Phospholipid compounds and their uses

Abstract

This invention discloses compounds for treating viral infections and methods for using said compounds alone or in combination with additional agents, as well as pharmaceutical compositions of said compounds (Formula (I)).

Description

[0001] This application is a divisional application of Chinese patent application No. 202180051637.1 (filed on August 23, 2021, entitled "Phospholipid Compounds and Their Uses").

[0002] Cross-reference This application claims priority to U.S. Provisional Application No. 63 / 069,449, filed August 24, 2020; U.S. Provisional Application No. 63 / 092,386, filed October 15, 2020; and U.S. Provisional Application No. 63 / 151,509, filed February 19, 2021, each of which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0003] There is a need for compounds and methods for treating viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae families. This disclosure addresses the above and other needs. Summary of the Invention

[0004] In one aspect, the present invention provides compounds of formula I: Formula I Or its pharmaceutically acceptable salt, wherein: Z 1 It is -CH2- or –CH2-CH2-; Z 2 It is -CH2- or –CH2-CH2-; X represents a chemical bond, -O-, or -(CR). 12A R 12B ) q -、-O(CR 12A R 12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-;in Each R 12A Independently, it is H, C1-C6 alkyl, or phenyl; Each R 12B Independently H or C1-C6 alkyl; or R on the same carbon 12A and R 12B They are linked together to form C3-C6 cycloalkylene groups; R 13 It is H, C1-C6 alkyl or phenyl; R 14 It is H, C1-C6 alkyl or phenyl; q is 1 or 2; R 1 For H, C1-C 20 Alkyl, C3-C 10 Cycloalkyl groups, containing one, two, or three heteroatoms selected from N, O, and S, consisting of 4 to 6-membered heterocyclic groups, C6-C. 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein when R 1 When R is not H, 1 The group is optionally surrounded by one or two R groups. 1A Group substitution; Each R 1A Independently, it is a C1-C3 alkyl, phenyl, haloyl, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; or two Rs on the same or adjacent carbons thereon. 1A Linked together to form a 3- to 6-membered cycloalkyl group or a 4- to 6-membered heterocyclic ring containing one, two or three heteroatoms selected from N, S and O; R 2 It is H or C1-C3 alkyl; Y is absent, or is a phenylene or a C3-C6 cycloalkylene group; R 3 It can be H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; Each R 4 Independently, it is H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R 4 The group and the R of an adjacent carbon atom 4 The groups together form a double bond; Each R 5 It can be independently H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; R 6 It is H or -C(O)C1-C6 alkyl; R 7 It is H or -C(O)C1-C6 alkyl; and m is an integer from 10 to 21.

[0005] In another aspect, this disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0006] On the other hand, this disclosure provides a method for treating or preventing viral infection in a person in need, wherein the method comprises administering to the person a compound of formula I or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, this disclosure provides a method for preparing a medicament for treating or preventing viral infections in people in need, characterized by using a compound of formula I or a pharmaceutically acceptable salt thereof.

[0008] On the other hand, this disclosure provides the use of compounds of formula I or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of viral infections in persons in need. Detailed Implementation

[0009] I. Overview The present invention relates to methods and compounds for treating or preventing viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxoviridae, and Coronaviridae families.

[0010] II. Definition Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings: As used herein, “compound of this disclosure” or “compound of formula I” means a compound of formula I or a pharmaceutically acceptable salt thereof. Similarly, the phrase “compound of formula (number)” means a compound of that formula or a pharmaceutically acceptable salt thereof.

[0011] "Alkyl" refers to a saturated hydrocarbon chain that is either unbranched or branched. For example, alkyl groups can have 1 to 20 carbon atoms (i.e., C1-C2). 20Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, ... -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl -1-Butyl (-CH2CH2CH(CH3)2), 2-Methyl-1-Butyl (-CH2CH(CH3)CH2CH3), 1-Hexyl (-CH2CH2CH2CH2CH2CH3), 2-Hexyl (-CH(CH3)CH2CH2CH2CH3), 3-Hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl ( -CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2) and 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0012] "Alkoxy" refers to an alkyl group having the formula -O-, wherein the alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C2). 20 alkoxy group), 1 to 12 carbon atoms (i.e., C1-C) 12Alkoxy groups are alkoxy groups with 1 to 8 carbon atoms (i.e., C1-C8 alkoxy groups), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy groups), or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy groups). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), tert-butoxy (-OC(CH3)3 or -OtBu), etc.

[0013] "Haloalkyl" is an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl moiety of a haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C2). 20 Halogenated alkyl groups), 1 to 12 carbon atoms (i.e., C1-C1), 12 Halogenated alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl groups), 1 to 6 carbon atoms (i.e., C1-C6 alkyl groups), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl groups). Examples of suitable alkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, etc.

[0014] "Aryl" refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracene, biphenyls, etc.

[0015] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic systems. As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C146 ... 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0016] As used herein, the term "halogenated group" refers to -F, -Cl, -Br, or -I. In one embodiment, the halogenated group is -F or -Cl. In another embodiment, the halogenated group is -F.

