4 apos; prodrugs of substituted nucleoside reverse transcriptase inhibitors

Abstract

The present invention relates to prodrugs of Compound A: which are nucleoside reverse transcriptase translocation inhibitors (NRTTI) and are useful for inhibiting HIV reverse transcriptase. The invention also relates to the use of these compounds for preventing, treating, and preventing, treating and delaying the onset or progression of AIDS and / or AIDS-related syndromes.

Description

Background Technology

[0001] The retrovirus known as Human Immunodeficiency Virus (HIV), particularly the strains called HIV-1 and HIV-2, is etiologically associated with an immunosuppressive disease called Acquired Immunodeficiency Syndrome (AIDS). HIV-positive individuals are initially asymptomatic but typically develop AIDS-related syndrome (ARC), which subsequently progresses to AIDS. Infected individuals exhibit severe immunosuppression, making them highly susceptible to debilitating and ultimately fatal opportunistic infections. Because HIV is a retrovirus, its replication cycle requires the transcription of the viral RNA genome into DNA via an enzyme called reverse transcriptase (RT).

[0002] Reverse transcriptase has three known enzymatic functions: it acts as an RNA-dependent DNA polymerase, a ribonuclease, and a DNA-dependent DNA polymerase. As an RNA-dependent DNA polymerase, RT transcribes single-stranded DNA copies of viral RNA. As a ribonuclease, RT destroys the original viral RNA, rendering the newly generated DNA free of the original RNA. As a DNA-dependent DNA polymerase, RT uses the first DNA strand as a template to generate a second complementary DNA strand. These two strands form a double-stranded DNA, which is then integrated into the host cell's genome via the viral integrase enzyme.

[0003] Compounds that inhibit the enzymatic function of HIV-RT are known to suppress HIV replication in infected cells. These compounds are suitable for the prevention or treatment of HIV infection in humans. Compounds approved for the treatment and / or prevention of HIV infection and AIDS include nucleoside (or nucleotide) analogs, including nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Known NRTIs include 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC), d4T, 3TC, abacavir, emtricitabine, and tenofovir disoproxil fumarate. One subtype of NRTI is the nucleoside reverse transcriptase translocation inhibitor (NRTTI), such as 4'-ethynyl-2-fluoro-2'-deoxyadenosine (islatravir). Known non-nucleoside RT inhibitors (nNRTIs) include nevirapine, delavirdine, doravirine, and efavirenz.

[0004] While each of the aforementioned RT inhibitors is effective in treating HIV infection and preventing the progression of AIDS, further development of other HIV antiretroviral drugs, including other RT inhibitors, is still needed. A specific challenge is developing active RT inhibitors suitable for extended dosing or sustained-release regimens. The use of long-acting RT inhibitors remains urgently needed to improve the treatment and prevention of HIV infection. Summary of the Invention

[0005] This invention relates to prodrugs of 4'-substituted nucleoside derivatives and their use in inhibiting HIV reverse transcriptase. The invention further relates to the use of these compounds in the prevention of HIV infection in subjects in need, the treatment of HIV infection in subjects in need, and the prevention, treatment, and delay of the onset or progression of AIDS and / or ARC in subjects in need. The invention provides compounds as cleavable prodrugs with solubility limitations for NRTIs, which can be adapted for extended dosing regimens in subjects in need.

[0006] In some aspects, this disclosure provides 4'-substituted fused heterocyclic compounds. In some aspects, this disclosure provides compounds as cleavable prodrugs of compound A:

[0007]

[0008] Compound A is a 4'-substituted heterocyclic nucleoside analog. The synthesis of compound A and its ability to inhibit HIV reverse transcriptase are described in International PCT Application WO 2015 / 148746 of Merck Sharp & Dohme Corp., published October 1, 2015, the entire contents of which are incorporated herein by reference.

[0009] In some respects, this article provides compounds having formula VI:

[0010]

[0011] Or its pharmaceutically acceptable salt, wherein:

[0012] X is selected from -C(=O)-, -C(=O)-O-, -CR 5 R 6 -OC(=O)-、-CR 5 R 6 -OC(=O)-O- and bonds;

[0013] Y is selected from -C(=O)-, -C(=O)-O-, -CR 5 R 6 -OC(=O)-、-CR 5 R 6 -OC(=O)-O-、-P(=O)(OC6-12 (aryl)-NH-CR 4 C(=O)-O- and bonds;

[0014] Z is selected from -C(=O)-, -C(=O)-O-, and bond;

[0015] W is selected from -C(=O)-, -C(=O)-O- and bond;

[0016] R 1 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl, (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups;

[0017] R 2 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl, (CR 5 R 6 ) z -C 5-12 heteroaryl and (CR) 5 R 6 ) z -C 1-6 Alkyl esters, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be selected independently by one to three groups selected from halogen, oxo, C... 1-6 Alkyl, C 3-12Substitution of cycloalkyl and hydroxyl groups;

[0018] R 3 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic or heteroaryl group may optionally be selected independently by one to three groups selected from halogen, oxo, C 1-6 Alkyl, C 3-12 The aryl group is substituted with a cycloalkyl or hydroxyl group, and the aryl group may optionally be replaced by one to three groups independently selected from halogen, oxo, C... 1-6 Alkyl, C 3-12 Cycloalkyl, hydroxyl and C 1-6 Alkyl ester group substitution;

[0019] R 4 Choose from the following groups: hydrogen, C 1-3 Alkyl groups and (CH2) z -cycloalkyl;

[0020] R 5 and R 6 Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl and C 3-6 cycloalkyl; and

[0021] R 7 Selected from hydrogen, C 1-21 Alkyl and (CR) 5 R 6 ) z -C 5-12 cycloalkyl,

[0022] Where R 1 R 2 and R 3 At least one of them is not hydrogen; and z is 0, 1, 2, 3, 4, 5 or 6.

[0023] In one embodiment of the invention, it is a compound of formula VI having structural formula I or a pharmaceutically acceptable salt thereof:

[0024] Therefore, in some respects, this paper provides compounds having formula I:

[0025]

[0026] Or its pharmaceutically acceptable salt, wherein:

[0027] X is selected from -C(=O)-, -C(=O)-O-, -CR 5 R 6 -OC(=O)-、-CR 5 R 6 -OC(=O)-O- or bond;

[0028] Y is selected from -C(=O)-, -C(=O)-O-, -CR 5 R 6 -OC(=O)-、-CR 5 R 6 -OC(=O)-O-、-P(=O)(OC 6-12 (aryl)-NH-CR 4 C(=O)-O- or bond;

[0029] Z is selected from -C (=O)- or the bond;

[0030] R 1 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl, (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups;

[0031] R 2 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl, (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups;

[0032] R 3 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl, (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups;

[0033] R 4 Choose from the following groups: hydrogen, C 1-3 Alkyl or (CH2) z -cycloalkyl;

[0034] R 5 and R 6 Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl and C 3-6 cycloalkyl; and wherein R 1 R 2 and R 3 At least one of them is not hydrogen; and

[0035] z can be 0, 1, 2, 3, 4, 5, or 6.

[0036] In some implementations of Formulas I and VI, X is -CR 5 R 6 -OC (=O)- and / or Y is -CR 5 R 6 -OC(=O)-,R 5 and R 6 None of them are halogens.

[0037] In one embodiment of the invention, it is a compound of formulas I and VI having structural formula II, or a pharmaceutically acceptable salt thereof:

[0038]

[0039] All variables (R2, R3, X, Y, etc.) are defined as in Equations I and VI.

[0040] In another embodiment of the invention, it is a compound of formulas I and VI having structural formula III, or a pharmaceutically acceptable salt thereof:

[0041]

[0042] All variables (R3, Y, etc.) are defined as in Equations I and VI.

[0043] In another embodiment of the invention, it is a compound of formula I and formula VI having structural formula IV, or a pharmaceutically acceptable salt thereof:

[0044]

[0045] All variables (R2, X, etc.) are defined as in Equations I and VI.

[0046] In another embodiment of the invention, it is a compound of formula I and formula VI having structural formula V, or a pharmaceutically acceptable salt thereof:

[0047]

[0048] All variables (R1, Z, etc.) are defined as in Equations I and VI.

[0049] Therefore, in various respects, this paper provides a cleavable prodrug of compound A, which is substituted at the 3' (or 3-) position, 5' (or 5-) position, or both positions of the tetrahydrofuran (“THF”) ring (also referred to herein as the sugar moiety).

[0050] This article further provides a cleavable prodrug of compound A, wherein the prodrug is substituted at the 5' position of the THF ring, the 4-amino position of the pyrrolopyrimidine core, or both of these positions. This article further provides a cleavable prodrug of compound A, wherein the prodrug is substituted at the 3' position of the THF ring, the 5' position of the THF ring, the 4-amino position of the pyrrolopyrimidine core, or all three positions.

[0051] All structural formulas, embodiments thereof, and categories described herein include pharmaceutically acceptable salts of the compounds defined therein. References to compounds of formulas I and VI herein cover compounds of each of formulas I, II, III, IV, V, and VI, and all embodiments thereof. Unless otherwise stated, references to compounds of the invention, such as compounds of a particular formula or embodiment, such as compounds of formulas I, II, III, IV, V, or VI or embodiments thereof, or compounds of any other general structural formula or specific compound described or claimed herein, are intended to cover one or more specific compounds falling within the scope of that formula or embodiment, including their salts, particularly pharmaceutically acceptable salts, solvates (including hydrates), and their solvated salt forms, wherein these forms are possible.

[0052] This invention includes each of the embodiments described herein and its pharmaceutically acceptable salt. This invention also covers pharmaceutical compositions comprising an effective amount of the compound of this invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. Attached Figure Description

[0053] Figure 1 The plasma concentration-time curve of compound A after a single intramuscular (IM) injection of compound A into rats is shown.

[0054] Figure 2 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 10 into rats are shown.

[0055] Figure 3 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 18 into rats are shown.

[0056] Figure 4 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 20 into rats are shown.

[0057] Figure 5 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 21 into rats are shown.

[0058] Figure 6 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 24 into rats are shown.

[0059] Figure 7 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 27 into rats are shown.

[0060] Figure 8 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 34 into rats are shown.

[0061] Figure 9 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 36 into rats are shown.

[0062] Figure 10 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 42 into rats are shown.

[0063] Figure 11 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 48 into rats are shown.

[0064] Figure 12 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 60 into rats are shown.

[0065] Figure 13 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 61 into rats are shown.

[0066] Figure 14 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 64 into rats are shown.

[0067] Figure 15 Plasma concentration-time curves of compound A after a single IM injection of the compound of Example 68 into rats are shown. Detailed Implementation

[0068] This invention relates to prodrugs of compound A suitable for use as NRTTIs, and methods of using these prodrugs to treat or prevent HIV infection in subjects. These compounds can be used as antiretroviral (ARV) agents, and particularly for the prevention, treatment, and delay of the onset or progression of AIDS and / or AIDS-related syndromes (ARC) in subjects in need. Pharmaceutical compositions, formulations, and medicaments comprising these compounds are further provided herein. In some embodiments, the compositions are suitable for use in a long-acting injectable dosage form.

[0069] This document also provides methods of treatment and prevention, comprising administering any of the disclosed compounds. This document further provides the use of these compounds as agents for the treatment or prevention of HIV, AIDS, or ARC. In some embodiments, a compound of formula VI or a pharmaceutically acceptable salt thereof is used to prepare an agent for: (a) treatment (e.g., treatment in a human body), (b) a drug, (c) inhibition of HIV reverse transcriptase, (d) treatment or prevention of HIV infection, or (e) treatment, prevention, or delay of the onset or progression of AIDS or ARC. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is used to prepare an agent for: (a) treatment (e.g., treatment in a human body), (b) a drug, (c) inhibition of HIV reverse transcriptase, (d) treatment or prevention of HIV infection, or (e) treatment, prevention, or delay of the onset or progression of AIDS or ARC. In these uses, the compounds of the present invention may optionally be used in combination with one or more anti-HIV agents (such as other ARVs).

[0070] In some embodiments, the disclosed pharmaceutical compositions and treatment methods are suitable for long-acting injection. In some embodiments, the pharmaceutical compositions and treatment methods are suitable for subcutaneous, intramuscular, intravenous, or other injections. In some embodiments, these compositions may be suitable for intramuscular injection. In some embodiments, the treatment methods are suitable for use with implantable devices in a subject.

[0071] In some embodiments, any of the compounds described in this invention and compositions comprising these compounds can be delivered intramuscularly and effectively release parent compound A into the systemic circulation. In some embodiments, intramuscular injection of any of the described compositions releases compound A into the systemic circulation of mammals within 5, 6, or 7 days (see [link to relevant documentation]). Figures 2 to 15 In some implementations, this release is substantially prolonged, slow, and / or linear over time.

[0072] In some embodiments, any of the compounds, compositions, and methods described in this invention can reduce the likelihood or severity of symptoms of HIV, AIDS, or ARC in one or more subjects. In some embodiments, any of these compounds, compositions, and methods can partially or completely reduce / suppress one or more symptoms. Any of the disclosed compounds, compositions, and methods can partially or completely suppress HIV infection. Any of the disclosed compounds, compositions, and methods can partially or completely suppress HIV viral replication.

[0073] In some embodiments, any of the disclosed prodrug compounds exhibits high antiviral potency (e.g., HIV replication inhibition). Antiviral potency can be evaluated by virokinetics in green cells (VIKING) analysis and can be expressed as IC50.50 or EC 50 In some embodiments, any of the disclosed prodrug compounds exhibits antiviral potency of less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 25 nM, less than 20 nM, less than 10 nM, or less than 5 nM. In a particular embodiment, the compound exhibits potency of less than 10 nM.

[0074] In some embodiments, the disclosed prodrug compound has reduced solubility relative to compound A. This reduced solubility provides a longer duration of action before the drug is metabolized and released into the subject's body. Therefore, the present invention provides long-acting and / or sustained-release compounds and formulations thereof.

[0075] In some embodiments, any phase of the disclosed compounds is crystalline. In some embodiments, any phase of the disclosed compounds is amorphous.

[0076] In various respects, this paper presents compounds of structure VI:

[0077]

[0078] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 7 As specified above.

[0079] In some implementations, W is the key, and R 7 It is hydrogen. In some implementations, Z is a bond, and R... 1 It is hydrogen. In some implementations, X is a bond, and R... 2 It is hydrogen. In some implementations, Y is a bond, and R... 2 It is hydrogen. In some implementations, any or all of the following hold: W is a bond, and R... 7 It is hydrogen, Z is a bond, and R 1 It is hydrogen. In some implementations, any or all of the following conditions hold: X is a bond, R... 2 It is hydrogen, Y is a bond, and R 3 It is hydrogen.

[0080] In some implementation schemes, R 2 Yes (CR) 5 R 6 ) z -C 5-12 cycloalkyl, wherein R 5 and R 6As specified above, and z is 0, 1, 2, 3, 4, 5, or . In some implementations, R 3 Yes (CR) 5 R 6 ) z -C 5-12 Cycloalkyl, wherein z is 0, 1, 2, 3, 4, 5 or 6.

[0081] In some implementation schemes, R 1 It is C 3-12 Cycloalkyl. In some embodiments, R 2 It is C 3-12 Cycloalkyl. In some embodiments, R 3 It is C 3-12 Cycloalkyl.

[0082] In some implementation schemes, R 7 It is C 1-12 alkyl.

[0083] In various respects, this article presents compounds of structural formula I:

[0084]

[0085] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 and R 3 As specified above.

[0086] In some implementations, Z is the key, and R 1 It is hydrogen. In some implementations, X is a bond, and R... 2 It is hydrogen. In some implementations, Y is a bond, and R... 3 It is hydrogen. In some implementations, any or all of the following conditions hold: X is a bond, R... 2 It is hydrogen, Y is a bond, and R 3 It is hydrogen.

[0087] In some implementations of Equations I and VI, X is -C (=O)- and R is... 2 It is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or alkyl-substituted aryl or heteroaryl group, such that the 3' position of the tetrahydrofuran (THF) ring of formula I is a substituted ester. In some embodiments, Y is -C (=O)- and R 3 The group is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or alkyl-substituted aryl or heteroaryl group, such that the 5' position of the THF ring is a substituted ester. In some embodiments, both the 3' and 5' positions of the THF ring are substituted esters (disubstituted esters). In any of these embodiments, Z can be a bond, and R... 1 It could be hydrogen.

[0088] In some implementations of Equations I and VI, X is -C (=O)- and R is... 2 It is an alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, such that the 3' position of the THF ring of formula I is a substituted carbonate. In some embodiments, Y is -C(=O)- and R 3 The group is an alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, such that the 5' position of the THF ring is a substituted carbonate. In some embodiments, both the 3' and 5' positions of the THF ring are substituted carbonates (disubstituted carbonates). In any of these embodiments, Z can be a bond, and R... 1 It could be hydrogen.

[0089] In some embodiments of Formulas I and VI, the 5' position of the THF ring is a substituted acetal. In any such embodiment, Z can be a bond, and R 1 It can be hydrogen. In any such implementation, X can be a bond, and R... 2 It could be hydrogen.

[0090] In some embodiments of Formulas I and VI, X is selected from -C (=O), -CR 5 R 6 -OC (=O) and the bond; Y is selected from -C (=O), -CR 5 R 6 -OC (=O) and bonds; Z is a bond, and R 1 It is hydrogen; R 2 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, (CR) 5 R 6 ) z -C 3-12 Substitution of cycloalkyl and hydroxyl groups; and R 3Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups.

[0091] In some embodiments of Formulas I and VI, X is selected from -C(=O)-O-, -CR 5 R 6 -OC(=O)-O- and bonds; Y is selected from -C(=O)-O-, -CR 5 R 6 -OC (=O)-O- and bonds; Z is a bond, and R 1 It is hydrogen; R 2 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups; and R 3 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 )z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups.

[0092] In some implementations of Equations I and VI, Y is -P(=O)(OC) 6-12 (aryl)-NH-CR 4 C(=O)-O-(aminophosphite group). In any such embodiment, Z can be a bond, and R 1 It can be hydrogen. In any such implementation, X can be a bond, and R... 2 It could be hydrogen.

[0093] In some implementations of Equations I and VI, Z is -C (=O)- and R 1 It is an alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, such that the N-position of formula I (and formula VI) is an amide. In any such embodiment, X can be a bond, and R 2 It can be hydrogen. In any such implementation, Y can be a bond, and R... 3 It could be hydrogen.

[0094] In some implementations of Formulas I and VI, R 1 Selected from (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups and (CR) 5 R 6 ) z -C 6-12 Aryl. In some implementations, R 2 Selected from (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups and (CR) 5 R 6 ) z -C 6-12Aryl. In some implementations, R 3 Selected from (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups and (CR) 5 R 6 ) z -C 6-12 Aryl.

[0095] In some implementations, X is selected from -C(=O)-, -C(=O)-O-, and bond; Y is selected from -C(=O)-, -C(=O)-O-, and bond; R 1 Selected from hydrogen and C 1-12 Alkyl; R 2 Selected from C 1-10 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl and (CR) 5 R 6 ) z -C6 aryl, wherein the aryl group may optionally be substituted with a halogen (e.g., chlorine); and R 3 Selected from C 1-10 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl and (CR) 5 R 6 ) z -C6 aryl, wherein the aryl group may optionally be substituted with a halogen, and wherein R 5 and R 6 It is hydrogen.

[0096] In some implementation schemes, R 2 Yes (CR) 5 R 6 ) z -C 5-12 Cycloalkyl. In some embodiments, R 3 Yes (CR) 5 R 6 ) z -C 5-12 Cycloalkyl. In some embodiments, R 2 Yes (CR) 5 R 6 ) z -C 5-12 heteroaryl. In some implementations, R 3 Yes (CR) 5 R 6 ) z -C5-12 Mixed aromatic compounds.

[0097] In some implementation schemes, R 2 Yes (CR) 5 R 6 ) z -C 6-12 Cycloalkyl. In some embodiments, R 3 Yes (CR) 5 R 6 ) z -C 6-12 Cycloalkyl. In some embodiments, R 2 Yes (CR) 5 R 6 ) z -C 6-12 heteroaryl. In some implementations, R 3 Yes (CR) 5 R 6 ) z -C 6-12 heteroaryl. In some implementations, R 1 Yes (CR) 5 R 6 ) z -C 6-12 Mixed aromatic compounds.

[0098] In some implementation schemes, R 3 It is pyridyl. In some embodiments, R 3 It is selected from one to three independent elements, C. 1-6 Alkyl, C 3-12 Pyridyl groups substituted with cycloalkyl and hydroxyl groups.

[0099] In some embodiments, the disclosed prodrug compound contains substituents (or variable groups) at the 3', 5', or both sites of the tetrahydrofuran ring. These substituents may be cleavable, for example, through one or more metabolic processes in the body.

[0100] In various embodiments, the disclosed prodrug compound exhibits a high degree of bioconversion (conversion) to parent compound A in the subject. In some embodiments, the disclosed compound exhibits a bioconversion to compound A of greater than 50%, greater than 60%, greater than 65%, greater than 70%, or greater than 75% (relative to the total amount of prodrug before any conversion) in cells or in vitro. In some embodiments, a bioconversion of greater than 75% is exhibited. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0101] In some embodiments, the disclosed prodrug compounds themselves do not have antiviral (e.g., anti-HIV) activity; however, the pharmacologically active form of these compounds produced after lysis in the subject has antiviral activity.

[0102] In some embodiments, the disclosed compounds are selected from any of the 59 compounds having the structures listed in Table A. The example numbers in the "Examples" column refer to specific examples in which the synthesis and properties of the compounds are discussed below. It should be understood that any of the compounds listed in Table A may be grouped or combined with any other compounds in that table.

[0103] In some embodiments, the compound contains the structure of Example 20 in Table A. In some embodiments, the compound contains the structure of Example 3. In some embodiments, the compound contains the structure of Example 10. In some embodiments, the compound contains the structure of Example 13. In some embodiments, the compound contains the structure of Example 15. In some embodiments, the compound contains the structure of Example 18. In some embodiments, the compound contains the structure of Example 20. In some embodiments, the compound contains the structure of Example 21. In some embodiments, the compound contains the structure of Example 24. In some embodiments, the compound contains the structure of Example 27. In some embodiments, the compound contains the structure of Example 34. In some embodiments, the compound contains the structure of Example 36. In some embodiments, the compound contains the structure of Example 42. In some embodiments, the compound contains the structure of Example 44. In some embodiments, the compound contains the structure of Example 48. In some embodiments, the compound contains the structure of Example 57. In some embodiments, the compound contains the structure of Example 55. In some embodiments, the compound contains the structure of Example 60, Example 61, Example 64, or Example 68.

[0104] Table A

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111] limited

[0112] The terms used herein have their common meanings and are independent of each other in each instance. Nevertheless, unless otherwise stated, the following limitations apply throughout this specification and the claims. Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. Unless otherwise stated, these limitations apply whether a term is used alone or in combination with other terms. Thus, the limitation of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc.

[0113] Unless otherwise stated, as used herein and throughout this disclosure, the following terms shall be understood to have the following meanings:

[0114] The “subject” is a human or a non-human mammal. In one embodiment, the subject is a human. In another embodiment, the subject is a primate. In yet another embodiment, the subject is a monkey. In another embodiment, the subject is a chimpanzee. In yet another embodiment, the subject is a rhesus monkey. In yet another embodiment, the subject is a rodent, such as a rat.

[0115] As used herein, the term "effective amount" refers to the amount of a compound and / or additional therapeutic agent or combination thereof that, when administered to a subject with HIV infection or AIDS, effectively inhibits HIV replication and produces the desired therapeutic, ameliorative, inhibitory, or preventative effect. In the combination therapies of this invention, an effective amount may refer to individual agents or the entire combination, wherein the amounts of all agents administered together are effective, but the component agents in the combination may not be present individually in an effective amount.

[0116] In this article, the term “treating” or “treatment” as used in relation to HIV infection, AIDS, or ARC includes suppressing the severity of HIV infection or AIDS, such as preventing or reducing the development of HIV infection or AIDS or their clinical symptoms; or alleviating HIV infection or AIDS, such as causing the severity of HIV infection or AIDS or their clinical symptoms to subside.

[0117] In this article, the terms “preventing” or “prophylaxis” used in relation to HIV infection or AIDS refer to reducing the likelihood or severity of HIV infection or AIDS.

