or limited activity in their original form as shown herein, and can be metabolized in vivo to exhibit the desired activity of a target drug, including reverse transcriptase inhibitor activity, reverse transcriptase chain terminator activity, DNA translocation inhibitor activity, or a combination thereof.

[0164] Without wishing to be bound by a specific mechanism or theory, the applicant has discovered that the adenosine derivatives disclosed herein can be metabolized in vivo to produce compounds or mixtures of compounds similar to or identical to 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), a target drug with reverse transcriptase inhibitor and other antiviral activities.

[0165] As disclosed herein, the adenosine derivatives of this disclosure may comprise isomers thereof (e.g., enantiomers, diastereomers and / or tautomers), one or more pharmaceutically acceptable salts thereof, one or more solvates thereof including hydrates, solvated salts thereof, or mixtures thereof.

[0166] This disclosure further relates to pharmaceutical compositions comprising the adenosine derivatives disclosed herein and pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises an adenosine derivative having formula (1):

[0167]

[0168] in,

[0169] R 1 R1’ and R 2 Each is independently -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 or -ZL 4 -R 5 , where R 1 and R 2 At least one of them is not -H;

[0170] R 3 R 3' and R 4 Each of them is independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0171] R 5 yes:

[0172]

[0173] R 6 It is -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3-to-10-membered heterocyclic alkyl, aryl or heteroaryl;

[0174] -L 1 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkyl)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5 -(C2-C10 imenoyl)-SR 5 -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL 2 -OR 5 -C(O)OL 2 -SR 5 -C(O)OL 2 -C(O)OR 5 -C(O)OL 2-C(O)N(R 7 )-R 5 、-C(O)O-L 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 、-C(O)O-L 2 -C(O)N(R 7 )-L 3 -O-R 5 、-C(O)O-L 2 -C(O)N(R 7 )-L 3 -S-R 5 、-C(O)N(R 7 )-R 5 、-C(O)N(R 7 )-L 2 -N(R 7 )-R 5 、-C(O)N(R 7 )-L 2 -O-R 5 、-C(O)N(R 7 )-L 2 -S-R 5 、-C(O)N(R 7 )-L 2 -C(O)O-R 5 、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 、-C(O)O-L 2 -N(R 7 )C(O)O-R 5 、-C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 、-C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 、-C(O)N(R 7 )-L 2 -N(R7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -OR 5 or -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -SR 5 ;

[0175] -Z- represents divalent -C(O)-, -C(O)O-, or -C(O)N(R). 7 )-;

[0176] -L 4 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkylene)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5 or -(C2-C10 imidene)-SR 5 ;

[0177] R 7 R 8 and R 9 Each is independently -H, C1-C10 alkyl, or C2-C10 alkenyl;

[0178] L 2 and L 3 Each is expected to be -(C1-C10 alkylene)- or -(C2-C10 alkenylene)-; and

[0179] X is a halogen atom.

[0180] As disclosed above, the pharmaceutical compositions of this disclosure comprising adenosine derivatives may be free of monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof. In some embodiments, the R of the adenosine derivatives disclosed herein... 1 and / or R 2 The group does not contain monophosphate groups, diphosphate groups, triphosphate groups, or combinations thereof.

[0181] In some embodiments, the C1-C10 alkyl and C2-C10 alkenyl groups are straight-chain or branched. In some embodiments, the adenosine derivative of the pharmaceutical composition comprises a combination of C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl, and heteroaryl groups.

[0182] In some embodiments of the pharmaceutical composition, the adenosine derivative includes a divalent linker L. 1 It contains one or more repetitions of the same or different groups as disclosed herein. Connector L 1 Non-limiting examples of other chemically possible combinations include those described above, such as those in equation (1).

[0183] In some embodiments, the adenosine derivative of the pharmaceutical composition is an isomer of formula (1)-(8), formula (1a), formula (1b), formula (1-A)-(8-A), formula (4-B), or formula (4-C). Such isomers, such as tautomers, enantiomers, diastereomers, cis / trans isomers, or combinations thereof, may be suitable. In some embodiments, the isomer is an inhibitor of a reverse transcriptase with in vivo activity.

[0184] In some embodiments, X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine (or referred to as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I)). In one embodiment, X is F. In another embodiment, X is Cl. In yet another embodiment, X is Br. Non-limiting examples of adenosine derivatives of this disclosure are shown in Figures 1A-1I middle.

[0185] In some embodiments, the pharmaceutical compositions of this disclosure comprise an adenosine derivative having a formula selected from the group consisting of:

[0186] Equation (2):

[0187]

[0188] Equation (3):

[0189]

[0190] Equation (4):

[0191]

[0192] Equation (5):

[0193]

[0194] Equation (6):

[0195]

[0196] Equation (7):

[0197] and

[0198] Equation (8):

[0199]

[0200] Equation (4-B):

[0201]

[0202] Or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or combination thereof.

[0203] In some implementations, X is Cl, F, or Br. In some implementations, X is F.

[0204] In some embodiments, the pharmaceutical compositions of this disclosure comprise an adenosine derivative having a formula selected from the group consisting of:

[0205] Equation (2-A):

[0206]

[0207] Equation (3-A):

[0208]

[0209] Equation (4-A):

[0210]

[0211] Equation (5-A):

[0212]

[0213] Equation (6-A):

[0214]

[0215] Equation (7-A):

[0216]

[0217] Equation (8-A):

[0218]

[0219] Equation (4-C):

[0220]

[0221] Its stereoisomers, its pharmaceutically acceptable salts, or combinations thereof ( Figures 2A-2I ).

[0222] In some embodiments, the adenosine compound of this disclosure is an isomer of formula (1)-(8), formula (1a), formula (1b), formula (1-A)-(8-A), formula (4-B), or formula (4-C). In some embodiments, the isomer is a stereoisomer, such as an enantiomer or a diastereomer. In some embodiments, the isomer is an inhibitor of a reverse transcriptase with in vivo activity.

[0223] As disclosed herein, the pharmaceutical compositions of this disclosure comprise an adenosine derivative selected from the group consisting of: isopropyl carbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)amino Isopropyl formate, methyl carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) ester ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester, methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) ) methyl ester, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one, (2-(methyl((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl)amino)ethyl)carbamic acid((2R,3S,5R)-5-( 6-Amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester, 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl]methyl ester, and any pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the pharmaceutical compositions of this disclosure include adenosine derivatives comprising R selected from formulas 9-24. 5 -L 1 -R 5 or -ZL 4 -R5 :

[0225]

[0226]

[0227] In some embodiments, the pharmaceutical compositions of this disclosure comprise an adenosine derivative, said adenosine derivative comprising R 1 and R 1’ Their respective values ​​are -H and -C(O)N(R). 3 (R) 3’ ) or -C(O)OR 4 ; and R 2 It is -C(O)N(R) 3 (R) 3’ -C(O)OR 4 , or one of formulas 9–24.

[0228] In another embodiment, the pharmaceutical composition of this disclosure comprises an adenosine derivative, said adenosine derivative comprising R 1 It is -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 ; and R 2 It is -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 , or one of formulas 9–24.

[0229] In yet another embodiment, the pharmaceutical composition of this disclosure comprises an adenosine derivative, said adenosine derivative comprising R 2 It is -H, -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 ; and R 1 It is -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 , or one of formulas 9–24.

[0230] In yet another embodiment, the pharmaceutical composition of this disclosure comprises an adenosine derivative, said adenosine derivative comprising R 2 It is -C(O)N(R) 3 (R) 3’ ) or -C(O)OR 4 ; and R 1 and R 1 ', which are respectively -H, -C(O)N(R) 3 (R)3’ -C(O)OR 4 , or one of formulas 9–24.

[0231] In yet another embodiment, the pharmaceutical composition of this disclosure comprises an adenosine derivative, said adenosine derivative comprising R 1 and R 1’ Their respective values ​​are -H and -C(O)N(R). 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 -ZL 4 -R 5 , or one of formulas 9–24; and R 2 It is selected from -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 -ZL 4 -R 5 , or one of formulas 9–24.

[0232] In yet another embodiment, the pharmaceutical composition of this disclosure comprises an adenosine derivative, said adenosine derivative comprising R 1 It is -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 -ZL 4 -R 5 , or one of formulas 9–24; and R 2 It is selected from -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 -ZL 4 -R 5 , or one of formulas 9–24.

[0233] In a further embodiment, the pharmaceutical composition of this disclosure comprises an adenosine derivative, said adenosine derivative comprising R 1 R 1’ and R 2 Each of them is independently selected from one of Equations 9-24.

[0234] In some implementation schemes, R 3 R 3’ and R 4 Each is independently -H, C1-C10 alkyl, C2-C10 alkenyl, or C3-C10 cycloalkyl. In some embodiments, R 3 R 3’ and R 4 Each is independently -H, C1-C5 alkyl, C2-C5 alkenyl, or C3-C6 cycloalkyl. In some embodiments, R 3 R 3’ and R 4 Each is independently -H or C1-C5 alkyl. In some embodiments, the C1-C5 alkyl group is methyl, ethyl, or isopropyl. In some embodiments, R... 3 R 3’ and R 4 Each can be independently -H, methyl, or isopropyl.

[0235] In some implementation schemes, R 6 It is -H, C1-C10 alkyl, C2-C10 alkenyl, or C3-C10 cycloalkyl. In some embodiments, R 6 It is -H, C1-C5 alkyl, C2-C5 alkenyl, or C3-C6 cycloalkyl. In some embodiments, R 6 It is -H, C1-C3 alkyl, or C2-C4 alkenyl. In some embodiments, R 6 Selected from the group consisting of: –H, methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R 6 It is a methyl group.

[0236] In some implementation schemes, R 7 and R 8 Each is independently -H, C1-C10 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 7 and R 8 Each is independently -H, C1-C5 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 7 and R 8 Each can be independently -H, methyl, ethyl, isopropyl, or cyclopropyl.

[0237] In some implementation schemes, R 9 It is -H, F, C1-C10 alkyl, or C2-C10 alkenyl. In some embodiments, R 9 It is -H, F, C1-C3 alkyl, or C2-C4 alkenyl. In some embodiments, R 9 It is -H, F, or C1-C3 alkyl. In some embodiments, R 9Yes, it's -H.

[0238] As described, the pharmaceutical compositions disclosed herein comprise a pharmaceutically acceptable carrier.

[0239] Non-limiting examples of pharmaceutically acceptable carriers include pharmaceutical excipients, surfactants, emulsifiers, fillers, carriers, isotonic agents, dispersants, viscosity modifiers, resuspending agents, buffers, or combinations thereof. Pharmaceutical excipients generally do not possess the properties of a pharmaceutical or active pharmaceutical ingredient (also known as an active pharmaceutical ingredient (API)) and are typically used to simplify the manufacturing process or packaging of the active ingredient, or to deliver the API to a patient or other subject. Pharmaceutically acceptable carriers, excipients, or inactive ingredients from the Inactive Ingredients Database available from the U.S. FDA (https: / / www.fda.gov / drugs / drug-approvals-and-databases / inactive-ingredients-database-download) may be appropriate. Some 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.

[0240] In some embodiments of this disclosure, pharmaceutically acceptable carriers include gum arabic, animal oils, benzyl alcohol, benzyl benzoate, calcium stearate, carbomer, cetearyl alcohol, cetyl alcohol, cholesterol, cyclodextrin, dextran, diethanolamine, emulsifying wax, ethylene palmitate stearate, glycerin, glyceryl monostearate, glyceryl stearate, glyceryl monooleate, glyceryl monostearate, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin (HPBCD), hydroxypropyl methylcellulose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohol, lecithin, medium-chain triglycerides, metallic soaps, methylcellulose, mineral oil, sodium dihydrogen phosphate, monoethanolamine, oleic acid, and polyethylene glycol (PEG 3350, PEG 4000, PEG...). 6000), polyoxyethylene-polyoxypropylene copolymer (poloxam), polyoxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene castor oil derivative, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene stearate, polysorbate, polyoxyethylene (20) sorbitol monolaurate (Tween 20, polysorbate 20), polyoxyethylene (20) sorbitol monooleate (Tween 80, polysorbate 80), povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium dodecyl sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sorbitol ester, stearic acid, stearyl alcohol, sunflower oil, tragacanth gum, triethanolamine, vegetable oil, water, xanthan gum or combinations thereof.

[0241] In a further embodiment, pharmaceutically acceptable carriers include dextran, glycerol, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin (HPBCD), hydroxypropyl methylcellulose (hydroxypropyl methylcellulose (HPMC)), polyoxyethylene (20) sorbitol monolaurate (Tween 20, polysorbate 20), polyethylene glycol (PEG 400, PEG 3350, PEG 4000, PEG 6000), polyoxyethylene-polyoxypropylene copolymer (poloxam 188, poloxamer 407), polyoxyethylene (20) sorbitol monooleate (Tween 80, polysorbate 80), physiological saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium dodecyl sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, or combinations thereof.

[0242] The pharmaceutical compositions disclosed herein may further comprise an effective dose of one or more anti-HIV agents selected from the following (also known as anti-HIV agents): abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bicretiravir, cabozantivir, darunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate, and tenofovir alafenamide. Amines, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, erteiravir, etravirine, fosamponavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobistat, maraviro, nelfinavivir, nelfinavivir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, telanavir, velivirol or a combination thereof.

[0243] In some embodiments, the pharmaceutical compositions of this disclosure comprise an adenosine derivative (e.g., formula (1)-(8), formula (1a), formula (1b), or formula (1-A)-(8-A)) and one or more anti-HIV agents, which are presented as a single formulation for simultaneous administration to a subject. The pharmaceutical compositions of this disclosure may comprise an adenosine derivative and one or more anti-HIV agents, which are presented as separate formulations for simultaneous or sequential administration to a subject. The pharmaceutical compositions of this disclosure may also be mixed with one or more anti-HIV agents in a separate formulation for simultaneous administration to a subject.

[0244] This disclosure further relates to a method for treating a disease. The method may include administering to a subject in need an effective dose of a pharmaceutical composition comprising an adenosine derivative having formula (1):

[0245]

[0246] in,

[0247] R 1 R 1’ and R 2 Each is independently -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 or -ZL 4 -R 5 , where R 1 and R 2 At least one of them is not -H;

[0248] R 3 R 3' and R4 Each of them is independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0249] R 5 yes:

[0250]

[0251] R 6 It is -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3-to-10-membered heterocyclic alkyl, aryl or heteroaryl;

[0252] -L 1 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkylene)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5 -(C2-C10 imenoyl)-SR 5 -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL 2 -OR 5 -C(O)OL 2 -SR 5 -C(O)OL 2 -C(O)OR 5 -C(O)OL 2 -C(O)N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -OR 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -SR5 , -C(O)N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )-R 5 , -C(O)N(R 7 )-L 2 -O-R 5 , -C(O)N(R 7 )-L 2 -S-R 5 , -C(O)N(R 7 )-L 2 -C(O)O-R 5 , -C(O)N(R 7 )-L 2 , -C(O)N(R 8 )-R 5 -, -C(O)N(R 7 )-L 2 , -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 , -C(O)O-L 2 -N(R 7 )C(O)O-R 5 , -C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 , -C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 , -C(O)N(R 7 )-L 2 , -C(O)N(R 8 )-L 3 -O-R 5 or -C(O)N(R 7 )-L 2 , -C(O)N(R 8 )-L 3 -S-R 5 ;

[0253] -Z- represents divalent -C(O)-, -C(O)O-, or -C(O)N(R). 7 )-;

[0254] -L 4 -R 5 It is -(C1-C10 alkylene)-N(R) 7 )-R 5 -(C1-C10 alkylene)-OR 5 -(C1-C10 alkylene)-SR 5 -(C2-C10 imidene)-N(R 7 )-R 5 -(C2-C10 alkenyl)-OR 5 or -(C2-C10 imidene)-SR 5 ;

[0255] R 7 R 8 and R 9 Each is independently -H, C1-C10 alkyl, or C2-C10 alkenyl;

[0256] L 2 and L 3 Each is expected to be divalent -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and

[0257] X is a halogen atom.

[0258] Any of the aforementioned adenosine derivatives (e.g., formulas (1)-(8), (1a), (1b), or (1-A)-(8-A)) or pharmaceutical compositions comprising adenosine derivatives may be suitable. X is a halogen atom and may be selected from fluorine, chlorine, bromine, and iodine (alternatively referred to as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I)). In some embodiments, X is F. In another embodiment, X is Cl. In yet another embodiment, X is Br.