[0017] "Heterocyclic" or "heterocyclic group" refers to a saturated or unsaturated cyclic alkyl group in which one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocyclic. As used herein, a heterocyclic group has 3 to 20 ring atoms (i.e., 3 to 20-membered heterocyclic group), 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclic group), 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclic group), 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclic group), 4 to 12 ring carbon atoms (i.e., 4 to 12-membered heterocyclic group), 4 to 8 ring atoms (i.e., 4 to 8-membered heterocyclic group), or 4 to 6 ring atoms (i.e., 4 to 6-membered heterocyclic group). Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, oxobutyl, dioxopentyl, aziroxybutyl, and morpholinyl. The terms heterocyclic or heterocyclic group do not cover heteroaryl as defined below or overlap with it.

[0018] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 ring atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-20 heteroaryl), 3 to 12 ring atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 ring atoms (i.e., C 3-8 (Heteroaryl); and 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl groups do not cover aryl groups as defined above or overlap with them.

[0019] The term "optionally substituted" in relation to a specific portion (e.g., an optionally substituted aryl group) of a compound of formula I means a portion in which all substituents are hydrogen or one or more hydrogens of said portion may be replaced by the listed substituents.

[0020] Unless otherwise specified, the carbon atoms in compounds of Formula I are intended to have a tetravalent oxidation state. If, in some chemical structural representation, the carbon atom is not connected to a sufficient number of variables to produce a tetravalent oxidation state, it should be assumed that the remaining carbon substituents required to provide the tetravalent oxidation state are hydrogen.

[0021] Unless otherwise specified, as used herein, the term "treatment" means reversing, alleviating, or inhibiting the progression of a disease or condition to which the term applies, or one or more symptoms of such a disease or condition, or preventing the occurrence of one or more symptoms of such a disease or condition. As used herein, the term "treatment" refers to the act of treatment, as "treatment" is as defined above.

[0022] As used herein, the term "therapeutic effective amount" is the amount of a compound of formula I present in the compositions described herein that is required to deliver a desired level of the drug in the secretions and tissues of the airways and lungs, or alternatively, that is required to produce the desired physiological response or desired biological effect in the bloodstream of the subject to be treated when such a composition is administered via a chosen route of administration. The precise amount will depend on many factors, such as the specific compound of formula I, the specific activity of the composition, the delivery device used, the physical properties of the composition and its intended use, and patient considerations such as the severity of the disease, patient cooperation, etc., and this precise amount can be readily determined by those skilled in the art based on the information provided herein.

[0023] As used in this article, the term "adjacent carbon" refers to consecutive carbon atoms that are directly connected to each other. For example, in In this context, C1 and C2 are adjacent carbon atoms, C2 and C3 are adjacent carbon atoms, C3 and C4 are adjacent carbon atoms, and C4 and C5 are adjacent carbon atoms. Similarly, in... In the diagram, C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, C4 and C5 are adjacent carbons, C5 and C6 are adjacent carbons, and C6 and C1 are adjacent carbons.

[0024] Certain commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl", divalent "aryl", and divalent "cycloalkyl" may also be referred to as "alkylene" ("alkylene" group or "alkylenyl" group or "alkylyl group"); "arylene" ("arylene" group or "arylenyl" group or "arylyl" group); and "cycloalkylene" ("cycloalkylene" group or "cycloalkylenyl" group or "cycloalkylyl" group).

[0025] III. Compounds This article provides compounds of formula I: Formula I Or its pharmaceutically acceptable salt, wherein: Z 1 It is -CH2- or –CH2-CH2-; Z 2 It is -CH2- or –CH2-CH2-; X represents a chemical bond, -O-, or -(CR). 12A R 12B ) q-、-O(CR 12A R 12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-;in Each R 12A Independently, it is H, C1-C6 alkyl, or phenyl; Each R 12B Independently H or C1-C6 alkyl; or R on the same carbon 12A and R 12B They are linked together to form C3-C6 cycloalkylene groups; R 13 It is H, C1-C6 alkyl or phenyl; R 14 It is H, C1-C6 alkyl or phenyl; q is 1 or 2; R 1 For H, C1-C 20 Alkyl, C3-C 10 Cycloalkyl groups, containing one, two, or three heteroatoms selected from N, O, and S, consisting of 4 to 6-membered heterocyclic groups, C6-C. 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein when R 1 When R is not H, 1 The group is optionally surrounded by one or two R groups. 1A Group substitution; Each R 1A Independently, it is a C1-C3 alkyl, phenyl, haloyl, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; or two Rs on the same or adjacent carbons thereon. 1A Linked together to form a 3- to 6-membered cycloalkyl group or a 4- to 6-membered heterocyclic ring containing one, two or three heteroatoms selected from N, S and O; R 2 It is H or C1-C3 alkyl; Y is absent, or is a phenylene or a C3-C6 cycloalkylene group; R 3 It can be H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; Each R 4 Independently, it is H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R 4 The group and the R of an adjacent carbon atom 4 The groups together form a double bond; Each R 5 It can be independently H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; R 6 It is H or -C(O)C1-C6 alkyl; R 7 It is H or -C(O)C1-C6 alkyl; and m is an integer from 10 to 21.