[0118] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one hydrogen atom is replaced by a single bond. Alkyl groups can be straight-chain or branched and contain about 1 to 21 or more carbon atoms. In one embodiment, the alkyl group contains about 1 to about 12 carbon atoms. In various embodiments, the alkyl group contains 1 to 6 carbon atoms (C1 to C2).1-6 Alkyl groups or about 3 to about 12 carbon atoms (C 3-12 Alkyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, and neohexyl. In one embodiment, the alkyl group is straight-chained. In another embodiment, the alkyl group is branched. Unless otherwise stated, the alkyl group is unsubstituted.

[0119] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I. For compounds of formula I and formula VI and their embodiments, halogen substituents of particular interest are each of fluorine (–F) and chlorine (–Cl). The term "haloalkyl" refers to an alkyl group defined above in which one or more hydrogen atoms are replaced by a halogen (i.e., -F, -Cl, -Br, and / or -I). Thus, for example, "C 1-6 "Halogenated alkyl" (or "C1-C6 halogenated alkyl") refers to a C1 to C6 straight-chain or branched alkyl group defined above having one or more halogen substituents.

[0120] The term "substituted" means that one or more hydrogen atoms on a specified atom are replaced by a group selected from the specified group, provided that the substitution does not exceed the normal valence of the specified atom under the existing conditions and the substitution produces a stable compound. Combinations of substituents and / or variables are only permitted if these combinations produce a stable compound. A "stable compound" or "stable structure" means a compound that is sufficiently robust to be separated from the reaction mixture at a suitable purity and continue to exist, and is formulated into an effective therapeutic agent. Unless otherwise stated, when any substituent or variable (e.g., R...) is... 1 When a substance appears more than once in any component or in Formula I or Formula VI, the definition of each occurrence is independent of the definition of each other occurrence. It should also be noted that any carbon and heteroatom with unsaturated valences in the text, schemes, examples, and tables herein are assumed to have a sufficient number of hydrogen atoms to satisfy the valence.

[0121] When a functional group in a compound is referred to as a “protecting group,” it means that the group is modified to prevent unwanted side reactions at the protected site when the compound reacts. Suitable protecting groups will be identified by those skilled in the art and by referring to standard textbooks such as T.W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0122] When a portion of Formula I or Formula VI or any embodiment thereof is designated as “optionally substituted,” this means that Formula I or Formula VI or embodiments thereof cover compounds in which the portion is substituted with one or more of the designated substituents, and compounds in which the portion does not contain one or more of the designated substituents (i.e., where the portion is unsubstituted). As an example, when R1 is a C that can be optionally substituted with a halogen... 1-21 When alkyl groups are used, R1 can be C1. 1-21 Alkyl or C 1-21 Halogenated alkyl groups.

[0123] When any variable (e.g., R1, R) X R Y When a component appears more than once in any component or in Formula I, Formula VI, or any other formula depicting and describing the compounds of the present invention, the limitation of each occurrence is independent of the limitation of each other occurrence. Furthermore, combinations of substituents and / or variables are permitted only if such combinations produce a stable compound. Unless expressly stated to the contrary, substitution of any atom of the ring (e.g., cycloalkyl, aryl, or heteroaryl) by a specified substituent is permitted, provided that such ring substitution is chemically permissible and produces a stable compound.

[0124] Unless explicitly stated otherwise, all ranges referenced herein include the listed endpoints and can be combined independently. For example, the range “between about 0.5% and about 95%” includes the endpoints (about) 0.5% and (about) 95% as well as all intermediate values.

[0125] As used herein, a "heteroaromatic" ring is a carbon-containing aryl ring that may contain 1, 2, 3, or 4 heteroatoms. For example, a "heteroaromatic" ring may contain one or more nitrogen atoms (e.g., 1 to 3 nitrogen atoms), one or more oxygen atoms, or one or more sulfur atoms. Heteroaromatic rings may be designated herein using subscripts indicating the total number of atoms constituting the ring. In some embodiments, a heteroaromatic ring may have 5 to 12 ring atoms, wherein each atom is selected from carbon, nitrogen, oxygen, and sulfur. For example, a 6-membered heteroaromatic substituent may contain 4 carbon atoms and two oxygen atoms.

[0126] As used herein, a "heterocycle" is a carbon-containing ring that may contain one, two, three, or four heteroatoms. For example, a "heterocycle" may contain one or more nitrogen atoms (e.g., one to three nitrogen atoms), one or more oxygen atoms, or one or more sulfur atoms. Similar to "heteroaromatic" rings, heterocycles may be designated herein using subscripts indicating the total number of atoms constituting the ring. In some embodiments, a heterocycle may have five to twelve ring atoms, wherein each atom is selected from carbon, nitrogen, oxygen, and sulfur. For example, a five-membered heterocyclic substituent may contain three carbon atoms and two oxygen atoms.

[0127] In some embodiments, the compounds disclosed herein contain a heteroaryl substituent comprising one nitrogen atom. It should also be understood that any scope referenced herein includes all subscopes within that scope. Thus, for example, "heterocycle" is intended to include heterocycles containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, or 4 heteroatoms as an aspect thereof. For example, the ring may contain one or more nitrogen atoms (e.g., 1 to 3 nitrogen atoms), one or more oxygen atoms, or one or more sulfur atoms. Any of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein may optionally be substituted with one or more groups. As used herein, “optionally substituted with one to five groups” is intended to include cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with 1 to 5 substituents, 2 to 5 substituents, 3 to 5 substituents, 4 to 5 substituents, 5 substituents, 1 to 4 substituents, 2 to 4 substituents, 3 to 4 substituents, 4 substituents, 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent as an aspect thereof. Similarly, as used herein, “optionally substituted with one to three groups” is intended to include cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent as an aspect thereof.

[0128] As used herein, the terms “heterocyclic,” “heteroaryl,” and “cycloalkyl” are intended to cover fused and polycyclic substituents. For example, these terms cover those having five total carbons (e.g., C5 cycloalkyl), six total carbons (e.g., C6 cycloalkyl), eight total carbons (e.g., C8 cycloalkyl), or ten total carbons (e.g., C5 cycloalkyl). 10 Fused (or polycyclic) rings of cycloalkyl groups. These terms also cover fused (or polycyclic) heterocyclic rings having a total of five, six, seven, eight, nine, or ten atoms, wherein at least one atom is carbon and at least one (e.g., 1, 2, 3, or 4) atom is a non-carbon atom, such as nitrogen, oxygen, and / or sulfur.

[0129] As used herein, an "alkyl ester" substituent refers to an alkyl group having a terminal ester, wherein the linking site with the relevant compound is the alcohol side of the ester.

[0130] As used herein, the term "composition" is intended to cover a product comprising a specified amount of a specified ingredient, and any product resulting from a combination of the specified amounts of the specified ingredients.

[0131] The term "prodrug" refers to a compound that is converted in vivo to yield a pharmacologically active compound (e.g., a drug prodrug). In vivo conversion can occur through various mechanisms (e.g., via metabolism or chemical processes), such as hydrolysis in the blood. The compound described herein is a prodrug of compound A. When compound A contains, for example, a hydroxyl group, the prodrug can be a derivative of the hydroxyl group, such as an ester (-OC(O)R), carbonate (-OC(O)OR), phosphate ester (-OP(=O)(OH)2), ether (-OR), or a monophosphate prodrug, such as a phosphoramide ester (which can be converted in vivo to the corresponding nucleoside monophosphate).

[0132] As used herein, the term "salt" refers to an acidic salt formed from inorganic and / or organic acids, and a basic salt formed from inorganic and / or organic bases. Additionally, when a compound contains both a basic moiety (e.g., but not limited to pyridine or imidazole) and an acidic moiety (e.g., but not limited to carboxylic acids), an amphoteric ion ("internal salt") may be formed, and this is included within the term "salt" as used herein. Compounds may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable (e.g., non-toxic and otherwise harmless to the recipient).

[0133] The compounds of the present invention may exist in amorphous form and / or one or more crystalline forms, and therefore all amorphous and crystalline forms of compounds of formulas I and VI, and mixtures thereof, are intended to be included within the scope of the present invention. Additionally, some compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates and hydrates of the compounds of the present invention (particularly pharmaceutically acceptable solvates and hydrates) are also covered within the scope of the present invention, along with their non-solventized and anhydrous forms. Therefore, the compounds within the general structural formulas, embodiments, and specific compounds described and claimed herein encompass their salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms, and any combination of these forms, as well as their salts.

[0134] Salts, solvates and stereoisomers

[0135] This document covers solvates of the disclosed compounds of formulas I and VI. One or more compounds of the present invention may exist in both solvated and pharmaceutically acceptable solvent forms (such as water, ethanol, etc.), and the present invention is intended to encompass both solvated and non-solventized forms. “Solvate” refers to the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates will be separable, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. “Solvate” encompasses both solution phases and separable solvates. Non-limiting examples of solvates include ethanolates, methanolates, etc. “Hydrate” is a solvate in which the solvent molecule is water.

[0136] One or more compounds of formula I or VI can optionally be converted into solvates. The preparation of solvates is generally known. Therefore, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3) 601-611 (2004) describes the preparation of antifungal fluconazole in ethyl acetate and its solvates in water. EC van Tonder et al., AAPS PharmSciTech. 5(1) Article 12 (2004) and ALBingham et al., Chem. Commun., 603-604 (2001) describe similar preparations of solvates, hemisols, hydrates, etc. Typical non-limiting methods involve dissolving the compound in a desired amount of a desired solvent (organic solvent or water or a mixture thereof) at above room temperature, cooling the solution at a rate sufficient to form crystals, and subsequently separating the crystals by standard methods. Analytical techniques (such as IR spectroscopy) show that the solvent (or water) in the crystals is present as a solvate (or hydrate).

[0137] Compounds of Formula I and VI can form salts, which are also within the scope of this invention. In some embodiments, the salts are pharmaceutically acceptable. In another embodiment, the salts are not pharmaceutically acceptable. Salts of compounds of Formula I and VI can be formed, for example, by reacting the compound with a certain amount (e.g., equivalent) of an acid or base in a medium (e.g., a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0138] Exemplary acid addition salts include acetates, ascorbic acid salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobroms, hydroiodates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates), and their similar salts. Additionally, acids generally considered suitable for forming pharmaceutically applicable salts from basic pharmaceutical compounds include, for example, those described in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977). 66(1) 1-19; P.Gould, InternationalJ.ofPharmaceutics(1986) 33 References 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on its website). These publications are incorporated herein by reference.

[0139] Exemplary basic salts include ammonium salts; alkali metal salts, such as sodium, lithium, and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts formed with organic bases (e.g., organic amines) such as dicyclohexylamine, tert-butylamine, and choline; and salts formed with amino acids (e.g., arginine, lysine, etc.). The basic nitrogen-containing group can be quaternized by reagents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long-chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and other reagents.

[0140] All these acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of this invention, and all acid salts and base salts are considered equivalent to the corresponding compounds in their free form for the purposes of this invention.

[0141] A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art, such as chromatography and / or stepwise crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher's acyl chloride) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to their corresponding pure enantiomers. Stereochemically pure compounds can also be prepared by using chiral starting materials or by employing salt resolution techniques. Furthermore, some compounds of formula I and / or formula VI can be transisomers (e.g., substituted biaryl groups) and are considered part of this invention. Chiral chromatography techniques can also be used to directly separate enantiomers.

[0142] Compounds of Formula I and / or Formula VI may also exist in different tautomeric forms, and all of these forms are covered within the scope of this invention. For example, all keto-enol and imine-enamine forms of the compounds are included in this invention. As another example, hydroxypyridine and pyridinone forms with oxy-substituted pyridine substituents are covered within the embodiments of the disclosed compounds.

[0143] Unless otherwise stated, all stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of this invention (including salts, solvates, hydrates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of prodrugs), such as those that may exist due to the asymmetric carbons on the substituents, including enantiomers (which may even exist in the absence of the asymmetric carbons), rotational isomers, trans-blocking isomers, and diastereomers, are covered within the scope of this invention. If the compound contains a double bond or a fused ring, the cis and trans forms, as well as mixtures thereof, are included within the scope of this invention.

[0144] When a substituent on a chiral carbon atom is drawn without a specific stereochemistry (by using a straight bond with the chiral center), it should be understood that both the α and β configurations of that substituent are considered part of this invention. It should be understood that the chiral center in a compound can exist in either the S or R absolute configuration or a mixture of both. Within the molecule, bonds drawn as straight lines from the chiral center include both R and S stereoisomers and mixtures thereof. An asterisk indicates a stereocenter in a single configuration (R or S). Unless otherwise stated in an example or explicitly stated by nomenclature, the absolute stereochemistry of individual stereoisomers in examples and intermediates is not determined.

[0145] Individual stereoisomers of the compounds of this invention may, for example, be substantially free of other isomers, or may be mixed, for example, in racemic form or with all other or other selected stereoisomers. The chiral center of this invention may have an S or R configuration as defined in IUPAC 1974. The terms “salt,” “solvent,” etc., are intended to be equally applied to salts and solvates of enantiomers, stereoisomers, rotational isomers, tautomers, or racemates of the disclosed compounds.

[0146] In compounds of formulas I and VI, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. This invention aims to include all suitable isotopic variants of compounds of general formulas VI and I. For example, different isotopic forms of hydrogen (H) include protium (… 1 H) and deuterium ( 2 H). Protium is the main hydrogen isotope found in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as prolonged in vivo half-life or reduced dosage requirements, or can provide compounds suitable as standards for characterizing biological samples. Isotope-enriched compounds of formula I and VI can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or using methods similar to those described in the schemes and examples herein, using appropriate isotope enrichment reagents and / or intermediates. In one embodiment, one or more hydrogen atoms of the compound of formula I or VI are replaced with deuterium.

[0147] Treatment or prevention of HIV infection

[0148] The disclosed compounds of formulas I and VI are suitable for inhibiting HIV, inhibiting HIV reverse transcriptase, treating HIV infection and / or reducing the likelihood of HIV infection or alleviating the severity of HIV infection symptoms, and inhibiting HIV viral replication and / or HIV viral production in cell-based systems. For example, compounds of formulas I and VI are suitable for treating HIV infection following suspected past exposure to HIV via methods such as blood transfusion, body fluid exchange, bite, accidental needlestick injury, or exposure to the blood of an infected person during surgery or other medical procedures. In one embodiment, compounds of formulas I and VI can be inhibitors of HIV-1 viral replication. Therefore, compounds of formulas I and VI are suitable for treating HIV infection and AIDS. According to the invention, compounds of formulas I and VI can be administered to subjects requiring treatment or prevention of HIV infection.

[0149] Therefore, in one embodiment, the present invention provides a method for treating HIV infection in a subject, the method comprising administering to the subject an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the administered amount effectively treats or prevents HIV infection in the subject. In some embodiments, the administered amount effectively inhibits HIV viral replication and / or viral production in the subject. In one embodiment, the HIV infection has progressed to AIDS.

[0150] Compounds of Formulas I and VI are also suitable for preparing and performing screening analyses for antiviral compounds. For example, Formula I compounds can be used to identify HIV-resistant cell lines containing mutations, making them an excellent screening tool for more potent antiviral compounds. Furthermore, Formulas I and VI compounds can be used to establish or determine the binding sites of other antiviral agents to HIV reverse transcriptase.

[0151] The compositions and combinations of the present invention are applicable to the treatment of subjects suffering from infections associated with any HIV genotype.

[0152] Composition and application

[0153] When administered to a subject, any of the disclosed compounds of formulas I and VI may be administered as a component of a composition comprising a pharmaceutically acceptable carrier. The present invention provides pharmaceutical compositions comprising an effective amount of at least one of the disclosed compounds and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredient is typically administered in combination with a suitable carrier material selected according to the intended form of administration and conforming to conventional pharmaceutical practice, such as oral tablets, capsules (solid-filled, semi-solid-filled, or liquid-filled), powder formulations, oral gels, elixirs, dispersible granules, syrups, suspensions, etc. For example, for oral administration in tablet or capsule form, the active pharmaceutical component may be combined with any pharmaceutically acceptable inert carrier. Solid form formulations include powders, tablets, dispersible granules, capsules, sachet, and suppositories. Tablets, powders, sachet, and capsules are suitable for oral administration. Powders and tablets may comprise between about 0.5% and about 95% of any of the disclosed pharmaceutical compositions.

[0154] Furthermore, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the composition, particularly in formulations intended for oral administration, when desired or required. The composition may be formulated for prolonged or controlled release. In other embodiments, the composition is formulated for immediate or modified release.

[0155] In some embodiments, any of the disclosed pharmaceutical compositions comprises a pharmaceutically acceptable carrier suitable for or adapted for administration to a subject by injection. In some embodiments, these carriers are suitable for long-acting injection. In some embodiments, these carriers are liquid formulations, including solutions, suspensions, emulsions, or nanoemulsions for intramuscular or subcutaneous administration. In some embodiments, any of the disclosed pharmaceutical compositions are suitable for long-acting injectable formulations.

[0156] Any of the disclosed compositions may comprise a pharmaceutically acceptable carrier suitable or adapted for parenteral administration in unit doses of the pharmaceutical composition for the treatment of HIV-infected subjects and / or for the prevention of HIV infection. Parenteral administration includes subcutaneous, intravenous, intramuscular, or intrasternal injection, or other infusion techniques (administered as needed at dosing intervals by one or more injections or infusions to deliver an appropriate amount of the active agent). The pharmaceutical composition contains an effective amount of the compound and conventional pharmaceutically acceptable carriers, adjuvants, and mediators. The composition may also be administered parenterally via an implantable pharmaceutical delivery composition or device suitable for providing an effective amount of the compound over an extended period. In some embodiments, the composition is administered parenterally from once a month to approximately once every twelve months, such as approximately once every three months, once every six months, or once every twelve months.

[0157] Parenteral compositions may be prepared according to techniques known in the art. These compositions may use sterile water as a carrier and optionally other selected components. Continuous dosing regimens are used to treat subjects infected with HIV. Any of the disclosed pharmaceutical formulations for parenteral injection may comprise a solution, suspension, or emulsion, and may include water, suspending agents, viscosity modifiers, tension modifiers, and / or pH adjusters.

[0158] This also includes solid formulations intended to be converted into liquid form for oral or parenteral administration before use. These liquid forms include solutions, suspensions, emulsions, and nanoemulsions.

[0159] In certain embodiments, the compositions of the present invention can be formulated in extended dosing or sustained-release forms to provide controlled-rate release of any one or more components or active ingredients, thereby optimizing therapeutic effects, such as antiviral activity. Suitable dosage forms for sustained release include long-acting injectable and implantable formulations. Other suitable dosage forms for sustained release include layered tablets containing layers with different disintegration rates, controlled-release polymer matrices impregnated with the active ingredient and shaped into tablets, or capsules containing such impregnated or encapsulated porous polymer matrices.

[0160] In some embodiments, the sustained-release formulation of the disclosed compositions is facilitated by the reduced solubility of the disclosed compounds of formulas I and VI relative to compound A. In various embodiments, any compound in the disclosed compositions exhibits water solubility lower than that of compound A at physiological pH (e.g., pH 7.4, 7.2, or 7.0). In some embodiments, any compound in the disclosed compositions exhibits solubility below 400 μg / mL, below 350 μg / mL, below 250 μg / mL, below 100 μg / mL, below 50 μg / mL, below 10 μg / mL, below 2.5 μg / mL, or below 1 μg / mL at pH 7.4. In a particular embodiment, any compound in the disclosed compositions exhibits solubility below 1 μg / mL at pH 7.4.

[0161] In some embodiments, any of the disclosed compounds exhibits a significantly short half-life (T1 / 2) in the presence of human plasma. In some embodiments, any of the disclosed compounds exhibits a long half-life in the presence of human plasma. In some embodiments, any of these compounds exhibits a significantly long half-life (T1 / 2) in the presence of rodent or non-human primate plasma. In some embodiments, any of these compounds exhibits a half-life of less than 2.5 hours, less than 1 hour, less than 0.5 hours, or less than 0.25 hours in human plasma, as measured by the percentage of drug loss over processes of 0, 0.25, 0.5, 1, and 3 hours. In some embodiments, any of these compounds exhibits a half-life significantly longer than that of compound A.

[0162] The compositions can be prepared using conventional mixing, granulation, or coating methods, and in one embodiment, the compositions of the present invention may contain about 0.1% to about 99% of the compound by weight or volume. In various embodiments, the compositions of the present invention may contain about 1% to about 70% or about 5% to about 60% of the compound by weight or volume.

[0163] formula

[0164] In some embodiments, any of the disclosed compositions is injectable, or suitable for injection. Injectable compositions can be prepared according to methods known in the art. Implantable compositions can be prepared according to methods known in the art, wherein the carrier comprises an active chemical component with a polymer and suitable excipients, or utilizes an implantable device or subcutaneous reservoir for drug delivery. Further description of methods suitable for preparing pharmaceutical compositions used in this invention and components suitable for said compositions is provided in Remington-THE SCIENCE AND PRACTICE OF PHARMACY, 22nd edition, Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012. Liquid formulations suitable for oral administration (e.g., suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art and can utilize any common media such as water, glycols, oils, alcohols, etc.

[0165] In some embodiments, any of the disclosed compounds or a pharmaceutically acceptable salt thereof is administered by injection using an injection device. In some embodiments, the injection device is or includes a syringe that can be used manually or as part of an injection device containing a syringe. A wide variety of injection devices can be used, including but not limited to handheld or wearable autoinjectors, handheld or wearable manual injectors, on-body injectors, syrettes, jet injectors, or pen injectors, each of which can be reusable or disposable.

[0166] In some embodiments, compounds of formula I, II, III, IV, V, or VI, or pharmaceutically acceptable salts thereof, are administered using a syringe suitable for administering the compound or an auto-injector containing a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with any of these compounds.

[0167] In some embodiments, the disclosed compounds are administered via an implantable device implanted in an individual to deliver the active agent during the interval between implantations. In some embodiments, the implantable device administers any of the disclosed compounds or salts thereof at dosing intervals ranging from about once a month to about once every six to twelve months. In specific embodiments, the dosing intervals range from about once every three months, or once every six months, or once every twelve months. In some embodiments, the implantable device administers the compound once a month, once every three months, or at a less frequent frequency. Implantable compositions can also be prepared according to methods known in the art, wherein, for example, a carrier comprises the active chemical ingredient and a suitable excipient (e.g., a polymer), or an implantable device is used for drug delivery.

[0168] Solid pharmaceutical preparations suitable for oral administration (e.g., powders, pills, capsules, and tablets) can be prepared according to techniques known in the art and can employ solid excipients such as starch, sugar, kaolin, lubricants, slurries, binders, disintegrants, etc. Formulations of Formula I and Formula VI compounds that cause drug supersaturation and / or rapid dissolution can be used to promote the absorption of oral drugs. Formulation methods that cause drug supersaturation and / or rapid dissolution include, but are not limited to, nanoparticle systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. These formulation methods and techniques used for their preparation are known in the art. For example, solid dispersions can be prepared using excipients and methods described in reviews (e.g., Serajuddin, JPharm Sci, 88:10, pp.1058-1066 (1999)). Nanoparticle systems based on both grinding and direct synthesis are also described in reviews such as Wu et al., Advanced Drug Delivery Reviews, 59:7, pp.631-644 (2007)).

[0169] The unit doses of the disclosed compounds of formulas I and VI can be administered at different frequencies. In some embodiments, a unit dose of any of these compounds is administered via intramuscular or subcutaneous injection once a month, once every two months, once every three months, once every four months, once every five months, once every six months, or at a frequency lower than once every six months. In some embodiments, a unit dose is administered every two months. In some embodiments, a unit dose is administered every three months. In some embodiments, a unit dose is administered every two to six months. In some embodiments, a unit dose is administered every six months. In some embodiments, a unit dose is administered every six to twelve months. In some embodiments, a unit dose is administered every twelve months.

[0170] In one embodiment, a unit dose of the disclosed compound may be administered once daily. In another embodiment, a unit dose of the disclosed compound may be administered twice weekly. In yet another embodiment, a unit dose may be administered once weekly. In still another embodiment, a unit dose may be administered every two weeks. In another embodiment, a unit dose may be administered monthly (e.g., by intramuscular or subcutaneous injection). In yet another embodiment, a unit dose may be administered every two months. In yet another embodiment, a unit dose may be administered quarterly. In yet another embodiment, a unit dose may be administered annually.