[0259] In some embodiments of this method, the adenosine derivative has a formula selected from the group consisting of:

[0260] Equation (2):

[0261]

[0262] Formula 3

[0263]

[0264] Equation (4):

[0265]

[0266] Equation (5):

[0267]

[0268] Equation (6):

[0269]

[0270] Equation (7):

[0271]

[0272] Equation (8):

[0273]

[0274] Equation (4-B):

[0275]

[0276] Or its isomers, or its pharmaceutically acceptable salts.

[0277] In some implementations, X is Cl, F, or Br. In some implementations, X is F.

[0278] In some embodiments of this method, the adenosine derivative has a formula selected from the group consisting of:

[0279] Equation (2-A):

[0280]

[0281] Equation (3-A):

[0282]

[0283] Equation (4-A):

[0284]

[0285] Equation (5-A):

[0286]

[0287] Equation (6-A):

[0288]

[0289] Equation (7-A):

[0290]

[0291] Equation (8-A):

[0292]

[0293] Equation (4-C):

[0294]

[0295] Or its isomers, or its pharmaceutically acceptable salts.

[0296] As disclosed herein, the method of the present invention includes administering a pharmaceutical composition comprising an adenosine derivative, wherein the adenosine derivative is isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester, (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate isopropyl ester, or ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-... 5-Hydroxytetrahydrofuran-2-yl)methyl ester ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester, methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester, 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one, or any pharmaceutically acceptable salt thereof.

[0297] In the methods disclosed herein, the pharmaceutical composition is administered to a subject via intramuscular (IM), subcutaneous (SC), intravenous (IV), oral, topical, implantation, or a combination thereof. Implantation may include an implantable device or film containing the pharmaceutical composition disclosed herein. Implantation may include vaginal rings, films, membranes, patches, other devices, or combinations thereof.

[0298] The method disclosed herein may further include measuring a sample of a subject to determine the measured level of the target drug in the sample, wherein the target drug may have the following formula (T-1):

[0299]

[0300] Or its isomers, or pharmaceutically acceptable salts thereof. In some embodiments, X is a halogen selected from the group consisting of F, Cl, Br, and I. In some embodiments, X is I.

[0301] In some implementations, the target drug may have formula (T-1A):

[0302]

[0303] or its isomers, or its pharmaceutically acceptable salts ( Figure 5A – Figure 5B ).

[0304] In some implementations, the target drug may be (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (also known as 4'-ethynyl-2-fluoro-2'-deoxyadenosine, EFdA), or a pharmaceutically acceptable salt thereof.

[0305] In some implementations, the target drug may be a degradation or metabolite of compound (T-1), (T-1A), or EFdA.

[0306] The sample may be a blood sample, urine sample, body fluid sample, tissue sample, or a combination thereof from the subject (such as a patient).

[0307] The level of the target drug can be determined by analytical methods known to those skilled in the art, such as, but not limited to, HPLC, GC, MS, GC-MS, or combinations thereof.

[0308] The method disclosed herein may further include adjusting the effective dose to produce a modified effective dose if the measured level of the target drug differs from the predetermined target level of the target drug, and administering the modified effective dose to the subject.

[0309] In some embodiments of this method, the disease is acquired immunodeficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multidrug-resistant HIV, or RNA virus infection.

[0310] In some embodiments, the method of this disclosure further includes administering to a subject an effective dose of one or more anti-HIV agents selected from the group consisting of: abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bicretiravir, cabozantinvir, darunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide. Claminophen, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, erteiravir, etravirine, fosampunavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobistat, maraviro, nelfinavivir, nelfinavivir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, telanavir, and velivirol, or combinations thereof. Other identified or developed anti-HIV agents or combinations thereof may also be suitable.

[0311] The adenosine derivatives disclosed herein (such as formulas (1)-(8), (1a), (1b), or (1-A)-(8-A)) in combination with one or more anti-HIV agents described herein may be used to treat or prevent AIDS or other HIV-related symptoms. The anti-HIV agents may be used in these combinations at their usual dosage ranges and regimens as reported in the art, including, for example, the dosages described in Physicians' Desk Reference, Thomson PDR, Thomson PDR, 57th edition (2003), 58th edition (2004), or 59th edition (2005) and the current Physicians' Desk Reference (68th edition). (2014), Montvale, NJ: PDR Network.

[0312] The adenosine derivatives disclosed herein and one or more anti-HIV agents described herein can be administered to subjects orally, parenterally, or in combination thereof, alone. The adenosine derivatives and the one or more anti-HIV agents can be administered to subjects according to a daily, weekly, bi-weekly, or monthly schedule.

[0313] This disclosure further relates to the use of pharmaceutical compositions for treating a disease in a subject of need, said disease being acquired immunodeficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with the K65R mutation, multidrug-resistant HIV, or RNA virus infection. Any of the aforementioned pharmaceutical compositions may be suitable. The pharmaceutical composition may be used in combination with one or more anti-HIV agents to treat the diseases mentioned herein. The adenosine derivative and said one or more anti-HIV agents may be administered to the subject orally, parenterally, or in combination thereof, alone. The adenosine derivative and said one or more anti-HIV agents may be administered to the subject on a daily, weekly, bi-weekly, or monthly dosing schedule.

[0314] This disclosure further relates to the use of the adenosine derivatives disclosed herein, optionally one or more pharmaceutically acceptable carriers, in the manufacture of medicaments for treating diseases, wherein the disease is acquired immunodeficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multidrug-resistant HIV, or RNA virus infection. The aforementioned adenosine derivatives may be suitable. The aforementioned pharmaceutically acceptable carriers may be suitable.

[0315] This disclosure further relates to a method for preventing infection in a subject in need, the method comprising administering to the subject an effective dose of a pharmaceutical composition of the method of the present invention disclosed herein, wherein the subject has no detectable symptoms of infection. In some embodiments, the infection includes a disease selected from: acquired immunodeficiency syndrome (AIDS) and the following infections: wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multidrug-resistant HIV, RNA virus infection, or a combination thereof.

[0316] The detectable symptoms include, but are not limited to, symptoms of acquired immunodeficiency syndrome (AIDS) and symptoms of HIV infection including: wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multidrug-resistant HIV, or combinations thereof. HIV detection can be performed by PCR, reverse PCR, or immunoassay for AIDS or HIV-related antigens or antibodies.

[0317] In some embodiments, the pharmaceutical composition of the method of the present invention is administered to the subject at a daily, weekly, bi-weekly, or monthly schedule.

[0318] In some embodiments, the method of this disclosure further includes administering to a subject an effective dose of one or more anti-HIV agents selected from: abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bicitiravir, cabozantivir, darunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, 4'-ethynyl-2-fluoro-2'-deoxy Adenosine, erteiravir, etravirine, fosampunavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobistat, maraviro, nelfinavivir, nelfinavivir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, titranavivir, vicriviroc, or combinations thereof. One or more of these anti-HIV agents may be administered to a subject, either together or alone, with the pharmaceutical compositions disclosed herein.

[0319] Unbound by any particular theory, the adenosine derivatives disclosed herein (such as formulas (1)-(8), (1a), (1b), (1-A)-(8-A), (4-B), or (4-C)) have the advantage of rapid conversion to the target drug. As described below, within approximately 30 minutes of contact with human plasma, more than approximately 60% of the adenosine derivatives of this disclosure can be surprisingly and unexpectedly converted to the target drug.

[0320] This disclosure will now be illustrated by example in the following non-limiting embodiments.

[0321] Example

[0322] The present invention is further defined in the following embodiments. It should be understood that while these embodiments point to preferred embodiments of the invention, they are given by way of example only. From the above discussion and these embodiments, those skilled in the art can determine the essential features of the invention, and various changes and modifications can be made to adapt the invention to various uses and conditions without departing from its spirit and scope.

[0323] Properties of adenosine derivatives

[0324] The properties of adenosine derivatives are listed in Table 1.

[0325] Table 1. Naming and Properties.

[0326]

[0327]

[0328] Synthesis of adenosine derivative prodrugs:

[0329] The preparation method, intermediates, and synthesis timeline are summarized below.

[0330] Intermediate 1

[0331] N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]tert-butyl carbamate

[0332]

[0333] Preparation of N-(2-fluoro-9H-purin-6-yl)carbamate tert-butyl ester

[0334]

[0335] (Boc)₂O (24.94 g, 114.29 mmol, 26.3 mL, 3.5 eq) in THF (25 mL) was added to a suspension of 2-fluoro-9H-purine-6-amine (5 g, 32.65 mmol, 1 eq) and DMAP (399 mg, 3.27 mmol, 0.1 eq) in THF (50 mL) under stirring at 0 °C. The resulting suspension was stirred at 10 °C for 16 h, diluted with MTBE (100 mL), and quenched with water (100 mL). The organic layer was separated and washed with citric acid aqueous solution (10 wt%, 100 mL), water (2 x 100 mL), and saturated sodium chloride aqueous solution (100 mL). The organic layer was concentrated under reduced pressure to obtain N-tert-butoxycarbonyl-N-(2-fluoro-9H-purin-6-yl)carbamate tert-butyl ester (11.5 g, crude product), which was a yellow oil and was used in the next step of the reaction without further purification.

[0336] NaOH (2.5 M, 78.1 mL, 6 eq) was added over 30 minutes to a mixture of N-tert-butoxycarbonyl-N-(2-fluoro-9H-purin-6-yl)carbamate tert-butyl ester (11.5 g, 32.55 mmol, 1 eq) and EtOH (100 mL) at 20 °C, and the resulting mixture was stirred at 20 °C for 48 hours. LCMS showed a main peak with the desired m / z. The mixture was post-treated by distilling the solvent under reduced pressure, cooling the aqueous solution to 0 °C, and neutralizing it with hydrochloric acid (1 M, 150 mL) to obtain a slurry. The solid was collected by filtration and dissolved in EtOAc (200 mL), washed with water (2 x 150 mL) and saturated sodium chloride aqueous solution (150 mL). The resulting solution was concentrated under reduced pressure to give N-(2-fluoro-9H-purin-6-yl)carbamate tert-butyl ester (4 g, 15.80 mmol, 48.5% yield) as a white solid. The crude product was used in the next reaction without further purification. LCMS (ESI) m / z, C 10 H 12 FN5O2: Calculated value 253.1, measured value (M+H) + 253.9; (M+Na) + :275.9.

[0337] Preparation of methyl 4-methylbenzoic acid [(2R,3S)-2-ethynyl-3-(4-methylbenzoyl)oxy-5-pent-4-enoxy-tetrahydrofuran-2-yl] ester

[0338]

[0339] A solution of 4-methylbenzoic acid hydrate (964 mg, 5.07 mmol, 1 eq) and pent-4-en-1-ol (480 mg, 5.58 mmol, 1.1 eq) in toluene (28 mL) was added to a solution of 4-methylbenzoic acid [(2R,3S)-2-ethynyl-5-hydroxy-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (2 g, 5.07 mmol, 1 eq) in toluene (32 mL). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with water (100 mL). The organic layer was separated and washed with saturated sodium bicarbonate aqueous solution (100 mL), water (100 mL), and saturated sodium chloride aqueous solution (100 mL). The organic layer was concentrated under reduced pressure. The crude product was subjected to rapid silica gel chromatography (…). 40g Purification with a Silica Flash Column (eluting at 40 mL / min using a gradient of 0–8% ethyl acetate / petroleum ether) yielded methyl 4-methylbenzoic acid [(2R,3S)-2-ethynyl-3-(4-methylbenzoyl)oxy-5-pent-4-enoxy-tetrahydrofuran-2-yl] ester (1.38 g, 58.2% yield) as a colorless oil. LCMS (ESI) m / z, C 28 H 30 O6: Calculated value 462.2, measured value (M+Na) + 485.1

[0340] Preparation of 4-methylbenzoic acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxytetrahydrofuran-2-yl]methyl ester

[0341]

[0342] 4-Methylbenzoic acid [(2R,3S)-2-ethynyl-3-(4-methylbenzoyl)oxy-5-pent-4-enoxy-tetrahydrofuran-2-yl]methyl ester (200 mg, 0.43 mmol, 1 eq), N-(2-fluoro-9H-purin-6-yl)carbamate tert-butyl ester (131 mg, 0.52 mmol, 1.2 eq) and The mixture of MS (1 g, 0.32 mmol) in MeCN (4 mL) was cooled to -25 °C. I2 (351 mg, 1.38 mmol, 3.2 eq) was added, and the resulting mixture was stirred at -25 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was then heated to 0 °C and stirred at 0 °C for 2 hours. The reaction was quenched with an aqueous sodium sulfite solution (10 mL), diluted with water (10 mL), and extracted with MTBE (30 mL). The resulting organic layer was washed with an aqueous sodium bicarbonate solution (10 mL) followed by an aqueous sodium chloride solution (10 mL). The organic layer was then concentrated under reduced pressure and analyzed by rapid silica gel chromatography (…). 4g Purified by silica flash column (eluting at 20 mL / min with a gradient of 0–50% ethyl acetate / petroleum ether) to give methyl 4-methylphenyl acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxytetrahydrofuran-2-yl] ester (155 mg, 50.0% yield) as a white solid. LCMS (ESI) m / z, C 35 H 32 FN5O7: Calculated value 629.2, measured value (M+H)+ 630.1

[0343] Preparation of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl] tert-butyl carbamate

[0344]

[0345] A mixture of 4-methylbenzoic acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxytetrahydrofuran-2-yl]methyl ester (155 mg, 0.246 mmol, 1 eq) in THF (1 mL) was added to NaOMe (133 mg, 0.739 mmol, 30%, 3 eq) in MeOH (0.5 mL), and the resulting mixture was stirred at -25 °C for 6 hours. The mixture was then neutralized with AcOH (0.2 mL) and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography (…). 12g The silica flash column was purified by elution with a 0–5% MeOH / DCM gradient at 30 mL / min to give N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tert-butyl ester (82 mg, 85.4% yield) as a white solid. LCMS (ESI) m / z, C 17 H 20 FN5O5: Calculated value 393.1, measured value (M+Na) + :416.2.

[0346] Intermediate 2 (Method 1):

[0347] (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0348]

[0349] Preparation of methyl 4-methylbenzoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester

[0350]

[0351] TFA (0.25 mL) was added to a solution of 4-methylbenzoic acid (2R,3S,5R)-5-(6-((tert-butoxycarbonyl)amino)-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl ester (220 mg, 0.35 mmol, 1 eq) in toluene (2.5 mL). The mixture was stirred at 10 °C for 48 hours. The mixture was quenched by adding saturated sodium bicarbonate (10 mL) and extracted with EtOAc (2 x 10 mL). The organic layer was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The silica flash column was used for purification (eluting at a rate of 20 mL / min with a gradient of 0–100% ethyl acetate / petroleum ether) to give 4-methylbenzoic acid (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl ester (130 mg, 70% yield) as a white solid. 28 H 24 LCMS (ESI) m / z of FN5O5: Calculated value 529.5, measured value (M+Na) + :552.1.

[0352] Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0353]

[0354] A mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl ester (130 mg, 0.246 mmol, 1 eq) in THF (1 mL) was cooled to -25 °C. Then, NaOMe (133 mg, 0.737 mmol, 30% purity, 3 eq) was added to MeOH (0.5 mL), and the mixture was stirred at -25 °C for 3 hours. The mixture was neutralized with AcOH (0.2 mL) and concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The silica flash column was purified by elution with a gradient of 0–8% MeOH / DCM at a rate of 20 mL / min to give (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (46 mg, 64% yield) as a white solid. 12 H 12 LCMS (ESI) m / z of FN5O3: Calculated value 293.2, measured value (M+H) + :294.1. 1 H NMR(DMSO-d6,400MHz)δ(ppm)8.30(s,1H),7.89(br s,2H),6.24(dd,J=7.2,5.2Hz,1H),5.58(d,J=5.6Hz,1H),5.30(t,J=6.4Hz,1H),4.52-4.61(m,1H), 3.62-3.68(m,1H),3.55(dd,J=12.0,6.8Hz,1H),3.52(s,1H),2.64-2.75(m,1H),2.37-2.47(m,1H). 19 F NMR(DMSO-d6,376MHz)δ(ppm)-51.98(br s,1F).

[0355] Intermediate 2 (Method 2):

[0356] (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0357]

[0358] Preparation of 4-methylbenzoic acid (2R,3S,5R)-2-ethynyl-5-(2-fluoro-6-((trimethylsilyl)amino)-9H-purin-9-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl ester

[0359]

[0360] CaH2 was added to acetonitrile and refluxed for 2 hours. Then, the vapor was blown out under nitrogen protection to obtain anhydrous CH3CN.