[0026] In some embodiments of the compound of formula I, Z 1 It is -CH2-, and Z 2 For -CH2-. In some implementations, Z 1 and Z 2 At least one of them is -CH2-CH2-. In some implementations, Z 1 and Z 2 Both are -CH2-CH2-. In some implementations, Z 1 It is -CH2-CH2-, and Z 2 For -CH2-. In some implementations, Z 1 It is -CH2-, and Z 2 It is -CH2-CH2-.

[0027] In some embodiments, the compound of formula I has formula II: Formula II, in R 8 It can be H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; R 9 It can be H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; w and v are independent integers from 10 to 21; u is 0 or 1; and w+u+v are integers from 10 to 21.

[0028] In some embodiments of the compounds of formula II, u is 0. In some embodiments, u is 1. In some embodiments, u is 1, R 8 It is H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl, and R 9 It can be H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, u is 1, R 8It is H, C1-C3 alkyl, halogroup or C1-C3 haloalkyl, and R 9 It is H, C1-C3 alkyl, halogroup, or C1-C3 haloalkyl. In some embodiments, u is 1, R 8 It is H, C1-C3 alkyl or halogroup, and R 9 It is H, C1-C3 alkyl, or halogroup. In some embodiments, u is 1, R 8 It is H or C1-C3 alkyl, and R 9 It is H or C1-C3 alkyl. In some embodiments, u is 1, R 8 It is H or methyl, and R 9 It is H or methyl. In some embodiments, u is 1, R 8 For H, and R 9 For H.

[0029] In some embodiments, the compound of formula I or II has formula III: Formula III, Where n is an integer from 8 to 19.

[0030] In some embodiments of the compounds of formulas I, II, and III, X is -O-, -(CR 12A R 12B ) q -、-O(CR 12A R 12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-, where q is 1 or 2. In some embodiments, X is a chemical bond, -O-, -(CR-) 12A R 12B )-、-O(CR 12A R 12B - or - OCR 12A R 12B -(CR 13 =CR 14 In some implementations, X is a chemical bond, -O-, -(CR-). 12A R 12B )2-、-O(CR 12A R 12B )2- or -OCR 12A R 12B -(CR 13 =CR 14 In some implementations, X is -O-, -O(CR) 12A R12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-, where q is 1 or 2. In some implementations, X is -O-, -O(CR) 12A R 12B - or - OCR 12A R 12B -(CR 13 =CR 14 In some implementations, X is -O-, -O(CR) 12A R 12B )2- or -OCR 12A R 12B -(CR 13 =CR 14 In some implementations, X is a chemical bond, -O-, -(CR-). 12A R 12B ) q -、-O(CR 12A R 12B ) q - where q is 1 or 2. In some embodiments, X is a chemical bond, -O-, -(CR 12A R 12B )2-、-O(CR 12A R 12B )2-. In some implementations, X is a chemical bond, -O-, -(CR 12A R 12B )-、-O(CR 12A R 12B In some implementations, X is 0. In some implementations, X is -(CR) 12A R 12B ) q -, where q is 1 or 2. In some implementations, X is -(CR 12A R 12B In some implementations, X is -(CR) 12A R 12B )2-. In some implementations, X is -O(CR) 12A R 12B ) q -, where q is 1 or 2. In some implementations, X is -O(CR 12A R 12B In some implementations, X is -O(CR). 12A R 12B )2-.

[0031] In some embodiments of the compounds of formulas I, II, and III, each R 12A Independently H, C1-C6 alkyl, or phenyl; each R 12B Independently H or C1-C6 alkyl; R 13 It is H, C1-C6 alkyl or phenyl; and R 14 It is H, C1-C6 alkyl, or phenyl. In some embodiments, each R 12A Independently H or C1-C6 alkyl; each R 12B Independently H or C1-C6 alkyl; R 13 It is H or C1-C6 alkyl; and R 14 It is an H or C1-C6 alkyl group. In some embodiments, each R 12A Independently H or C1-C3 alkyl, each R 12B Independently H or C1-C3 alkyl, R 13 It is H or C1-C3 alkyl, and R 14 It is an H or C1-C3 alkyl group. In some embodiments, each R 12A For H, each R 12B For H, R 13 For H, and R 14 For H.

[0032] In some embodiments of compounds of formulas I, II, and III, X is a chemical bond, -O-, -(CR) 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H, C1-C6 alkyl or phenyl; and each R 12B Independently, it is H or a C1-C6 alkyl group. In some embodiments of compounds of formula I, X is a chemical bond, -O-, -(CR) 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H or C1-C6 alkyl; and each R 12B Independently, it is H or a C1-C6 alkyl group. In some embodiments of compounds of formula I, X is a chemical bond, -O-, -(CR) 12A R 12B ) q -、-O(CR 12A R 12B )q -; where q is 1 or 2; each R 12A Independently H or C1-C3 alkyl; and each R 12B Independently, it is H or a C1-C3 alkyl group. In some embodiments of compounds of formula I, X is a chemical bond, -O-, -(CR) 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A For H; and for each R 12B H is used. In some embodiments of compounds of Formula I, X is a chemical bond, -O-, -CH2-, -CH2CH2-, -OCH2-, or -O(CH2)2-. In some embodiments of compounds of Formula I, X is a chemical bond, -O-, -OCH2, or -CH2CH2.