[0171] In some aspects, effective amounts of Formula I and Formula VI compounds for prophylactic use may be administered by injection, for example, but not limited to once weekly, once every two weeks, twice monthly, once monthly, once quarterly, twice annually, once annually, or at longer intervals (e.g., but not limited to once every 18 months or once every two years). The longer the interval between each administration of the active agent, the greater the amount of active agent that may be required at each administration. Therefore, one or more unit doses may be administered as needed at each dosing interval to deliver an appropriate amount of the active agent, such as one or more injections or infusions of Formula I and Formula VI compounds, or one or more implantable compositions or devices. Any dosing regimen for prophylactic use may be a continuous dosing regimen or an intermittent dosing regimen.

[0172] In one embodiment, the pharmaceutical formulation comprising at least one disclosed compound is further divided into unit doses containing an effective amount of the active ingredient. In some embodiments, the compounds of formula I and VI are administered in a single dose or divided doses in a dosage range of 0.001 to 1000 mg per kilogram of mammalian (e.g., human) body weight per day. One dosage range is 0.01 to 500 mg per kilogram of body weight per day, administered orally in a single dose or divided doses. Another dosage range is 0.1 to 100 mg per kilogram of body weight per day, administered orally in a single dose or divided doses. For oral administration, the composition may be provided in tablet or capsule form containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient, for dose adjustment to the symptoms in the treated subject. The specific dose level and frequency of administration for any particular subject may vary and will depend on a variety of factors including: the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, administration pattern and time, excretion rate, drug combination, severity of the specific condition, and the subject being treated.

[0173] For convenience, the total daily dose may be divided into multiple doses and administered in portions throughout the day, if necessary. In one embodiment, the daily dose is administered once. In another embodiment, the total daily dose is administered twice within 24 hours. In yet another embodiment, the total daily dose is administered three times within 24 hours. In still another embodiment, the total daily dose is administered four times within 24 hours.

[0174] The dosage and frequency of administration of compounds of formulas I and VI will be adjusted based on the judgment of the attending clinician, taking into account factors such as the subject's age, condition, body type, and the severity of the symptoms being treated. The compositions of the present invention may further comprise one or more additional therapeutic agents selected from those listed above herein.

[0175] The specific dosage level and frequency of administration for any given patient may vary and will depend on a variety of factors, including the activity of the specific compound used, its metabolic stability and duration of action, age, weight, general health condition, sex, diet, administration pattern and time, excretion rate, the effects of other medications the patient is taking while using any of the compounds or pharmaceutical compositions described herein, the severity of the specific condition, and the host being treated. In some cases, depending on the potency of the compound or individual response, it may be necessary to deviate upwards or downwards from the given dose. The dosage and frequency will be adjusted based on the attending clinician's judgment, taking these factors into account.

[0176] The compounds of this invention are also suitable for preparing and performing screening analyses against antiviral compounds. For example, the compounds of this invention are suitable for isolating enzyme mutants, which are excellent screening tools for more potent antiviral compounds. Furthermore, the compounds of this invention are suitable for establishing or determining binding sites for other antiviral agents.

[0177] Combination therapy

[0178] In some aspects, the method of the present invention for treating or preventing HIV infection may further include the administration of one or more additional therapeutic agents not of any of the disclosed compounds.

[0179] In one implementation, the additional therapeutic agent is an antiviral agent. In another implementation, the additional therapeutic agent is an immunomodulatory agent such as an immunosuppressant.

[0180] In some implementations, the additional treatment agent is an HIV capsid inhibitor. In some implementations, the additional treatment agent is lenacapavir. The method of action of lenakapavir is described in U.S. Publication No. 2018 / 0051005, published on February 22, 2018, which is incorporated herein by reference in its entirety. In some embodiments, the additional therapeutic agent is GS-CA1 (see Vidal et al. Long-acting capsid inhibitor protects macaques from repeat SHIV challenges. Nature 601, 612–616 (2022), which is incorporated herein by reference in its entirety).

[0181] Therefore, in one embodiment, the present invention provides a method for treating a subject with a viral infection, the method comprising administering to the subject: (i) at least one compound of formula I or formula VI (which may include two or more different compounds) or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent other than any of the disclosed compounds of formula I and formula VI, wherein the amounts administered together effectively treat or prevent the viral infection.

[0182] When administering the combination therapy of the present invention to a subject, the therapeutic agents in the combination, or one or more pharmaceutical compositions containing therapeutic agents, may be administered in any order, such as sequentially, concurrently, together, simultaneously, etc. The amounts of the various active agents in this combination therapy may be different amounts (different doses) or the same amount (same dose). Therefore, for non-limiting illustrative purposes, the compounds and additional therapeutic agents may be present in fixed amounts (dosages) in a single dose unit (e.g., capsules, tablets, etc.).

[0183] In some embodiments, one or more injection devices are used to administer any of the disclosed compounds or their pharmaceutically acceptable salts via injection, and to further administer additional therapeutic agents via injection. In some embodiments, the one or more injection devices are or include syringes that can be used manually or as part of an injection device containing a syringe (such as an autoinjector). A wide variety of injection devices can be used, including but not limited to handheld or wearable autoinjectors, handheld or wearable manual injectors, body syringes, syrettes, jet injectors, or pen injectors, each of which can be reusable or disposable.

[0184] In one implementation, at least one compound is administered during the period when the additional therapeutic agent exerts its preventive or therapeutic effect, or vice versa.

[0185] In another embodiment, at least one compound and additional therapeutic agent are administered at the dosage typically used when these agents are used as a monotherapy for treating viral infections.

[0186] In another embodiment, at least one compound and additional therapeutic agent are administered at a lower dose than those typically used when these agents are used as a monotherapy for treating viral infections.

[0187] In another embodiment, at least one compound and an additional therapeutic agent work synergistically and are administered at a lower dose than is typically used when these agents are used as a monotherapy for treating viral infections.

[0188] In one embodiment, at least one compound and an additional therapeutic agent are present in the same composition. In one embodiment, the composition is suitable for subcutaneous administration. In another embodiment, the composition is suitable for intramuscular administration. In yet another embodiment, the composition is suitable for oral administration. In still another embodiment, the composition is suitable for intravenous administration.

[0189] Viral infections and virus-related conditions that can be treated or prevented using the combination therapy methods of the present invention include, but are not limited to, those listed above. In some embodiments, the viral infection is HIV infection. In some embodiments, the viral infection is AIDS.

[0190] At least one compound and an additional therapeutic agent may act additively or synergistically. Synergistic combinations may allow the use of lower doses of one or more agents and / or lower frequency of administration of one or more agents in combination therapy. Lower doses or lower frequency of administration of one or more agents may reduce the toxicity of the therapy without diminishing its efficacy. In one embodiment, administration of at least one compound and an additional therapeutic agent may suppress viral resistance to these agents.

[0191] In some embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with at least one long-acting HIV therapy, such as a long-acting injectable formulation. Examples of drugs developed as long-acting regimens include cabotegravir, rilpivirine, lenapapvir, tenofovir implant, islavravir implant, doravirine, raltegravir, and long-acting dolutegravir. In some embodiments, the disclosed compound is combined with long-acting lenapapvir.

[0192] As mentioned above, this invention also relates to the use of compounds of formula I or VI with one or more anti-HIV agents. An "anti-HIV agent" is any agent that directly or indirectly and effectively inhibits HIV reverse transcriptase or another enzyme required for HIV replication or infection, or that treats or prevents HIV infection and / or treats, prevents, or delays the onset or progression of AIDS. It should be understood that anti-HIV agents effectively treat, prevent, or delay HIV infection or AIDS and / or the onset or progression of disease or symptoms arising from or associated with them. For example, the compounds of this invention can be effectively administered before and / or after exposure in combination with an effective amount of one or more anti-HIV agents selected from those suitable for treating HIV infection or AIDS, including antiviral agents, immunomodulators, anti-infective agents, or vaccines. HIV antiviral agents suitable for use in combination with the compounds of this invention include, for example, those listed in Table B below:

[0193] Table B

[0194]

[0195]

[0196]

[0197] Some of the drugs listed in the table are used in salt form, such as abacavir sulfate, indinavir sulfate, atazanavir sulfate, and nelfinavir mesylate.

[0198] In one implementation, one or more anti-HIV drugs are selected from lenakapavir, GS-CA1, lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine, doravirine, islatrevir, and lopinavir.

[0199] In some implementations, compounds of formula I or VI are used in combination with lenakapavir or GS-CA1.

[0200] In yet another embodiment, the compound of formula I or VI is used in combination with atazanavir. In another embodiment, the compound of formula I or VI is used in combination with darunavir. In yet another embodiment, the compound of formula I or VI is used in combination with rilpivirine. In one embodiment, the compound of formula I or VI is used in combination with lamivudine and abacavir.

[0201] In another embodiment, the compound of formula I or VI is used in combination with isratrivir. In another embodiment, the compound of formula I or VI is used in combination with emtricitabine and tenofovir. In yet another embodiment, the compound of formula I or VI is used in combination with doravirine. In yet another embodiment, the compound of formula I or VI is used in combination with doravirine, lamivudine, and tenofovir DF. In another embodiment, the compound of formula I or VI is used in combination with ritonavir and lopinavir. In one embodiment, the compound of formula I or VI is used in combination with abacavir and lamivudine. In another embodiment, the compound of formula I or VI is used in combination with lopinavir and ritonavir.

[0202] In one embodiment, the present invention provides a pharmaceutical composition comprising: (i) a compound of formula I or VI or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable carrier; and (iii) one or more additional anti-HIV agents selected from lenakapavir, lamivudine, abacavir, ritonavir, isratrovir, doravirin, and lopinavir, or pharmaceutically acceptable salts or prodrugs thereof, wherein the presence of components (i) and (iii) together is effective in treating or preventing HIV infection in a subject in need, or in treating, preventing, or delaying the onset or progression of AIDS in a subject in need.

[0203] In another embodiment, the present invention provides a method for treating or preventing HIV infection in a subject in need or for treating, preventing or delaying the onset or progression of AIDS in a subject in need, comprising administering to the subject: (i) a compound of formula I or VI or a pharmaceutically acceptable salt thereof; and (ii) one or more additional anti-HIV agents selected from lenakapavir, lamivudine, abacavir, ritonavir, isratrovir, doravirin and lopinavir, or a pharmaceutically acceptable salt or prodrug thereof, wherein the dosage of components (i) and (ii) together is effective in treating or preventing HIV infection in a subject in need, or in treating, preventing or delaying the onset or progression of AIDS in a subject in need.

[0204] It should be understood that the scope of combinations of the compounds of the present invention with anti-HIV agents is not limited to the HIV antiviral agents listed in Table B, but in principle includes any combination with any pharmaceutical composition suitable for the treatment or prevention of AIDS. HIV antiviral agents and other agents will generally be used in these combinations at their conventional dosage ranges and regimens reported in the art, including, for example... Physicians' Desk Reference Thomson PDR, Thomson PDR, 57 th edition (2003), the 58 th edition (2004), the 59th The dosages described in edition (2005), etc., are the same as those described above for the dosage ranges of the compounds of the present invention in these combinations.

[0205] The dosage and administration regimen of other agents used in the combination therapy of the present invention for the treatment or prevention of HIV infection can be determined by the attending clinician by considering the following factors: the dosage and administration regimen approved in the drug's package insert; the subject's age, sex, and general health condition; and the type and severity of the viral infection or related disease or condition. When administered in combination, the compound and one or more other agents can be administered simultaneously (i.e., in the same composition or one after another in separate compositions) or sequentially. This is particularly suitable when the components of the combination are administered at different times of administration (e.g., one component is administered once daily and another component is administered every six hours), or when the drug compositions are different (e.g., one is a tablet and the other is a capsule). Therefore, kits containing individual dosage forms are advantageous.

[0206] Reagent test kit

[0207] In some aspects, the present invention provides a kit comprising a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, medium or diluent.

[0208] This document further provides articles comprising any of the disclosed compounds or a pharmaceutically acceptable salt thereof in a suitable container. The container may be a vial, wide-mouth bottle, ampoule, pre-filled syringe, implant, or intravenous bag. Any of the disclosed kits may contain any of these articles.

[0209] In another aspect, the present invention provides a kit comprising an amount of at least one compound or a pharmaceutically acceptable salt thereof and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients produce the desired therapeutic effect. In one embodiment, one or more compounds of formula I or VI and one or more additional therapeutic agents are provided in the same container. In one embodiment, one or more compounds of formula I or VI and one or more additional therapeutic agents are provided in separate containers.

[0210] Several methods for preparing compounds of formulas I and VI are described in the following procedures and schemes. These schemes may use readily available starting materials, reagents, and conventional synthetic procedures. Variations known to those skilled in the art but not described in more detail may also be used in these reactions. Furthermore, other methods for preparing the compounds of the present invention will be readily apparent to those skilled in the art.

[0211] General Program

[0212] Starting materials and intermediates were purchased or prepared using known procedures described in chemical synthesis literature or elsewhere. The preparation of the various starting materials used herein is entirely within the skill of those skilled in the art. The routes applied to the synthesis of compounds of formulas I and VI are described in the following schemes. In some cases, the order of reaction steps may be varied to promote the reaction or avoid undesirable reaction products. In some cases, the final product may be further modified, for example, by manipulating substituents. These operations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions commonly known to those skilled in the art. Since the schemes are illustrative, the invention should not be considered limited to the chemical reactions and conditions represented. Examples described below are provided to provide a more complete understanding of the invention. These examples are merely illustrative and should not be considered as limiting the invention in any way.

[0213] The substituent numbers shown in the embodiments are not necessarily related to the substituent numbers used in the claims, and for clarity, a single substituent is typically shown connected to a compound permitted to have multiple substituents as defined above. The reactions used to generate the compounds of the invention are carried out by employing the reactions shown in the embodiments and examples herein, except for other standard operations that may be known in the literature or exemplified in experimental procedures (such as ester hydrolysis, protecting group cleavage, etc.).

[0214] Reactions sensitive to moisture or air are carried out under nitrogen or argon atmosphere using anhydrous solvents and reagents. The reaction process is typically mediated by using Merck KGaA glass-backed TLC plates and silica gel 60F. 254 The determination was performed using liquid chromatography-mass spectrometry (LCMS) or analytical thin-layer chromatography (TLC).

[0215] Analytical LCMS is typically performed on a Waters SQD single quadrupole mass spectrometer using electrospray ionization in positive ion detection mode (mass range set to 150 to 900 Daltons, data collected in center-of-centrifuge mode, and scan time set to 0.2 seconds) and a Waters Acquity UPLC system (binary solvent manager, sample manager, and TUV). The column is typically a Waters Acquity BEH C181 × 50 mm, 1.7 μm column heated to 50 °C. The mobile phase used is modified with acidic or basic additives. The acidic mobile phase consists of water containing 0.1% trifluoroacetic acid (solvent A) and 100% acetonitrile (solvent B). A two-minute run is performed at a flow rate of 0.3 mL / min, with initial conditions of 95% solvent A, gradually increased to 99% solvent B at 1.60 min, and maintained at 99% solvent B for 0.40 min. Partial ring needle overflow mode is used, with an injection volume of 0.5 μL. TUV monitoring was performed at wavelengths of 215 or 254 nm, with a sampling rate of 20 points / second, using normal filter constant and absorbance data modes. A five-minute run was conducted at a flow rate of 0.3 ml / min, with initial conditions of 90% solvent A, gradually increased to 99% solvent B at 4.90 minutes, and maintained at 99% solvent B for 0.10 minutes.

[0216] Alternatively, the commonly used system is Shimadzu LCMS-2020. TM The platform utilizes electrospray ionization in positive ion detection mode. The column is typically a Kinetix EVO C18, 3.0 × 30 mm, 2.6 μm. The flow rate is 1.5 mL / min, and the injection volume is 2 μL. The UV detection range is 190 to 400 nm. The mobile phase consists of solvent A (water plus 5 mM NH4HCO3) and solvent B (MeCN), with a gradient of 10% solvent A to 60% solvent B over 1.85 min. Alternatively, the column is typically an XSelect HSS T3, 2.1 × 30 mm, 2.5 μm. The flow rate is 1.2 mL / min, and the injection volume is 1 μL. The UV detection range is 190 to 400 nm. The mobile phase consists of solvent A (water plus 0.05% TFA) and solvent B (MeCN plus 0.05% TFA), with a gradient of 95% solvent A to 100% solvent B over 1.30 min. Alternatively, the column is typically a ShimNex HE C18-AQ, 3.0 x 30 mm, 3.0 μm. The flow rate is 1 mL / min, and the injection volume is 0.8 μL. The UV detection range is 190 to 400 nm. The mobile phase consists of solvent A (water plus 0.1% TFA) and solvent B (MeCN plus 0.1% TFA), with a gradient of 95% solvent A changing to 100% solvent B over 1.20 min.

[0217] Preparative reversed-phase chromatography is typically performed on Teledyne ISCO CombiFlashRf, Teledyne ISCO ACCQPrep HP125, or HP150 systems equipped with UV detectors, or on Waters systems. UV detectors typically monitor wavelengths of 215 and 254 nm. The mobile phase consists of solvent A (water with or without modifiers such as FA or NH4HCO3) and solvent B (MeCN). The mobile phase gradient is optimized for individual compounds.

[0218] Flash chromatography typically uses the ISCO CombiFlash Rf instrument. Flash chromatography equipment (Dyax Corp.) or ISCO Silicone in the pre-filled column of the CompanionXL device ( The process is carried out at the pore size. The mobile phase typically consists of a mixture of hexane, petroleum ether, or dichloromethane with EtOAc, a 3:1 EtOAc:EtOH, or MeOH. The mobile phase gradient is optimized for individual compounds.

[0219] 1 HNMR data are typically acquired using a Bruker NMR spectrometer at 300 to 500 MHz. Chemical shift values ​​are reported in deltas (δ) and parts per million (ppm). 1 The chemical shift in the 1H NMR spectrum is given by the signal relative to the residual undeuterated solvent (CDCl3 reference is δ).

[0220] 7.26 ppm; DMSO-d6 reference δ 2.50 ppm; and CD3OD reference δ 3.31 ppm). Multiplets are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, m = multiplet or overlap of non-equivalent resonances. Coupling constants (J) are reported in Hertz (Hz). When a compound presents as a mixture of rotational isomers by NMR, the spectral data corresponding to the dominant substance observed in solution are reported.

[0221] The abbreviations used in this article include the following:

[0222] Table C

[0223]

[0224]

[0225] As illustrated in Scheme A, generally, the compounds of the present invention can be prepared by acylation of A-1 to give compounds of formula A-2 and A-3. Ester coupling of the 5' alcohol of A-1 with an O-acylprop-2-one oxime can preferentially occur in the presence of an enzyme (such as NOVO enzyme-435) to give compound A-2. Alternatively, A-1 can be acylated by an acyl chloride in the presence of a base (such as pyridine) to give compound A-2. Diesterification can occur when A-1 is treated with an acyl chloride in the presence of a base (such as pyridine), or when A-1 is treated with a carboxylic acid in the presence of a coupling agent (such as DIC) and a base (such as DMAP), to give compound A-3. The carboxylic acid is commercially available or can be synthesized from a suitable precursor.

[0226] Option A

[0227]

[0228] As illustrated in Scheme B, generally speaking, the compounds of the present invention can be prepared by acylation of A-1 to obtain compound B-1. Coupling of A-1 with a phosphoramide ester (such as Int-1) can occur in the presence of a base (such as LiTMP).

[0229] Option B

[0230]

[0231] As illustrated in Scheme C, generally, the compounds of the present invention can be prepared by first placing a protecting group (such as a trialkylsilyl group) onto a 5' alcohol to obtain C-1. The 3' alcohol of C-1 can then be reacted with a chloroformate or an alkyl-4-nitrobenzene carbonate in the presence of a base (such as DMAP or TEA) to give the product of formula C-2. The protecting group in C-2 can then be removed under suitable conditions, including treatment with TBAF or triethylamine trihydrofluoride, to give the product of formula C-3.

[0232] Option C

[0233]

[0234] As illustrated in Scheme D, generally, the compounds of the present invention can be prepared by treating C-1 with an acyl chloride in the presence of a base (such as pyridine) or with a carboxylic acid in the presence of a coupling agent (such as DIC) and a base (such as DMAP) to obtain the product of formula D-1. The protecting group in D-1 can then be removed under suitable conditions, including treatment with TBAF or triethylamine trihydrofluoride, to obtain the product of formula D-2.

[0235] Option D

[0236]

[0237] As illustrated in Scheme E, generally, the compounds of the present invention can be prepared by the following method: First, by reacting C-1 with 4-methoxytriphenylmethyl chloride in the presence of an activator (such as silver nitrate) and a base (such as 2,4,6-trimethylpyridine) to protect the 3' alcohol and amino groups of C-1 with 4-methoxytriphenylmethyl, yielding E-1. The protecting group of the 5' alcohol in E-1 is selectively removed by treatment with a fluorine source (such as TBAF) to yield E-2. Alcohol E-2 can be treated with a chloroformate or alkyl-4-nitrobenzene carbonate in the presence of a base (such as DMAP, pyridine, or TEA) to yield the product of formula E-3. The triphenylmethyl protecting group in E-3 can then be removed under acidic conditions (such as formic acid, aqueous TFA solution, or acetic acid) to yield the product of formula E-4.

[0238] Option E

[0239]

[0240] As illustrated in Scheme F, generally, the compounds of the present invention can be prepared by treating E-2 with an acyl chloride in the presence of a base (such as DMAP or TEA), or by treating E-2 with a carboxylic acid in the presence of a coupling agent (such as DIC) and a base (such as DMAP), to obtain the product of formula F-1. The triphenylmethyl protecting group in F-1 can then be removed under acidic conditions (such as formic acid or aqueous TFA solution) to obtain the product of formula F-2.

[0241] Option F

[0242]

[0243] As illustrated in scheme G, generally, the compounds of the present invention can be prepared by first placing a protecting group (such as a trialkylsilyl group) on a 3' alcohol and a 5' alcohol to obtain G-1. The amine can be reacted by acylation of G-1 with an acyl chloride in the presence of a base (such as DMAP or pyridine) to give the product of formula G-2. Alternatively, it can be acylated by preparing a reactive intermediate of a carboxylic acid using a reagent such as TCFH and imidazole or POCl3 and a base. The protecting group in G-2 can then be removed under suitable conditions, including treatment with TBAF or triethylamine trihydrofluoride, to give the product of formula G-3.

[0244] Option G

[0245]

[0246] As illustrated in scheme H, in general, the compounds of the present invention can be prepared by treating A-2 with an acyl chloride in the presence of a base (such as pyridine) to obtain the product of formula H-1.

[0247] Option H

[0248]

[0249] As illustrated in Scheme I, generally, the compounds of the present invention can be prepared by reacting the amine of G-1 with a chloroformate, an alkyl-4-nitrobenzene carbonate, or an alkyl (2,5-dioxopyrrolidone-1-yl) carbonate in the presence of a base (such as DMAP, NaH, or K2CO3) to give products of formula I-1 and I-2. The protecting groups in formula I-1 and I-2 can then be removed under suitable conditions, including treatment with TBAF or triethylamine trihydrofluoride, to give products of formula I-3 and I-4.

[0250] Option I

[0251]

[0252] As illustrated in Scheme J, generally, the compounds of the present invention can be prepared by reacting the 3' alcohol of C-1 with 4-nitrobenzene chloroformate and a base (such as pyridine or TEA) to give J-1. J-1 can then be reacted with an alcohol in the presence of a base (such as DMAP or TEA) to give the product of formula J-2. The protecting group in J-2 can then be removed under suitable conditions, including treatment with TBAF or triethylamine trihydrofluoride, to give the product of formula J-3.

[0253] Scheme J

[0254]

[0255] As illustrated in scheme K, generally speaking, the compounds of the present invention can be prepared by treating E-2 with a halomethyl ester or halomethyl carbonate in the presence of a base (such as NaH) to obtain the product of formula K-1. The triphenylmethyl protecting group in K-1 can then be removed under acidic conditions (such as formic acid or aqueous TFA) to obtain the product of formula K-2.

[0256] Option K

[0257]

[0258] Synthesis of intermediates

[0259] The following sections describe the preparation of certain intermediates suitable for the preparation of the compounds of the present invention.