[0361] BSA (13.98 g, 68.74 mmol, 16.99 mL, 3 eq) was added to a solution of 2-fluoro-9H-purine-6-amine (4.39 g, 28.64 mmol, 1.25 eq) in anhydrous CH3CN (60 mL) under N2. The mixture was stirred at 80 °C for 1 hour. After the reaction mixture was cooled to 25 °C, TMSOTf (6.11 g, 27.49 mmol, 4.97 mL, 1.2 eq) was added, and the reaction mixture was stirred at 25 °C for 1 hour. Then, 4-methylbenzoic acid [(2R,3S)-5-acetoxy-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (10 g, 22.91 mmol, 1 eq) was added to anhydrous CH3CN (60 mL) for 1 hour at 80 °C, and the mixture was stirred at 80 °C under N2 for 16 hours. The reaction mixture was cooled to room temperature (15°C) and allowed to stand for 24 hours. The slurry was filtered and washed with cold anhydrous MeCN (10 mL), and the mixture was dried under vacuum to give methyl 4-methylbenzoic acid [(2R,3S,5R)-2-ethynyl-5-[2-fluoro-6-(trimethylsilylamino)purine-9-yl]-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester (6.58 g, 47.7% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.02 (d, J = 8.0Hz, 2H), 7.93 (d, J = 8.0Hz, 2H), 7.86 (s, 1H), 7.29 (d, J = 8.0Hz, 2H), 7.23 (d, J = 8.0Hz, 2H), 6.51 (t, J = 12Hz, 1H ),6.05(m,1H),4.82(d,J=20Hz,1H),4.67(d,J=20Hz,1H),3.23-3.19(m,1H ),2.90-2.85(m,1H),2.68(s,1H),2.43(d,J=16Hz,6H),0.49-0.29(m,9H). 19 F NMR (376MHz, CDCl3) δ (ppm)-49.34 (s, 1F).

[0362] Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0363]

[0364] NaOMe (6.96 g, 38.64 mmol, 30% purity, 1.5 eq) was slowly added to a solution of 4-methylbenzoic acid [(2R,3S,5R)-2-ethynyl-5-[2-fluoro-6-(trimethylsilylamino)purin-9-yl]-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (15.5 g, 25.76 mmol, 1 eq) in THF (150 mL) at -25 °C. The reaction mixture was stirred at -25 °C for 16 hours. The mixture was neutralized to pH ~7 with AcOH (0.5 mL) and then concentrated. The crude product was ground at 5 °C with CH3CN:H2O = 7:3 (100 mL) for 16 hours to obtain (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (6.76 g, 89%) as a white solid. 12 H 12 LCMS (ESI) m / z of FN5O3: Calculated value 293.2, measured value (M+H) + :294.1. 1 H NMR(400MHz,CD3CN)δ(ppm)7.99(s,1H),6.35(br s,2H),6.29(t,J=12Hz,1H),4.65(t,J=5.6Hz,1H),4.41(brs,1H),3.81-3.78(m,1H),3.71-3.68(m,1H),3.55(br s,1H),2.93(s,1H),2.82-2.77(m,1H),2.49-2.45(m,1H). 19 F NMR (376MHz, CD3CN) δ (ppm)-53.4 (s, 1F).

[0365] Intermediate 3:

[0366] (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideutero-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0367]

[0368] Preparation of tert-butyl trideuterium acetate

[0369]

[0370] DCC (167.02 g, 809.49 mmol, 1.5 eq) and DMAP (13.19 g, 107.93 mmol, 0.2 eq) were added to a mixture of 2-methylpropane-2-ol (40 g, 539.66 mmol, 51.61 mL, 1 eq) and deuterio-2,2,2-trideuterioacetate (51.87 g, 809.49 mmol, 1.5 eq) in DMF (700 mL). The mixture was stirred at 25 °C for 64 h. The reaction mixture was then distilled under vacuum (105 °C, 0.1 MPa) to give tert-butyl 2,2,2-trideuterioacetate as a colorless liquid (25.3 g, 39.3% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 1.45 (s, 9H).

[0371] Preparation of (4R)-2,2-dimethyl-4-(2-triisopropylsilylethynyl)-1,3-dioxopentane-4-carboxaldehyde

[0372]

[0373] Add IBX (108.06 g, 385.90 mmol, 3 eq) to a solution of [(4S)-2,2-dimethyl-4-(2-triisopropylsilylethynyl)-1,3-dioxonane-4-yl]methanol (40.2 g, 128.63 mmol, 1 eq) in MeCN (220 mL). Stir the mixture at 85 °C for 2 hours. Filter and concentrate the mixture to give (4R)-2,2-dimethyl-4-(2-triisopropylsilylethynyl)-1,3-dioxonane-4-carboxaldehyde (40 g, crude product) as a yellow oil.

[0374] Preparation of tert-butyl (3S)-2,2-dideuterated-3-[(4R)-2,2-dimethyl-4-(2-triisopropylsilylethynyl)-1,3-dioxopentan-4-yl]-3-hydroxypropionate

[0375]

[0376] LDA (2M in THF, 24.15 mL, 1.5 eq) was added to a solution of THF (45 mL) at -78 °C. 2,2,2-Trideuterated tert-butyl acetate (6.14 g, 51.53 mmol, 1.6 eq) was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. (4R)-2,2-dimethyl-4-(2-triisopropylsilylethynyl)-1,3-dioxonane-4-carboxaldehyde (10 g, 32.21 mmol, 1 eq) was added to THF (30 mL) at -78 °C, and the mixture was stirred at -78 °C for 2 hours. D₂O (20 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 330g The Silica Flash Column was purified by elution at 75 mL / min with a gradient of 0–70% DCM / petroleum ether to give tert-butyl (3S)-2,2-dideuterated-3-[(4R)-2,2-dimethyl-4-(2-triisopropylsilylethynyl)-1,3-dioxonane-4-yl]-3-hydroxypropionate (5.17 g, 37.5% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 4.22 (d, J = 8.8 Hz, 1H), 4.11 (d, J = 8.4 Hz, 1H), 4.01 (d, J = 4. 8Hz, 1H), 2.71 (d, J = 5.2Hz, 1H), 1.60 (s, 3H), 1.48 (s, 9H), 1.42 (s, 3H), 1.08 (s, 21H).

[0377] Preparation of tert-butyl (3S)-2,2-dideuterated-3-[(4R)-4-ethynyl-2,2-dimethyl-1,3-dioxonane-4-yl]-3-hydroxypropionate

[0378]

[0379] TBAF (1M in THF, 30.33mL, 1eq) was added to a solution of (3S)-2,2-dideuterated-3-[(4R)-2,2-dimethyl-4-(2-triisopropylsilylethynyl)-1,3-dioxono-4-yl]-3-hydroxy-propionate tert-butyl ester (13g, 30.33mmol, 1eq) in THF (130mL). The mixture was stirred at 25°C for 1 hour. Ethyl acetate (100mL) and H2O (100mL) were added, and the mixture was then extracted with ethyl acetate (100mL x 2). The combined organic layers were washed with brine (100mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 120g The silica flash column was purified by elution with a gradient of 0–15% ethyl acetate / petroleum ether at 60 mL / min to give tert-butyl (3S)-2,2-dideuterated-3-[(4R)-4-ethynyl-2,2-dimethyl-1,3-dioxonane-4-yl]-3-hydroxy-propionate (6.7 g, 81.1% yield) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 4.26 (d, J = 8.8Hz, 1H), 4.16 (d, J = 8.4Hz, 1H), 3.96 (d, J = 4.0Hz,1H),3.24–3.20(m,1H),2.55(s,1H),1.62(s,3H),1.50(s,9H),1.42(s,3H).

[0380] Preparation of 4-methylbenzoic acid [(1S)-3-tert-butoxy-2,2-dideuterated-1-[(4R)-4-ethynyl-2,2-dimethyl-1,3-dioxonane-4-yl]-3-oxopropyl] ester

[0381]

[0382] Add (3S)-2,2-dideuterated-3-[(4R)-4-ethynyl-2,2-dimethyl-1,3-dioxonane-4-yl]-3-hydroxy-propionate tert-butyl ester (6.7 g, 24.60 mmol, 1 eq) to a solution of 4-methylbenzoyl chloride (5.71 g, 36.90 mmol, 4.88 mL, 1.5 eq) in pyridine (60 mL). Stir the mixture at 0 °C for 16 hours. Add ice water (15 mL), and then stir the mixture at 0 °C for 15 minutes. Filter the mixture. Assay the resulting residue by rapid silica gel chromatography (…). 80g The silica flash column was used to elute the product with a gradient of 0–100% ethyl acetate / petroleum ether at a flow rate of 60 mL / min to give 4-methylbenzoic acid [(1S)-3-tert-butoxy-2,2-dideutero-1-[(4R)-4-ethynyl-2,2-dimethyl-1,3-dioxonane-4-yl]-3-oxopropyl] ester as a colorless oil (9.2 g, 95.8% yield).

[0383] Preparation of 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-2-(hydroxymethyl)-5-oxo-tetrahydrofuran-3-yl] ester

[0384]

[0385] To a solution of 4-methylbenzoic acid [(1S)-3-tert-butoxy-2,2-dideutero-1-[(4R)-4-ethynyl-2,2-dimethyl-1,3-dioxono-4-yl]-3-oxopropyl] ester (9.2 g, 23.56 mmol, 1 eq) in DME (90 mL), HCl (conc.) (7.16 g, 70.68 mmol, 7.02 mL, 36% purity, 3 eq) was added. The mixture was stirred at 50 °C for 16 hours. The mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 25g The Silica Flash Column was purified by elution with a gradient of 0–30% ethyl acetate / petroleum ether at a flow rate of 30 mL / min to give 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-2-(hydroxymethyl)-5-oxo-tetrahydrofuran-3-yl] ester (6.4 g, 98.3% yield) as a colorless oil.

[0386] Preparation of methyl 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-3-(4-methylbenzoyl)oxy-5-oxo-tetrahydrofuran-2-yl] ester

[0387]

[0388] Add 4-methylbenzoyl chloride (1.68 g, 10.86 mmol, 1.5 eq) to a mixture of 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-2-(hydroxymethyl)-5-oxo-tetrahydrofuran-3-yl] ester (2 g, 7.24 mmol, 1 eq) and pyridine (15 mL). Stir the resulting mixture at 0 °C for 16 h. Add water (50 mL) at 0 °C and extract with DCM (2 x 100 mL). Dry the combined organic phases over Na₂SO₄, filter, and concentrate. Examine the residue by rapid silica gel chromatography (…). 80g Purified by silica flash column (eluting at 60 mL / min with a gradient of 0–15% ethyl acetate / petroleum ether) to give methyl 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-3-(4-methylbenzoyl)oxy-5-oxo-tetrahydrofuran-2-yl] ester (2.5 g, 87.6% yield) as a white solid.

[0389] Preparation of methyl 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-5-hydroxy-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester

[0390]

[0391] At -78 °C, sodium bis(2-methoxyethoxy)aluminum hydride (2.75 g, 9.51 mmol, 2.64 mL, 70% purity, 1.5 eq) was added dropwise to a solution of methyl 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-3-(4-methylbenzoyl)oxy-5-oxo-tetrahydrofuran-2-yl] ester (2.5 g, 6.34 mmol, 1 eq) in DCM (16 mL) and toluene (36 mL). The mixture was stirred at -78 °C for 2 hours. The reaction was quenched by adding acetic acid (5 mL) in DCM (20 mL) over 10 minutes. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (50 x 3 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give methyl 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-5-hydroxy-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester (2.5 g, 99.5% yield) as a pale yellow liquid.

[0392] Preparation of methyl 4-methylbenzoic acid [(2R,3S)-5-acetoxy-4,4-dideuterated-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester

[0393]

[0394] At 0 °C, 4-(dimethylamino)pyridine (131 mg, 1.07 mmol, 0.17 eq) and TEA (747 mg, 7.38 mmol, 1.03 mL, 1.17 eq) were added to a mixture of 4-methylbenzoic acid [(2R,3S)-4,4-dideuterated-2-ethynyl-5-hydroxy-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (2.5 g, 6.31 mmol, 1 eq) and toluene (25 mL), followed by acetic anhydride (644 mg, 6.31 mmol, 0.60 mL, 1 eq). The resulting mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched with H₂O (10 mL). The resulting mixture was heated to ambient temperature and washed successively with aqueous citric acid solution (10 wt%, 30 mL), aqueous sodium bicarbonate solution (5 wt%, 30 mL), and water (30 mL), concentrating the organic layer. The resulting residue was subjected to rapid silica gel chromatography (…). 40g The silica flash column was used to elute the product with a gradient of 0–20% ethyl acetate / petroleum ether at a flow rate of 30 mL / min to give methyl 4-methylbenzoic acid [(2R,3S)-5-acetoxy-4,4-dideuterated-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester (2.2 g, 79.6% yield) as a colorless oil.

[0395] Preparation of methyl 4-methylbenzoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideuterated-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester

[0396]

[0397] Bis(trimethylsilyl)acetamide (3.06 g, 15.05 mmol, 3 eq) was added to a solution of 2-fluoro-9H-purine-6-amine (960 mg, 6.27 mmol, 1.25 eq) in MeCN (20 mL). The mixture was stirred at 80 °C for 1 hour. When the reaction mixture was cooled to 25 °C, TMSOTf (1.34 g, 6.02 mmol, 1.09 mL, 1.2 eq) was added and the reaction mixture was stirred at 25 °C for 1 hour. Then, methyl 4-methylbenzoic acid [(2R,3S)-5-acetoxy-4,4-dideuterated-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester (2.2 g, 5.02 mmol, 1 eq) was added to MeCN (15 mL) at 80 °C for 1 hour, and the mixture was stirred at 80 °C for 16 hours. Add DCM (50 mL) and H2O (50 mL), then extract the mixture with DCM (50 x 2 mL). Wash the combined organic layers with brine (50 mL), dry to Na2SO4, filter, and concentrate. Separately, pass the resulting residue by rapid silica gel chromatography (…). 40g The silica flash column was purified by elution with 0–40% ethyl acetate / DCM at a rate of 30 mL / min to give methyl 4-methylbenzoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideuterated-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester (1.43 g, 53.6% yield) as a pale yellow solid.

[0398] Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideuterated-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0399]

[0400] A mixture of methyl 4-methylbenzoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideutero-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (1.4 g, 2.63 mmol, 1 eq) in THF (16 mL) was mixed with NaOMe (1.42 g, 7.90 mmol, 30% purity, 3 eq) in MeOH (8 mL). The mixture was stirred at -25 °C for 3 hours. The mixture was neutralized with AcOH (0.5 mL) and concentrated under reduced pressure to obtain a residue. The residue was subjected to rapid silica gel chromatography (…). 12g The Silica Flash Column was purified by elution with a gradient of 0–10% methanol / dichloromethane at a rate of 30 mL / min to give (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideuterated-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (710 mg, 91.3% yield) as a white solid.

[0401] Purification of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideutero-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0402]

[0403] (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-4,4-dideuterated-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (20 mg, 0.068 mmol, 1 eq) was purified by preparative-TLC (SiO2, DCM:MeOH = 10:1) to give (2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-4,4-dideuterated-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (6.2 mg, 31.0% yield) as a white solid. LCMS (ESI) m / z, C 12 H 10 D2FN5O3: Calculated value 295.10, measured value (M+H) + :296.1. 1 H NMR(400MHz,CD3CN)δppm 8.01(s,1H),6.40-6.31(m,3H),4.67(d,J=4.8Hz,1H),4.40-4.37(m,1H),3.84-3.72(m,1H),3.56(d,J=5.2Hz,1H),2.96(s,1H). 19 FNMR (376MHz, CD3CN) δppm-53.40 (s, 1F).

[0404] Intermediate 4:

[0405] (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl-d2)tetrahydrofuran-4,4-d2-3-ol

[0406]

[0407] Preparation of 9-[(2R,4S,5R)-4-[tert-butyl(dimethyl)silyl]oxy-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,3-dideuterated-5-ethynyl-tetrahydrofuran-2-yl]-2-fluoro-purine-6-amine

[0408]

[0409] TBSCl (1.41 g, 9.36 mmol, 1.15 mL, 4 eq) and 1H-imidazol (956 mg, 14.04 mmol, 6 eq) were added to a mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideuterated-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (690 mg, 2.34 mmol, 1 eq) in DMF (3 mL). The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated and diluted with H2O (30 mL) and extracted with EtOAc (30 x 3 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was subjected to rapid silica gel chromatography (…). 4g The silica flash column was used for purification (eluting with a gradient of 0–10% methanol / dichloromethane at a rate of 20 mL / min) to give 9-[(2R,4S,5R)-4-[tert-butyl(dimethyl)silyl]oxy-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,3-dideuterated-5-ethynyl-tetrahydrofuran-2-yl]-2-fluoro-purine-6-amine (1.1 g, 89.8% yield) as a white solid. 24 H 38 LCMS (ESI) m / z of D2FN5O3Si2: Calculated value 523.3, measured value (M+H) + :524.6.