[0033] In some embodiments of the compounds of formulas I, II, and III, X is -O-, -(CR 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H, C1-C6 alkyl or phenyl; and each R 12B Independently, it is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, -O-, -(C1-, -O ... 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H or C1-C6 alkyl; and each R 12B Independently, it is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, -O-, -(C1-, -O ... 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H or C1-C3 alkyl; and each R 12B Independently, it is an H or C1-C3 alkyl group. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B )q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A For H; and for each R 12B For H.

[0034] In some embodiments of the compounds of formulas I, II, and III, X is -O-, -(CR 12A R 12B )-、-O(CR 12A R 12B )-; where R 12A It is H, C1-C6 alkyl or phenyl; and R 12B It is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B )-、-O(CR 12A R 12B )-, where R 12A It is H or C1-C6 alkyl, and R 12B It is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B )-、-O(CR 12A R 12B )-, where R 12A It is H or C1-C3 alkyl, and R 12B It is H or C1-C3 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B )-、-O(CR 12A R 12B )-; where R 12A For H, and R 12B For H.

[0035] In some embodiments of the compounds of formulas I, II, and III, X is -O-, -(CR 12A R 12B )2-、-O(CR 12A R 12B )2-; where each R 12A Independently H or C1-C6 alkyl or phenyl; and each R 12B Independently, it is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, -O-, -(C1-, -O ... 12A R 12B )2-、-O(CR 12A R 12B )2-, where each R12A Independently H or C1-C6 alkyl, and each R 12B Independently, it is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, -O-, -(C1-, -O ... 12A R 12B )2-、-O(CR 12A R 12B )2-, where each R 12A Independently H or C1-C3 alkyl, and each R 12B Independently, it is an H or C1-C3 alkyl group. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B )2-、-O(CR 12A R 12B )2-; where each R 12A For H, and for each R 12B For H.

[0036] In some embodiments of compounds of formulas I, II, and III, X is -O-, -OCH2-, -OCH2-CH2-, -CH2-, -CH2-CH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -O-. In some embodiments, X is -CH2- or -CH2-CH2-. In some embodiments, X is -CH2-CH2-. In some embodiments, X is -CH2-.

[0037] In some embodiments of compounds of formulas I, II, and III, X is -O-, -OCH2-, -OCH2-CH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -O-. In some embodiments, X is -OCH2-. In some embodiments, X is -OCH2-CH2-. In some embodiments, X is -OCH2-(CH=CH)-.

[0038] In some embodiments of compounds of formula I, II, or III, X is a chemical bond. In some embodiments of compounds of formula I, II, or III, Y is a phenylene or C3-C6 cycloalkylene group. In some embodiments, Y is... or In some embodiments, Y is phenylene. In some embodiments, Y is... In some embodiments, Y is a C3-C6 cycloalkylene group. In some embodiments, Y is a cyclohexylene group. In some embodiments, Y is... In some embodiments, Y is absent. In some embodiments, Y is absent or is phenylene. In some embodiments, Y is absent or is a C3-C6 cycloalkylene group.

[0039] In some embodiments, compounds of formula I, II, or III have formula IV: Formula IV, Where n is an integer from 8 to 19.

[0040] In some embodiments of compounds of formula I, II, III or IV, R 2 For H. In some implementations, R 2 It is a C1-C3 alkyl group. In some embodiments, R 2 It is methyl or ethyl. In some embodiments, R 2 It is methyl. In some embodiments, R 2 It is ethyl. In some embodiments, R 2 It is H, methyl, or ethyl. In some embodiments, R 2 It is H or methyl. In some embodiments, R 2 It is H or ethyl.

[0041] In some embodiments of compounds of formula III or IV, n is an integer from 11 to 18. In some embodiments, n is an integer from 13 to 18. In some embodiments, n is an integer from 14 to 18. In some embodiments, n is 15, 16, 17, or 18. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18.

[0042] In some embodiments of compounds of formula I, II, III, or IV, each R 5 Independently, it is H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, each R 5 Independently, it is H, C1-C3 alkyl, halogroup, or C1-C3 haloalkyl. In some embodiments, each R 5 Independently, it is H, C1-C3 alkyl, or halogroup. In some embodiments, each R... 5 Independently, it is an H or C1-C3 alkyl group. In some embodiments, each R... 5 Independently, it is H, methyl, or ethyl. In some embodiments, each R... 5Independently, it is either H or methyl. In some embodiments, each R 5 Independently H or ethyl. In some embodiments, each R 5 For H. In some implementations, each R 5 For methyl. In some embodiments, each R 5 It is an ethyl group.

[0043] In some embodiments of the compounds of formulas I, II, III, and IV, each R 4 Independently, it is H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, each R 4 Independently, it is H, C1-C3 alkyl, halogroup, or C1-C3 haloalkyl. In some embodiments, each R 4 Independently, it is H, C1-C3 alkyl, or halogroup. In some embodiments, each R... 4 Independently, it is an H or C1-C3 alkyl group. In some embodiments, each R... 4 Independently, it is H, methyl, or ethyl. In some embodiments, each R... 4 For H. In some implementations, each R 4 For methyl. In some embodiments, each R 4 It is an ethyl group.