[0260] Intermediates 1 and 2

[0261] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethyl) (Intermediate 1) (Syryl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol

[0262] and 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy) (Intermediate 2)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0263]

[0264] Under an argon atmosphere at room temperature, tert-butyldimethylchlorosilane (0.37 g, 2.4 mmol) and imidazole (0.44 g, 6.5 mmol) were added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (0.5 g, 1.6 mmol) in DMF (7 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic fractions were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1 to 40% EtOAc / petroleum ether, to give (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1), MS: m / z = 421.25 [MH] - , and 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (intermediate 2), m / z = 537.40 [M+H] + .

[0265] Intermediate 3

[0266] ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methanol

[0267]

[0268] Step 1: 7-((2R,4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyl-4-((4- (4-Methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)-2-chloro-N-((4-methoxyphenyl)diphenylmethyl)-7H- Pyrrolo[2,3-d]pyrimidine-4-amine.

[0269] Under an argon atmosphere at room temperature, silver nitrate (0.29 g, 1.7 mmol), 4-methoxytriphenylmethyl chloride (0.53 mg, 1.7 mmol), and 2,4,6-trimethylpyridine (0.41 g, 3.4 mmol) were added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1, 0.24 g, 0.57 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (100 mL). The combined organic fractions were washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1 to 40% EtOAc / petroleum ether to give the title compound. MS: m / z = 967.40 [M+H] + .

[0270] Step 2: ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methanol

[0271] Tetrabutylammonium fluoride (1 M in THF) (0.57 mL, 0.57 mmol) was added to a stirred mixture of 7-((2R,4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyl-4-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)-2-chloro-N-((4-methoxyphenyl)diphenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.50 g, 0.52 mmol) in THF (5 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1 to 50% EtOAc / petroleum ether, to give the title compound. MS: m / z = 851.30 [MH] - .

[0272] Intermediate 4

[0273] 2-(adamantane-1-yl)ethyl(4-nitrophenyl) carbonate

[0274]

[0275] TEA (1.2 mL, 8.2 mmol) was added to a solution of 2-(adamantane-1-yl)ethanol (1.0 g, 5.5 mmol) and 4-nitrobenzene chloroformate (1.6 g, 8.2 mmol) in DCM (2 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 16 hours. The residue was purified by silica gel column chromatography, eluting with 0–70% EtOAc / petroleum ether to give the title compound. 1 H NMR (500MHz, CDCl3) δ8.28 (d, J = 9.1Hz, 2H), 7.38 (d, J = 9.0Hz, 2H), 4.36 (t, J = 7.4Hz, 2H), 1.98 (s, 3H), 1.75-1.52 (m, 14H).

[0276] Intermediate 5

[0277] (2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0278]

[0279] Step 1: 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)) (Oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-N-((4-methoxyphenyl)

[0280] (diphenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0281] Under a nitrogen atmosphere at 25°C, 4-methoxytriphenylchloromethane (3.1 g, 10 mmol), silver nitrate (1.7 g, 10 mmol), and 2,4,6-trimethylpyridine (2.4 g, 20 mmol) were added to a solution of intermediate 2 (1.8 g, 3.4 mmol) in DCM (20 mL). The resulting mixture was stirred at 25°C for 16 hours. The mixture was then quenched with a saturated aqueous solution of NH4Cl (100 mL). The reaction mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 10%–60% gradient of ethyl acetate / petroleum ether as eluent. Fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound. MS: m / z = 809.40 [M+H] + .

[0282] Step 2: (2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo [2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0283] Tetrabutylammonium fluoride (1.9 g, 7.4 mmol) was added to a solution of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-N-((4-methoxyphenyl)diphenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.0 g, 3.7 mmol) in THF (30 mL). The resulting mixture was stirred at 25 °C for 2 hours. The mixture was then quenched with a saturated aqueous solution of NH4Cl (200 mL). The reaction mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 10%–70% gradient of ethyl acetate / petroleum ether as eluent. The appropriate fractions were combined and concentrated under reduced pressure to obtain the title compound. MS: m / z = 581.20 [M+H] + .

[0284] Intermediate 6

[0285] (2R,3S,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2-chloro-4-(((4-methoxy) (2,3-d)pyrimidin-7-yl)-2-ethynyltetrahydrofuran-3-ol

[0286]

[0287] Under a nitrogen atmosphere at 0°C, a solution of intermediate 5 (1.3 g, 2.2 mmol) in pyridine (20 mL) was added with 4,4'-dimethoxytriphenylmethyl chloride (0.91 g, 2.7 mmol). The resulting mixture was stirred at 25°C for 2 hours. The mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography using a 10%–70% gradient of ethyl acetate / petroleum ether as eluent. Fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound. MS: m / z = 883.45 [M+H] + .

[0288] The intermediates in the table below are prepared in a similar manner to intermediate 4.

[0289]

[0290]

[0291]

[0292] Intermediates 24a and 24b

[0293] (S or R)((naphthalene-2-yloxy)(4-nitrophenoxy)phosphoyl)-L-alanine isopropyl ester and (R or S)((naphthalene- 2-(4-nitrophenoxy)phosphoryl)-L-alanine isopropyl ester

[0294]

[0295] Under an argon atmosphere at -78°C, a solution of triethylamine (0.24 g, 2.4 mmol) and naphthyl-2-ol (0.43 g, 3.0 mmol) in DCM (5 mL) was added to a stirred mixture of 4-nitrobenzene dichlorophosphate (0.76 g, 3.0 mmol) in DCM (5 mL). The resulting mixture was stirred at -78°C for 30 min. Subsequently, a mixture of L-alanine isopropyl hydrochloride (0.50 g, 3.0 mmol) and triethylamine (0.76 g, 7.5 mmol) in DCM (10 mL) was added to the resulting solution. The resulting mixture was stirred at -78°C for 30 min, then the mixture was heated to room temperature and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue was subjected to silica gel chromatography, eluting with 0-30% ethyl acetate / petroleum ether to give the crude product. The crude product was purified by preparative chiral HPLC under the following conditions: column: (S,S)-Whelk-O 15μm Kromasil 3*25cm, 5μm; mobile phase A: CO2, mobile phase B: MEOH; flow rate: 100mL / min; gradient: isocratic 30% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220nm; RT1 (min): 7.12; RT2 (min): 9.1.

[0296] The first elution peak (RT1: 7.12 min) was combined and assumed to be a compound, as S or R ((naphthyl-2-yloxy)(4-nitrophenoxy)phosphoryl)-L-alanine isopropyl ester of intermediate 24a. MS: m / z = 459.05 [M+H] + .

[0297] The second elution peak (RT2: 9.1 min) was combined and assumed to be a compound, as R or S((naphthyl-2-yloxy)(4-nitrophenoxy)phosphoryl)-L-alanine isopropyl ester of intermediate 24b. MS: m / z = 459.05 [M+H] + .

[0298] Intermediate 25

[0299] Chloromethyl dodecyl carbonate

[0300]

[0301] At 0 °C, 5 mL of DCM containing dodecane-1-ol (1.0 g, 5.4 mmol) and Py (0.43 mL, 5.4 mmol) was added dropwise to a solution of chloromethyl chloroformate (0.69 g, 5.4 mmol) in 20 mL of DCM. The resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was heated to ambient temperature, diluted with 20 mL of DCM, and washed with 0.5 M hydrochloric acid (3×), sodium bicarbonate aqueous solution (3×), and brine (3×). The mixture was dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0–4% EtOAc / petroleum ether to give the title compound. 1 HNMR(400MHz, CDCl3)δ5.73(s,2H),4.24–4.10(m,2H),1.75–1.64(m,2H),1.44–1.18(m,18H),0.90–0.83(m,3H).

[0302] Intermediate 26

[0303] Chloromethyl phenyl carbonate

[0304]

[0305] Intermediate 26 was prepared in a similar manner to intermediate 25.

[0306] Example

[0307] This invention is not limited to the specific embodiments disclosed in the examples, which are intended to illustrate some aspects of the invention, and any functionally equivalent embodiments are within the scope of this invention. In fact, various modifications to the invention, as well as those shown and described herein, will become apparent to those skilled in the art, and are intended to fall within the scope of the appended claims.

[0308] Example 1

[0309] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ylisopropyl ester

[0310]

[0311] Step 1: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylisopropyl ester

[0312] Under an argon atmosphere at 25 °C, DMAP (14 mg, 0.12 mmol), TEA (0.016 mL, 0.12 mmol), and isopropyl chloroformate (29 mg, 0.24 mmol) were added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (50 mg, 0.12 mmol) in CH2Cl2 (2 mL). The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with MeOH (0.1 mL). The reaction mixture was purified by preparative TLC (EtOAc / petroleum ether (1 / 2)) to give the title compound. MS: m / z = 509.30 [M+H] + .

[0313] Step 2: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl isopropyl ester

[0314] TBAF (0.13 mL, 0.13 mmol, 1 M in THF) was added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl isopropyl ester (45 mg, 0.088 mmol) in THF (2 mL). The resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-FLASH chromatography, eluting with 0–60% acetonitrile / water to give the title compound. MS: m / z = 395.05 [M+H] + . 1 HNMR(300MHz, DMSO-d6)δ7.60(s,2H),7.38(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),6.46–6.41(m,1H),5.60(t,J=6.0H z,1H),5.38–5.37(m,1H),4.84–4.80(m,1H),3.66–3.63(m,3H),3.32(s,1H),2.81–2.75(m,1H),1.27(d,J=6.3Hz,6H).

[0315] Example 2

[0316] Isobutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0317]

[0318] Step 1: Isobutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0319] DIC (0.055 mL, 0.36 mmol), isobutyric acid (16 mg, 0.18 mmol), and (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (50 mg, 0.12 mmol) were added to a stirred mixture of DMAP (2.9 mg, 0.024 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with NH4Cl (10 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic fractions were washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (EtOAc / petroleum ether = 1:1) to give the title compound. MS: m / z = 493.25 [M+H] + .

[0320] Step 2: Isobutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethyl alkynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0321] Tetrabutylammonium fluoride (0.10 mL, 0.10 mmol, 1 M in THF) was added to a stirred mixture of isobutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester (50 mg, 0.10 mmol) in THF (3 mL). The resulting mixture was heated to 25 °C and stirred for 4 hours. The reaction mixture was purified by RP-FLASH chromatography, eluting with 35–40% acetonitrile / water (0.5% aqueous FA solution) to give the title compound. MS: m / z = 379.0 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ7.62(s,2H),7.41-7.40(m,1H),6.63–6.64(m,1H),6.44–6.48(m,1H),5.59–5.62(m,1H) ,5.51–5.53(m,1H),3.61–3.65(m,3H),2.75–2.80(m,1H),2.60–2.66(m,1H),2.40–2.45(m,1H),1.14–1.19(m,6H).

[0322] Example 3

[0323] Valeronic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yl ester

[0324]

[0325] The title compound was prepared in a similar manner to that of Example 2, except that valeric acid was used in step 1. MS: m / z = 393.10 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ7.76(s,2H),7.40-7.39(m,1H),6.64–6.63(m,1H),6.47–6.44(m,1H),5.61–5.53(m,2H),3.64–3. 61(m,2H),3.33–3.31(m,1H),2.77–2.75(m,1H),2.44–2.40(m,3H),1.60–1.54(m,2H),1.36–1.33(m,2H),0.94–0.87(m,3H).

[0326] Example 4

[0327] Decanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yl ester

[0328]

[0329] The title compound was prepared in a similar manner to that of Example 2, except that decanoic acid was used in step 1. MS: m / z = 463.00 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ7.33-7.30(m,1H),6.59–6.47(m,2H),5.67–5.64(m,1H),3.89–3.78(m,2H),3.1 3(s,1H),2.90–2.83(m,1H),2.51–2.42(m,3H),1.70-1.60(m,2H),1.40-1.25(m,12H),0.91–0.81(m,3H).

[0330] Example 5

[0331] Benzoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0332]

[0333] The title compound was prepared in a similar manner to that of Example 2, except that benzoic acid was used in step 1. MS: m / z = 413.00 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ8.14(s,2H),7.67–7.63(m,1H),7.54–7.50(m,2H),7.39–7.37(m,1 H),6.67–6.61(m,2H),5.88(s,1H),3.93–3.89(m,2H),3.10–2.97(m,2H),2.67–2.63(m,1H).

[0334] Example 6

[0335] Benzoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((benzoyl) oxy(methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0336]

[0337] Benzoic acid (71 mg, 0.58 mmol) was added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (compound A) (30 mg, 0.097 mmol), 4-dimethylaminopyridine (4.8 mg, 0.039 mmol), and DCC (40 mg, 0.19 mmol) in DMF (2 mL) under an argon atmosphere at room temperature. The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with NH4Cl (10 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic fractions were washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC using 40% EtOAc / petroleum ether to give the title compound. MS: m / z = 517.05 [M+H] + . 1 HNMR (300MHz, CD3Cl) δ8.13(d,J=1.2Hz,2H),8.04(d,J=7.2Hz,2H),7.65–7.40(m,6H),7.10(d,J=3.6Hz,1H),6.79(t,J=6.6Hz,1H),6 .42(d,J=3.6Hz,1H),5.98–5.94(m,1H),5.81(s,2H),4.82(d,J=11.7Hz,1H),4.65(d,J=12.0Hz,1H),2.99–2.81(m,2H),2.69(s,1H).

[0338] Example 7

[0339] Valeronic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- ((valeroyloxy)methyl)tetrahydrofuran-3-yl ester

[0340]

[0341] The title compound was prepared in a similar manner to that of Example 6, except that valeric acid was used in step 1. MS: m / z = 477.15 [M+H] + . 1 H NMR (300MHz, CD3Cl)δ

[0342] 7.12(d,J=3.9Hz,1H),6.71(t,J=6.6Hz,1H),6.43(d,J=3.9Hz,1H),5.60–5.56(m,1H),5.47(s,2H),4.45(d,J=12.0Hz,1H ), 4.35 (d, J = 11.7Hz, 1H), 2.73–2.63 (m, 3H), 2.45–2.36 (m, 4H), 1.70–1.61 (m, 4H), 1.43–1.32 (m, 4H), 0.97–0.89 (m, 6H).

[0343] Example 8

[0344] ((S)-(((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 3-Hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester

[0345]

[0346] Under an argon atmosphere at 0°C, a solution of a 2,2,6,6-tetramethylpiperidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (30 mg, 0.097 mmol) complex of 2,2,6,6-tetramethylpiperidinyl magnesium lithium chloride was added to a stirred mixture in DMF (1 mL). The resulting mixture was stirred at 0°C for 0.5 h. Subsequently, a solution of ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (44 mg, 0.097 mmol) in DMF (0.2 mL) was added to the reactants. The resulting mixture was stirred at 0°C for 1 h. The reactants were purified by RP-FLASH chromatography, eluting with 0–30% acetonitrile / water (5 mM NH4HCO3) to give the title compound. MS: m / z = 578.15 [M+H] + . 1H NMR (300MHz, CDCl3) δ7.32–7.29(m,2H),7.23–7.15(m,3H),7.07(d,J=3.6Hz,1 H),6.62(dd,J=7.5,4.8Hz,1H),6.35(d,J=3.6Hz,1H),5.25(s,2H),5.05–4.96( m,1H),4.73–4.71(m,1H),4.35–4.30(m,2H),4.00–3.94(m,1H),3.72–3.65(m,1 H),3.29–3.27(m,1H),2.71–2.60(m,3H),1.38–1.36(m,3H),1.26–1.20(m,6H). 31 P NMR (121MHz, CDCl3) δ2.86 (s, 1P).

[0347] Example 9

[0348] Benzoic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 3-Hydroxytetrahydrofuran-2-yl)methyl ester

[0349]

[0350] To a solution of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (0.10 g, 0.32 mmol) in THF (20 mL), propion-2-one O-benzoyl oxime (57 mg, 0.32 mmol), immobilized NOVO enzyme-435 (400 U), and molecular sieve (1 g) were added. The resulting mixture was stirred at 50 °C for 48 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by RP-FLASH chromatography, eluting with 0–56% acetonitrile / water (5 mM NH4HO3) to give the title compound. MS: m / z = 411.05 [MH] - . 1 HNMR (300MHz, CD3OD) δ7.97–7.94(m,2H),7.60–7.57(m,1H),7.48–7.45(m,2H),7.14(d,J=3.9Hz,1H),6.49–6.45( m,2H),4.90–4.85(m,1H),4.73–4.69(m,1H),4.49–4.45(m,1H),3.17(s,1H),2.78–2.76(m,1H),2.70–2.63(m,1H).

[0351] Example 10

[0352] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yldecyl ester

[0353]

[0354] The title compound was prepared in a similar manner to that of Example 12, except that decyl chloroformate was used in step 1. MS: m / z = 493.15 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ7.60(s,2H),7.38(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),6.46–6.42(m,1H),5.60(s,1H),5.39–5.37(m,1H), 4.14–4.11(m,2H),3.65–3.62(m,3H),3.18–3.12(m,1H),2.84–2.77(m,1H),1.64–1.59(m,2H),1.34–1.25(m,12H),0.95–0.84(m,5H).

[0355] Alternatively, Example 10 can be prepared as follows:

[0356] Step 1: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yldecyl ester

[0357] Under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (2.2 g, 5.3 mmol) was dissolved in anhydrous pyridine (25 mL) and placed in a cold water bath. Decyl chloroformate (1.8 mL, 8.0 mmol) was added dropwise to this solution, and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was quenched with water, concentrated under reduced pressure, and subsequently partitioned between water and diethyl ether. The organic matter was washed with water (3×) and then with brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (120 g ISCO-gold) by elution with 0–40% EtOAc / hexane to give the title compound. MS: m / z = 607.7 [M+H] + .

[0358] Step 2: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yldecyl ester

[0359] Under a nitrogen atmosphere, a solution of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yldecyl ester (2.5 g, 4.1 mmol) in anhydrous THF (30 mL) was placed in a cold water bath. TBAF (1 M in THF) (4.1 mL, 4.1 mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes and then diluted with ether and water. The organic matter was washed with water (3×) and then with brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (120 g ISCO-gold) eluted with 0–60% EtOAc / hexane. The appropriate fraction was concentrated under reduced pressure, then redissolved in ether and concentrated under reduced pressure (2×). The residue was recrystallized from diethyl ether to give the title compound. MS: m / z = 493.8 [M+H] + . 1 H NMR(500MHz, CDCl3) δ6.96(d,J=2.5Hz,1H),6.33(d,J=2.4Hz,1H),6.25(dd,J=9.5,5 .3Hz,1H),5.83(d,J=12.0Hz,1H),5.63(d,J=6.2Hz,1H),5.48(s,2H),4.27–4.14(m,2 H),4.08-4.03(m,1H),3.96(t,J=12.3Hz,1H),3.37–3.27(m,1H),2.62(s,1H),2.47( dd,J=13.9,5.4Hz,1H),1.75-1.67(m,2H),1.42-1.23(m,14H),0.88(t,J=6.4Hz,3H).

[0360] Example 11

[0361] Isobutyric acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 3-Hydroxytetrahydrofuran-2-yl)methyl ester

[0362]

[0363] The title compound was prepared in a similar manner to that of Example 9, except that acetone-2-one O-isobutyryl oxime was used in step 1. MS: m / z = 379.15 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.57(s,2H),7.31(d,J=3.6Hz,1H),6.62(d,J=3.6Hz,1H),6.40–6.36(m,1H),6.06(s,1H),4.56– 4.52(m,1H),4.41–4.38(m,1H),4.08–4.05(m,1H),3.67(s,1H),2.66–2.58(m,2H),2.51–2.33(m,1H),1.07–1.03(m,6H).

[0364] Example 12

[0365] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ylphenyl ester

[0366]

[0367] Step 1: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylphenyl ester

[0368] To a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (50 mg, 0.118 mmol) in DCM (3 mL), TEA (0.025 mL, 0.177 mmol), DMAP (14.44 mg, 0.118 mmol), and phenyl chloroformate (22.21 mg, 0.142 mmol) were added. The resulting mixture was heated to 25 °C and stirred for 16 h. The reactants were quenched with MeOH (0.1 mL) and subsequently concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc / petroleum ether = 1:1) to give the title compound. MS: m / z = 543.25 [M+H] + .

[0369] Step 2: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-ylphenyl ester

[0370] Triethylamine trifluoride (119 mg, 0.737 mmol) was added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylphenyl ester (50 mg, 0.092 mmol) in THF (3 mL). The resulting mixture was heated to 25 °C and stirred for 4 hours. The reaction mixture was purified by RP-FLASH chromatography, eluting with 0–60% acetonitrile / water to give the title compound. MS: m / z = 428.90 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ7.47–7.43(m,2H),7.35(d,J=3.6Hz,1H),7.29–7.33(m,1H),7.23–7.26(m,2H),6.62(d,J=3. 6Hz,1H),6.58–6.54(m,1H),5.64–5.61(m,1H),3.94–3.86(m,2H),3.32(s,1H),3.06–2.98(m,1H),2.70–2.64(m,1H).

[0371] Example 13

[0372] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ylpentyl ester

[0373]

[0374] The title compound was prepared in a similar manner to that of Example 12, except that amyl chloroformate was used in step 1. MS: m / z = 423.10 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.00(d,J=3.6Hz,1H),6.37(d,J=3.6Hz,1H),6.29–6.25(m,1H),5.63–5.59(m,4H),4.26–4.15(m,2H),4.07–4.04 (m,1H),3.97–3.94(m,1H),3.33–3.26(m,1H),2.62(s,1H),2.48–2.46(m,1H),1.75–1.68(m,2H),1.39–1.34(m,4H),0.94–0.90(m,3H).

[0375] Example 14

[0376] Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- Hydroxytetrahydrofuran-2-yl)methylpentyl ester

[0377]

[0378] Step 1: Carbonic acid ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl) Methylpentyl ester

[0379] Under a nitrogen atmosphere at 0°C, TEA (0.024 mL, 0.18 mmol) and amyl chloroformate (35 mg, 0.23 mmol) were added to a solution of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methanol (intermediate 3) (0.10 g, 0.12 mmol) and 4-dimethylaminopyridine (14 mg, 0.12 mmol) in DCM (5 mL). The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was purified by preparative TLC, eluting with DCM:MeOH = 10:1 to give the title compound. MS: m / z = 967.55 [M+H] + .

[0380] Step 2: Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethyl alkynyl-3-hydroxytetrahydrofuran-2-yl)methylpentyl ester

[0381] Formic acid (4.0 mL, 0.10 mmol) was added to a mixture of (2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methylpentyl ester (0.10 g, 0.10 mmol) in water (1 mL) under a nitrogen atmosphere at 25 °C. The resulting mixture was stirred at 25 °C for 16 h. The residue was purified by RP-Flash (column: C1840 g column; mobile phase A: water (0.1% NH4HCO3), mobile phase B: MeCN; flow rate: 50 mL / min; gradient: 2% B to 30% B over 30 min; detector: UV 210 nm; RT = 28 min) to give the title compound. MS: m / z = 423.10 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.63–7.56(m,2H),7.30–7.29(m,1H),6.62–6.61 (m,1H),6.39–6.36(m,1H),5.76–5.73(m,1H),4.56–4.52(m,1H),4.41–4 .36(m,1H),4.22-4.17(m,1H),4.08–4.05(m,2H),3.61–3.58(m,1H),2.6 2–2.35(m,2H),1.60-1.50(m,2H),1.30–1.20(m,4H),0.88–0.80(m,3H).

[0382] Example 15

[0383] Valeronic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- Hydroxytetrahydrofuran-2-yl)methyl ester

[0384]

[0385] The title compound was prepared in a similar manner to that of Example 14, except that hexanoyl chloride was used in step 1. MS: m / z = 393.05 [M+H] + . 1 H-NMR (300MHz, CD3OD): δ7.21-7.18(m,1H),6.62-6.59(m,1H),6.47-6.41(m,1H),4.79-4.70(m,1H),4.51-4.45(m,1H),4.2 3-4.18(m,1H),3.12(s,1H),2.77-2.57(m,2H),2.40-2.20(m,2H),1.60-1.48(m,2H),1.35-1.22(m,2H),0.94-0.85(m,3H).