[0410] Preparation of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-yl]methanol

[0411]

[0412] 9-[(2R,4S,5R)-4-[tert-butyl(dimethyl)silyl]oxy-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,3-dideuterated-5-ethynyl-tetrahydrofuran-2-yl]-2-fluoro-purine-6-amine (1.1 g, 2.10 mmol, 1 eq) was mixed with THF (12 mL), H2O (3 mL), and TFA (3 mL). The reaction mixture was stirred at 0 °C for 16 hours. The resulting mixture was concentrated. The residue was subjected to rapid silica gel chromatography (…). 12g The Silica Flash Column was purified by elution with a gradient of 0–10% ethyl acetate / petroleum ether at a flow rate of 30 mL / min to give [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-yl]methanol (590 mg, 68.6% yield) as a white solid. 18 H 24 LCMS (ESI) m / z of D2FN5O3Si: Calculated value 409.19, measured value (M+H) + :410.1.

[0413] Preparation of (2S,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-carboxylic acid

[0414]

[0415] TEMPO (45 mg, 0.29 mmol, 0.2 eq) and PhI(OAc)2 (557 mg, 1.73 mmol, 1.2 eq) were added to a mixture of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-yl]methanol (590 mg, 1.44 mmol, 1 eq) in H2O (0.05 mL). The reaction mixture was stirred at 25 °C for 2 hours, and then DCM (10 mL) and CH3CN (0.05 mL) were added. The resulting mixture was stirred at 25 °C for 14 hours. The reaction mixture was filtered, and the filter cake was washed with petroleum ether (5 mL) and then concentrated to give (2S,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-carboxylic acid (330 mg, 54.1% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.30 (s, 1H), 7.87 (s, 2H), 6.34 (s, 1H), 4.94 (s, 1H), 3.66 (s, 1H), 0.92 (s, 9H), 0.13-0.12 (d, J = 4Hz, 6H).

[0416] Preparation of (2S,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-carboxylic acid methyl ester

[0417]

[0418] TMSCHN2 (2.0 M, 0.22 mL, 3 eq) was added to a mixture of (2S,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-carboxylic acid (60 mg, 0.14 mmol, 1 eq) in toluene (4 mL) and MeOH (3.2 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g Purification was performed using a SilicaFlash Column with a gradient elution of 0–10% methanol / dichloromethane at a rate of 20 mL / min to give (2S,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-carboxylic acid methyl ester (41 mg, 67% yield) as a white solid. 19 H 24 LCMS (ESI) m / z of D2FN5O4Si: Calculated value 437.54, measured value (M+H) + :438.5. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.20 (s, 1H), 6.52 (s, 1H), 5.81 (s, 2H), 4.88 (s, 1H), 3.86 (s, 3H), 2.70 (s, 1H), 0.96 (s, 9H), 0.18-0.17 (d, J = 4Hz, 6H). 19 F NMR (376MHz, CDCl3) δ (ppm)-50.588 (s, 1F).

[0419] Preparation of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-yl]-dideutero-methanol

[0420]

[0421] Sodium borohydride (29 mg, 0.68 mmol, 2 eq) was added to a mixture of (2S,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-carboxylic acid methyl ester (150 mg, 0.34 mmol, 1 eq) in i-PrOH (8 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The SilicaFlash Column was purified by elution with a gradient of 0–10% methanol / dichloromethane at a rate of 20 mL / min to give [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-yl]-dideutero-methanol (107 mg, 76.4% yield) as a white solid. 1 H NMR (400MHz, CD3CN) δ (ppm) 7.98 (s, 1H), 6.38 (s, 2H), 6.27 (s, 1H), 4.78 (s, 1H), 4.28 (s, 1H), 2.86 (s, 1H), 0.94 (s, 9H), 0.15-0.14 (d, J = 4Hz, 6H). 19 F NMR (376MHz, CD3CN) δ (ppm)-53.40 (s, 1F).

[0422] Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideuterated-2-[dideuterated (hydroxy)methyl]-2-ethynyl-tetrahydrofuran-3-ol

[0423]

[0424] At 0 °C, N,N-diethylethylamine trihydrofluorate (4.68 g, 29.06 mmol, 4.74 mL, 66.5 eq) was added to a mixture of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4,4-dideutero-2-ethynyl-tetrahydrofuran-2-yl]-dideutero-methanol (180 mg, 0.437 mmol, 1 eq) in pyridine (2.34 g, 29.28 mmol, 2.38 mL, 67 eq) and Et3N (1.72 g, 17.04 mmol, 2.37 mL, 39 eq). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The Silica Flash Column was used for purification (eluting with a 0–10% methanol / dichloromethane gradient at a rate of 20 mL / min) to give (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideuterated-2-[dideuterated(hydroxy)methyl]-2-ethynyl-tetrahydrofuran-3-ol as a white solid (80 mg, 61.5% yield). 12 LCMS (ESI) m / z of H8D4FN5O3: Calculated value 297.12, measured value (M+H) + :298.1. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.30 (s, 1H), 7.85 (s, 2H), 6.23 (s, 1H), 5.57-5.55 (d, J = 8Hz, 1H), 5.25 (s, 1H), 4.56-4.55 (d, J = 4Hz, 1H), 3.51 (s, 1H). 19 F NMR(376MHz,DMSO-d6)δ(ppm)-51.98(s,1F).

[0425] Example 1:

[0426] Isopropyl carbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0427]

[0428] Preparation of [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (4-nitrophenyl) ester

[0429]

[0430] A solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tert-butyl ester (80 mg, 0.203 mmol, 1 eq) in pyridine (0.8 mL) was added to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tert-butyl ester (80 mg, 0.203 mmol, 1 eq) at 10 °C. The mixture was stirred at 10 °C for 16 hours, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a crude product, [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (4-nitrophenyl) ester (114 mg, crude), which was used in the next reaction without further purification. LCMS(ESI) m / z, C 24 H 23 FN6O9: Calculated value 558.2, measured value (M+H) + :559.1.

[0431] Preparation of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(isopropylcarbamoyloxymethyl)tetrahydrofuran-2-yl]-2-fluoropurine-6-yl]tert-butyl carbamate

[0432]

[0433] Propane-2-amine (1.3 mg, 0.021 mmol, 1.2 eq) was added to a mixture of [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (10 mg, 0.018 mmol, 1 eq) and triethylamine (3.6 mg, 0.035 mmol, 2 eq) in THF (0.5 mL). The mixture was stirred at 15 °C for 2.5 h, water (5 mL) was added, and the mixture was extracted with EtOAc (2 x 10 mL). The organic layer was concentrated under reduced pressure. The crude product was purified by preparative-HPLC (column: Waters Xbridge Prep OBD C18 150*30 10u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 15%-45%, 11 min) to obtain N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(isopropylcarbamoyloxymethyl)tetrahydrofuran-2-yl]-2-fluoropurine-6-yl]carbamate tert-butyl ester (3.6 mg, 45.0% yield) as a white solid. LCMS (ESI) m / z, C 21 H 27 FN6O6: Calculated value 478.2, measured value (M+H) + 479.3; (M+Na) + :501.2.

[0434] Preparation of isopropyl carbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester

[0435]

[0436] TFA (77 mg, 0.68 mmol, 0.05 mL, 89.8 eq) was added to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(isopropylcarbamoyloxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate (3.6 mg, 0.0075 mmol, 1 eq) in DCM (0.5 mL) at 10 °C. The mixture was stirred at 10 °C for 40 hours. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Agela DuraShell 150mm x 25mm x 5um; mobile phase: [water (0.05% HCl)-ACN]; B%: 10%-40%, 8 min) to give isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester (1.2 mg, 40.0% yield) as a white solid. LCMS (ESI) m / z, C 16 H 19 FN6O4: Calculated value 378.2, measured value (M+H) + 379.3; (M+Na) + :401.2. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.27 (s, 1H), 7.85 (br s, 2H), 7.13 (br d, J = 4.8Hz, 1H), 6.24 (dd, J = 7.6, 5.2Hz, 1H), 4.55 (br t, J = 6.8Hz, 1H), 4.35 (br d,J=11.6Hz,1H),4.00(br d,J=11.6Hz,1H),3.61(s,1H),2.70-2.79(m,1H),2.40-2.43(m,1H),0.98-1.07(m,7H). 19 F NMR(376MHz,DMSO-d6)δ(ppm)-51.79(s).

[0437] Example 2:

[0438] Methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester

[0439] Preparation of methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester

[0440]

[0441] Methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester was prepared using the same procedure as isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester, but with propane-2-amine replaced by methylamine. LCMS(ESI) m / z, C 14 H 15 FN6O4: Calculated value 350.1, measured value (M+H) + :351.2. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.26 (s, 1H), 7.87 (br s, 2H), 7.13 (br d, J = 4.4Hz, 1H), 6.24 (dd, J = 7.6, 5.0Hz, 1H), 5.76 (br d, J = 4.4Hz, 1H), 4.55 (br d,J=5.2Hz,1H),4.35(d,J=11.6Hz,1H),4.03(d,J=11.6Hz,1H),3.60(s,1H),2.70-2.79(m,1H),2.54(s,3H),2.40-2.45(m,1H). 19 F NMR(376MHz,DMSO-d6)δ(ppm)-51.75(s).

[0442] Example 3:

[0443] (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate isopropyl ester

[0444]

[0445] Preparation of 4-methylbenzoic acid (2R,3S,5R)-5-[6-[bis(isopropoxycarbonyl)amino]-2-fluoro-9H-purin-9-yl]-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)-tetrahydrofuran-3-yl ester

[0446]

[0447] Isopropyl chloroformate (23 mg, 0.19 mmol, 2 eq) was added to a mixture of methyl 4-methylbenzoic acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (50 mg, 0.094 mmol, 1 eq) and Et3N (10 mg, 0.094 mmol, 1 eq) in DCM (1 mL) at 0 °C. The mixture was stirred at 15 °C for 16 hours. The mixture was concentrated under reduced pressure and 2 mL of water was added, followed by extraction with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure to give crude 4-methylbenzoic acid (2R,3S,5R)-5-(6-(bis(isopropoxycarbonyl)amino)-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl ester, which was used in the next reaction without further purification. LCMS(ESI) m / z, C 36 H 36 FN5O9: Calculated value 701.3, measured value (M+H) + :702.1.

[0448] Preparation of isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate

[0449]

[0450] NaOMe (34 mg, 0.19 mmol, 30%, 2 eq) was added to a solution of 4-methylbenzoic acid (2R,3S,5R)-5-[6-[bis(isopropoxycarbonyl)amino]-2-fluoro-9H-purin-9-yl]-2-ethynyl-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl] ester (66 mg, 0.094 mmol) in THF (1 mL) at -20 °C, and the resulting mixture was stirred at -20 °C for 16 h. Additional NaOMe (17 mg, 0.095 mmol, 30%, 1 eq) was added, and the mixture was stirred at -20 °C for another 40 h. The mixture was neutralized with AcOH (0.1 mL), concentrated under reduced pressure, and analyzed by rapid silica gel chromatography (…). 4g The Silica Flash Column was purified by elution at 20 mL / min with a 0–8% MeOH / DCM gradient and then purified again by preparative HPLC (column: Waters Xbridge Prep OBD C18 150x30 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5%–30%, 7 min) to give isopropyl 9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)carbamate (3.5 mg, 11% yield) as a white solid. LCMS (ESI) m / z, C 16 H 18 FN5O9: Calculated value 379.1 (Measured value (M+Na)) + :402.1). 1 HNMR (400MHz, CDCl3) δ (ppm) 8.17 (s, 1H), 7.98 (s, 2H), 6.41 (dd, J = 8.8, 5.6Hz, 1H), 5.13 (dt, J = 12.4, 6.4Hz, 1H), 5.04 (dd, J = 11.0, 3.0Hz, 1H) ,4.70-4.75(m,1H),4.09(dd,J=12.4,2.4Hz,1H),3.84-3.93(m,1H),3. 06-3.15(m,1H),2.83(s,1H),2.48-2.56(m,2H),1.36(d,J=6.0Hz,6H). 19 F NMR (376MHz, CDCl3) δ (ppm)-46.89 (s).

[0451] Example 4 (Method 1):

[0452] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester

[0453]

[0454] Preparation of S-ethyl thiocarbonate O-((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester

[0455]

[0456] A mixture of ethanethiol (16 g, 257.5 mmol, 19.1 mL, 1 eq) and triethylamine (26.1 g, 257.5 mmol, 35.8 mL, 1 eq) in THF (1 L) at -15 °C was added to bis(trichloromethyl) carbonate (76.4 g, 257.5 mmol, 1 eq) in THF (50 mL). The mixture was heated to 18 °C and stirred at 18 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to give S-ethylchlorothiocarbamate (13 g, crude), a yellow oil, which was used directly in the next reaction without further purification.

[0457] A mixture of 4-(hydroxymethyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one (13 g, 99.9 mmol, 1 eq) in Et2O (800 mL) at 0 °C was supplemented with pyridine (7.90 g, 99.9 mmol, 8.1 mL, 1 eq) and S-ethylchlorothiocarbamate (12.45 g, 99.9 mmol, 1.0 eq) in Et2O (200 mL). The mixture was stirred at 0 °C for 1 hour, then heated to 18 °C and stirred at 18 °C for 16 hours. The mixture was filtered and concentrated under vacuum, then absorbed into DCM (150 mL) and washed with saturated NaHCO3 (150 mL x 2) aqueous solution and water (150 mL x 2). The mixture was concentrated under reduced pressure and subjected to rapid silica gel chromatography (…). 120g The Silica Flash Column was purified by elution with a gradient of 0–15% ethyl acetate / petroleum ether at a flow rate of 70 mL / min to give methyl ethyl thioalkylcarboxylic acid (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) as a pale yellow oil (9.2 g, 42.2% yield). 1 H NMR (400MHz, CDCl3) δ4.95 (s, 2H), 2.89 (q, J = 7.2Hz, 2H), 2.19 (s, 3H), 1.32 (t, J = 7.2Hz, 3H).

[0458] Preparation of methyl chloroformate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)

[0459]

[0460] Thionyl chloride (618.5 mg, 4.58 mmol, 0.46 mL, 2 eq) was added to a mixture of methyl 5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl chloroformate (500 mg, 2.29 mmol, 1 eq) in DCM (50 mL). The resulting mixture was stirred at 20 °C for 1 hour. The reaction mixture was washed with water (50 mL x 2), 5% aq Na₂CO₃ (50 mL x 2), and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give methyl 5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl chloroformate (350 mg, crude) as a yellow oil. The product was dissolved in 10 mL of DCM and stored in a refrigerator.

[0461] Preparation of tert-butyl carbamate (9-(((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(((((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methoxy)carbonyl)oxy)methyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)carbamate

[0462]

[0463] To a mixture of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tert-butyl ester (100 mg, 0.25 nmol, 1 eq) in pyridine (2 mL) at 20 °C, methyl chloroformate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) (140 mg, 0.73 mmol, 4 mL, 2.86 eq, 35 mg / mL in DCM) was added, and the mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure and analyzed by rapid silica gel chromatography (…). 4g The silica flash column was purified by elution at 25 mL / min using a 0–5% MeOH / DCM gradient to give a yellow solid of [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purin-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester (45 mg, 32.2% yield). LCMS (ESI) m / z, C 23 H 24 FN5O 10 Calculated value: 549.2, Measured value (M+H) + :550.1.