[0044] In some embodiments, compounds of formula I, II, III, or IV have formula V: Formula V.

[0045] In some embodiments, compounds of formula I, II, III, IV, or V have formula Va: Formula Va.

[0046] In some embodiments, compounds of formula I, II, III, IV, or V have formula Vb: Formula Vb.

[0047] In some embodiments of compounds of formula I, II, III, IV, V, Va, or Vb, R 3 It can be H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 It is H, C1-C3 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 It can be H, methyl, ethyl, propyl, or cyclopropyl. In some embodiments, R 3It can be H, methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R 3 For H. In some implementations, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is cyclopropyl.

[0048] In some embodiments of compounds of formula V, Va, or Vb, R 4 It can be H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R 4 It is H, C1-C3 alkyl, halogroup, or C1-C3 haloalkyl. In some embodiments, R 4 It is H, C1-C3 alkyl, or halogroup. In some embodiments, R 4 It is an H or C1-C3 alkyl group. In some embodiments, R 4 It is H, methyl, or ethyl. In some embodiments, R 4 For H. In some implementations, R 4 It is methyl. In some embodiments, R 4 It is an ethyl group.

[0049] In some embodiments of compounds of formula V, Va, or Vb, R 5 Independently, it is H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R 5 It is H, C1-C3 alkyl, halogroup, or C1-C3 haloalkyl. In some embodiments, R 5 It is H, C1-C3 alkyl, or halogroup. In some embodiments, R 5 It is an H or C1-C3 alkyl group. In some embodiments, R 5 It is H, methyl, or ethyl. In some embodiments, R 5 Independently, it is H or methyl. In some embodiments, R 5 Independently, it is H or ethyl. In some embodiments, R 5 For H. In some implementations, R 5 It is methyl. In some embodiments, R 5 It is an ethyl group.

[0050] In some embodiments, compounds of formula I, II, III, IV, V, Va, or Vb have compounds of formula VI: Formula VI.

[0051] In some embodiments, compounds of formula I, II, III, IV, V, Va, or VI have compounds of formula VIa: Formula VIa.

[0052] In some embodiments, compounds of formula I, II, III, IV, V, Vb, or VI have compounds of formula VIb: Formula VIb.

[0053] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 For C1-C 20 Alkyl, C3-C 10 Cycloalkyl groups, containing one, two, or three heteroatoms selected from N, O, and S, consisting of 4 to 6-membered heterocyclic groups, C6-C. 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 H, C1-C6 alkyl, C3-C 10 Cycloalkyl groups, containing one, two, or three heteroatoms selected from N, O, and S, consisting of 4 to 6-membered heterocyclic groups, C6-C. 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein when R 1 When R is not H, 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 For C1-C 20 Alkyl, C3-C 10 Cycloalkyl or a 5- to 6-membered heterocyclic group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 It is a C1-C6 alkyl group, C3-C 10 Cycloalkyl or a 5- to 6-membered heterocyclic group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 For C1-C 20 Alkyl, C3-C 10 cycloalkyl, C6-C10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 It is a C1-C6 alkyl group, C3-C 10 cycloalkyl, C6-C 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 For C1-C 20 Alkyl, C3-C 10 cycloalkyl or C6-C 10 Aryl; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 C1-C6 alkyl, C3-C 10 cycloalkyl or C6-C 10 Aryl; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 For C1-C 20 Alkyl or C6-C 10 Aryl; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 It is a C1-C6 alkyl or C6-C 10 Aryl; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 To be optionally controlled by one or two R 1A C1-C substituent 20 Alkyl group. In some embodiments, R 1 To be optionally controlled by one or two R 1A C1-C6 alkyl groups substituted with radicals.

[0054] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 To be optionally controlled by one or two R 1A C6-C substituent 10 Aryl. In some implementations, R 1It can be phenyl, naphthyl, thiophene, cyclohexyl, methyl, ethyl, or propyl.

[0055] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 It has not been replaced. In some implementations, R 1 By an R 1A Group substitution. In some embodiments, R 1 By two R 1A Group substitution. In some embodiments, each R 1A Independently, it is a C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, R 1A Independently, it is methyl, phenyl, chloro, fluorine, methoxy, cyano, or CF3. In some embodiments, two Rs on the same or adjacent carbons... 1A They are linked together to form a 3- to 6-membered cycloalkyl group or a 4- to 6-membered heterocyclic ring containing one, two, or three heteroatoms selected from N, S, and O. In some embodiments, two R atoms on the same or adjacent carbons... 1A They are linked together to form a 3- to 6-membered cycloalkyl group. In some embodiments, two R groups on the same or adjacent carbons... 1A They are linked together to form a 5-membered cycloalkyl group. In some embodiments, two R groups on the same or adjacent carbons... 1A They are linked together to form a 4- to 6-membered heterocyclic base ring containing one, two, or three heteroatoms selected from N, S, and O.