[0386] Example 16

[0387] Palmitic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 3-Hydroxytetrahydrofuran-2-yl)methyl ester

[0388]

[0389] The title compound was prepared in a similar manner to that of Example 14, except that palmitoyl chloride was used in step 1. MS: m / z = 547.00 [M+H] + . 1HNMR(500MHz, CDCl3)δ7.05(d,J=3.6Hz,1H),6.60–6.54(m,1H),6.37(d,J=3.7Hz,1H),5.31(s,2H),4.65(q,J=7.2Hz,1H),4.48–4 .36(m,2H),2.76–2.69(m,2H),2.66–2.56(m,1H),2.40–2.31(m,3H),1.65–1.55(m,2H),1.30–1.26(m,24H),0.88(t,J=6.5Hz,3H).

[0390] Example 17

[0391] Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- Hydroxytetrahydrofuran-2-yl)methylphenyl ester

[0392]

[0393] The title compound was prepared in a similar manner to that of Example 14, except that phenyl chloroformate was used in step 1. MS: m / z = 428.95 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.38–7.35(m,2H),7.33–7.22(m,2H),7.06–7.04(m,2H),6.59–6.52(m,2H) ,4.89–4.77(m,1H),4.66–4.65(m,1H),4.46–4.40(m,1H),3.31–3.12(m,1H),2.69–2.59(m,2H).

[0394] Example 18

[0395] Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- Hydroxytetrahydrofuran-2-yl)methyldecyl ester

[0396]

[0397] Step 1: Carbonic acid ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl) Methyl decyl ester

[0398] Under a nitrogen atmosphere at 0°C, TEA (0.024 mL, 0.176 mmol) and decyl chloroformate (51.7 mg, 0.234 mmol) were added to a solution of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methanol (intermediate 3) (100 mg, 0.117 mmol) and 4-dimethylaminopyridine (14.32 mg, 0.117 mmol) in DCM (2 mL). The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was purified by preparative TLC, eluting with DCM:MeOH = 10:1 to give the title compound. MS: m / z = 1037.55 [M+H] + .

[0399] Step 2: Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethyl alkynyl-3-hydroxytetrahydrofuran-2-yl)methyldecyl ester

[0400] TFA (4 mL, 51.9 mmol) was added to a solution of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methyldecyl ester (100 mg, 0.096 mmol) in water (1 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 16 hours. The residue was purified by RP-Flash (column: C1840 g column; mobile phase A: water (0.1% NH4HCO3), mobile phase B: MeCN; flow rate: 40 mL / min; gradient: 2% B to 30% B over 30 min; detector: UV 210 nm; RT = 28 min). The fractions containing the desired product were combined and concentrated under reduced pressure to obtain the title compound. MS: m / z = 493.05 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.21–7.20(m,1H),6.59–6.58(m,1H),6.53–6.50(m,1H),4.68–4.65(m,1H),4.58–4.48(m,1H),4.36–4. 28(m,1H),4.17–4.03(m,2H),3.21–3.14(m,1H),2.63–2.55(m,2H),1.65–1.62(m,2H),1.41–1.19(m,14H),0.96–0.86(m,3H).

[0401] Alternatively, Example 18 can be prepared as follows:

[0402] In a flame-dried flask under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (compound A) (2.5 g, 8.1 mmol) was dissolved in anhydrous pyridine (50 mL) and placed in an ice bath. Decyl chloroformate (2.1 mL, 8.9 mmol) was added dropwise over 5 minutes, followed by stirring at 0 °C for 80 minutes. The reaction mixture was quenched with anhydrous methanol (5 mL) and stirred for 5 minutes. The mixture was concentrated under reduced pressure and then partitioned between water and ether. The organic matter was washed with water (3×) and brine (1×), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM / toluene and purified on an NP silica gel column (120 g ISCO-gold) eluted with 0–50% EtOAc / hexane. The appropriate fraction was concentrated under reduced pressure, then redissolved in ether and concentrated under reduced pressure (2×). The residue was recrystallized from diethyl ether to give the title compound. MS: m / z = 493.5 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.13(d,J=3.6Hz,1H),6.66(t,J=6.3Hz,1H),6.37(d,J=3.6H z,1H),5.39(s,2H),4.67(q,J=6.5Hz,1H),4.51(d,J=11.6Hz,1H),4.41(d,J=11.6H z,1H),4.16(t,J=6.7Hz,2H),2.79(s,1H),2.75-2.68(m,1H),2.63-2.56(m,1H),2 .40(d,J=6.4Hz,1H),1.71-1.64(m,2H),1.40-1.22(m,14H),0.88(t,J=6.7Hz,3H).

[0403] Example 19

[0404] N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyridine pyrimidin-4-yl)benzamide

[0405]

[0406] Step 1: N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy) (yl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0407] At room temperature, DMAP (23 mg, 0.19 mmol) and benzoyl chloride (20 mg, 0.14 mmol) were added to a stirred mixture of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (intermediate 2) (50 mg, 0.093 mmol) in pyridine (1 mL). The resulting mixture was stirred at room temperature for 16 hours. The reactants were diluted with EtOAc (50 mL) and washed with water (2 × 50 mL) and brine (saturated, 2 × 50 mL), dried over Na2SO4, and concentrated. The residues were purified by silica gel column chromatography, eluting with 0–50% EtOAc / petroleum ether, to give the title compound. MS: m / z = 641.35 [M+H] + .

[0408] Step 2: N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0409] Tetrabutylammonium fluoride (0.062 mL, 0.062 mmol) was added to a mixture of N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (33 mg, 0.051 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-Combiflash under the following conditions: column: C18 40 g column, 20-35 μm; Mobile phase A: water, mobile phase B: MeCN; Flow rate: 50 mL / min; 0% B to 100% B over 15 min; Detector: UV 254 and 210 nm, yielding the title compound. MS: m / z = 411.00 [MH] - . 1 H-NMR(400MHz,CD3OD)δ7.92–7.91(m,2H),7.57–7.43(m,4H),6.80–6.78(m,1H),6.5 8–6.56(m,1H),4.63–4.59(m,1H),3.76–3.66(m,2H),2.98(s,1H),2.60–2.47(m,2H).

[0410] Example 20

[0411] Decanoic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- Hydroxytetrahydrofuran-2-yl)methyl ester

[0412]

[0413] Step 1: Decanoic acid ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl) Methyl ester

[0414] To a stirred mixture of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methanol (intermediate 3) (100 mg, 0.117 mmol) in DMF (1.5 mL), DIC (0.082 mL, 0.527 mmol), DMAP (4.29 mg, 0.035 mmol), and decanoic acid (60.6 mg, 0.352 mmol) were added to a dimethyl ether (DMF) solution. The resulting mixture was heated to 25 °C and stirred for 18 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic fractions were washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (EtOAc / petroleum ether = 1:2) to give the title compound. MS: m / z = 1007.60 [M+H] + .

[0415] Step 2: Decanoic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethyl alkynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0416] Formic acid (4 mL) was added to a stirred mixture of decanoic acid ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methyl ester (150 mg, 0.149 mmol) in water (1 mL). The resulting mixture was heated to 25 °C and stirred overnight. The reaction mixture was purified by RP-FLASH chromatography, eluting with 0–80% acetonitrile / water to give the title compound. MS: m / z = 463.15 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ

[0417] 7.20(d,J=3.6Hz,1H),6.59(d,J=3.6Hz,1H),6.46–6.43(m,1H),4.74(t,J=7.6Hz,1H),4.48–4.45(m,1H),4.24–4 .21(m,1H),3.13(s,1H),2.70–2.59(m,2H),2.32–2.27(m,2H),1.53(s,2H),1.25(s,12H),0.88(t,J=7.2Hz,3H).

[0418] Alternatively, Example 20 can be prepared as follows:

[0419] In a flame-dried flask under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (compound A) (2.0 g, 6.5 mmol) was dissolved in anhydrous pyridine (40 mL) and placed in an ice bath. Decanoyl chloride (1.5 mL, 7.1 mmol) was added dropwise over 5 minutes, followed by stirring at 0 °C for 150 minutes. The reaction mixture was quenched with anhydrous methanol (5 mL) and stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure and then partitioned between water and ether. The organic matter was washed with water (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM / toluene and purified on an NP silica gel column (120 g ISCO-gold) eluted with 0–65% EtOAc / hexane. The appropriate fraction was concentrated under reduced pressure, then redissolved in ether and concentrated under reduced pressure (2×). The residue was recrystallized from diethyl ether to give the title compound. MS: m / z = 463.5 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.05(d,J=3.5Hz,1H),6.60–6.54(m,1H),6.38(d,J=3.5Hz,1H),5.36(s,2H),4.65(q,J=7.0Hz,1H),4.45(d,J=11.8Hz,1H) ,4.39(d,J=11.9Hz,1H),2.78–2.69(m,2H),2.65-2.58(m,1H),2.42–2. 30(m,3H),1.66–1.59(m,2H),1.35-1.19(m,12H),0.88(t,J=6.7Hz,3H).

[0420] Example 21

[0421] N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyridine pyrimidin-4-yl)dodecanoamide

[0422]

[0423] The title compound was prepared in a similar manner to that of Example 19, except that dodecanoyl chloride was used in step 1 and triethylamine trihydrofluoride was used in step 2 (Example 12 - step 2). MS: m / z = 491.15 [M+H] + . 1 H-NMR(400MHz,CD3OD)δ7.59–7.45(m,1H),6.95–6.89(m,1H),6.70–6.60(m,1H),4.71–4.65(m,1H),3.85–3 .70(m,2H),3.07–3.05(m,1H),2.70–2.50(m,4H),1.80–1.69(m,2H),1.44–1.25(m,16H),0.93–0.82(m,3H).

[0424] Alternatively, Example 21 can be prepared as follows:

[0425] Step 1: N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy) (yl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-dodecanoyl Dodecylamide

[0426] To a solution of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.0 g, 1.9 mmol) (intermediate 2) in anhydrous dichloroethane (14 mL), DIEA (1.6 mL, 9.3 mmol) and dodecyl chloride (1.7 mL, 7.4 mmol) were added. The reaction mixture was heated in a microwave at 130 °C for 4 hours. The reaction mixture was cooled and ammonia (9.3 mL, 18 mmol, 2 M in MeOH) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and diethyl ether. The organic matter was washed with water (3×) and then with brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (120 g ISCO-gold) by elution with 0–100% EtOAc / hexane to give the title compound. MS: m / z = 719.5 [M+H] + .

[0427] Step 2: N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)dodecanoamide

[0428] A mixture of N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)dodecanoamide (3.7 g, 5.1 mmol) in THF (100 mL) was cooled in an ice bath, and tetrabutylammonium fluoride (10 mL, 10 mmol, 1 M in THF) was added. The resulting mixture was heated to room temperature and stirred for three hours. The reactants were partitioned between water and diethyl ether. The organic matter was washed with water (3×) and then with brine (1×), dried over Mg2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (330 g ISCO-gold) eluted with 0–50% EtOAc / hexane. The appropriate fraction was concentrated under reduced pressure, then redissolved in ether and concentrated under reduced pressure (2×). The residue was recrystallized from diethyl ether to give the title compound. MS: m / z = 491.5 [M+H] + . 1 HNMR (500MHz, CDCl3) δ7.99 (s, 1H), 7.12 (d, J = 3.8Hz, 1H), 7.05 (d, J = 3.8Hz, 1H), 6.38 (dd, J = 8. 5,6.0Hz,1H),4.85(dd,J=11.4,3.0Hz,1H),4.72(dt,J=5.9,3.0Hz,1H),4.06(dd,J=12.4,3.0H z,1H),3.92–3.83(m,1H),3.16–3.06(m,1H),2.80(s,1H),2.53–2.40(m,3H),2.37(dd,J=3.4,1 .2Hz,1H),1.80-1.70(m,2H),1.43-1.35(m,2H),1.28(d,J=18.2Hz,14H),0.88(t,J=7.0Hz,3H).

[0429] Example 22

[0430] N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyridine [2,3-d]pyrimidin-4-yl)pentanamide

[0431]

[0432] The title compound was prepared in a similar manner to that of Example 20, except that valeryl chloride was used in step 1 and triethylamine trihydrofluoride was used in step 2 (Example 12 - step 2). MS: m / z = 393.10 [M+H] + . 1H-NMR (400MHz, CD3OD): δ7.54–7.52(m,1H),6.91–6.89(m,1H),6.65–6.62(m,1H),4.71–4.67(m,1H),3.84–3.81(m, 1H),3.77–3.74(m,1H),3.07(s,1H),2.63–2.52(m,4H),1.73–1.67(m,2H),1.46–1.13(m,2H),0.97(t,J=7.2Hz,3H).

[0433] Example 23

[0434] Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- Hydroxytetrahydrofuran-2-yl)methyl isopropyl ester

[0435]

[0436] Step 1: ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrole [2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)

[0437] Tetrahydrofuran-2-yl)methanol

[0438] Under a nitrogen atmosphere at 0 °C, TEA (0.024 mL, 0.18 mmol) and isopropyl chloroformate (29 mg, 0.23 mmol) were added to a solution of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methanol (intermediate 3) (0.10 g, 0.12 mmol) and 4-dimethylaminopyridine (14 mg, 0.12 mmol) in DCM (2 mL). The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by preparative TLC, developed using DCM:MeOH (10:1), to give the title compound. MS: m / z = 939.45 [M+H] + .

[0439] Step 2: Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethyl alkynyl-3-hydroxytetrahydrofuran-2-yl)methyl isopropyl ester

[0440] Formic acid (4.0 mL, 0.11 mmol) was added to a solution of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methyl isopropyl ester (0.10 g, 0.11 mmol) in water (1 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 16 h. The residue was purified by RP-Flash under the following conditions: C1840 g column; mobile phase A: water (0.1% NH4HCO3, mobile phase B: MeCN; flow rate: 50 mL / min; gradient: 2% B to 30% B over 30 min, detector: UV 210 nm) to give the title compound. MS: m / z = 393.05 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ7.61–7.56(m,2H),7.28–7.26(m,1H),6.63–6.62(m,1H),6.42–6.38(m,1H),5.81(s,1H),4.76–4.6 9(m,1H),4.51–4.38(m,2H),4.18–4.15(m,1H),3.63–3.61(m,1H),2.62–2.51(m,1H),2.45–2.38(m,1H),1.21–1.18(m,6H).

[0441] Example 24

[0442] Octanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yl ester

[0443]

[0444] The title compound was prepared in a similar manner to that of Example 1, except that octanoyl chloride was used in step 1. MS: m / z = 435.10 [M+H] + . 1 H-NMR (300MHz, CDCl3): δ7.03(s,1H),6.37(s,1H),6.30–6.27(m,1H),5.79(s,1H),5.55(s,3H),4.07–3.9 7(m,2H),3.35–3.19(m,1H),2.59(s,1H),2.44–2.39(m,3H),1.90–1.78(m,2H),1.30(s,8H),1.15(s,3H).

[0445] Alternatively, Example 24 can be prepared as follows:

[0446] Step 1: Octanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0447] At room temperature under an argon atmosphere, octanoyl chloride (1.4 g, 8.9 mmol) was added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (2.5 g, 5.9 mmol), TEA (0.90 g, 8.9 mmol), and DMAP (0.72 g, 5.9 mmol) in DCM (25 mL). The resulting mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the residue was purified by NP silica gel column chromatography, eluting with 0-73% EtOAc / petroleum ether, to give the title compound. MS: m / z = 549.2 [M+H] + .

[0448] Step 2: Octanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0449] Triethylamine trifluoride (5.9 g, 36 mmol) was added to a stirred mixture of (2.0 g, 3.6 mmol) octanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester (2.0 g, 3.6 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 16 hours. The reactants were purified by RP-FLASH chromatography, eluted with 0–48% acetonitrile / water, and subsequently recrystallized from ether-heptane to give the title compound. MS: m / z = 435.4 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.04–6.99(m,1H),6.37–6.32(m,1H),6.31–6.25(m,1H),5.79(d,J=6.4Hz,1H),5.57(d,J=11.6Hz,1H),5.42(s,2H),4.04(d, J=12.2Hz,1H),3.94(t,J=12.1Hz,1H),3.30–3.21(m,1H),2.59(s,1H),2. 45–2.35(m,3H),1.72–1.64(m,2H),1.35–1.28(m,8H),0.92–0.86(m,3H).

[0450] Example 25

[0451] Dodecanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0452]

[0453] The title compound was prepared in a similar manner to that of Example 12, except that dodecanoyl chloride was used in step 1. MS: m / z = 490.95 [M+H] + . 1 HNMR(300MHz,DMSO-d6)δ7.60(s,2H),7.39(s,1H),6.64-6.479(m,1H),6.46-6.43(m,1H),5.59–5.52(m,2H),3. 64–3.57(m,3H),2.76–2.72(m,1H),2.51–2.34(m,3H),1.61–1.54(m,2H),1.27–1.24(m,16H),0.87–0.82(m,3H).

[0454] Example 26

[0455] Tetradecanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0456]

[0457] The title compound was prepared in a similar manner to that of Example 12, except that tetradecyl chloride was used in step 1. MS: m / z = 519.00 [M+H] + . 1 HNMR(300MHz,DMSO-d6)δ7.59(s,2H),7.40–7.38(s,1H),6.64–6.46(m,1H),6.45–5.59(m,1H),5.57–5.52(m,2H), 3.66–3.59(m,3H),2.81–2.72(m,1H),2.25–2.37(m,3H),1.61–1.54(m,2H),1.27–1.23(m,20H),0.87–0.83(m,3H).

[0458] Example 27

[0459] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ylbenzyl ester

[0460]

[0461] The title compound was prepared in a similar manner to that of Example 12, except that benzyl chloroformate was used in step 1. MS: m / z = 443.05 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ7.41–7.32(m,6H),6.60(s,1H),6.50–6.46(m,1H),5.53–5.5 1(m,1H),5.25–5.17(m,2H),3.87–3.78(m,2H),2.95–2.88(m,2H),2.58–2.52(m,1H).

[0462] Alternatively, Example 27 can be prepared as follows.

[0463] Step 1: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylbenzyl ester

[0464] In an argon atmosphere at room temperature, methyl chloroformate (2.0 g, 12 mmol) was added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (2.5 g, 5.9 mmol), TEA (0.90 g, 8.9 mmol), and DMAP (0.72 g, 5.9 mmol) in DCM (25 mL). The resulting mixture was stirred at 40 °C for 16 hours. The solution was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0–56% EtOAc / petroleum ether, to give the title compound. MS: m / z = 557.2 [M+H] + .

[0465] Step 2: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-ylbenzyl ester

[0466] Triethylamine trifluoride (5.8 g, 36 mmol) was added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylbenzyl ester (2.0 g, 3.6 mmol) in THF (2 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reactants were purified by RP-FLASH chromatography, eluted with 0–48% acetonitrile / water, and subsequently recrystallized in EtOAc-heptane to give the title compound. MS: m / z = 443.4 [M+H] + . 1H NMR(500MHz, CDCl3)δ7.46–7.34(m,5H),6.95(d,J=3.7Hz,1H),6.32(d,J=3.7Hz,1H), 6.22(dd,J=9.9,5.3Hz,1H),5.85(dd,J=12.1,2.4Hz,1H),5.64(d,J=6.0Hz,1H),5.32 (s,2H),5.28(d,J=12.0Hz,1H),5.18(d,J=12.0Hz,1H),4.04(dd,J=12.3,2.4Hz,1H), 3.94(t,J=12.3Hz,1H),3.38–3.28(m,1H),2.45(dd,J=14.0,5.4Hz,1H),2.33(s,1H).

[0467] Example 28

[0468] Pyridinecarboxylic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0469]

[0470] The title compound was prepared in a similar manner to that of Example 12, except that pyridine carboxyl chloride was used in step 1. MS: m / z = 414.05 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ8.73(s,1H),8.34–8.32(m,1H),8.09–8.07(m,1H),7.70–7.67(m,1H),7.3 7(s,1H),6.73–6.61(m,2H),5.97–5.95(m,1H),3.93(s,2H),3.07–3.00(m,2H),2.76–2.67(m,1H).

[0471] Example 29

[0472] 2-(4-fluorophenyl)acetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-Ethynyl-2-((2-(4-fluorophenyl)acetoxy)methyl)tetrahydrofuran-3-yl ester

[0473]

[0474] The title compound was prepared in a similar manner to that of Example 6, except that 2-(4-fluorophenyl)acetic acid was used in step 1. MS: m / z = 581.15 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ7.62(s,2H),7.39–7.35(m,4H),7.29–7.07(m,5H),6.64–6.63(m,1H),6.48–6.4 5(m,1H),5.65–5.45(m,1H),4.37–4.22(m,2H),3.83–3.72(m,5H),2.85–2.76(m,1H),2.53–2.49(m,1H). 19 H NMR(376MHz,DMSO-d6)δ-115.93.

[0475] Example 30

[0476] 3-((adamantane-1-yl)propionic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- 2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0477]

[0478] The title compound was prepared in a similar manner to that of Example 2, except that 3-(adamantane-1-yl)propionic acid was used in step 1 and triethylamine trihydrofluoride was used in step 2 (Example 12, step 2). MS: m / z = 499.15 [M+H] + . 1 H-NMR (400MHz, CD3OD-d4): δ7.32(s,1H),6.60–6.59(m,1H),6.53–6.48(m,1H),5.65–5.62(m,1H),3.86–3.78 (m,2H),3.12(s,1H),2.90–2.83(m,1H),2.52–2.37(m,3H),1.96(s,3H),1.78–1.67(m,6H),1.54–1.46(m,8H).

[0479] Example 31

[0480] 2-(4-fluorophenyl)acetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-Ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0481]

[0482] The title compound was prepared in a similar manner to that of Example 2, except that 2-(4-fluorophenyl)acetic acid was used in step 1 and triethylamine trihydrofluoride was used in step 2 (Example 12, step 2). MS: m / z = 445.05 [M+H] + . 1H-NMR (400MHz, CD3OD): δ7.39–7.36(m,3H),7.10–7.06(m,2H),6.63–6.62(m,1H),6.56–6.52(m ,1H),5.59–5.66(m,1H),3.84–3.79(m,4H),3.06(s,1H),2.92–2.85(m,1H),2.54–2.48(m,1H). 19 F NMR (376MHz, CD3OD) δ-118.03.

[0483] Example 32

[0484] 2-(4-Chlorophenyl)acetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-Ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0485]

[0486] The title compound was prepared in a similar manner to that of Example 2, except that 2-(4-chlorophenyl)acetic acid was used in step 1 and triethylamine trihydrofluoride was used in step 2 (Example 12, step 2). MS: m / z = 461.05 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ7.34–7.32(m,5H),6.60–6.49(m,2H),5.67–5.64(m ,1H),3.84–3.73(m,4H),3.04(s,1H),2.88–2.83(m,1H),2.51–2.46(m,1H).

[0487] Example 33

[0488] 2-(4-chlorophenyl)acetic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- 2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0489]

[0490] The title compound was prepared in a similar manner to that of Example 20, except that 2-(4-chlorophenyl)acetic acid was used in step 1. MS: m / z = 461.05 [M+H] + . 1H-NMR (400MHz, CD3OD): δ7.26–7.24(m,2H),7.17–7.15(m,2H),7.10–7.09(m,1H),6.62–6.61(m,1H),6.47–6.44(m ,1H),4.79–4.71(m,1H),4.51–4.48(m,1H),4.28–4.25(m,1H),3.68–3.46(m,2H),3.14(s,1H),2.68–2.54(m,2H).

[0491] Example 34

[0492] 2-(4-Chlorophenyl)acetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-((2-(4-chlorophenyl)acetoxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0493]

[0494] The title compound was prepared in a similar manner to that of Example 6, except that 2-(4-chlorophenyl)acetic acid was used in step 1. MS: m / z = 613.05 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ7.36–7.19(m,8H),7.14–7.00(m,1H),6.59–6.49(m,2H),5.66–5.63(m ,1H),4.43–4.31(m,2H),3.82–3.71(m,4H),3.16(s,1H),2.79–2.72(m,1H),2.59–2.56(m,1H).

[0495] Alternatively, Example 34 can be prepared as follows.

[0496] In a flame-dried flask under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (compound A) (2.0 g, 6.5 mmol) and 2-(4-chlorophenyl)acetic acid (2.8 g, 16 mmol) were dissolved in anhydrous DMF (7.0 mL). Anhydrous DCM (70 mL), DIEA (5.6 mL, 32 mmol), and 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (7.2 g, 16 mmol) were added. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with DCM (3×). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 0-50% EtOAc / hexane. The appropriate fractions were concentrated under reduced pressure and subsequently recrystallized in iPrOH to give the title compound. MS: m / z = 613.5 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.35–7.30(m,2H),7.29–7.24(m,4H),7.21–7.16(m,2H),6.77–6.73(m,1H),6.62(t,J=6.7Hz,1H),6.36–6.32(m,1H),5. 55–5.49(m,1H),5.44(s,2H),4.45(d,J=11.9Hz,1H),4.35(d,J=11.8H z,1H),3.70(s,2H),3.65(s,2H),2.60–2.53(m,2H),2.49–2.45(m,1H).