[0464] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester

[0465]

[0466] TFA (154 mg, 1.35 mmol, 0.1 mL, 16.5 eq) was added to a mixture of [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester (45 mg, 0.082 mmol, 1 eq) and toluene (1 mL) at 20 °C. The mixture was stirred at 20 °C for 16 hours and then concentrated under reduced pressure. The resulting residue was purified by preparative-HPLC (column: Boston Green ODS 150x30mmx5um; mobile phase: [water (0.2% FA)-ACN]; B%: 13%-43%, 8 min) to give a white solid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester (11 mg, 25.4% yield). LCMS (ESI) m / z, C 18 H 16 FN5O6: Calculated value 449.1, measured value (M+H) + :450.1. 19 FNMR(376MHz,CD3OD)δ(ppm)-53.00(s). 1 H NMR(400MHz,CD3CN)7.92(s,1H),6.41-6.21(m,3H),4.87(d,J=5.2Hz,2H),4.77-4.67(m,1H),4.51(d,J=11.6Hz,1 H), 4.30 (d, J = 11.6Hz, 1H), 3.75 (d, J = 6.4Hz, 1H), 3.00 (s, 1H), 2.89-2.81 (m, 1H), 2.61-2.52 (m, 1H), 2.10 (s, 3H).

[0467] Example 4 (Method 2):

[0468] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester

[0469]

[0470] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate (4-nitrophenyl) ester

[0471]

[0472] Add 4-nitrophenyl chloroformate (82 mg, 0.41 mmol, 1.2 eq) to a mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (100 mg, 0.34 mmol, 1 eq) in pyridine (5 mL), and stir the mixture at 26 °C for 16 h. Then add 4-nitrophenyl chloroformate (82 mg, 0.41 mmol, 1.2 eq) and stir the mixture at 26 °C for 24 h. Perform rapid silica gel chromatography (…). 4g The silica flash column was purified by elution with a 0–5% DCM / MeOH gradient at 25 mL / min to give methyl carbonate [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (4-nitrophenyl) ester (80 mg, 51.2% yield) as a white solid. LCMS (ESI) m / z, C 19 H 15 FN6O7: Calculated value 458.4, measured value (M+H) + :459.1.

[0473] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester

[0474]

[0475] DMAP (3.6 mg, 0.023 mmol, 0.1 eq) was added to a mixture of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (4-nitrophenyl) ester (150 mg, 0.298 mmol, 1 eq) and 4-(hydroxymethyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one (96 mg, 0.745 mmol, 2.5 eq) in THF (3 mL). The mixture was stirred at 25 °C for 2 hours. The reaction solution was subjected to rapid silica gel chromatography (…). 24g The silica flash column was purified by elution with a gradient of 0–2.5% DCM / MeOH at a rate of 25 mL / min to give methyl carbonate [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl] methyl carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) methyl ester (85 mg, 63.5% yield) as a white solid. LCMS (ESI) m / z, C 18 H 16 The calculated value of FN5O8 is 449.4, and the measured value is 450.1 (M+H). + . 1 H NMR(400MHz,CD3CN)δ(ppm)7.91(s,1H),6.42-6.16(m,3H),4.93-4.79(m,2H),4.76-4.67(m,1H),4.53-4.46( m,1H),4.34-4.25(m,1H),3.77-3.69(m,1H),3.00(s,1H),2.90-2.78(m,1H),2.62-2.50(m,1H),2.10(s,3H). 19 F NMR (376MHz, CD3CN) δ (ppm)-52.87 (s, 1F).

[0476] Example 4 (Method 3):

[0477] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester

[0478]

[0479] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate (4-nitrophenyl) ester

[0480]

[0481] A mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (5 g, 17.05 mmol, 1 eq) in pyridine (50 mL) was added dropwise to DCM (16 mL) containing chloroformic acid (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester (16.42 g, 85.25 mmol, 5 eq). The mixture was then stirred at 16 °C for 10 min. The mixture was diluted with DCM (200 mL), washed with water (150 mL) and brine (150 mL x 2), dried over Na₂SO₄, filtered, and concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 80g The silica flash column was purified by elution with a 0–5% MeOH / DCM gradient at 65 mL / min to give methyl carbonate [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl] methyl carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) methyl ester (5.10 g, 11.35 mmol, 66.6% yield) as a pale yellow solid. LCMS (ESI) m / z, C 18 H 16 FN5O8: Calculated value 449.4, measured value (M+H) + :450.1. 1 H NMR (400MHz, CD3CN) δ (ppm) 7.92 (s, 1H), 6.34 (br s,2H),6.29-6.23(m,1H),4.93-4.81(m,2H),4.77-4.69(m,1H),4.51(d,J=11.6Hz,1H),4.30(d,J= 11.6Hz, 1H), 3.74 (d, J = 6.4Hz, 1H), 3.00 (s, 1H), 2.91-2.79 (m, 1H), 2.62-2.51 (m, 1H), 2.10 (s, 3H). 19 F NMR (376MHz, CD3CN) δ (ppm)-52.84 (s, 1F).

[0482] Recrystallization of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate (4-nitrophenyl) ester

[0483]

[0484] A mixture of methyl [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester (9.5 g, 21.14 mmol, 1 eq) in MeCN (50 mL) and EtOAc (50 mL) was heated at 80 °C for 30 min, and solid dissolution was observed. After cooling to room temperature (20 °C), the mixture was stirred at 20 °C for 16 h. The mixture was filtered and the filter cake was vacuum dried to give [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester (8.0 g, 17.80 mmol, 84.2% yield) as a white solid. LCMS(ESI) m / z, C 18 H 16 FN5O8: Calculated value 449.4, measured value (M+H) + :450.1. 1 H NMR (400MHz, CD3CN) δ (ppm) 7.92 (s, 1H), 6.31 (br s,2H),6.27-6.24(m,1H),4.92-4.81(m,2H),4.77-4.69(m,1H),4.51(d,J=11.6Hz,1H),4.30(d,J= 11.6Hz, 1H), 3.73 (d, J = 6.4Hz, 1H), 3.00 (s, 1H), 2.89-2.81 (m, 1H), 2.62-2.51 (m, 1H), 2.10 (s, 3H). 19 F NMR (376MHz, CD3CN) δ (ppm)-52.84 (s, 1F).

[0485] Example 5 (Method 1):

[0486] 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one

[0487]

[0488] Preparation of tert-butyl carbamate (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl)

[0489]

[0490] To a mixture of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tert-butyl ester (100 mg, 0.25 nmol, 1 eq) in DMF (5 mL), K₂CO₃ (70 mg, 0.51 mmol, 2 eq) and 4-(bromomethyl)-5-methyl-1,3-m-dioxanepentenyl-2-one (147 mg, 0.76 mmol, 3 eq) were added. The reaction mixture was then heated at 60 °C for 12 hours, concentrated, and diluted with H₂O (30 mL). The resulting mixture was extracted with EtOAc (30 x 3 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The Silica Flash Column was purified by elution with a gradient of 0–10% methanol / dichloromethane at a rate of 30 mL / min to obtain N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl] tert-butyl carbamate (45 mg, 35.0% yield). 1 HNMR (400MHz, CDCl3) δ (ppm) 8.02 (s, 1H), 6.40-6.43 (m, 1H), 5.02 (s, 2H), 4.70-4.73 (m, 2H), 4.09 (d, J = 12Hz, 1H ),3.90-3.92(m,1H),3.11-3.14(m,1H),2.85(s,1H),2.50-2.55(m,1H),2.45(bs,1H),2.22(s,3H),1.53(s,9H).

[0491] Preparation of 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one

[0492]

[0493] TFA (0.5 mL) was added to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl]carbamate (40 mg, 0.079 mmol, 1 eq) in dichloromethane (DCM) (3 mL) at 25 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated and purified by preparative HPLC (column: Boston Green ODS150*30mm*5um; mobile phase: [water (0.2% FA)-ACN]; B%: 15%-45%, 8 min) to give 4-(((9-(((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one (1.7 mg, 5% yield) as a white solid. LCMS (ESI) m / z, C 17 H 16 FN5O6: Calculated value 405.1, measured value (M+H) + 406.1. (M+Na) + :428.1. 1 H NMR (400MHz, CD3OD) δ (ppm) 8.26 (s, 1H), 6.38-6.35 (m, 1H), 4.76-4.72 (m, 1H), 4.51 (s, 1H), 3.87-3.84 (d ,J=12Hz,1H),3.78-3.75(d,J=12Hz,1H),3.09(s,2H),2.80-2.75(m,1H),2.64-2.57(m,1H),2.24(s,3H). 19 F NMR (376MHz, CD3OD) δ (ppm) -53.00.

[0494] Example 5 (Method 2):

[0495] 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one

[0496]

[0497] Preparation of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl] tert-butyl carbamate

[0498]

[0499] To a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tert-butyl ester (300 mg, 0.76 mmol, 1 eq) in DMF (5 mL), NaHCO3 (128 mg, 1.52 mmol, 2 eq) was added, followed by the addition of 4-(bromomethyl)-5-methyl-1,3-m-dioxanepentenyl-2-one (294 mg, 1.52 mmol, 2 eq). The mixture was stirred at 25 °C for 48 hours. The mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The silica flash column was purified by elution with a gradient of 0–100% ethyl acetate / petroleum ether at a rate of 20 mL / min to give N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl] tert-butyl carbamate (200 mg, 52% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.98 (s, 1H), 6.45-6.33 (m, 1H), 4.99 (s, 1H), 5.03-4.94 (m, 1H), 4.78 (br d, J = 11.2Hz, 1H), 4.71 (br s,1H),4.16-4.02(m,2H),3.11(br s,1H),2.80(s,1H),2.49(br d,J=7.2Hz,1H),2.42(br s,1H),2.19(s,3H),1.55(s,9H).

[0500] Preparation of 4-[[[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]amino]methyl]-5-methyl-1,3-m-dioxacyclopentenyl-2-one

[0501]

[0502] Add ZnBr2 (45 mg, 0.20 mmol, 2 eq) to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]-N-[(5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl]carbamate (5 mL) in CH3CN. Stir the mixture at 25 °C for 48 hours. Filter the reaction mixture and concentrate the filtrate. The resulting residue was purified by preparative-HPLC (FA conditions; column: 3-Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.2% FA)-ACN]; B%: 22%-52%, 6 min) to give a white solid 4-[[[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]amino]methyl]-5-methyl-1,3-m-dioxacyclopentenyl-2-one (19.8 mg, 48.8% yield). LCMS (ESI) m / z, C 17 H 16 FN5O6: Calculated value 405.34, measured value (M+H) + :406.1. 1 H NMR (400MHz, CD3OD) δ (ppm) 8.26 (s, 1H), 6.38-6.35 (m, 1H), 4.76-4.72 (m, 1H), 4.51 (br s,2H),3.87-3.84(d,J=12Hz,1H),3.78-3.75(d,J=12Hz,1H),3.09(s,1H),2.80-2.75(m,1H),2.64-2.57(m,1H),2.24(s,3H). 19 F NMR (376MHz, CD3OD) δ (ppm) -52.33.

[0503] Example 6:

[0504] (2-(methyl((5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl)amino)ethyl)carbamate((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester)

[0505]

[0506]

[0507] Preparation of tert-butyl (2-(methyl((5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl)amino)ethyl)carbamate

[0508]

[0509] Add 4-(bromomethyl)-5-methyl-1,3-m-dioxanepentenyl-2-one (500 mg, 2.59 mmol, 1 eq) to a mixture of N-[2-(methylamino)ethyl]carbamate (451 mg, 2.59 mmol, 1 eq) and K₂CO₃ (393.9 mg, 2.85 mmol, 1.1 eq) in DMF (15 mL), and stir the mixture at 20 °C for 16 hours. Concentrate the mixture under reduced pressure and analyze by rapid silica gel chromatography (…). 12g The Silica Flash Column was purified by elution with a gradient of 0-20% ethyl acetate / petroleum ether at a flow rate of 30 mL / min to give N-[2-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl]amino]ethyl]carbamate tert-butyl ester (500 mg, 1.75 mmol, 67.4% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 6.65 (m, 1H), 3.37 (s, 2H), 2.99 (m, 2H), 2.39 (m, 2H), 2.18 (s, 3H), 2.09 (s, 3H), 1.37 (s, 9H).

[0510] Preparation of 4-(((2-aminoethyl)(methyl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one

[0511]

[0512] TFA (1.54 g, 13.51 mmol, 1 mL, 1 eq) was added to a mixture of N-[2-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl]amino]ethyl]carbamate tert-butyl ester (200 mg, 0.699 nmol, 1 eq) and dichloromethane (2 mL) at 20 °C. The mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure to give 4-[[2-aminoethyl(methyl)amino]methyl]-5-methyl-1,3-m-dioxopentenyl-2-one (120 mg, crude product, 3 TFA) as a yellow oil. LCMS (ESI) m / z, C8H 14 N₂O₃: Calculated value 186.1, measured value (M+H) + :187.2.

[0513] Preparation of tert-butyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-((((2-(methyl((5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl)amino)ethyl)carbamoyl)oxy)methyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)carbamate

[0514]

[0515] To a mixture of [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (4-nitrophenyl) ester (34 mg, 0.060 mmol, 1 eq) and triethylamine (30 mg, 0.30 mmol, 5 eq) in dichloromethane (2 mL) at 20 °C, 4-[[2-aminoethyl(methyl)amino]methyl]-5-methyl-1,3-m-dioxacyclopentenyl-2-one (38 mg, 0.072 mmol, 1.2 eq, 3 TFA) was added, and the mixture was stirred at 20 °C for 16 hours. The mixture was then concentrated under reduced pressure and analyzed by rapid silica gel chromatography (…). 4g The silica flash column was purified by elution with a 0–5% dichloromethane / MeOH gradient at 25 mL / min to give N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-[2-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl]amino]ethylcarbamoyloxymethyl]tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tert-butyl ester (34 mg, 92.1% yield) as a yellow solid. LCMS (ESI) m / z, C 26 H32 FN7O9: Calculated value 605.2, measured value (M+Na) + :628.2.

[0516] Preparation of (2-(methyl((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl)amino)ethyl)carbamate((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester)

[0517]

[0518] TFA (129 mg, 1.13 mmol, 0.084 mL, 20.45 eq) was added to a mixture of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-[2-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl]amino]ethylcarbamoyloxymethyl]tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate tert-butyl (34 mg, 0.055 mmol, 1 eq) and toluene (1 mL), and the mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Gemini-NX 150x30mmx5um; mobile phase: [water (0.05% HCl)-ACN]; B%: 0%-30%, 7 min), and then repurified by preparative HPLC (column: Welch Xtimate C18 150x25mmx5um; mobile phase: [water (0.2% FA)-ACN]; B%: 1%-20%, 8 min) to give 4-(((9-(((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one (2.0 mg, 20.0% yield) as a white solid. LCMS (ESI) m / z, C 21 H 24 FN7O7: Calculated value 505.2, measured value (M+H) + 506.3, (M+Na) + :528.2. 1H NMR(400MHz,CD3OD)δ(ppm)8.15(s,1H),6.32(dd,J=8.0,4.0Hz,1H),4.80(m,1H),4.47(d,J=11.6Hz,1H),4.24(d,J=11.6Hz ,1H),3.45(s,2H),3.19(t,J=6.8,2H),3.17(s,1H),2.84(m,1H),2.66(m,1H),2.51(t,J=6.8,2H),2.30(s,3H),2.14(s,3H). 19 F NMR (376MHz, CD3OD) δ (ppm)-52.93 (s).

[0519] Example 7:

[0520] 4-(methyl(((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methoxy)carbonyl)amino)butyric acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0521]

[0522] Preparation of 4-(methylamino)butyric acid

[0523]

[0524] A mixture of 1-methylpyrrolidone-2-one (5.0 g, 50.44 mmol, 4.90 mL, 1 eq) and HCl (51.0 g, 531.53 mmol, 50 mL, 38% purity, 10.54 eq) was stirred at 165 °C for 16 hours. The reaction mixture was concentrated. The resulting residue was ground from acetone to give 4-(methylamino)butyric acid (4 g, 51.6% yield, HCl salt) as a white solid.

[0525] Preparation of 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyl]amino]butyric acid

[0526]

[0527] To a solution of 4-(methylamino)butyric acid HCl salt (1.36 g, 8.83 mmol, 1 eq) in H₂O (25 mL), NaHCO₃ (2.23 g, 26.49 mmol, 1.03 mL, 3 eq) was added, followed by the addition of chloroformic acid (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) methyl ester (1.7 g, 8.83 mmol, 1 eq) to THF (25 mL). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated and analyzed by rapid silica gel chromatography (…). 12g The Silica Flash Column was purified by elution with 0–5% methanol / dichloromethane at a rate of 20 mL / min to give 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methoxycarbonyl]amino]butyric acid (1.5 g, 62.2% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.07 (br s, 1H), 4.89 (s, 2H), 3.22 (br t, J = 7.2Hz, 2H), 2.81 (s, 3H), 2.28-2.03 (m, 5H), 1.69 (m, 2H).