[0056] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 By an R 1A Group substitution. In some embodiments, R 1 By two R 1A Group substitution. In some embodiments, each R 1A Independently, it is a C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, each R 1A Independently, it is methyl, phenyl, chlorine, fluorine, methoxy, cyano, CHF2, or CF3. In some embodiments, each R 1A Independently, it is methyl, phenyl, chloro, fluorine, methoxy, cyano, or CF3. In some embodiments, each R 1A Independently, it is methyl, phenyl, chlorine, fluorine, methoxy, ethoxy, cyano, CHF2, or CF3. In some embodiments, each R 1AIndependently, it is methyl, phenyl, chlorine, fluorine, methoxy, ethoxy, cyano, or CF3. In some embodiments, each R 1A It is independently chlorine, fluorine, or cyanide. In some embodiments, at least one R 1A It is cyano. In some embodiments, at least one R 1A It is cyano, and another R 1A If present, it is either cyano or halogroup.

[0057] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 For C3-C 10 Cycloalkyl groups, containing one, two, or three heteroatoms selected from N, O, and S, consisting of 4 to 6-membered heterocyclic groups, C6-C. 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is surrounded by one or two R 1A Group substitution. In some embodiments, at least one R 1A It is cyano. In some embodiments, at least one R 1A It is cyano, and another R 1A If present, it is selected from the group consisting of: C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, at least one R 1A It is cyano, and another R 1A If present, it is either cyano or halogroup.

[0058] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 For C6-C 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is surrounded by one or two R 1A Group substitution. In some embodiments, at least one R 1A It is cyano. In some embodiments, at least one R 1A It is cyano, and another R 1A If present, it is selected from the group consisting of: C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, at least one R 1A It is cyano, and another R 1A If present, it is either cyano or halogroup.

[0059] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 It is a phenyl group; where R is a phenyl group. 1 The group is surrounded by one or two R 1A Group substitution. In some embodiments, at least one R 1A It is cyano. In some embodiments, at least one R 1A It is cyano, and another R 1A If present, it is selected from the group consisting of: C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, at least one R 1A It is cyano, and another R 1A If present, it is either cyano or halogroup.

[0060] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 for ; Each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 Independently, it is H, C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein R 1A2 R 1A3 and R 1A4 At least one of them is CN, and R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 At least three of them are H. In some implementations, each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 Independently H, halogroup, or cyanogroup; wherein R 1A2 R 1A3 and R 1A4 At least one of them is CN; and R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 At least three of them are H.

[0061] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1Choose the group consisting of the following items: H, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , -CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -C(CH3)2CH2CH3 and -C 16 H 33 .

[0062] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 Choose the group consisting of the following items: H, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , -CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -C(CH3)2CH2CH3 and C 16 H 33 .

[0063] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , -CH3, -C(CH3)3 and -C(CH3)2CH2CH3.

[0064] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 Choose from the following groups: , , , , , , , , , and .

[0065] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0066] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , and .

[0067] In some embodiments, compounds of formula I, II, III, IV, V, Va, or Vb have compounds of formula VII: Equation VII Each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 Independently, it is H, C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein R 1A2 R 1A3 and R 1A4 At least one of them is CN, and R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 At least three of them are H.

[0068] In some embodiments, compounds of formula I, II, III, IV, V, Va, or VII have compounds of formula VIIa: Formula VIIa Each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 Independently, it is H, C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein R 1A2 R 1A3 and R 1A4 At least one of them is CN, and R 1A1R 1A2 R 1A3 R 1A4 and R 1A5 At least three of them are H.

[0069] In some embodiments, compounds of formula I, II, III, IV, V, Vb, or VII have compounds of formula VIIb: Equation VIIb.

[0070] Each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 Independently, it is H, C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein R 1A2 R 1A3 and R 1A4 At least one of them is CN, and R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 At least three of them are H.

[0071] In some embodiments of compounds of formula VII, VIIa, or VIIb, each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 Independently H, halogroup, or cyanogroup; wherein R 1A2 R 1A3 and R 1A4 At least one of them is CN, and R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 At least three of them are H.

[0072] In some embodiments of compounds of formula VII, VIIa, or VIIb, R 3 It can be H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 It is H, C1-C3 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 It can be H, methyl, ethyl, propyl, or cyclopropyl. In some embodiments, R 3 It can be H, methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R 3For H. In some implementations, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is cyclopropyl.

[0073] In some embodiments of compounds of formula I, II, III, IV, V, Va, Vb, VI, VIa, VIb, VII, VIIa, or VIIb, R 6 and R 7 All are H. In some implementations, each R 6 and R 7 Independently, it is a -C(O)C1-C6 alkyl group. In some embodiments, each R 6 and R 7 Independently, it is an H or -C(O)C1-C3 alkyl group. In some embodiments, each R 6 and R 7 Independently, it is H or -C(O)CH(CH)2. In some implementations, R 6 For H, and R 7 It is a -C(O)C1-C6 alkyl group. In some embodiments, R 6 For H, and R 7 It is a -C(O)C1-C3 alkyl group. In some embodiments, R 6 For H, and R 7 It is -C(O)CH(CH)2. In some implementations, R 7 For H, and R 6 It is a -C(O)C1-C6 alkyl group. In some embodiments, R 7 For H, and R 6 It is a -C(O)C1-C3 alkyl group. In some embodiments, R 7 For H, and R 6 It is -C(O)CH(CH)2.