[0497] Example 35

[0498] 2-(adamantane-1-yl)ethyl(((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidine) (P-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl) ester

[0499]

[0500] The title compound was prepared in a similar manner to Example 39, except that 2-(adamantane-1-yl)ethyl(4-nitrophenyl) carbonate (intermediate 4) was used in step 1. MS: m / z = 515.10 [M+H] + . 1H-NMR (400MHz, CD3OD): δ7.20–7.19(m,1H),6.59–6.50(m,2H),4.84–4.70(m,1H),4.52–4.47(m,1H),4.33-4.28(m,1H),4.1 6–4.12(m,2H),3.16(s,1H),2.62–2.58(m,2H),2.01–1.92(m,3H),1.75–1.72(m,6H),1.68–1.65(m,6H),1.54–1.53(m,2H).

[0501] Example 36

[0502] 2-(adamantane-1-yl)ethyl((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidine)carbonate (Pyridine-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl) ester

[0503]

[0504] The title compound was prepared in a similar manner to that of Example 12, except that 2-(adamantane-1-yl)ethyl(4-nitrophenyl) carbonate (intermediate 4) was used in step 1. MS: m / z = 515.10 [M+H] + . 1 H-NMR (400MHz, CD3OD-d4): δ7.30(s,1H),6.59–6.51(m,1H),6.48–6.47(m,1H),5.52–5.50(m,1H),4.28–4.23(m,2H),3.89–3.81(m, 2H),3.11(s,1H),2.96–2.88(m,1H),2.58–2.54(m,1H),2.03–1.95(m,3H),1.78–1.68(m,6H),1.60–1.58(m,6H),1.51–1.47(m,2H).

[0505] Alternatively, Example 36 can be prepared as follows.

[0506] Step 1: Carbonic acid 2-(adamantane-1-yl)ethyl((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2, [3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl) ester

[0507] Under N2 conditions, DMAP (1.4 g, 12 mmol) and triethylamine (3.9 mL, 28 mmol) were added to a solution of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (5.0 g, 12 mmol) and intermediate 4 (6.1 g, 18 mmol) dissolved in anhydrous pyridine (90 mL). The reactants were placed in a preheated oil bath at 75 °C and stirred for 13 hours. The reactants were concentrated under reduced pressure. The residue was partitioned between water and ether, and the organic layer was washed with water (2×), dilute HCl (pH 4), and brine. The organic fraction was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 0-45% EtOAc / hexane to give the title compound. MS: m / z = 629.7 [M+H] + .

[0508] Step 2: Carbonic acid 2-(adamantane-1-yl)ethyl((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2, [3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl) ester

[0509] Under N2, tetrabutylammonium carbonate (1 M in THF) (11 mL, 11 mmol) was added to a cold solution of 2-(adamantane-1-yl)ethyl((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl) ester (6.8 g, 11 mmol) in anhydrous THF (100 mL). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with ether and water, and the organic layer was washed with water (4×) and brine. The organic fraction was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 0–55% EtOAc / hexane. The appropriate fraction was concentrated under reduced pressure and subsequently recrystallized in ether to give the title compound. MS: m / z = 515.6 [M+H] + . 1H NMR (500MHz, CDCl3) δ6.99–6.94(m,1H),6.35–6.31(m,1H),6.29–6.22(m,1 H),5.83(d,J=12.1Hz,1H),5.63(d,J=6.1Hz,1H),5.49(s,2H),4.34–4.21( m,2H),4.06(d,J=12.4Hz,1H),3.96(t,J=12.3Hz,1H),3.37–3.27(m,1H),2 .62(s,1H),2.47(dd,J=13.9,5.4Hz,1H),1.96(s,3H),1.74-1.47(m,14H).

[0510] Example 37

[0511] 2-(4-fluorophenyl)acetic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- 2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0512]

[0513] The title compound was prepared in a similar manner to that of Example 20, except that 2-(4-fluorophenyl)acetic acid was used in step 1. MS: m / z = 445.00 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ7.20–7.17(m,2H),7.10-7.08(m,1H),7.03–6.97(m,2H),6.59–6.58(m,1H),6.46–6.43(m ,1H),4.73–4.71(m,1H),4.69–4.50(m,1H),4.47–4.25(m,1H),3.69–3.59(m,2H),3.13(s,1H),2.68–2.54(m,2H).

[0514] Example 38

[0515] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ylnonyl ester

[0516]

[0517] The title compound was prepared in a similar manner to that of Example 12, except that nonyl chloroformate was used in step 1. MS: m / z = 479.15 [M+H] +1HNMR(300MHz, CDCl3)δ6.98(d,J=3.0Hz,1H),6.35(d,J=3.0Hz,1H),6.29–6.24(m,1H),5.64–5.59(m,3H),4.25–4.16(m,2H),4.08–4.04 (m,1H),3.98–3.93(m,1H),3.33–3.28(m,1H),2.62(s,1H),2.51–2.45(m,1H),1.75–1.70(m,3H),1.39–1.20(m,12H),1.02–0.68(m,3H).

[0518] Example 39

[0519] Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- Hydroxytetrahydrofuran-2-yl)methyloctyl ester

[0520]

[0521] Step 1: Carbonic acid ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl) Methyl octyl ester

[0522] Octyl chloroformate (54.2 mg, 0.281 mmol) was added to a stirred mixture of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methanol (intermediate 3) (120 mg, 0.141 mmol) and 4-dimethylaminopyridine (25.8 mg, 0.211 mmol) in Py (2 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated, diluted with water (10 mL), extracted with EtOAc (50 mL), the organic layer was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0-30% EtOAc / petroleum ether to give the title compound. MS: m / z = 1010.35 [M+H] + .

[0523] Step 2: Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethyl alkynyl-3-hydroxytetrahydrofuran-2-yl)methyloctyl ester

[0524] A mixture of (2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methyloctyl ester (110 mg, 0.109 mmol) in 80% aqueous formic acid (2.5 mL, 0.109 mmol) was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by RP-Flash elution with 0–60% acetonitrile / water to give the title compound. MS: m / z = 465.20 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ7.20(s,1H),6.59–6.49(m,2H),4.89–4.84(m,1H),4.71–4.49(m,2H),4.3 2–4.04(m,2H),3.16(s,1H),2.65–2.55(m,2H),1.64–1.57(m,2H),1.23(s,10H),0.97–0.86(m,3H).

[0525] Example 40

[0526] 2-Ethylbutyric acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethylbutyric acid alkynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0527]

[0528] In a flame-dried flask under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (50 mg, 0.162 mmol) was dissolved in anhydrous pyridine (2 mL). The solution was cooled in an ice bath, and 2-ethylbutyryl chloride (23 μL, 0.168 mmol) was added dropwise. The result was stirred at 0 °C for 30 min, quenched with methanol (100 μL, 2.472 mmol), and then stirred for another 5 min. The reaction mixture was then concentrated under reduced pressure and partitioned between water and EtOAc. The organic matter was washed with water (3×) and then with brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (24 g ISCO-gold) by elution with 0–80% EtOAc / hexane to give the title compound. MS: m / z = 407.4 [M+H] + . 1H NMR(500MHz, CDCl3)δ7.06(d,J=3.7Hz,1H),6.63–6.57(m,1H),6.38(d,J=3.7Hz,1H),5.26(s,2H),4.62(q,J=6.9Hz,1H),4.47–4.37(m,2H ),2.78–2.70(m,2H),2.66–2.57(m,1H),2.37–2.33(m,1H),2.32–2.24(m,1H),1.69–1.60(m,2H),1.60–1.51(m,2H),0.89(q,J=7.3Hz,6H).

[0529] Example 41

[0530] 2-Phenylacetic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethyl alkynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0531]

[0532] The title compound was prepared in a similar manner to that of Example 40, except that 2-phenylacetyl chloride was used, and further purified by RP chromatography (14 min 10-50% ACN-water (5 mM NH4CO3), maintained at 50% ACN, Waters Xbridge 30×150 mm). Appropriate fractions were combined, diluted with brine, and extracted with DCM (3×). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m / z = 427.4 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.36–7.27(m,5H),6.84(d,J=3.7Hz,1H),6.59–6.52(m,1H),6.34(d,J=3.7Hz,1H),5.3 1(s,2H),4.56–4.51(m,1H),4.43(s,2H),3.70(s,2H),2.73(s,1H),2.65–2.49(m,2H),2.26(d,J=5.7Hz,1H).

[0533] Example 42

[0534] Isobutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl- 2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl ester

[0535]

[0536] In a flame-dried flask under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (305 mg, 0.988 mmol) was dissolved in anhydrous pyridine (12 mL). The solution was cooled in an ice bath, and 2-ethylbutyryl chloride (300 μL, 2.86 mmol) was added dropwise over 5 minutes. The result was stirred at 0 °C for 10 minutes, then quenched with methanol (400 μL, 9.88 mmol) and stirred for another 5 minutes. The reaction mixture was then concentrated under reduced pressure and partitioned between water and EtOAc. The organic matter was washed with water (3×) and then with brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (24 g ISCO-gold) by elution with 0–55% EtOAc / hexane to give the title compound. MS: m / z = 449.4 [M+H] + . 1 H NMR(500MHz, CDCl3)δ7.12(d,J=3.7Hz,1H),6.71(t,J=6.7Hz,1H),6.41(d,J=3.7Hz,1H),5.59–5.53(m,1H),5.40 (s,2H),4.44(d,J=11.8Hz,1H),4.36(d,J=11.8Hz,1H),2.78–2.70(m,1H),2.70–2.59(m,4H),1.27–1.17(m,12H).

[0537] Alternatively, the compound of Example 42 can be further recrystallized from ether-heptane. MS: m / z = 449.4 [M+H] + .

[0538] Example 43

[0539] 2-Phenylacetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl ester

[0540]

[0541] The title compound was prepared in a similar manner to that of Example 42, except that 2-phenylacetyl chloride was used, and further purified by RP chromatography (14 mM N25-80% ACN-water (5 mM NH4CO3), maintained at 68% ACN, Waters Xbridge 30 × 150 mm). The appropriate fractions were lyophilized overnight. The resulting solids were redissolved between DCM and dilute brine and extracted with DCM (3 ×). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m / z = 545.5 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.38–7.26(m,10H),6.73(d,J=3.7Hz,1H),6.65(t,J=6.9Hz,1H),6.31(d,J=3.7Hz,1H),5.4 9–5.43(m,1H),5.29(s,2H),4.43(d,J=12.0Hz,1H),4.36(d,J=12.0Hz,1H),3.74–3.65(m,4H),2.54–2.36(m,3H).

[0542] Example 44

[0543] 2-Ethylbutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((2-Ethylbutyryl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0544]

[0545] The title compound was prepared in a similar manner to that of Example 42, except that 2-ethylbutyryl chloride was used. MS: m / z = 505.5 [M+H] + . 1 HNMR (500MHz, CDCl3) δ7.14(d,J=3.6Hz,1H),6.71(t,J=6.4Hz,1H),6.41(d,J=3.6Hz,1H),5.57(t,J=6.6Hz,1H),5.43(s ,2H),4.46–4.36(m,2H),2.82–2.73(m,1H),2.69–2.60(m,2H),2.38–2.24(m,2H),1.76–1.49(m,8H),0.97–0.85(m,12H).

[0546] Example 45

[0547] 2-Ethylbutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0548]

[0549] Step 1: 2-Ethylbutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0550] In a flame-dried flask under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (1.1 g, 0.24 mmol) was dissolved in anhydrous pyridine (3 mL). The solution was cooled in an ice bath, and 2-ethylbutyryl chloride (36 μL, 0.263 mmol) was added. The result was stirred at 0 °C for 20 min, followed by stirring at room temperature for 1 h. Then, 2-ethylbutyryl chloride (36 μL, 0.263 mmol) was added, and the result was stirred at room temperature for 30 min. This step was repeated twice. The reaction mixture was then quenched with methanol (2 mL) and stirred for another 5 min. The reaction mixture was then concentrated under reduced pressure and partitioned between water and EtOAc. The organic compound was washed with water (3×) followed by brine (1×), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (24 g ISCO-gold) by elution with 0–40% EtOAc / hexane to give the title compound. MS: m / z = 521.5 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.33(d,J=3.7Hz,1H),6.78(t,J=6.7Hz,1H),6.37(d,J =3.7Hz,1H),5.66–5.60(m,1H),5.23(s,2H),3.96(d,J=10.9Hz,1H),3.89(d, J=11.0Hz,1H),2.70–2.60(m,1H),2.58–2.49(m,2H),2.36–2.30(m,1H),1.7 7–1.65(m,2H),1.64–1.54(m,2H),0.97–0.91(m,15H),0.12(d,J=4.6Hz,6H).

[0551] Step 2: 2-Ethylbutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-Ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0552] TBAF (1M THF) (0.255 mL, 0.255 mmol) was added to a solution of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester (95 mg, 0.18 mmol) dissolved in anhydrous THF (4 mL). The reaction mixture was stirred at room temperature for one hour, then diluted with water and brine, and extracted with DCM (3×). The organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (24 g ISCO-gold) eluted with 0–80% EtOAc / hexane to give the title compound. MS: m / z = 407.4 [M+H] + . 1 H NMR(500MHz, CDCl3)δ7.03(d,J=3.6Hz,1H),6.34(d,J=3.6Hz,1H),6.32–6.26(m,1H),5.81–5.75(m,1H),5.56–5.42(m,3H),4.08–4.01 (m,1H),3.97–3.89(m,1H),3.29–3.19(m,1H),2.59(s,1H),2.43–2.28(m,2H),1.80–1.66(m,2H),1.66–1.53(m,2H),0.99–0.91(m,6H).

[0553] Example 46

[0554] 2-Phenylacetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0555]

[0556] Step 1: 2-Phenylacetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0557] In a flame-dried flask under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (100 mg, 0.236 mmol) was dissolved in anhydrous pyridine (3 mL). The solution was cooled in an ice bath, and 2-phenylacetyl chloride (63 μL, 0.476 mmol) was added. The result was stirred at room temperature for one hour. Additional 2-ethylbutyryl chloride (63 μL, 0.476 mmol) was added. The result was stirred at room temperature for 60 minutes, then quenched with methanol (2 mL), and then stirred for another 5 minutes. The reaction mixture was then concentrated under reduced pressure and partitioned between water and EtOAc. The organic compound was washed with water (3×) followed by brine (1×), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (40 g ISCO-gold) by elution with 0–60% EtOAc / hexane to give the title compound. MS: m / z = 541.5 [M+H] + .

[0558] Step 2: 2-Phenylacetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-Ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0559] TBAF (1M THF) (0.204 mL, 0.204 mmol) was added to a solution of 2-phenylacetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester (79 mg, 0.146 mmol) dissolved in anhydrous THF (4 mL). The reaction mixture was stirred at room temperature for one hour, then diluted with water and brine, and extracted with DCM (3×). The organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RP chromatography (14 min 15-60% ACN-water (5 mM NH4CO3), and maintained at 50% ACN, Waters Xbridge 30×150 mm). The appropriate fractions were combined, diluted with brine, and extracted with DCM (3×). The combined organic compounds were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was further purified on an NP silica gel column (4 g ISCO-gold) by elution with 0–100% EtOAc / hexane to give the title compound. MS: m / z = 427.4 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.38–7.24(m,5H),6.99(d,J=3.6Hz,1H),6.34(d,J=3.6Hz,1H),6.26–6.20(m,1H),5.78(d,J=6. 1Hz,1H),5.68–5.59(m,3H),4.04–3.98(m,1H),3.95–3.87(m,1H),3.73(s,2H),3.30–3.21(m,1H),2.41–2.33(m,2H).

[0560] Example 47

[0561] Decanoic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- (propionyloxy)tetrahydrofuran-2-yl)methyl ester

[0562]

[0563] Under a nitrogen atmosphere, methyl decanoic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl) ester (Example 20) (60 mg, 0.130 mmol) was dissolved in anhydrous pyridine (3 mL). Propionyl chloride (14 μL, 0.160 mmol) was added to this solution, and the mixture was stirred overnight at room temperature. Then, more propionyl chloride (28 μL, 0.32 mmol) was added, and the solution was stirred again at room temperature for one hour. The reaction mixture was quenched with methanol (2 mL), and the solution was stirred for another 20 minutes. The reaction mixture was then concentrated under reduced pressure and partitioned between water and diethyl ether. The organic matter was washed with water (3×) and subsequently with brine (1×), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (40 g ISCO-gold) eluted with 0–60% EtOAc / hexane. The appropriate fraction was concentrated under reduced pressure, redissolved in ether, and concentrated under reduced pressure (2×). The residue was recrystallized in ether / hexane, with gentle heating to remove most of the ether and slow addition of hexane. The solid was filtered and washed with 10:1 hexane-ether to give the title compound. MS: m / z = 519.5 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.14–7.10(m,1H),6.75–6.69(m,1H),6.42–6.39(m ,1H),5.61–5.56(m,1H),5.27(s,2H),4.45(d,J=11.8Hz,1H),4.36(d,J=1 1.5Hz,1H),2.75–2.68(m,1H),2.67–2.60(m,2H),2.49–2.42(m,2H),2.4 1–2.34(m,2H),1.68–1.61(m,2H),1.35–1.17(m,15H),0.91–0.84(m,3H).

[0564] Example 48

[0565] Decanoic acid ((2R,3S,5R)-3-acetoxy-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-Ethynyltetrahydrofuran-2-yl)methyl ester

[0566]

[0567] The title compound was prepared in a similar manner to that of Example 47, except that acetyl chloride was used. MS: m / z = 505.5 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.11(d,J=3.7Hz,1H),6.72(t,J=6.7Hz,1H),6.40(d,J=3.8Hz,1H),5.60–5.54(m,1H),5.25(s,2H),4.45(d,J=11.8Hz, 1H),4.36(d,J=11.8Hz,1H),2.76–2.59(m,3H),2.42–2.34(m,2H),2.1 8(s,3H),1.67–1.61(m,2H),1.35–1.22(m,12H),0.88(t,J=6.9Hz,3H).

[0568] Examples 49 and 50

[0569] Implementation 49: Pyridinecarboxylic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-Ethynyl-2-((pyridinecarboxyloxy)methyl)tetrahydrofuran-3-yl ester–

[0570] Example 50: Pyridinecarboxylic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- 3-hydroxy-2-methyltetrahydrofuran-2-yl)methyl ester

[0571]

[0572] The title compound was prepared in a similar manner to Example 6, except that pyridine carboxylic acid was used in step 1, and diester Example 49 and monoester Example 50 were separated.

[0573] Example 49: MS: m / z = 519.05 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ8.83–8.77(m,2H),8.22–8.20(m,1H),8.16–8.13(m,1H),8.09–8.02(m,2H),7.74–7.69(m,2H),7.66-7.61( m,3H),6.71-6.68(m,1H),6.60(d,J=3.9Hz,1H),6.01–5.98(m,1H),4.67(s,2H),3.77(s,1H),3.25–3.16(m,1H),2.83–2.73(m,1H).

[0574] Example 50: MS: m / z = 414.00 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.73–8.72(m,1H),8.05–7.95(m,2H),7.69–7.68(m,1H),7.40–7.38(m,1H),6.52–6.50(m,1H ),6.44–6.41(m,1H),4.69–4.64(m,2H),4.43–4.40(m,1H),3.57–3.50(m,1H),2.74-2.62(m,1H),2.48–2.45(m,1H).

[0575] Example 51

[0576] Pyridinecarboxylic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy- 2-Methyltetrahydrofuran-2-yl)methyl ester

[0577]

[0578] Step 1: Benzoic acid (((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2- methyl methoxy ester

[0579] Under an argon atmosphere at 0°C, a mixture of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)-tetrahydrofuran-2-yl)methanol (0.20 g, 0.23 mmol) and NaH (17 mg, 0.70 mmol) in DMF (2 mL) was formed. The reaction mixture was stirred at 0°C for 10 min. Subsequently, methyl iodide benzoate (92 mg, 0.35 mmol) was added at 0°C, and the mixture was stirred at 25°C for 15 min. The reaction mixture was diluted with NH4Cl (3 mL), extracted with EtOAc (100 mL), washed with brine (3 × 50 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM) to give the title compound. MS: m / z = 987.45 [M+H] + .

[0580] Step 2: Pyridinecarboxylic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 3-Hydroxy-2-methyltetrahydrofuran-2-yl)methyl ester

[0581] A mixture of benzoic acid (((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)-tetrahydrofuran-2-yl)methoxy)methyl ester (0.15 g, 0.15 mmol) in water (0.50 mL), THF (1.0 mL), and formic acid (2.0 mL) was stirred at 25 °C for 30 minutes. The reaction mixture was diluted with toluene (5 mL) and concentrated. The reactants were purified by preparative HPLC under the following conditions: column: SunFire C18 OBD Prep column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 40% B over 15 min; wavelength: UV 254 nm / 210 nm; RT1: 5.5 min, yielding the title compound. MS: m / z = 443.05 [M+H] + . 1 H-NMR (300MHz, CD3OD): δ

[0582] 7.98–7.95(m,2H),7.59–7.54(m,1H),7.44–7.39(m,2H),7.25(d,J=3.6Hz,1H),6.56(d,J=3.9Hz,1H),6.50(t ,J='6.6Hz,1H),5.55–5.50(m,2H),4.70(t,J=7.5Hz,1H),4.06–4.05(m,2H),3.10(s,1H),2.59–2.54(m,2H).

[0583] Example 52

[0584] 2-Propylvaleric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0585]

[0586] The title compound was prepared in a similar manner to that of Example 12, except that 2-propylpentanoyl chloride was used in step 1. MS: m / z = 435.10 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ7.59–7.39(m,3H),6.63-6.45(m,2H),5.57–5.55(m,2H),3.6 5–3.61(m,3H),2.86–2.75(m,1H),2.50–2.42(m,2H),1.58–1.28(m,8H),0.89(s,6H).

[0587] Example 53

[0588] Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- ((((5-methyl-2-oxo-1,3-dioxolane-4-yl)methoxy)carbonyl)oxy)tetrahydrofuran-2-yl)methyl((5-methyl) 2-oxo-1,3-dioxolane-4-yl)methyl) ester

[0589]

[0590] At room temperature, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (50 mg, 0.16 mmol) in a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (50 mg, 0.16 mmol) in DCM / DMF (2.5 mL, 2:1) was supplemented with (5-methyl-2-oxo-1,3-dioxolane-4-yl)methyl(4-nitrophenyl) carbonate (96 mg, 0.32 mmol) and TEA (0.045 mL, 0.32 mmol). The resulting mixture was heated to 40 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-Combiflash under the following conditions: column: C18 40 g column. 20-35 μm; Mobile phase A: water, mobile phase B: MeCN; Flow rate: 50 mL / min; 0% B to 100% B over 20 min; Detector: UV 254 and 210 nm, yielding the title compound. MS: m / z = 621.05 [M+H] + . 1 H-NMR(400MHz,CD3OD)δ7.20(d,J=3.6Hz,1H),6.70–6.46(m,2H),5.65–5.50(m,1H),5.09-4.91(m,4H),4. 60–4.51(m,1H),4.50–4.30(m,1H),3.26(s,1H),3.00–2.81(m,1H),2.79–2.51(m,1H),2.27–2.10(m,6H).

[0591] Example 54

[0592] Isobutyric acid (((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 3-hydroxytetrahydrofuran-2-yl)methoxy)methyl ester

[0593]

[0594] The title compound was prepared in a similar manner to that of Example 51, except that methyl isobutyrate was used in step 1. MS: m / z = 409.05 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ7.56–7.30(m,2H),7.30–7.28(m,1H),6.62(d,J=3.6Hz,1H),6.42–6.39(m,1H),5.70–5.68(m ,1H),5.25–5.21(m,2H),4.77–4.45(m,2H),3.85–3.56(m,3H),2.56–2.50(m,1H),2.50–2.36(m,1H),1.07–1.06(m,6H).