[0528] Preparation of N-(4-chloro-4-oxo-butyl)-N-methyl-carbamate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester

[0529]

[0530] DMF (0.2 mg, 0.0026 mmol, 0.01 eq) and oxaloyl chloride (65 mg, 0.512 mmol, 0.045 mL, 2 eq) were added to a solution of 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyl]amino]butyric acid (70 mg, 0.256 mmol, 1 eq) in DCM (5 mL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to dryness to give N-(4-chloro-4-oxo-butyl)-N-methyl-carbamate (5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl) methyl ester (50 mg, crude) as a yellow oil, which was used in the next reaction without further purification.

[0531] Preparation of 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester]

[0532]

[0533] Add (66 mg, 0.226 mmol, 4.45 eq) of (4-chloro-4-oxo-butyl)-N-methyl-carbamate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester to a solution of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]carbamate (20 mg, 0.0508 mmol, 1 eq) in pyridine (2 mL). Stir the mixture at 20 °C for 16 hours. The reactants were concentrated to obtain 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (35 mg, crude), which was used in the next reaction without further purification.

[0534] Preparation of 4-(methyl(((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methoxy)carbonyl)amino)butyric acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0535]

[0536] TFA (770 mg, 0.675 mmol, 0.50 mL, 10%, 17.52 eq) was added to a solution of 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester (25 mg, 0.0386 mmol, 1 eq) in toluene (2 mL). The mixture was stirred at 20 °C for 16 hours and then concentrated to dryness. The residue was purified by preparative-HPLC (TFA conditions; column: Boston Green ODS 150*30mm*5um; mobile phase: [water (0.075% TFA)-ACN]; B%: 20%-50%, 12 min) to give 4-(methyl(((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methoxy)carbonyl)amino)butyric acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester (1.8 mg, 8.51% yield), which was a pale yellow solid. LCMS (ESI) m / z, C 23 H 26 FN6O 9,计算值 548.2, measured value (M+H) + : 549.2. 1 H NMR (400MHz, CD3OD) δ (ppm) 8.14 (s, 1H), 6.29 (m, 1H), 4.88 (s, 2H), 4.44 (t, J = 11.2Hz, 1H), 4.25 (t, J = 11.2Hz, 1H), 3.2 6-3.13(m,3H),2.96-2.86(m,2H),2.82(s,2H),2.64(m,1H),2.25(m,2H),2.16-2.07(m,3H),1.74(m,2H),1.31(s,1H). 19 F NMR (376MHz, CD3OD) δ (ppm)-52.82 (s).

[0537] Example 8:

[0538] N-(9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purin-6-yl)butyramide

[0539]

[0540] Preparation of 4-methylbenzoic acid [(2R,3S,5R)-5-[6-[butyryl(tert-butoxycarbonyl)amino]-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester

[0541]

[0542] To a solution of 4-methylbenzoic acid [(2R,3S,5R)-5-[6-(tert-butoxycarbonylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (74 mg, 0.118 mmol, 1 eq) in DCM (5 mL), DMAP (1.5 mg, 0.012 mmol, 0.1 eq), TEA (36 mg, 0.354 mmol, 3.0 eq), and butyryl chloride (25 mg, 0.235 mmol, 2 eq) were added. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated and diluted with H2O (30 mL), then extracted with EtOAc (15 x 3 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The silica flash column was used for purification (eluting at 18 mL / min with a gradient of 0–20% ethyl acetate / petroleum ether) to give methyl 4-methylbenzoic acid [(2R,3S,5R)-5-[6-[butyryl(tert-butoxycarbonyl)amino]-2-fluoro-purin-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester (30 mg, 30% yield), a pale yellow oil. LCMS (ESI) m / z, C 37 H 38 FN5O8: Calculated value 700.3, measured value (M+H) + :701.3.

[0543] Preparation of 4-methylbenzoic acid [(2R,3S,5R)-5-[6-(butyrylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester

[0544]

[0545] TFA (0.1 mL) was added to a solution of 4-methylbenzoic acid [(2R,3S,5R)-5-[6-[butyryl(tert-butoxycarbonyl)amino]-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (30 mg, 0.0428 mmol, 1 eq) in toluene (1 mL). The mixture was stirred at 25 °C for 16 hours. The mixture was diluted with H₂O (2 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (15 x 3 mL), dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by preparative-TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to give methyl 4-methylbenzoic acid [(2R,3S,5R)-5-[6-(butyrylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl] ester (18 mg, 64% yield), a pale yellow oil. LCMS (ESI) m / z, C 32 H 30 FN5O6: Calculated value 600.2, measured value (M+H) + :601.3.

[0546] Preparation of N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]butyramide

[0547]

[0548] CH3ONa (54 mg, 0.30 mmol, 30% purity in MeOH, 10 eq) was added to a solution of 4-methylbenzoic acid [(2R,3S,5R)-5-[6-(butyrylamino)-2-fluoro-purine-9-yl]-2-ethynyl-3-(4-methylbenzoyl)oxy-tetrahydrofuran-2-yl]methyl ester (18 mg, 0.030 mmol, 1 eq) in THF (2 mL). The mixture was stirred at -25 °C for 4 hours. The mixture was acidified with HOAc to pH 7 and then concentrated. The resulting residue was purified by preparative-HPLC (FA conditions; column: 3-Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.2% FA)-ACN]; B%: 15%–45%, 6 min) to give N-[9-[(2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-fluoro-purine-6-yl]butyramide (4.4 mg, 40% yield) as a white solid. LCMS (ESI) m / z, C 16 H 18FN5O4: Calculated value 364.1, measured value (M+H) + 365.2. 1 H NMR (400MHz, CD3CN) δ (ppm) 9.15 (bs, 1H), 8.26 (s, 1H), 6.37-6.34 (m, 1H), 4.70 (t, J = 6.4Hz, 1H), 3.82-3.78 (m, 1H), 3.74-3.69 ( m,1H),2.96-2.93(m,1H),2.84-2.75(m,2H),2.66(t,J=7.6Hz,2H),2.59-2.52(m,2H),1.74-1.67(m,2H),0.99(t,J=7.6Hz,3H). 19 F NMR (376MHz, CD3CN) δ (ppm)-51.9 (s, 1F).

[0549] Example 9:

[0550] [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideutero-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester

[0551]

[0552] Preparation of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideutero-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl carbonate

[0553]

[0554] To a mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideutero-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (60 mg, 0.203 mmol, 1 eq) in pyridine (0.5 mL), methyl chloroformate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) in DCM (0.5 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The silica flash column was used to purify the product by elution with a 0–5% methanol / dichloromethane gradient at 18 mL / min to give a white solid [(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-4,4-dideutero-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl carbonate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl ester (21 mg, 22.9% yield). LCMS (ESI) m / z, C 18 H 14 D2FN5O8: Calculated value 451.11; Measured value (M+H) + :452.1. 1 H NMR (400MHz, CD3CN) δ (ppm) 7.92 (s, 1H), 6.31 (s, 2H), 6.25 (s, 1H), 4.9-4.82 (m, 2H), 4.73-4.71 (d, J=8Hz, 1H ),4.52-4.50(d,J=8Hz,1H),4.32-4.29(d,J=12Hz,1H),3.74-3.72(d,J=8Hz,1H),3.00(s,1H),2.10(s,3H). 19 F NMR (376MHz, CD3CN) δ (ppm)-52.84 (s, 1F).

[0555] Example 10:

[0556] [[(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideutero-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]-dideutero-methyl] ester (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) methyl ester

[0557]

[0558] Preparation of methyl carbonate [[(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideuter-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]-dideuter-methyl] ester (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) ester

[0559]

[0560] Add dropwise to a mixture of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-4,4-dideutero-2-[dideutero(hydroxy)methyl]-2-ethynyl-tetrahydrofuran-3-ol (50 mg, 0.168 mmol, 1 eq) in pyridine (0.5 mL) to DCM (0.5 mL) methyl chloroformate (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) (162 mg, 0.84 mmol, 5 eq). Stir the resulting mixture at 25 °C for 3 hours. Concentrate the reaction mixture. Examine the resulting residue by rapid silica gel chromatography (…). 4g The silica flash column was purified by elution with a 0–5% methanol / dichloromethane gradient at 18 mL / min to give a white solid [[(2R,3S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-4,4-dideuter-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]-dideuter-methyl] ester (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) methyl ester (40.6 mg, 53% yield). LCMS (ESI) m / z, C 18 H 12 D4FN5O8: Calculated value 453.3, measured value (M+H) + :454.2. 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.92(s,1H),6.31(s,2H),6.25(s,1H),4.91-4.82(m, 2H), 4.72-4.71 (d, J = 4Hz, 1H), 3.74-3.72 (d, J = 8Hz, 1H), 3.00 (s, 1H), 2.10 (s, 3H). 19 F NMR(376MHz,DMSO-d6)δ(ppm)-52.85(s,1F).

[0561] Example 11:

[0562] ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl butyl carbonate

[0563]

[0564] Preparation of ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl butyl carbonate

[0565]

[0566] Butyl chloroformate (26 mg, 0.187 mmol, 1 eq) was slowly added 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 eq) in pyridine (0.5 mL) at 0 °C, and the mixture was stirred for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to rapid silica gel chromatography (…). 4g The compound was purified by silica flash column elution at 30 mL / min with 0–5% MeOH / DCM to give a white solid of methyl butyl carbonate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) (7.6 mg, 11.3% yield). LCMS (ESI) m / z, C 17 H 20 FN5O5: Calculated value 393.14, measured value (M+H) + :394.1. 1 H NMR (400MHz, CD3CN) δ (ppm): 7.96 (s, 1H), 6.27 (m, 3H), 4.73 (q, J = 6.8Hz, 1H), 4.46 (d, J = 11.6Hz, 1H), 4.31-4.23 (m, 1H), 4.1 0-3.99(m,2H),3.75-3.66(m,1H),2.99(s,1H),2.85(m,1H),2.57(m,1H),1.61-1.52(m,2H),1.28(m,2H),0.94-0.87(m,3H); 19 F NMR (376MHz, CD3CN) δ (ppm): -52.86 (s, 1F).

[0567] Example 12:

[0568] (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester

[0569]

[0570] Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol

[0571]

[0572] Imidazole (349 mg, 5.13 mmol, 3 eq) and TBSCl (386 mg, 2.56 mmol, 1.5 eq) were added to a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (0.5 g, 1.71 mmol, 1 eq) in DMF (5 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The Silica Flash Column was purified by elution with 0–5% MeOH / DCM at 18 mL / min to give (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (331 mg, 47.5% yield) as a pale yellow solid. 1 H NMR (400MHz, CD3CN) δ (ppm) 8.03 (s, 1H), 6.39-6.17 (m, 3H), 4.71 (q, J = 6.8Hz, 1H), 3.93-3.87 (m, 1H), 3.84-3.76 (m, 1H), 3.49(d,J=6.4Hz,1H),2.91(s,1H),2.85-2.73(m,1H),2.55(m,1H),2.50(s,2H),0.88-0.82(m,9H),0.02(d,J=16Hz,6H); 19 F NMR (376MHz, CD3CN) δ (ppm)-53.04 (s, 1F).

[0573] Preparation of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-yl] ester (4-nitrophenyl) ester

[0574]

[0575] Add pyridine (0.40 mL, 20 eq) and (4-nitrophenyl) chloroformate (494 mg, 2.45 mmol, 10 eq) to a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (100 mg, 0.245 mmol, 1 eq) in THF (2 mL). Stir the mixture at 25 °C for 50 hours. Concentrate the reaction mixture. Examine the resulting residue by rapid silica gel chromatography (…). 4g The compound was purified by silica flash column (eluting with 0-5% MeOH / DCM at 18 mL / min) to give the compound [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-yl] ester (4-nitrophenyl) ester (178 mg, crude) as a pale yellow solid.

[0576] Preparation of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-yl] ester (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) methyl ester

[0577]

[0578] To a solution of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-yl] ester (4-nitrophenyl) ester (249 mg, 0.435 mmol, 1 eq) in THF (4 mL), DMAP (5 mg, 0.043 mmol, 0.1 eq) and 4-(hydroxymethyl)-5-methyl-1,3-m-dioxanepentenyl-2-one (170 mg, 1.30 mmol, 3 eq) were added. The mixture was stirred at 30 °C for 2 hours. The reaction mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The compound was purified by silica flash column (eluting at 18 mL / min with 0–5% MeOH / DCM) to give the compound [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-ethynyl-tetrahydrofuran-3-yl] ester (5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) methyl ester (239 mg, 97.6% yield) as a brown solid. 1 H NMR (400MHz, CD3CN) δ (ppm): 8.06-7.95 (m, 1H), 6.42-6.26 (m, 3H), 5.61 (m, 1H), 4.97 (m, 2H), 3.98-3.93 (m, 1H), 3 .89-3.83(m,1H),3.16-3.03(m,1H),2.95(s,1H),2.70(m,1H),2.15(s,3H),0.86(s,9H),0.04(d,J=10.3Hz,6H); 19 F NMR (376MHz, CD3CN) δ (ppm): -52.66 (s, 1F).

[0579] Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester

[0580]

[0581] At 0 °C, methyl 5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl) carbonate (359 mg, 0.637 mmol, 1 eq) was added to a solution of pyridine (3.5 mL) and TEA (3.5 mL), followed by stirring of N,N-diethylethylamine trihydrofluoride (3.55 g, 22.02 mmol, 34.58 eq). The mixture was then stirred at 25 °C for 1 hour. The reaction mixture was concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g Silica Flash Column was purified at 18 mL / min with 0–5% MeOH / DCM to give a white solid (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester (230 mg, 80% yield). LCMS (ESI) m / z, C 18 H 16 FN5O8: 449.1, measured value (M+H) + :450.1. 1 H NMR(400MHz,CD3CN)δ(ppm):7.95(s,1H),6.47(s,2H),6.34(m,1H),5.53(m,1H),5.02 -4.93(m,3H),3.92-3.70(m,2H),3.07(m,1H),2.95(s,1H),2.61(m,1H),2.15(s,3H); 19 F NMR (376MHz, CD3CN) δ (ppm): -53.27 (s, 1F).

[0582] Example 13:

[0583] Carbonic acid ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-((((5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxy)carbonyl)oxy)tetrahydrofuran-2-yl)methyl ester((5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl) ester

[0584]

[0585] Preparation of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-[(4-nitrophenoxy)carbonyloxymethyl]tetrahydrofuran-3-yl] ester (4-nitrophenyl) ester

[0586]

[0587] Pyridine (674 mg, 8.53 mmol, 25 eq) and (4-nitrophenyl) chloroformate (1.03 g, 5.12 mmol, 15 eq) were added to a solution of (2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (100 mg, 0.341 mmol, 1 eq) in DCM (5 mL) at 26 °C. The mixture was stirred at 26 °C for 4 hours. The mixture was quenched with H2O (30 mL). DCM (30 mL) was added to the mixture and the mixture was washed with H2O (30 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was subjected to rapid silica gel chromatography (…). 4g The silica flash column was used to purify the product by elution with a 0–6% methanol / dichloromethane gradient at 18 mL / min to give a white solid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-[(4-nitrophenoxy)carbonyloxymethyl]tetrahydrofuran-3-yl] ester (4-nitrophenyl) ester (137 mg, 51% yield, 80% purity). LCMS (ESI) m / z, C 26 H 18 FN7O 11 Calculated value: 623.10, measured value: 624.1 (M+H) + .

[0588] Preparation of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyloxymethyl]tetrahydrofuran-3-yl] ester (5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl) methyl ester

[0589]

[0590] DMAP (1.9 mg, 0.016 mmol, 0.1 eq) and 4-(hydroxymethyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one (248 mg, 1.91 mmol, 12 eq) were added to a solution of [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-[(4-nitrophenoxy)carbonyloxymethyl]tetrahydrofuran-3-yl] ester (4-nitrophenyl) ester (99 mg, 0.159 mmol, 1 eq) in THF (5 mL). The mixture was stirred at 25 °C for 16 hours. The mixture was quenched with H2O (30 mL). DCM (30 mL) was added to the mixture. The mixture was washed with H2O (30 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated. The resulting residue was subjected to rapid silica gel chromatography (…). 4g The silica flash column was purified by elution with a 0–10% methanol / dichloromethane gradient at 18 mL / min to give [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyloxymethyl]tetrahydrofuran-3-yl] ester (5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl ester (89 mg, 56% yield, 60% purity). The substance was further purified by rapid silica gel chromatography and recrystallized (CH3CN / Hep) to provide a white solid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-2-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyloxymethyl]tetrahydrofuran-3-yl] ester (5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl ester). LCMS (ESI) m / z, C 24 H 20 FN5O 13 Calculated value: 605.10, Measured value (M+H) + :606.1. 1H NMR(400MHz,DMSO-d6)δ(ppm)8.30(s,1H),7.89(br s,2H),6.38-6.34(m,1H),5.62-5.59(m,1H),5.14-5.06(m,2H),4.99(s,2H),4.53(d,J=11.6Hz,1H), 4.37(d,J=11.6Hz,1H),3.83(s,1H),3.21-3.17(m,1H),2.73-2.70(m,1H),2.19(s,3H),2.14(s,3H). 19 F NMR(376MHz,DMSO-d6)δ(ppm)-51.47(s,1F).