[0074] In some embodiments, compounds of formula I, II, III, IV, V, Va, Vb, VIa, or VIb are selected from the group consisting of: , , , , , , , , , , , , , , , , , And their pharmaceutically acceptable salts.

[0075] In some embodiments, compounds of formula I, II, III, IV, V, Va, Vb, VIa, or VIb are selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or their pharmaceutically acceptable salts.

[0076] In some embodiments, compounds of formula I, II, III, IV, V, Va, Vb, VIa, or VIb are selected from the group consisting of: , , and , or their pharmaceutically acceptable salts.

[0077] In some embodiments, compounds of formula I, II, III, IV, V, Va, Vb, VI, VIa, VIb, VII, VIIa, or VIIb are selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or their pharmaceutically acceptable salts.

[0078] In some embodiments, the compounds of formula I, II, III, IV, V, Va, Vb, VIa, VIb, VII, VIIa, or VIIb are selected from the group consisting of the compounds described in Examples 9, 16, 23, 26, 30, 31, 34 to 36, 39, 50, 51, 53, 54, 65 to 86, 93 to 96, 98 to 109, 111 to 119, and 124 to 130 below.

[0079] In some embodiments, the compounds of formula I, II, III, IV, V, Va, Vb, VIa, VIb, VII, VIIa, or VIb are selected from the group consisting of the compounds described in Examples 9, 16, 23, 26, 30, 31, 34 to 36, 39, 50, 51, 53, 65 to 71, 73, 75 to 82, 84, 86, 93 to 96, 98 to 103, 107 to 109, 111 to 113, 116 to 119, and 124 to 130, or pharmaceutically acceptable salts thereof.

[0080] Any reference to the compounds of the invention described herein also includes reference to their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable bases such as alkali metals or alkaline earth metals (e.g., Na₂O₃). + Li + K + Ca +2 and Mg +2 ), ammonium and NR4 + (where R is defined in this paper) salt. Pharmaceutically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.); (b) salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, ethanesulfonic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalactobionic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthyl ester, dihydroxynaphthyl salt, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.; and (c) salts formed by elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of hydroxyl compounds include the anion of the compound with a suitable cation such as Na+. + and NR4 + The combination of .

[0081] The compounds disclosed herein (e.g., compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb) and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystal polymorphism means the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can be caused by differences in crystal packing (packing polymorphism) or by differences in packing between different conformational isomers of the same molecule (conformational polymorphism). As used herein, crystal pseudopolymorphism means the ability of a hydrated or solvated compound to exist in different crystal structures. The pseudopolymorphs of the present invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformational isomers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, or IIIc and their pharmaceutically acceptable salts.

[0082] The compounds disclosed herein (e.g., compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb) and their pharmaceutically acceptable salts may also exist as amorphous solids. As used herein, an amorphous solid is a solid in which the atomic positions are not long-range ordered. This definition also applies when the crystal size is 2 nanometers or smaller. Additives (including solvents) may be used to produce the amorphous forms of the present invention. The present invention includes all amorphous forms of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb and their pharmaceutically acceptable salts.

[0083] For therapeutic purposes, the salts of the active ingredients of the compounds of the present invention will be pharmaceutically acceptable, i.e., they will be salts derived from pharmaceutically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be used, for example, to prepare or purify pharmaceutically acceptable compounds. All salts, whether or not derived from pharmaceutically acceptable acids or bases, are within the scope of the present invention.

[0084] It should also be understood that the compositions herein include the non-ionic and zwitterionic forms of the compounds of the present invention, and combinations thereof with stoichiometric amounts of water in hydrates.

[0085] It should be noted that this invention covers all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of compounds within the range of formulas I, II, III, IV, V, Va, Vb, VI, VIa, or VIb, and their pharmaceutically acceptable salts. All such mixtures of enantiomers and diastereomers are within the scope of this invention.

[0086] The compounds of the present invention, exemplified by formulas I, II, III, IV, V, Va, Vb, VI, VIa, or VIb, may have a chiral center, such as a chiral carbon or phosphorus atom. Therefore, the compounds of the present invention comprise racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and transisomers. Furthermore, the compounds of the present invention comprise optical isomers enriched or resolved at any or all asymmetric, chiral atoms. In other words, the chiral center, as apparent from the description, is provided as a chiral isomer or a racemic mixture. Both racemic mixtures and diastereomer mixtures, as well as isolated or synthesized individual optical isomers (substantially free of their enantiomers or diastereomer conjugates), are within the scope of the present invention. Racemic mixtures are isolated into their individual, substantially optically pure isomers by suitable techniques, for example, by isolating diastereomers formed with optically active auxiliaries (e.g., acids or bases), and subsequently converting the diastereomers back into the optically active substance. In most cases, the desired optical isomers are synthesized via stereospecific reactions, starting with appropriate stereoisomers of the desired raw materials.

[0087] The stereochemical definitions and conventions used in this article generally follow the editing of SP Parker, McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E and Wilen, S, Stereochemistry of Organic Compounds (John Wiley & Sons, Inc., New York, 1994) Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarization of light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the plane-polarized rotation symbol of the compound, where S, (-), or 1 indicates that the compound is levorotatory, while compounds prefixed with R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are generally called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur without stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0088] In some cases, the compounds of the present invention may also exist as tautomers. Although only one delocalized resonance structure can be described, all such forms are considered within the scope of the present invention. For example, for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazolium systems, olefin-amine tautomers may exist, and all their possible tautomer forms are within the scope of the present invention.