[0595] Example 55

[0596] Nonanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yl ester

[0597]

[0598] The title compound was prepared in a similar manner to that of Example 12, except that nonanoyl chloride was used in step 1. MS: m / z = 449.10 [M+H] + . 1H NMR (300MHz, methanol-d4) δ7.32(d,J=3.9Hz,1H),6.59(d,J=3.9Hz,1H),6.51(dd,J=8.1,6.0Hz,1H),5.65(dd,J=6.9,3.3Hz,1H),3. 90–3.75(m,2H),3.10(s,1H),2.92–2.82(m,1H),2.55–2.38(m,3H),1.70–1.63(m,2H),1.45–1.25(m,10H),0.92–0.88(m,3H).

[0599] Example 56

[0600] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yl((5-methyl-2-oxo-1,3-dioxolane-4-yl)methyl) ester

[0601]

[0602] The title compound was prepared in a similar manner to that of Example 12, except that in step 1, methyl (5-methyl-2-oxo-1,3-dioxolane-4-yl) carbonate (4-nitrophenyl) ester was used. MS: m / z = 465.05 [M+H] + . 1 H-NMR (400MHz, CD3OD) δ7.30(d,J=4.0Hz,1H),6.59(d,J=4.0Hz,1H),6.50–6.46(m,1H),5.60–5.40(m,1H ),5.10–5.00(m,2H),3.91–3.72(m,2H),3.11(s,1H),3.01–2.85(m,1H),2.64–2.50(m,1H),2.25(s,3H).

[0603] Example 57

[0604] Octanoic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- Hydroxytetrahydrofuran-2-yl)methyl ester

[0605]

[0606] The title compound was prepared in a similar manner to that of Example 14, except that octanoyl chloride was used in step 2. MS: m / z = 435.10 [M+H] + . 1HNMR(300MHz, DMSO-d6)δ7.55(s,2H),7.29(d,J=3.6Hz,1H),6.61(d,J=3.6Hz,1H),6.39–6.35(m,1H),5.77(s,1H),4.54(t,J=6.9Hz,1H),4.4 0–4.36(m,1H),4.10–4.06(m,1H),3.60(s,1H),2.45–2.38(m,2H),2.29 –2.23(m,2H),1.48–1.44(m,2H),1.24–1.20(m,8H),0.86–0.81(m,3H).

[0607] Example 58

[0608] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yl ester

[0609]

[0610] The title compound differs in that it uses heptanyl chloride in step 1. MS: m / z = 421.10 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ7.60(s,2H),7.40(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,1H),6.48–6.43(m,1H),5.59–5.53(m,2 H),3.66–3.57(m,3H),2.81–2.72(m,1H),2.46–2.37(m,3H),1.64–1.54(m,2H),1.36–1.23(m,6H),0.92–0.82(m,3H).

[0611] Example 59

[0612] Hexanoic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yl ester

[0613]

[0614] The title compound was prepared in a similar manner to that of Example 12, except that hexanoyl chloride was used in step 1. MS: m / z = 407.10 [M+H] + . 1H-NMR (400MHz, CD3OD) δ7.32(d,J=4.0Hz,1H),6.65–6.57(m,1H),6.57–6.49(m,1H),5.70–5.60(m,1H),3.90–3.72( m,2H),3.13(s,1H),2.92–2.80(m,1H),2.52–2.40(m,3H),1.80–1.60(m,2H),1.42–1.29(m,4H),1.01–0.82(m,3H).

[0615] Example 60

[0616] 4-Phenylacetic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0617]

[0618] The title compound was prepared in a similar manner to that of Example 12, except that 4-phenylbutyryl chloride was used in step 1. MS: m / z = 455.05 [M+H] + . 1 H-NMR (400MHz, CD3OD): δ7.32–7.31 (m, 1H), 7.29–7.20 (m, 2H), 7.18–7.16 (m, 3H), 6.59 (d, J = 4.0Hz, 1H). 6.52–6.48(m,1H),5.66–5.64(m,1H),3.84–3.82(m,2H),3.08(s,1H),2.99 –2.82(m,1H),2.69(d,J=7.6Hz,2H),2.47–2.43(m,3H),2.03–1.98(m,2H).

[0619] Alternatively, Example 60 can be prepared as follows.

[0620] Step 1: 4-Phenylacetic butyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0621] Under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (2.0 g, 4.5 mmol) was dissolved in anhydrous pyridine (22 mL). The solution was cooled in an ice bath, and 4-phenylbutyryl chloride (1.5 mL, 9.2 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 20 min, and then stirred at room temperature for 1 hour. The reaction mixture was recooled to 0 °C, and additional 4-phenylbutyryl chloride (0.75 mL, 4.6 mmol) was added. The resulting mixture was warmed to room temperature and stirred for another 30 min. The reaction mixture was quenched with methanol (5 mL) and stirred for another 5 min. The reaction mixture was then concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (120 g ISCO-gold) by elution with 0-50% 3:1 EtOAc:EtOH / hexane to give the title compound. MS: m / z = 569.5 [M+H] + .

[0622] Step 2: 4-Phenylacetic butyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-Ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0623] A mixture of 4-phenylbutyric acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester (2.4 g, 4.3 mmol) in THF (85 mL) was cooled in an ice bath, and tetrabutylammonium fluoride (4.5 mL, 4.5 mmol, 1 M in THF) was added. The resulting mixture was heated to room temperature and stirred for 30 min. The reactants were partitioned between water and diethyl ether. The organic matter was washed with water (3×) and then with brine (1×), dried over Mg2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (330 g ISCO-gold) eluted with 0–50% 3:1 EtOAc:EtOH / hexane. The appropriate fraction was concentrated under reduced pressure, then redissolved in ether and concentrated under reduced pressure (2×). The residue was recrystallized by stirring in heptane / EtOAc (85:15). After stirring overnight, crystals precipitated, and the solid was filtered off and washed with heptane:EtOAc to give the title compound. MS: m / z = 455.4 [M+H] + . 1¹H NMR (500 MHz, chloroform-d) δ 7.33–7.27 (m, 3H), 7.21 (t, J = 6.8 Hz, 3H), 7.00 (d, J = 3.7 Hz, 1H), 6.33 (d, J = 3.7 Hz, 1H), 6.25 (dd, J = 9.5, 5.5 Hz, 1H), 5.78 (d, J = 5.1 Hz, 1H), 5.59 (dd, J = 11.7 Hz, 1H). ,2.8Hz,1H),5.33(s,2H),4.04(dd,J=12.4,2.8Hz,1H),3.94(t,J=12.1Hz,1H),2.71(t, J=7.5Hz,2H),2.55(s,1H),2.45(t,J=7.5Hz,2H),2.40-2.30(m,1H),2.10-2.00(m,2H).

[0624] Example 61

[0625] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-ylhexyl ester

[0626]

[0627] Step 1: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylhexyl ester

[0628] Under a nitrogen atmosphere, (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (2.3 g, 5.4 mmol) was dissolved in anhydrous pyridine (25 mL). The solution was placed in a cold water bath, and hexyl chloroformate (1.2 mL, 7.4 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. Another hexyl chloroformate (0.4 mL) was added, and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was quenched with methanol (5 mL) and stirred for another 5 minutes. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between water and diethyl ether. The organic matter was washed with water (3×) and then with brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (120 g ISCO-gold) by elution with 0–50% EtOAc / hexane to give the title compound. MS: m / z = 551.5 [M+H] + .

[0629] Step 2: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-ylhexyl ester

[0630] A mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylhexyl ester (2.5 g, 4.6 mmol) in anhydrous THF (20 mL) was placed in a cold water bath, and tetrabutylammonium fluoride (4.8 mL, 4.8 mmol, 1 M in THF) was added to raise the reactants to room temperature and stir for 90 minutes. The reactants were partitioned between water and diethyl ether. The organic matter was washed with water (3×) and then with brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM and purified on an NP silica gel column (80 g ISCO-gold), eluted with 0–60% EtOAc / hexane, and subsequently recrystallized in iPrOH to give the title compound. MS: m / z = 437.5 [M+H] + . 1 H-NMR (500MHz, CDCl3): δ6.97(d,J=3.6Hz,1H),6.33(d,J=3.6Hz,1H),6.26(dd,J=9.7,5.4Hz ,1H),5.83(dd,J=12.0,2.3Hz,1H),5.63(d,J=6.2Hz,1H),5.43(s,2H),4.28–4.14(m,2H),4.0 6(dd,J=12.3,2.3Hz,1H),3.96(t,J=12.2Hz,1H),3.36-3.29(m,1H),2.62(s,1H),2.47(dd,J= 13.9,5.4Hz,1H),1.75-1.67(m,2H),1.43-1.35(m,2H),1.35-1.29(m,4H),0.95-0.88(m,3H).

[0631] Example 62

[0632] 3-(adamantane-1-yl)propionic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-) 2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0633]

[0634] Step 1: 3-(adamantane-1-yl)propionic acid ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenyl) (Methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy) Tetrahydrofuran-2-yl)methyl ester

[0635] Under a nitrogen atmosphere, 3-(adamantane-1-yl)propionic acid (49 mg, 0.23 mmol), DMAP (14 mg, 0.12 mmol), and DCC (48 mg, 0.23 mmol) were added to a solution of ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methanol (0.10 g, 0.12 mmol) in DCM (3 mL). The resulting mixture was stirred at 25 °C for 16 hours. The residue was purified by preparative TLC, developed with ethyl acetate / petroleum ether (1 / 1), to give the title compound. MS: m / z = 1043.5 [M+H] + .

[0636] Step 2: 3-(adamantane-1-yl)propionic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]) Pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0637] Formic acid (4.0 mL, 0.14 mmol) was added to a solution of 3-(adamantane-1-yl)propionic acid ((2R,3S,5R)-5-(2-chloro-4-(((4-methoxyphenyl)diphenylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-((4-methoxyphenyl)diphenylmethoxy)tetrahydrofuran-2-yl)methyl ester in water (1 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 16 h. The residue was purified by RP-Flash (column: C1840 g column; mobile phase A: water, mobile phase B: MeCN; flow rate: 40 mL / min; gradient: 2% B to 30% B over 30 min; detector: UV 210 nm; RT = 28 min). Fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound. MS: m / z = 499.25 [M+H] + . 1 HNMR(400MHz,CD3OD)δ7.24–7.19(m,1H),6.60–6.59(m,1H),6.45–6.42(m,1H),4.85–4.76(m,1H),4.46–4.43(m,1H),4.23–4.20(m,1H),3 .16(s,1H),2.78–2.59(m,2H),2.35–2.17(m,2H),1.94(s,3H),1.74– 1.70(m,3H),1.65–1.62(m,3H),1.50–1.39(m,6H),1.37–1.29(m,2H).

[0638] Example 63

[0639] (2-Chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrole [2,3-d]pyrimidin-4-yl)tetradecyl carbamate

[0640]

[0641] Step 1: (7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy) )yl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamic acid Tetradecyl ester

[0642] Sodium hydride (23 mg, 0.94 mmol, washed with hexane) was added to a mixture of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (intermediate 2) (0.50 g, 0.93 mmol) in anhydrous DMF (6 mL). The resulting mixture was stirred at room temperature for 30 min. Intermediate 19 (0.42 g, 1.1 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reactants were diluted with ethyl acetate and washed with brine (3×), dried over Na2SO4, filtered, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE, to give the title compound. MS: m / z = 777.60 [M+H] + .

[0643] Step 2: (2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetradecyl carbamate

[0644] TEA·3HF (1.0 mL, 6.3 mmol) was added to a mixture of (0.30 g, 0.39 mmol) of tetradecyl 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate (3 mL). The resulting mixture was stirred overnight at 50 °C. The reactants were purified by RP-CombiFlash elution with acetonitrile / water to give the title compound. MS: m / z = 549.35 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.54(br,1H),7.63(d,J=3.6Hz,1H),6.90(d,J=3.6Hz,1H),6.55–6.52(m,1H),5.56(d,J=5.6Hz,1H),5.27–5.25(m,1H),4. 52–4.50(m,1H),4.14(t,J=6.4Hz,2H),3.61–3.55(m,2H),3.50(s,1H),2. 53–2.42(m,2H),1.65–1.61(m,2H),1.36–1.31(m,22H),0.90–0.79(m,3H).

[0645] Example 64

[0646] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ylphenethyl ester

[0647]

[0648] Step 1: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylphenethyl ester

[0649] At room temperature, TEA (0.066 mL, 0.47 mmol), DMAP (29 mg, 0.24 mmol), and 4-nitrobenzene phenethyl carbonate (intermediate 9) (0.14 g, 0.47 mmol) were added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (0.10 g, 0.24 mmol) in pyridine (0.5 mL). The resulting mixture was stirred at 80 °C for 16 h and then concentrated under reduced pressure. The residue was diluted with DCM, and the solution was purified by TLC (developed with petroleum ether / ethyl acetate (2:1)) to give the title compound. MS: m / z = 571.15 [M+H] + .

[0650] Step 2: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-ylphenylethyl ester

[0651] Triethylamine trifluoride (1.0 mL, 6.3 mmol) was added to a mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylphenethyl ester (0.11 g, 0.19 mmol) in THF (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-combiflash under the following conditions: C18, 40 g, mobile phase A: water (1‰ FA), mobile phase B: acetonitrile, gradient: 0 to 100% B over 30 min, flow rate: 40 mL / min, UV detector: 254 nm, to give the title compound. MS: m / z = 457.05 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.36–7.20(m,5H),6.97(d,J=3.6Hz,1H),6.34(d,J=3.6Hz,1H),6.26–6.22(m,1H),5.78(s,1H),5.61(d,J=6.0Hz, 1H),5.53(s,2H),4.51–4.35(m,2H),4.05–4.02(m,1H),3.94–3.87(m,1H),3.34–3.26(m,1H),3.03(t,J=6.8Hz,2H),2.48–2.46(m,2H).

[0652] Alternatively, step 2 can be performed as follows:

[0653] Under a nitrogen atmosphere, a solution of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ylphenethyl ester (2.9 g, 5.1 mmol) in anhydrous THF (40 mL) was placed in a cold water bath. TBAF (5.1 mL, 5.1 mmol, 1 M in THF) was added, and the reaction mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with ether and washed with water (3×) and brine (1×). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and purified on an NP silica gel column (120 g ISCO-gold) eluted with 0–60% EtOAc-hexane. The appropriate fraction was concentrated under reduced pressure and subsequently recrystallized in 1:1 EtOAc / heptane to give the title compound. MS: m / z = 457.4 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.35–7.29(m,2H),7.28–7.24(m,3H),6.98–6.94(m,1H),6 .35–6.31(m,1H),6.27–6.20(m,1H),5.82(d,J=12.0Hz,1H),5.62(d,J=6.0Hz,1H ),5.49(s,2H),4.52–4.43(m,1H),4.43–4.35(m,1H),4.04(d,J=12.5Hz,1H),3.9 3(t,J=12.3Hz,1H),3.36–3.26(m,1H),3.03(t,J=6.9Hz,2H),2.48–2.42(m,2H).

[0654] Example 65

[0655] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0656]

[0657] Step 1: Propionic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester

[0658] At room temperature, propionic acid (0.11 g, 1.4 mmol) was added to a mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (0.30 g, 0.71 mmol), DCC (0.29 g, 1.4 mmol), and DMAP (87 mg, 0.71 mmol) in DMF (2 mL). The reaction mixture was heated to 50 °C and stirred for 16 hours. The mixture was diluted with EtOAc (20 mL), washed with water (2×) and brine (2×), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0–50% EtOAc / petroleum ether to give the title compound. MS: m / z = 479.20 [M+H] + .

[0659] Step 2: Propionic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ester

[0660] Triethylamine trifluoride (1.0 mL, 6.3 mmol) was added to a stirred mixture of propionic acid propionate (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl ester (0.10 g, 0.21 mmol) in THF (2 mL). The reaction mixture was stirred at 25 °C for 16 hours and then concentrated under reduced pressure. The residue was purified by RP-Combiflash under the following conditions: column: C18 column, 40 g. 20-35 μm; Mobile phase A: water, mobile phase B: MeCN; Flow rate: 50 mL / min; 0% B to 100% B over 15 min; Detector: UV 254 and 210 nm, yielding the title compound. MS: m / z = 364.95 [M+H] + . 1 H-NMR (400MHz, CD3OD) δ7.33 (d, J=3.6Hz, 1H), 6.59–6.49 (m, 2H), 5.67–5.65 (m, 1H), 3. 87–3.79(m,2H),3.11(s,1H),2.91–2.86(m,1H),2.51–2.43(m,3H),1.28–1.18(m,3H).

[0661] Example 66

[0662] N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)octamide

[0663]

[0664] Step 1: N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy) 5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octamide

[0665] At room temperature, octanoyl chloride (68 mg, 0.42 mmol) was added to a stirred mixture of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (intermediate 2) (0.15 g, 0.28 mmol) and DMAP (34 mg, 0.28 mmol) in pyridine (1 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (2×) and brine (2×), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0–30% EtOAc / petroleum ether, to give the title compound. MS: m / z = 663.50 [M+H] + .

[0666] Step 2: N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)octamide

[0667] At 25°C, triethylamine trifluoride (1.0 mL, 6.3 mmol) was added to a stirred mixture of N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octamide (0.11 g, 0.17 mmol) in THF (2 mL). The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-Combiflash under the following conditions: column: C18 column, 40 g, 20-35 μm; Mobile phase A: water, mobile phase B: MeCN; Flow rate: 50 mL / min; 0% B to 100% B over 15 min; Detector: UV 254 and 210 nm, yielding the title compound. MS: m / z = 435.05 [M+H] + . 1 H-NMR (400MHz, CD3OD) δ7.52(d,J=4.0Hz,1H),6.89(d,J=4.0Hz,1H),6.63(t,J=6.8Hz,1H),4.88–4.71(m,1H), 4.85–3.73(m,2H),3.05(s,1H),2.76–2.51(m,4H),1.75–1.68(m,2H),1.55–1.32(m,8H),0.88(t,J=6.4Hz,3H).

[0668] Example 67

[0669] (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-yl((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) ester

[0670]

[0671] Step 1: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl(4-nitrophenyl) ester

[0672] Add 0.19 g, 0.95 mmol of 4-nitrobenzene chloroformate to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-ol (intermediate 1) (0.20 g, 0.47 mmol) in DCM (2 mL) and pyridine (0.2 mL). Stir the reaction mixture at room temperature for 3 hours, followed by concentration under reduced pressure. Purify the residue by silica gel column chromatography, eluting with 0–50% EtOAc / petroleum ether, to give the title compound. MS: m / z = 588.20 [M+H] + .

[0673] Step 2: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl((1-methyl-2-oxo-1,2-dihydro) pyridin-3-yl)methyl) ester

[0674] To a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl(4-nitrophenyl) ester (0.16 g, 0.27 mmol) in pyridine (2 mL), 3-(hydroxymethyl)-1-methylpyridin-2(1H)-one (76 mg, 0.55 mmol), TEA (0.057 mL, 0.41 mmol), and DMAP (67 mg, 0.55 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The residue was purified by silica gel column chromatography, eluting with 0-100% EtOAc / petroleum ether, to give the title compound. MS: m / z = 588.30 [M+H] + .

[0675] Step 3: Carbonic acid (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-acetylene 2-(hydroxymethyl)tetrahydrofuran-3-yl ((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) ester

[0676] Triethylamine trifluoride (0.50 mL, 3.1 mmol) was added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) ester (80 mg, 0.14 mmol) in THF (1 mL). The reaction mixture was stirred at 25 °C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-Combiflash under the following conditions: column: C18 column, 40 g. 20-35 μm; Mobile phase A: water, mobile phase B: MeCN; Flow rate: 50 mL / min; 0% B to 100% B over 30 min; Detector: UV 254 and 210 nm, yielding the title compound. MS: m / z = 474.15 [M+H] + . 1 H-NMR (400MHz, CD3OD) δ7.67–7.64(m,2H),7.31(d,J=3.6Hz,1H),6.58(d,J=3.6Hz,1H),6.51–6.47(m,1H),6.40(t,J=7.2H z,1H),5.54–5.52(m,1H),5.12(s,2H),3.88–3.80(m,2H),3.59(s,3H),3.08(s,1H),2.96–2.91(m,1H),2.60–2.55(m,1H).

[0677] Example 68

[0678] Carbonic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3- (((hexyloxy)carbonyl)oxy)tetrahydrofuran-2-yl)methylbenzyl ester

[0679]

[0680] Hexyl chloroformate (0.41 g, 2.5 mmol) was added to a stirred mixture of ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methylbenzyl ester (Example 114) (1.1 g, 2.5 mmol), TEA (0.33 g, 3.2 mmol), and DMAP (0.30 g, 2.5 mmol) in DCM (15 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-FLASH chromatography, eluting with 0–77% acetonitrile / water to give the title compound. MS: m / z = 571.00 [M+H] + . 1 HNMR(300MHz, methanol-d4)δ7.37–7.34(m,5H),7.19(d,J=3.9Hz,1H),6.60–6.55 (m,2H),5.55(dd,J=4.8,7.2Hz,1H),5.17(s,2H),4.56(d,J=11.4Hz,1H),4 .44(d,J=11.4Hz,1H),4.20–4.15(m,2H),3.22(s,1H),2.85–2.78(m,1H),2 .68–2.61(m,1H),1.71–1.64(m,2H),1.48–1.31(m,6H),0.99–0.92(m,3H).

[0681] Example 69

[0682] 3-(adamantane-1-yl)-N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydro) (Furan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)propionamide

[0683]

[0684] Step 1: 3-(adamantane-1-yl)-N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5- (((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (Pyridine-4-yl)propionamide

[0685] At room temperature, TCFH (0.52 g, 1.9 mmol) and 1-methylimidazolium (0.23 g, 2.8 mmol) were added to a mixture of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (intermediate 2) (0.50 g, 0.93 mmol) and 3-(adamantane-1-yl)propionic acid (0.29 g, 1.4 mmol) in DMA (5 mL). The resulting mixture was heated to 120 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3×). The combined organic matter was washed with brine, dried over anhydrous sodium sulfate, and filtered. The residue was purified by silica gel column chromatography, eluting with 0-50% EtOAc / petroleum ether to give the title compound. MS: m / z = 727.45 [M+H] + .

[0686] Step 2: 3-(adamantane-1-yl)-N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl) (2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)propionamide

[0687] Triethylamine trifluoride (1.0 mL, 6.3 mmol) was added to a stirred mixture of 0.20 g (0.28 mmol) of 3-(adamantane-1-yl)-N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)propionamide (2 mL) in THF at 25 °C under an argon atmosphere. The reaction mixture was stirred at room temperature and then concentrated under reduced pressure. The residue was purified by RP-Combiflash under the following conditions: column: C18 column, 40 g. 20-35 μm; Mobile phase A: water, mobile phase B: MeCN; Flow rate: 50 mL / min; 0% B to 100% B over 30 min; Detector: UV 254 and 210 nm, yielding the title compound. MS: m / z = 499.20 [M+H] + . 1 H-NMR (400MHz, CD3OD) δ7.52(d,J=3.6Hz,1H),6.88(d,J=3.6Hz,1H),6.64–6.62(m,1H),4.69(t,J=7.2Hz,1H), 3.86–3.70(m,2H),3.07(s,1H),2.66–2.50(m,4H),1.96(d,J=3.6Hz,3H),1.78–1.67(m,6H),1.56–1.53(m,8H).

[0688] Example 70

[0689] N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyridine [2,3-d]pyrimidin-4-yl)tetradecanoamide

[0690]

[0691] Step 1: N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy) (2-(2,3-d)pyrimidin-4-yl)tetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetradecanoamide

[0692] Under an argon atmosphere at 0 °C, tetradecanoic acid (0.19 g, 0.84 mmol) and phosphorus oxychloride (V) (0.26 g, 1.7 mmol) were added to a stirred mixture of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (intermediate 2) (0.30 g, 0.56 mmol) in pyridine (4 mL). The resulting mixture was stirred for 3 hours. The reaction mixture was quenched with water (70 mL) and extracted with ethyl acetate (3×). The combined organic fractions were washed with brine (3×), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1 to 10% ethyl acetate / petroleum ether, to give the title compound. MS: m / z = 747.50 [MH] - .