[0591] Example 14:

[0592] Conversion and stability of adenosine derivative prodrugs

[0593] The stability of the prodrug and its conversion to the parent EFdA (formula T-1A) were measured in plasma and liver S9 assays, and the data are presented in Table 2.

[0594] plasma stability

[0595] Before the experiment, the collected frozen plasma was thawed in a water bath at 37°C. The plasma was centrifuged at 4000 rpm for 5 minutes, and any clots were removed. If necessary, the pH was adjusted to 7.4 ± 0.1.

[0596] Preparation of the test compound and positive control (bromopropylamine): A 1 mM intermediate solution was prepared by diluting 10 μL of the stock solution with 90 μL MeOH; a 1 mM positive control propylamine intermediate solution was prepared by diluting 10 μL of the stock solution with 90 μL ultrapure water. A 100 μM dosing solution was prepared by diluting 20 μL of the intermediate solution (1 mM) with 180 μL MeOH. Two aliquots of the dosing solution (100 μM) were added to 98 μL of blank plasma to achieve a final concentration of 2 μM, and the sample was incubated in a water bath at 37 °C. At each time point (0, 10, 30, 60, and 120 min), 400 μL of stop solution (0.1% FA in MeOH containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) was added to precipitate the protein and mix thoroughly. The sample plate was centrifuged at 4,000 rpm for 10 min. Transfer equal portions of the supernatant (100 μL) from each well to another plate.

[0597] Data Analysis: The remaining percentage of the test compound after incubation in plasma was calculated using the following equation:

[0598] Remaining % = 100 x (PAR at specified incubation time / PAR at time T0)

[0599] Where PAR is the peak area ratio of the analyte to the internal standard (IS) (LC / MS / MS mobile phase conditions: water containing 0.1% formic acid / acetonitrile containing 0.1% formic acid. The specified incubation time points are T0 (0 minutes) and Tn (n = 0, 10, 30, 60, 120 minutes).

[0600] Liver S9 stability

[0601] Intermediate solution: Dilute 5 μL of the compound or control (7-ethoxycoumarin) from the stock solution (10 mM) with 495 μL 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 of the test compound or control working solution / well to all plates except the matrix blank (T0, T5, T10, T20, T30, T60, NCF60). Add 600 μL / well of stop solution (cold at 4°C, containing 100 ng / mL tolbutamide / 100 ng / mL labetalol) to terminate the T0 plate and then place it on ice. Dispense 840 μL / well of S9 solution into 96-well plates as reservoirs according to the plate plot. Then add 100 μL / well to each plate via Apricot. Except for NCF60 and T0, the S9 solution and compounds were incubated at 37°C for approximately 10 minutes. After adding the S9 solution and 98 μL LPB buffer to NCF60, incubation was performed at 37°C without preheating, and timer 1 was started. After 60 minutes, 600 μL / well stop solution was added to terminate the reaction. After preheating, 760 μL / well of cofactor solution was dispensed into 96-well plates, which served as reservoirs, according to the plate plot. Then, 98 μL / well of Apricot was added to each plate to start the reaction. Incubation was performed at 37°C, timer 2 was started, and 600 μL / well stop solution (cold at 4°C, containing 100 ng / mL tolbutamide and labetalol) was added to terminate the reaction. The samples were centrifuged at 4000 rpm for 20 minutes. During centrifugation, 300 μL of HPLC water was loaded into a new 8×96-well plate, followed by the transfer of 100 μL of supernatant, which was then mixed with water for LC / MS / MS analysis. The mixture was then transferred to Bioanalytical Services for LC-MS / MS analysis. t was calculated using a first-order kinetic equation. 1 / 2 And CL: First-order dynamic equations:

[0602]

[0603]

[0604] CL int(S9) =Vd·k e

[0605] Vd = 1 mL / mg

[0606] The stability results of the exemplary compounds in human plasma and human liver S9 are listed in Table 2 below.

[0607] Table 2. Conversion and half-life data.

[0608]

[0609]

[0610] Half-life range: A: >200 minutes; B: 50-200 minutes; C: <50 minutes.

[0611] Data indicate that adenosine derivatives 4-A and 4-C can be efficiently converted into the target drug in human plasma and liver S9 assays, and 6-A can be efficiently converted into the target drug in liver S9 assays.

[0612] Example 15:

[0613] Plasma exposure after oral administration of prodrug to beagle dogs

[0614] The pharmacokinetics of EFdA and prodrug 4-A were investigated in dogs following oral administration of a dose of 5 mg-equivalent / kg EFdA.

[0615] Preparation: 0.5 hours before administration, prepare a 1.65 mg / mL solution of the prodrug in a 20% PEG400 aqueous solution.

[0616] Dosing and Sample Collection: The life-cycle of this study was conducted at the Charles River Laboratory (CRL) in Worcester, MA, in accordance with the CRL Institutional Animal Care and Use Committee (IACUC) standard animal procedures and the IACUC guidelines in accordance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals, and was approved by the IACUC Committee. Fasted male beagle dogs (10 ± 2 kg) were used for the study. Each drug was administered as a single dose via oral feeding (5 ml / kg). The prodrug formula 4-A dose (8.25 mg / kg) is equivalent to 5 mg / kg EFdA. Plasma samples were collected at 0 (before administration), 30 minutes after administration, and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. Blood (approximately 0.1 to 0.2 mL) was immediately processed into plasma by centrifugation at 3,500 rpm for 10 minutes at 5 °C upon collection. Plasma samples were frozen and maintained at -70 °C until analysis. To stabilize the prodrug during sample collection and subsequent analysis, the following stabilizing agents were added to the blood collection K2EDTA tubes on wet ice prior to sample collection: For every 100 mL of blood, 15 mL of a pre-prepared inhibitor mixture consisted of: 1 mM DFP, 100 mM dichlorvos, 100 mM 2-hydroxyquinoline, 100 mM PCMB, 1 mM paraoxon, 100 mM PMSF, 100 mM NaF, 30.0 mM EDTA, 15 mM citric acid, 10 mL of 0.2 M ethseripine, and 10 mL of 0.2 M BNPP solution.

[0617] Determination of EFdA and prodrug in plasma: In short, plasma (20 μL) was mixed with 100 μL acetonitrile to precipitate proteins. Consistent with the sample collection procedure, the same mixing protocol was also used to stabilize the prodrug in the standard and QC samples.

[0618] Bioanalysis: Quantitative analysis of plasma samples was performed using a Sciex API-6500 quadrupole mass spectrometer coupled with a Shimadzu HPLC system (Framingham, MA 01701). The column was a Waters HSS T3 column (2.1 x 50 mm, 1.8 mm). The mobile phases used were: A, 5% acetonitrile in 2 mM ammonium formate buffer; B, 95% acetonitrile in 2 mM ammonium formate buffer (pH 6.0). The flow rate was 0.6 mL / min and the total run time was 3.0 min. The HPLC gradient started at 98% A / 2% B and continued for 0.20 min, then increased linearly to 25% over the next 1.40 min; the gradient was then increased to 100% mobile phase B over the next 1.0 min, held for 0.2 min, and then gradually decreased to 2% mobile phase B over the next 0.2 min. Detection of prodrugs and EFdA was achieved using positive ion electrospray mass spectrometry in unit resolution mode. Multiple response monitoring (MRM) mode was used to quantify both the prodrug and EFdA; for example, the MRM for EFdA shifted to 294.0–153.90 Da, while that for the prodrug 4-A shifted to 450.0–153.9 Da. Peak areas were determined using the Sciex program running on a Windows 7 computer. Version 1.6.3 integrals, where the concentration is determined by a weighted (1 / x2) linear regression of the peak area ratio (peak area of ​​EFdA / peak area of ​​the corresponding IS) with respect to the nominal concentration of the plasma calibration standard. Unrounded numbers are calculated. In summary, The precision and accuracy of the calibration standards and QC samples were determined.

[0619] Pharmacokinetic calculations: Non-compartmental (NCA) analyses of EFdA and prodrug individual plasma concentration-time data were performed using the WinNonlin module in the Phoenix PK / PD platform (version 8.3.0.5005, Certara Inc., Princeton, NJ 08540). Calculations were performed before rounding, and the nominal sampling time was used in the pharmacokinetic analyses. Exposure is expressed as the area under the plasma concentration curve from 0 h to 24 h (AUC). 0-24h The AUC value is calculated using the linear trapezoidal rule.

[0620] Plasma Concentrations: Results of the PK studies are presented in Tables 3 and 4. These data confirm in vivo that prodrug formulation 4-A can be readily delivered orally and efficiently releases EFdA in vivo with minimal prodrug detection in systemic circulation. For example, prodrug formulation 4-A releases significantly more EFdA in vivo than an equivalent dose of EFdA, specifically 91%, 102%, 55%, 79%, and 200% more at 0.25, 0.5, 1, 2, and 4-hour time points, respectively (see Table 3). Furthermore, prodrug formulation 4-A produces higher AUC and C0 than an equivalent dose of EFdA. max (See Table 4.)

[0621] Table 3: Plasma concentrations of EFdA and prodrug 4-A after a single oral administration to male beagle dogs.

[0622]

[0623]

[0624] BQL = Below quantitative level; NA = Not applicable

[0625] Table 4: EFdA exposure in plasma from dogs orally administered EFdA and prodrug 4-A

[0626]

[0627]

[0628] The implementation scheme numbered in this disclosure

[0629] Other subject matter statements considered in this disclosure are provided in the following numbered embodiments:

[0630] 1. An adenosine derivative having formula (1) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof:

[0631]

[0632] in,

[0633] R 1 R 1’ and R 2 Each is independently -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 or -ZL 4 -R 5 , where R1 and R 2 At least one of them is not -H;

[0634] R 3 R 3' and R 4 Each of them is independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0635] R 5 yes:

[0636]

[0637] R 6 It is -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3-to-10-membered heterocyclic alkyl, aryl or heteroaryl;

[0638] -L 1 -R 5 It is -(C1-C10 alkyl)-N(R) 7 )-R 5 ,-(C1-C10 alkyl)-OR 5 -(C1-C10 alkyl)-SR 5 -(C2-C10 alkenyl)-N(R) 7 )-R 5 -(C2-C10 alkenyl)-OR 5 -(C2-C10 alkenyl)-SR 5 -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 ,-C(O)OL 2 -OR 5 -C(O)OL 2 -SR 5 ,、-C(O)OL 2 -C(O)OR 5 -C(O)OL 2 -C(O)N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L3 -O-R 5 、-C(O)O-L 2 -C(O)N(R 7 )-L 3 -S-R 5 、-C(O)N(R 7 )-R 5 、-C(O)N(R 7 )-L 2 -N(R 7 )-R 5 、-C(O)N(R 7 )-L 2 -O-R 5 ,-C(O)N(R 7 )-L 2 -S-R 5 、-C(O)N(R 7 )-L 2 -C(O)O-R 5 ,、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-R 5 -、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 、-C(O)O-L 2 -N(R 7 )C(O)O-R 5 、-C(O)N(R 8 )-L 2 -N(R 7 )C(O)O-R 5 、-C(O)O-L 2 -N(R 7 )C(O)N(R 8 )-R 5 、-C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -O-R 5 或-C(O)N(R 7 )-L 2-C(O)N(R 8 )-L 3 -SR 5 ;

[0639] -Z- represents divalent -C(O)-, -C(O)O-, or -C(O)N(R). 7 )-;

[0640] -L 4 -R 5 It is -(C1-C10 alkyl)-N(R) 7 )-R 5 -(C1-C10 alkyl)-OR 5 -(C1-C10 alkyl)-SR 5 -(C2-C10 alkenyl)-N(R) 7 )-R 5 -(C2-C10 alkenyl)-OR 5 or -(C2-C10 alkenyl)-SR 5 ;

[0641] R 7 R 8 and R 9 Each is independently -H, C1-C10 alkyl, or C2-C10 alkenyl;

[0642] L 2 and L 3 Each is expected to be divalent -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and

[0643] X is a halogen atom.

[0644] 2. The adenosine derivative as described in embodiment 1, wherein the adenosine derivative has formula (2):

[0645]

[0646] Formula 3

[0647]

[0648] Equation (4):

[0649]

[0650] Formula 5

[0651]

[0652] Equation (6):

[0653]

[0654] Equation (7):

[0655]

[0656] Equation (8):

[0657]

[0658] Equation (4-B):

[0659]

[0660] Or its pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate.

[0661] 3. The adenosine derivative as described in embodiment 1, wherein the adenosine derivative has the formula (2-A):

[0662]

[0663] Equation (3-A):

[0664]

[0665] Equation (4-A):

[0666]

[0667] Equation (5-A):

[0668]

[0669] Equation (6-A):

[0670]

[0671] Equation (7-A):

[0672]

[0673] Equation (8-A):

[0674]

[0675] Equation (4-C):

[0676]

[0677] Or its pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate.

[0678] 4. The adenosine derivative as described in Embodiment 1, wherein the adenosine derivative is isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester.

[0679] 5. The adenosine derivative as described in Embodiment 1, wherein the adenosine derivative is isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)carbamate.

[0680] 6. The adenosine derivative as described in Embodiment 1, wherein the adenosine derivative is ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester.

[0681] 7. The adenosine derivative as described in Embodiment 1, wherein the adenosine derivative is methyl carbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester.

[0682] 8. The adenosine derivative as described in Embodiment 1, wherein the adenosine derivative is 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one.

[0683] 9. The adenosine derivative as described in Embodiment 1, wherein the adenosine derivative is (2-(methyl((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl)amino)ethyl)carbamate((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester.

[0684] 10. The adenosine derivative as described in Embodiment 1, wherein the adenosine derivative is 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester.

[0685] 11. The adenosine derivative as described in embodiment 1, wherein the R 5 -L1 -R 5 or -ZL 4 -R 5 Selected from Equation 9–24:

[0686]

[0687]

[0688] 12. The adenosine derivative as described in any one of embodiments 1-11, 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.

[0689] 13. A pharmaceutical composition comprising an adenosine derivative having formula (1):

[0690]

[0691] in,

[0692] R 1 R 1’ and R 2 Each is independently -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 or -ZL 4 -R 5 , where R 1 and R 2 At least one of them is not -H;

[0693] R 3 R 3' and R 4 Each of them is independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0694] R 5 yes:

[0695]

[0696] R 6 It is -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3-to-10-membered heterocyclic alkyl, aryl or heteroaryl;

[0697] -L 1 -R 5 It is -(C1-C10 alkyl)-N(R)7 )-R 5 -(C1-C10 alkyl)-OR 5 -(C1-C10 alkyl)-SR 5 -(C2-C10 alkenyl)-N(R) 7 )-R 5 -(C2-C10 alkenyl)-OR 5 -(C2-C10 alkenyl)-SR 5 -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL 2 -OR 5 -C(O)OL 2 -SR 5 -C(O)OL 2 -C(O)OR 5 -C(O)OL 2 -C(O)N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -OR 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -SR 5 -C(O)N(R) 7 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )-R 5 -C(O)N(R) 7 )-L 2 -OR 5 -C(O)N(R) 7 )-L 2 -SR 5 -C(O)N(R) 7 )-L 2 -C(O)OR 5 -C(O)N(R) 7 )-L2 -C(O)N(R 8 )-R 5 -、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5 ,、-C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -OR 5 or -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -SR 5 ;

[0698] -Z- represents divalent -C(O)-, -C(O)O-, or -C(O)N(R). 7 )-;

[0699] -L 4 -R 5 It is -(C1-C10 alkyl)-N(R) 7 )-R 5 -(C1-C10 alkyl)-OR 5 -(C1-C10 alkyl)-SR 5 -(C2-C10 alkenyl)-N(R) 7 )-R 5 -(C2-C10 alkenyl)-OR 5 or -(C2-C10 alkenyl)-SR 5 ;

[0700] R 7 R 8 and R 9 Each is independently -H, C1-C10 alkyl, or C2-C10 alkenyl;

[0701] L 2 and L 3 Each is expected to be divalent -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and

[0702] X is a halogen atom.