[0693] Step 2: N-(2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetradecanoamide

[0694] Triethylamine trifluoride (0.52 mL, 3.3 mmol) was added to a stirred mixture of N-(7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetradecanoic acid (0.24 g, 0.32 mmol) in THF (3 mL). The reaction mixture was heated to 25 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-FLASH chromatography, eluting with 0–100% acetonitrile / water to give the title compound. MS: m / z = 519.30 [M+H] + . 1H NMR (300MHz, DMSO-d6) δ11.01(s,1H),7.63(d,J=3.6Hz,1H),6.86(d,J=3.9Hz,1H),6.55(t,J=6.6Hz,1H),5.56(d,J=5.4Hz,1H),5.27(t,J=6.0Hz,1H ),4.54–4.48(m,1H),3.65–3.52(m,2H),3.50(s,1H),2.66–2.53(m,2H),2. 47–2.34(m,2H),1.62–1.58(m,2H),1.27–1.23(m,20H),0.87–0.84(m,3H).

[0695] Example 71

[0696] (2-Chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrole [2,3-d]pyrimidin-4-yl)decyl carbamate

[0697]

[0698] Step 1: (7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy) )yl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamic acid decyl ester

[0699] At room temperature, DMAP (68 mg, 0.56 mmol) and decyl chloroformate (0.62 g, 2.8 mmol) were added to a mixture of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (intermediate 2) (0.30 g, 0.56 mmol) and triethylamine (0.56 g, 5.6 mmol) in DCM (5 mL). The resulting mixture was heated to 40 °C and stirred for 16 hours. The reactants were purified by silica gel column chromatography, eluting with 0–50% EtOAc / petroleum ether to give the title compound. MS: m / z = 721.50 [M+H] + .

[0700] Step 2: (2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)decyl carbamate

[0701] Triethylamine trifluoride (1.0 mL, 6.3 mmol) was added to a stirred mixture of (7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate (0.14 g, 0.19 mmol) in THF (2 mL). The resulting mixture was stirred at 50 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-Combiflash under the following conditions: column: C18 column, 40 g. 20-35 μm; Mobile phase A: water, mobile phase B: MeCN; Flow rate: 50 mL / min; 0% B to 100% B over 30 min; Detector: UV 254 and 210 nm, yielding the title compound. MS: m / z = 493.20 [M+H] + . 1 H-NMR (400MHz, CD3OD) δ7.52(d,J=4.0Hz,1H),6.99(d,J=3.6Hz,1H),6.64–6.62(m,1H),4.69(t,J=7.2Hz,1H),4.22(t,J= 6.8Hz,2H),3.87–3.71(m,2H),3.07(s,1H),2.72–2.52(m,2H),1.74–1.68(m,2H),1.45–1.29(m,14H),0.91–0.87(m,3H).

[0702] Example 72

[0703] (2-Chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrole [2,3-d]pyrimidin-4-yl)benzyl carbamate

[0704]

[0705] Step 1: (7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy) )yl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamic acid benzyl ester

[0706] At room temperature, K₂CO₃ (2.1 g, 15 mmol) was added to a mixture of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (intermediate 2) (0.40 g, 0.74 mmol) and benzyl carbonate (2,5-dioxopyrrolidine-1-yl) ester (1.9 g, 7.5 mmol) in DMF (30 mL). The resulting mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3×). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0-50% EtOAc / petroleum ether to give the title compound. MS: m / z = 671.35 [M+H] + .

[0707] Step 2: (2-chloro-7-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate benzyl ester

[0708] Under an argon atmosphere at 25°C, TEA.3HF (0.50 mL, 3.1 mmol) was added to a stirred mixture of (20 mg, 0.030 mmol) of 7-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethynyltetrahydrofuran-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate (1 mL) in THF. The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-Combiflash under the following conditions: column: C18 column, 40 g. 20-35 μm; Mobile phase A: water, mobile phase B: MeCN; Flow rate: 50 mL / min; 0% B to 100% B over 30 min; Detector: UV 254 and 210 nm, yielding the title compound. MS: m / z = 440.95 [MH] - . 1 H-NMR (400MHz, CD3OD) δ7.50-7.45(m,3H),7.41–7.27(m,3H),6.98(d,J=3.6Hz,1H),6.63–6.61 (m,1H),5.26(s,2H),4.69(t,J=7.2Hz,1H),3.84–3.72(m,2H),3.07(s,1H),2.66–2.55(m,2H).

[0709] Example 73

[0710] 2-(4-bromophenyl)acetic acid ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- 2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl ester

[0711]

[0712] Under an argon atmosphere at room temperature, DMAP (40 mg, 0.32 mmol), 2-(4-bromophenyl)acetyl chloride (0.23 g, 0.97 mmol), and TEA (0.090 mL, 0.65 mmol) were added to a stirred mixture of (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (compound A) (0.10 g, 0.32 mmol) in pyridine (5 mL). The resulting mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was purified by RP-FLASH chromatography, eluting with 0–100% acetonitrile / water to give the title compound. MS: m / z = 505.05 [M+H] + . 1 HNMR(300MHz, DMSO-d6)δ7.58(s,2H),7.48(d,J=3.2Hz,2H),7.26(d,J=3.9Hz,1H),7.18–7.15(m,2H),6.63(d,J=3.6Hz,1H),6.40–6.36(m,1H),5 .78(d,J=5.4Hz,1H),4.58–4.51(m,1H),4.40(d,J=11.7Hz,1H),4.12(d, J=11.7Hz,1H),3.74–3.61(m,3H),2.82–2.75(m,1H),2.50–2.40(m,1H).

[0713] The examples in the table below were prepared using a procedure similar to that described in Example 6, from suitable starting materials.

[0714]

[0715] The examples in the table below were prepared using a procedure similar to that described in Example 8, with intermediate 24b used in Example 75 and intermediate 24a used in Example 76, and with tert-butylmagnesium chloride (1M in THF) used instead of the solution of 2,2,6,6-tetramethylpiperidinylmagnesium lithium chloride complex.

[0716]

[0717]

[0718] The examples in the table below were prepared using a procedure similar to that described in Example 12, from suitable starting materials.

[0719]

[0720]

[0721]

[0722] The examples in the table below were prepared using a procedure similar to that described in step 1 of Example 12, from suitable starting materials.

[0723]

[0724]

[0725] The examples in the table below were prepared using a procedure similar to that described in Example 14, from suitable starting materials.

[0726]

[0727]

[0728] The examples in the table below are prepared using a procedure similar to that described in the alternative procedure of Example 18, and from suitable starting materials.

[0729]

[0730] The examples in the table below are prepared using a procedure similar to that described in the alternative procedure of step 1 of Example 27, and are made from suitable starting materials.

[0731]

[0732] The examples in the table below are prepared using a procedure similar to that described in the alternative procedure of Example 34, and from suitable starting materials.

[0733]

[0734]

[0735]

[0736]

[0737]

[0738] The examples in the table below are prepared using a procedure similar to that described in the alternative procedure of Example 36, and from suitable starting materials.

[0739]

[0740]

[0741] The examples in the table below are prepared using a procedure similar to that described in the alternative procedure of step 1 of Example 36, and are made from suitable starting materials.

[0742]

[0743] The examples in the table below are prepared using a procedure similar to that described in the alternative procedure of Example 39, and from suitable starting materials.

[0744]

[0745] The examples in the table below are prepared using a procedure similar to that described in the alternative procedure of Example 39, with suitable starting materials and 2 equivalents of TEA.

[0746]

[0747]

[0748]

[0749] The examples in the table below were prepared using a procedure similar to that described in Example 51, from suitable starting materials.

[0750]

[0751]

[0752] The examples in the table below were prepared using a procedure similar to that described in Example 53, from suitable starting materials.

[0753]

[0754] The examples in the table below were prepared using a procedure similar to that described in Example 60, from suitable starting materials.

[0755]

[0756] The examples in the table below were prepared using a procedure similar to that described in step 1 of Example 61, from suitable starting materials.

[0757]

[0758]

[0759] The examples in the table below were prepared using a procedure similar to that described in Example 62, with appropriate starting materials and NMP instead of DMF.

[0760]

[0761] The examples in the table below were prepared using a procedure similar to that described in step 1 of Example 62, from suitable starting materials.

[0762]

[0763]

[0764] The examples in the table below were prepared using a procedure similar to that described in Example 63, from suitable starting materials.

[0765]

[0766]

[0767] The examples in the table below were prepared using a procedure similar to that described in Example 64, from suitable starting materials.

[0768]

[0769]

[0770]

[0771]

[0772] The examples in the table below were prepared using a procedure similar to that described in step 1 of Example 64, from suitable starting materials.

[0773]

[0774]

[0775]

[0776]

[0777]

[0778] The examples in the table below were prepared using a procedure similar to that described in Example 65, from suitable starting materials.

[0779]

[0780]

[0781]

[0782] The examples in the table below were prepared using a procedure similar to that described in step 1 of Example 65, from suitable starting materials.

[0783]

[0784]

[0785]

[0786]

[0787] The examples in the table below were prepared using a procedure similar to that described in Example 66, from suitable starting materials.

[0788]

[0789]

[0790] The examples in the table below were prepared using a procedure similar to that described in Example 67, from suitable starting materials.

[0791]

[0792]

[0793] The examples in the table below were prepared using a procedure similar to that described in steps 1 and 2 of Example 61, from suitable starting materials.

[0794]

[0795]

[0796] The examples in the table below are prepared using a procedure similar to that described in steps 1 and 2 of Example 67, with step 2 of Example 23 replacing step 3, and are made from suitable starting materials.

[0797]

[0798]

[0799] The examples in the table below were prepared using a procedure similar to that described in Example 68, from suitable starting materials.

[0800]

[0801]

[0802]

[0803] The examples in the table below were prepared using a procedure similar to that described in Example 69, from suitable starting materials.

[0804]

[0805] The examples in the table below were prepared using a procedure similar to that described in Example 71, from suitable starting materials.

[0806]

[0807]

[0808]

[0809] The examples in the table below were prepared using a procedure similar to that described in Example 73, from suitable starting materials.

[0810]

[0811]

[0812] water solubility of compounds

[0813] The water solubility of the compounds was determined by suspending an excess of solid (typically 0.3 to 0.5 mg) in PBS at a concentration of 0.5 mg / mL at pH 7.4. The suspension was vortexed for 10 to 30 seconds to wet the material and stirred at 600 rpm for 24 hours. For UPLC analysis, 150 μL aliquots were transferred to a 0.45 μm PVDF spin filter and centrifuged at 14,000 rpm for 5 minutes. 100 μL of the filtrate was diluted with 100 μL of 1:1 acetonitrile (ACN):H2O. The resulting samples were analyzed using UPLC, and quantification was performed based on a standard curve of the compound of interest dissolved in 1:1 ACN:H2O. Solid retention was examined by XRPD and PLM to determine whether the phase of the material was crystalline or amorphous. The compounds in Table 1 showed lower water solubility than the parent compound A (0.5 mg / mL in water).

[0814] Table 1. Water solubility (μg / mL) of examples in pH 7.4 phosphate buffered saline in amorphous or crystalline form.

[0815]

[0816]

[0817]

[0818] The potency of the compound

[0819] The antiviral efficacy of compounds was determined based on their ability to block HIV-1 replication in GFP reporter cell lines; this analysis is referred to as viral kinetics in green cells or the VIKING assay. HIV-1 replication was monitored using MT4-gag-GFP clone D3 (hereinafter referred to as MT4-GFP) cells, which were MT4 cells modified to have the GFP reporter gene, whose expression depended on the HIV-1 proteins tat and rev. (MT4 is a human T cell line that is particularly sensitive to HIV-1 replication). HIV-1 infection of MT4-GFP cells induced GFP expression approximately 24 hours post-infection. MT4-GFP cells were maintained at 37°C / 5% CO2 / 90% relative humidity in RPMI 1640 supplemented with 10% fetal bovine serum, 100 U / mL penicillin / streptomycin, and 400 mg / mL G418 to maintain the reporter gene. For infection, MT4-GFP cells were placed in the same medium lacking G418 and infected overnight with HIV-1 wild-type (R8) virus at an infection fold of approximately 0.01 under the same culture conditions. Cells were then washed and infected with 2 × 10⁻⁶ cells / mL. 5Cells / mL were resuspended in RPMI 1640 containing 10% normal human serum. Compound disks were prepared by dispensing the compounds dissolved in DMSO into each of 384 wells coated with poly-D-lysine (0.2 μL / well) using an ECHO acoustic dispenser. Each compound was tested with 10-point serial 3-fold dilutions (typical final concentration: 4 μM to 0.2 nM). Controls included no inhibitor (DMSO only) and a combination of three antiviral agents (efavirenz, indinavir, and an integrase transfer inhibitor, each at a final concentration of 4 μM) as positive controls. Infected cells were added to the compound disks (50 μL / well) and maintained at 37°C / 5% CO2 / 90% relative humidity. The number of green cells in each well was counted using an Acumen eX3 scanner, and the number of infected cells was quantified at two time points (approximately 48 hours and 72 hours post-infection). The increase in the number of green cells within approximately 24 hours was given by the reproduction rate R, which was calculated by dividing the number of green cells at 72 hours post-infection by the number at 48 hours post-infection. The percentage of inhibition caused by the test compound was calculated using the following formula:

[0820] Inhibition % = [1-(R 测试化合物 –R 阳性对照 ) / (R 仅DMSO –R 阳性对照 )]×100%

[0821] The dose-response curves for each tested compound were plotted as the relationship between inhibition % and compound concentration. The IC50 was determined by nonlinear 4-parameter fitting of the dose-response curves. 50 Value. In Viking analysis, the IC50 value of parent compound A. 50 It is 3.3 nM.

[0822] Table 2. ECGs in the HIV Viking analysis using 10% normal human serum (NHS) 50 Value (nM).

[0823]

[0824]

[0825]

[0826]

[0827]

[0828] The plasma stability of the compounds was evaluated in frozen human plasma at 37°C and 10% CO2. The stability of the analytes was assessed by determining the percentage of drug loss over 0, 0.25, 0.5, 1, and 3 hours. Additionally, the appearance of compound A was determined over the same time periods. The percentage of drug loss was expressed as a ratio to an internal standard. Analytical concentrations were measured by LC / MS / MS. Regression analysis was performed on the percentage of the logarithm of the mean TO values ​​against the linear time values. The elimination rate constant (ke) was calculated based on the slope of this regression line, and the half-life (T1 / 2) was calculated based on the elimination rate constant.

[0829] Table 3. Stability report of the examples: half-life (T1 / 2) in the presence of human plasma.

[0830]

[0831]

[0832] The in vitro metabolic stability of prodrug-formed compound A.

[0833] The formation of compound A of 14 disclosed prodrug compounds was measured in the presence of cryopreserved human hepatocytes. Cultures were performed in a 37°C incubator with a 5% CO2 controlled atmosphere in Williams E medium containing 4 mM L-glutamic acid at a cell density of 1 × 10⁻⁶ cells / year. 6 Cells / mL. Aliquots were collected at 0, 30, and 60 minutes and quenched with ice-cold acetonitrile containing appropriate internal standards. The samples were then vortexed and centrifuged at approximately 2,900 × g for 15 minutes. For analysis, the supernatant was diluted with water containing 0.1% (v / v) formic acid and analyzed by LC / MS-MS.

[0834] The results are reported in Table 4, and it is confirmed that Examples 10, 18, 20, 21, 24, 27, 34, 36, 42, 48, 60, 61, 64, and 68 can be efficiently converted to Compound A by human hepatocytes. Specifically, all these prodrug compounds exhibited more than 75% Compound A formation in the presence of cryopreserved human hepatocytes. That is, more than 75% of the prodrug compounds added to the hepatocytes were converted to Compound A.

[0835] Table 4. Formation of compound A in the presence of human hepatocytes.

[0836]

[0837] Plasma exposure after administration of prodrug to the muscles of WistarHan rats.

[0838] Exposure to parent compound A was evaluated in Wistar Han rats following a single intramuscular (IM) administration of one of the following compounds at a concentration of 47 mg / kg or less: Compound A, Example 10, Example 18, Example 20, Example 21, Example 24, Example 27, Example 34, Example 36, Example 42, Example 48, Example 60, Example 61, Example 64, or Example 68. The test compounds were prepared as homogeneous suspensions containing functional excipients including surfactants, suspending agents, and buffer solutions at a concentration of 200 mg / mL, except for Example 68, which was also prepared as solutions (also at 200 mg / mL).

[0839] WistarHan rats (n=4) were administered a single 14 mg dose of each test compound via intramuscular injection (0.07 mL). Blood samples were collected at 0.5, 1, 2, 4, 6, 24, 48, 120 (5 days), and 168 (7 days) hours post-administration. Approximately 0.25 mL of blood was collected in a pre-cooled blood collection tube containing 12.5 μL of 2 mM dichlorvos aqueous solution. Plasma was processed by centrifugation at 6,000 rpm for 10 min, and the plasma samples were frozen and maintained at -80°C until analysis. For analysis, 50 mL of plasma was mixed with 200 mL of acetonitrile containing internal standards and analyzed by LC / MS-MS.

[0840] The results of these pharmacokinetic studies are presented in Figures 1 to 15 The concentration versus time curve is shown in the graph. Figures 2 to 15 Examples 10, 18, 20, 21, 24, 27, 34, 36, 42, 48, 60, 61, 64, and 68 demonstrate the release of compound A into systemic circulation within 168 hours. This data confirms that these compounds can be readily delivered via muscle and that compound A can be efficiently released into systemic circulation in mammals.

Claims

1. A compound of formula (VI): Or its pharmaceutically acceptable salt, wherein: X is selected from -C(=O)-, -C(=O)-O-, -CR 5 R 6 -OC(=O)-、-CR 5 R 6 -OC(=O)-O- and bonds; aryl Y is selected from -C(=O)-, -C(=O)-O-, -CR 5 R 6 -OC(=O)-、-CR 5 R 6 -OC(=O)-O-、-P(=O)(OC 6-12 (aryl)-NH-CR 4 C(=O)-O- and bonds; Z is selected from -C(=O)-, -C(=O)-O-, and bond; W is selected from -C(=O)-, -C(=O)-O- and bond; R 1 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl, (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups; R 2 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl, (CR 5 R 6 ) z -C 5-12 heteroaryl and (CR) 5 R 6 ) z -C 1-6 Alkyl esters, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be selected independently by one to three groups selected from halogen, oxo, C... 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups; R 3 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, or heteroaryl group may optionally be selected independently by one to three groups selected from halogen, oxo, C... 1-6 Alkyl, C 3-12 The aryl group is substituted with a cycloalkyl or hydroxyl group, and the aryl group may optionally be replaced by one to three groups independently selected from alkyl, oxo, C... 1-6 Alkyl, C 3-12 Cycloalkyl, hydroxyl and C 1-6 Alkyl ester group substitution; R 4 Choose from the following groups: hydrogen, C 1-3 Alkyl groups and (CH2) z -cycloalkyl; R 5 and R 6 Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl and C 3-6 cycloalkyl; and R 7 Selected from hydrogen, C 1-21 Alkyl and (CR) 5 R 6 ) z -C 5-12 cycloalkyl, Where R 1 R 2 and R 3 At least one of them is not hydrogen; and z is 0, 1, 2, 3, 4, 5 or 6.

2. A compound of formula (I): Or its pharmaceutically acceptable salt, wherein: X is selected from -C(=O)-, -C(=O)-O-, -CR 5 R 6 -O-C(=O)-, -CR 5 R 6 -O-C(=O)-O- and a bond; Y is selected from -C(=O)-, -C(=O)-O-, -CR 5 R 6 -OC(=O)-、-CR 5 R 6 -OC(=O)-O-、-P(=O)(OC 6-12 (aryl)-NH-CR 4 C(=O)-O- and bonds; Z is selected from -C(=O)- and bonds; R 1 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups; R 2 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups; R 3 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups; R 4 Choose from the following groups: hydrogen, C 1-3 Alkyl groups and (CH2) z -cycloalkyl; R 5 and R 6 Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl and C 3-6 cycloalkyl; and Where R 1 R 2 and R 3 At least one of them is not hydrogen; and z is 0, 1, 2, 3, 4, 5 or 6.

3. The compound according to claim 1 or 2, wherein the compound has formula (II): Or its pharmaceutically acceptable salt.

4. The compound according to claim 1 or 2, wherein the compound has formula (III): Or its pharmaceutically acceptable salt.

5. The compound according to claim 1 or 2, wherein the compound has formula (IV): Or its pharmaceutically acceptable salt.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein X is selected from -C(=O)- and -CR. 5 R 6 -OC (=O) and bonds; Y is selected from -C(=O)-, -CR 5 R 6 -OC (=O) and bonds; Z is a bond, and R 1 It is hydrogen; R 2 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups; and R 3 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups, Where z is 0, 1, 2, 3, 4, 5 or 6.

7. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein... X is selected from -C(=O)-O-, -CR 5 R 6 -OC(=O)-O- and bonds; Y is selected from -C(=O)-O-, -CR 5 R 6 -O-C(=O)-O- and a bond; Z is a bond, and R 1 It is hydrogen; R 2 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups; and R 3 Choose from the following groups: hydrogen, C 1-21 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl, (CR) 5 R 6 ) z -C 5-12 Heterocyclic groups, (CR) 5 R 6 ) z -C 6-12 Aryl and (CR 5 R 6 ) z -C 5-12 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be selected independently by one to three halogens, C 1-6 Alkyl, C 3-12 Substitution of cycloalkyl and hydroxyl groups, Where z is 0, 1, 2, 3, 4, 5 or 6.

8. The compound according to claim 1 or 2, wherein the compound has formula (V): Or its pharmaceutically acceptable salt.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein: X is selected from -C(=O)-, -C(=O)-O-, and bond; Y is selected from -C(=O)-, -C(=O)-O-, and bond; Z is a bond, and R 1 It is hydrogen; R 1 Selected from hydrogen and C 1-14 alkyl; R 2 Selected from C 1-10 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl and (CR) 5 R 6 ) z -C6 aryl, wherein the aryl group may optionally be substituted with a halogen; and R 3 Selected from C 1-10 Alkyl, (CR) 5 R 6 ) z -C 3-12 cycloalkyl and (CR) 5 R 6 ) z -C6 aryl, wherein the aryl group may optionally be substituted with a halogen, and Where R 5 and R 6 It's hydrogen. Where z is 0, 1, 2, 3, 4, 5 or 6.

10. The compound according to any one of claims 1-9, having the following structure: Or its pharmaceutically acceptable salt.

11. The compound according to any one of claims 1-9, having the following structure: Or its pharmaceutically acceptable salt.

12. A pharmaceutical composition comprising a compound or salt as described in any one of claims 1-11, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein the composition is injectable or suitable for injection.

14. The pharmaceutical composition of claim 12 or 13, further comprising one or more additional therapeutic agents selected from the group consisting of: lenakapavir, raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, darunavir, atazanavir, emtricitabine, tenofovir, erticavir, rilpivirine, lopinavir, doravirine, and islatrevir.

15. A method of inhibiting HIV reverse transcriptase in a subject in need, comprising administering to the subject an effective amount of a compound or salt as described in any one of claims 1-11, or a pharmaceutical composition as described in any one of claims 12-14.

16. A method of treating HIV infection in a subject in need or treating, preventing, or delaying the onset or progression of AIDS in a subject in need, comprising administering to the subject an effective amount of a compound or salt as described in any one of claims 1-11, or a pharmaceutical composition as described in any one of claims 12-14.

17. The method of claim 16, further comprising administering to the subject one or more additional therapeutic agents selected from the group consisting of: lenakapavir, raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, darunavir, atazanavir, emtricitabine, tenofovir, erticagvir, rilpivirine, lopinavir, and doravirine, wherein the compound or salt administered in any one of claims 1-11, together with the amount of the one or more additional therapeutic agents, is effective in treating HIV infection or in treating, preventing, or delaying the onset or progression of AIDS.

18. The method of claim 17, wherein the additional therapeutic agent is lenakapavir.

19. The method according to any one of claims 15-18, wherein the method comprises administering the compound or salt at a dosing interval ranging from about once a month to about once every twelve months.

20. The method of claim 19, wherein the dosing interval ranges from about once every three months, once every six months, or once every twelve months.

21. The compound or salt of any one of claims 1-11, or the pharmaceutical composition of any one of claims 12-14, for use in preparing an agent for inhibiting HIV reverse transcriptase in a subject in need; for treating or preventing HIV infection in a subject in need; or for treating, preventing, or delaying the onset or progression of AIDS in a subject in need.

22. The compound or salt of any one of claims 1-11, or the pharmaceutical composition of any one of claims 12-14, for therapeutic purposes.

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