[0703] 14. The pharmaceutical composition according to embodiment 13, wherein the adenosine derivative has formula (2):

[0704]

[0705] Equation (3):

[0706]

[0707] Equation (4):

[0708]

[0709] Equation (5):

[0710]

[0711] Equation (6):

[0712]

[0713] Equation (7):

[0714]

[0715] Equation (8):

[0716]

[0717] Equation (4-B):

[0718]

[0719] Or its pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate.

[0720] 15. The pharmaceutical composition according to embodiment 13, wherein the adenosine derivative has the formula (2-A):

[0721]

[0722] Equation (3-A):

[0723]

[0724] Equation (4-A):

[0725]

[0726] Equation (5-A):

[0727]

[0728] Equation (6-A):

[0729]

[0730] Equation (7-A):

[0731]

[0732] Equation (8-A):

[0733]

[0734] Equation (4-C):

[0735]

[0736] Or its pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate.

[0737] 16. The pharmaceutical composition of embodiment 13, wherein the adenosine derivative comprises isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester or a pharmaceutically acceptable salt thereof.

[0738] 17. The pharmaceutical composition of embodiment 13, wherein the adenosine derivative comprises isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)carbamate or a pharmaceutically acceptable salt thereof.

[0739] 18. The pharmaceutical composition of embodiment 13, wherein the adenosine derivative comprises ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester or a pharmaceutically acceptable salt thereof.

[0740] 19. The pharmaceutical composition of embodiment 13, wherein the adenosine derivative comprises methylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester or a pharmaceutically acceptable salt thereof.

[0741] 20. The pharmaceutical composition of embodiment 13, wherein the adenosine derivative comprises 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one or a pharmaceutically acceptable salt thereof.

[0742] 21. The pharmaceutical composition of embodiment 13, wherein the adenosine derivative is (2-(methyl((5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl)amino)ethyl)carbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester or a pharmaceutically acceptable salt thereof.

[0743] 22. The pharmaceutical composition of embodiment 13, wherein the adenosine derivative is 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester or a pharmaceutically acceptable salt thereof.

[0744] 23. The pharmaceutical composition as described in embodiment 13, wherein the R 5 -L 1 -R 5 or -ZL 4 -R 5 Selected from Equation 9–24:

[0745]

[0746]

[0747] 24. The pharmaceutical composition as described in any one of embodiments 13-23, further comprising a pharmaceutically acceptable carrier.

[0748] 25. The pharmaceutical composition according to any one of embodiments 13-24, further comprising an effective dose of one or more HIV antiviral agents selected from: abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bicitiravir, cabozantinvir, darunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate ... Viagra, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, erteiravir, etravirine, fosamponavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobistat, maraviro, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, telanavir, velivirol or a combination thereof.

[0749] 26. A method for treating a disease, the method comprising administering an effective dose of a pharmaceutical composition to a subject in need, said pharmaceutical composition comprising an adenosine derivative having formula (1) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof:

[0750]

[0751] in,

[0752] R 1 R 1’ and R 2 Each is independently -H, -C(O)N(R) 3 (R) 3’ -C(O)OR 4 -R 5 -L 1 -R 5 or -ZL 4 -R 5 , where R 1 and R 2 At least one of them is not -H;

[0753] R 3 R 3' and R 4 Each of them is independently -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic alkyl, aryl or heteroaryl;

[0754] R 5 yes:

[0755]

[0756] R6 It is -H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, 3-to-10-membered heterocyclic alkyl, aryl or heteroaryl;

[0757] -L 1 -R 5 It is -(C1-C10 alkyl)-N(R) 7 )-R 5 -(C1-C10 alkyl)-OR 5 -(C1-C10 alkyl)-SR 5 -(C2-C10 alkenyl)-N(R) 7 )-R 5 -(C2-C10 alkenyl)-OR 5 -(C2-C10 alkenyl)-SR 5 -C(O)OR 5 -C(O)OL 2 -N(R 7 )-R 5 -C(O)OL 2 -OR 5 -C(O)OL 2 -SR 5 -C(O)OL 2 -C(O)OR 5 -C(O)OL 2 -C(O)N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -OR 5 -C(O)OL 2 -C(O)N(R 7 )-L 3 -SR 5 -C(O)N(R) 7 )-R 5 -C(O)N(R) 7 )-L 2 -N(R 7 )-R 5 -C(O)N(R) 7 )-L 2 -OR 5 -C(O)N(R)7 )-L 2 -SR 5 -C(O)N(R) 7 )-L 2 -C(O)OR 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-R 5 -、-C(O)N(R 7 )-L 2 -C(O)N(R 8 )-L 3 -N(R 7 )-R 5 -C(O)OL 2 -N(R 7 )C(O)OR 5 -C(O)N(R) 8 )-L 2 -N(R 7 )C(O)OR 5 -C(O)OL 2 -N(R 7 )C(O)N(R 8 )-R 5 ,、-C(O)N(R 7 )-L 2 -N(R 7 )C(O)N(R 8 )-R 5 -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -OR 5 or -C(O)N(R) 7 )-L 2 -C(O)N(R 8 )-L 3 -SR 5 ;

[0758] -Z- represents divalent -C(O)-, -C(O)O-, or -C(O)N(R). 7 )-;

[0759] -L 4 -R 5 It is -(C1-C10 alkyl)-N(R) 7 )-R 5 -(C1-C10 alkyl)-OR 5 -(C1-C10 alkyl)-SR5 -(C2-C10 alkenyl)-N(R) 7 )-R 5 -(C2-C10 alkenyl)-OR 5 or -(C2-C10 alkenyl)-SR 5 ;

[0760] R 7 R 8 and R 9 Each is independently -H, C1-C10 alkyl, or C2-C10 alkenyl;

[0761] L 2 and L 3 Each is expected to be divalent -(C1-C10 alkyl)- or -(C2-C10 alkenyl)-; and

[0762] X is a halogen atom.

[0763] 27. The method of embodiment 26, wherein the adenosine derivative has formula (2):

[0764]

[0765] Equation (3):

[0766]

[0767] Equation (4):

[0768]

[0769] Equation (5):

[0770]

[0771] Equation (6):

[0772]

[0773] Equation (7):

[0774]

[0775] Equation (8):

[0776]

[0777] Equation (4-B):

[0778]

[0779] Or its pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate.

[0780] 28. The method of embodiment 26, wherein the adenosine derivative has the formula (2-A):

[0781]

[0782] Equation (3-A):

[0783]

[0784] Equation (4-A):

[0785]

[0786] Equation (5-A):

[0787]

[0788] Equation (6-A):

[0789]

[0790] Equation (7-A):

[0791]

[0792] Equation (8-A):

[0793]

[0794] Equation (4-C):

[0795]

[0796] Or its pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate.

[0797] 29. The method of embodiment 26, wherein the adenosine derivative comprises isopropylcarbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester or a pharmaceutically acceptable salt thereof.

[0798] 30. The method of embodiment 26, wherein the adenosine derivative comprises isopropyl (9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)carbamate or a pharmaceutically acceptable salt thereof.

[0799] 31. The method of embodiment 26, wherein the adenosine derivative comprises ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl carbonate ((5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methyl) ester or a pharmaceutically acceptable salt thereof.

[0800] 32. The method of embodiment 26, wherein the adenosine derivative comprises methyl carbamate ((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester or a pharmaceutically acceptable salt thereof.

[0801] 33. The method of embodiment 26, wherein the adenosine derivative comprises 4-(((9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-fluoro-9H-purine-6-yl)amino)methyl)-5-methyl-1,3-m-dioxacyclopentenyl-2-one or a pharmaceutically acceptable salt thereof.

[0802] 34. The method of embodiment 26, wherein the adenosine derivative is (2-(methyl((5-methyl-2-oxo-1,3-m-dioxopentenyl-4-yl)methyl)amino)ethyl)carbamate((2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) methyl ester or a pharmaceutically acceptable salt thereof.

[0803] 35. The method of embodiment 26, wherein the adenosine derivative is 4-[methyl-[(5-methyl-2-oxo-1,3-m-dioxacyclopentenyl-4-yl)methoxycarbonyl]amino]butyric acid [(2R,3S,5R)-5-(6-amino-2-fluoro-purine-9-yl)-2-ethynyl-3-hydroxy-tetrahydrofuran-2-yl]methyl ester or a pharmaceutically acceptable salt thereof.

[0804] 36. The method of embodiment 26, wherein the adenosine derivative comprises R selected from formulas 9–24. 5 -L 1 -R 5 or -ZL 4 -R 5 :

[0805]

[0806]

[0807] 37. The method of any one of embodiments 26-36, wherein the pharmaceutical composition is administered to the subject via intramuscular (IM), subcutaneous (SC), intravenous (IV), oral, topical, implantation, or a combination thereof.

[0808] 38. The method of any one of embodiments 26-37, further comprising measuring a sample of the subject to determine the measured level of the target drug in the sample, wherein the target drug has the formula (T-1):

[0809]

[0810] Or its isomers, or its pharmaceutically acceptable salts.

[0811] 39. The method of embodiment 38, wherein the target drug has the formula (T-1A):

[0812]

[0813] Or its isomers, or its pharmaceutically acceptable salts.

[0814] 40. The method of embodiment 38, wherein the target drug is (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol or a pharmaceutically acceptable salt thereof.

[0815] 41. The method of any one of embodiments 38-40, further comprising adjusting the effective dose to produce a modified effective dose if the measured level of the target drug is different from a predetermined target level of the target drug, and administering the modified effective dose to the subject.

[0816] 42. The method as described in any one of embodiments 26-41, wherein the disease is acquired immunodeficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0817] 43. The method as described in any one of embodiments 26-42, further comprising administering to the subject an effective dose of one or more anti-HIV agents selected from: abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bicitiravir, cabozantivir, darunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate, etc. Norfovir alafenamide, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, erteiravir, etravirine, fossaponaponavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobistat, maraviro, nelfinavivir, nelfinavivir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, telanavir, velivirol or a combination thereof.

[0818] 44. The method of embodiment 43, wherein the adenosine derivative and the one or more anti-HIV agents are administered to the subject orally, parenterally, or in combination thereof, alone.

[0819] 45. The method of embodiment 44, wherein the adenosine derivative and the one or more anti-HIV agents are administered to the subject according to a daily, weekly, bi-weekly or monthly administration schedule.

[0820] 46. ​​Use of the pharmaceutical composition according to any one of embodiments 13-25 for treating a disease in a subject in need, wherein said disease is acquired immunodeficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0821] 47. Use of the method of any one of embodiments 26-45 for treating a subject in need of a disease, wherein said disease is acquired immunodeficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0822] 48. Use of the adenosine derivative as described in any one of embodiments 1-12 in the manufacture of a medicament for treating a disease, wherein said disease is acquired immunodeficiency syndrome (AIDS), wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0823] 49. A method for preventing infection in a subject in need, the method comprising administering to the subject an effective dose of a pharmaceutical composition as described in any one of embodiments 13-25, wherein the subject has no detectable symptoms of said infection.

[0824] 50. The method of embodiment 49, wherein the infection includes a disease selected from: acquired immunodeficiency syndrome (AIDS) and the following infections: wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV, or a combination thereof.

[0825] 51. The method of embodiment 50, wherein the detectable symptoms include symptoms of acquired immunodeficiency syndrome (AIDS) and symptoms of infection with HIV including: wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, multidrug-resistant HIV, or a combination thereof.

[0826] 52. The method of embodiment 51, wherein the pharmaceutical composition is administered to the subject according to a daily, weekly, bi-weekly, or monthly administration schedule.

[0827] 53. The method of embodiment 52, further comprising administering to the subject an effective dose of one or more anti-HIV agents selected from: abacavir, abacavir sulfate, lamivudine, ampravir, atazanavir, atazanavir sulfate, AZT, bicitiravir, cabozantivir, darunavir, dideoxycytidine, dideoxyinosine, dolutegravir, doravirin, efavirenz, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide. Lafenamide, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, erteiravir, etravirine, fosamponavir calcium, indinavir, indinavir sulfate, lamivudine, lopinavir, a combination of lopinavir and ritonavir, darunavir, a combination of darunavir and cobistat, maraviro, nelfinavivir, nelfinavivir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, stavudine, telanavir, velivirol or a combination thereof.

[0828] 54. The method of embodiment 53, wherein the one or more anti-HIV agents are administered to the subject together with or alone with the pharmaceutical composition.

[0829] 55. A method for treating HIV infection, comprising: administering to a subject in need an effective dose of a pharmaceutical composition as described in any one of embodiments 1-25.

[0830] 56. A method for preventing HIV infection, comprising: administering to a subject in need an effective dose of a pharmaceutical composition as described in any one of embodiments 1-25.

[0831] 57. The method as described in embodiment 55 or 56, wherein the HIV infection is caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with the M184V mutation, HIV with K65R, or multidrug-resistant HIV.

[0832] 58. The method of any one of embodiments 55-57, wherein the application is performed orally.

[0833] 59. The method of any one of embodiments 55-57, wherein the administration is performed via parenteral administration.

[0834] 60. The method of embodiment 59, wherein the parenteral administration is performed by intramuscular or subcutaneous injection.

[0835] 61. The method of any one of embodiments 55-60, wherein the administration of the pharmaceutical composition results in a higher plasma concentration of EFdA compared to the administration of an equivalent dose of EFdA under the same conditions.

[0836] 62. The method of embodiment 61, wherein the administration of the pharmaceutical composition results in an EFdA plasma concentration that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% higher than that of an equivalent dose of EFdA under the same conditions.

[0837] 63. The method of embodiment 61, wherein the administration of the pharmaceutical composition results in a plasma concentration of EFdA that is 50%-80%, 50%-100%, or 50%-200% higher than that of EFdA when administered at an equivalent dose under the same conditions.

[0838] 64. The method of any one of embodiments 55-63, wherein the administration of the pharmaceutical composition results in prolonged EFdA release compared to the administration of an equivalent dose of EFdA under the same conditions.

[0839] 65. The method of any one of embodiments 55-64, wherein the administration of the pharmaceutical composition results in a higher AUC of EFdA compared to the administration of an equivalent dose of EFdA under the same conditions.

[0840] 66. The method of embodiment 65, wherein the administration of the pharmaceutical composition results in an AUC that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than that of EFdA when an equivalent dose of EFdA is administered under the same conditions.

[0841] 67. The method of embodiment 65, wherein the administration of the pharmaceutical composition results in an AUC that is 50%-200%, 50%-150%, or 80%-120% higher than that of EFdA when compared to an equivalent dose of EFdA administered under the same conditions.

[0842] 68. The method as described in any one of embodiments 55-67, wherein the administration of the pharmaceutical composition results in a higher C of EFdA compared to the administration of an equivalent dose of EFdA under the same conditions. max .

[0843] 69. The method of embodiment 68, wherein, compared to the administration of an equivalent dose of EFdA under the same conditions, the administration of the pharmaceutical composition results in a Cg of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than that of EFdA. max .

[0844] 70. The method of embodiment 68, wherein, compared to the application of an equivalent dose of EFdA under the same conditions, the application of the pharmaceutical composition results in a Cg of EFdA that is 50%-200%, 50%-150%, or 80%-100% higher than that of EFdA. max .

Claims

1. A compound of formula 4-A or a pharmaceutically acceptable salt thereof:

2. A compound having formula 4-A:

3. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising the compound according to claim 2 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is in a liquid dosage form suitable for oral administration.

6. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration.

7. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in a liquid dosage form suitable for oral administration.

8. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration.

9. Use of the compound or pharmaceutically acceptable carrier thereof according to any one of claims 1 to 2 or the pharmaceutical composition according to any one of claims 3 to 4 in the preparation of a medicament for preventing HIV infection in a subject.

10. The use according to claim 9, wherein the HIV infection is caused by wild-type HIV-1, NRTI-resistant HIV-1, HIV-2, HIV with M184V mutation, HIV with K65R, or multi-drug resistant HIV.

11. The use according to claim 9, wherein the compound or pharmaceutical composition is administered to the subject orally.

12. The use of claim 9, wherein the compound or pharmaceutical composition is administered to the subject parenterally.

13. The use according to claim 12, wherein the parenteral administration is by intramuscular or subcutaneous injection.

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