[0089] Any formula or structure given herein, including compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, is also intended to represent the unlabeled form and isotopically labeled form of the compound. Isotopically labeled compounds have the structure described by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35S, 36 Cl and 125 I. Various isotope-labeled compounds disclosed herein, such as those in which radioactive isotopes such as 3 H, 13 C and 14 C is incorporated. These isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or for radiation therapy of patients.

[0090] This disclosure also includes compounds of Formula I, wherein one to x hydrogen atoms bonded to carbon atoms are replaced by deuterium, where x is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore used to prolong the half-life of any compound of Formula I when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). In view of this disclosure, such compounds are synthesized by methods known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0091] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, or by following the procedures disclosed in the examples and formulations described below. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I.

[0092] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means that atom represents any stable isotope. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position is understood to be hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means that deuterium is represented.

[0093] Whenever a compound described herein is substituted with more than one of the same designated groups (e.g., “R” or “R”), it should be understood that these groups may be the same or different, i.e., each group is chosen independently.

[0094] Waveform, It indicates the position where a covalent bond is attached to an adjacent substructure, group, part, or atom.

[0095] IV. Pharmaceutical Preparations The compounds disclosed herein (e.g., compounds of formulas I, II, III, IV, V, Va, Vb, VIa, and VIb) can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and are typically isotonic when intended for delivery by non-oral administration. All formulations may optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH range of the formulation is from about 3 to about 11, but is typically from about 7 to 10. In some embodiments, the pH range of the formulation is from about 2 to about 5, but is typically from about 3 to 4.

[0096] While the compounds of this disclosure (“active ingredients”) can be administered alone, they are preferably provided as pharmaceutical formulations. Both veterinary and human formulations of the present invention comprise at least one active ingredient as defined above, together with one or more of its acceptable carriers and optional other therapeutic ingredients, particularly those additional therapeutic ingredients discussed herein. The carrier must be “acceptable,” meaning it is compatible with the other components of the formulation and physiologically harmless to the recipient.

[0097] These formulations include those suitable for the aforementioned routes of administration. Formulations are readily available in unit dosage forms and can be prepared by any suitable method known in the pharmaceutical field. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve the step of associating the active ingredient with a carrier constituting one or more auxiliary ingredients. Generally, formulations are prepared by uniformly and tightly associating the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then, if desired, shaping the product.

[0098] In some embodiments, the disclosed compounds have pharmacokinetic properties suitable for oral administration (e.g., good oral bioavailability). In some embodiments, the formulations of the present invention are suitable for oral administration and are present as discrete units such as capsules, granules, or tablets each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be administered as pills, granules, or pastes.

[0099] In some embodiments, tablets are made by compression or molding, optionally using one or more excipients. Compressed tablets are prepared by compressing an active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets are prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored, and optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0100] For infections of the eyes or other external tissues (e.g., the mouth and skin), the formulation is applied as a topical ointment or cream containing active ingredients in amounts, for example, from 0.075 to 20% w / w (including active ingredients in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably from 0.2% w / w to 15% w / w, and most preferably from 0.5% w / w to 10% w / w. When formulated as an ointment, the active ingredient may be used with a paraffin base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water emulsion base.

[0101] If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w polyols, i.e., alcohols having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG400), and mixtures thereof. Topical formulations may ideally include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0102] The oil phase of the emulsion of the present invention can be composed of known components in a known manner. While this phase may consist only of emulsifiers (or simply emulsifiers), it ideally includes at least one emulsifier with fats or oils, or a mixture of both. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. It is also preferable to include both oils and fats. Emulsifiers, with or without stabilizers, together constitute a so-called emulsified wax, and the wax, together with the oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the ointment formulation.

[0103] Emulsifiers and emulsion stabilizers suitable for the formulations of this invention include Tween. ® 60. Span ® 80. Cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Other emulsifiers and emulsion stabilizers suitable for the formulations of this invention include Tween. ® 80.

[0104] The appropriate oil or fat is selected for the formulation based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining, and washable product with a suitable consistency to prevent leakage from tubes or other containers. Straight-chain or branched monoalkyl or dialkyl esters can be used, such as diisohexadecanate, isohexadecanate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or mixtures of branched esters known as Crodamol CAP, the last three being preferred esters. These esters can be used alone or in combination, depending on the desired properties. Alternatively, high-melting-point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, can be used.

[0105] Pharmaceutical formulations according to the invention comprise compounds according to the invention, as well as one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when intended for oral use, they can be prepared as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0106] Formulations intended for oral use may also be available as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0107] The aqueous suspension of the present invention contains an active substance mixed with excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of olefinic oxygen and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), and condensation products of ethylene oxide and esters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin. Other non-limiting examples of suspending agents include cyclodextrin. In some embodiments, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol. ® .

[0108] Oily suspensions can be prepared by suspending the active ingredients in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those mentioned above) and flavoring agents may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

[0109] The dispersible powders and granules of the present invention, suitable for preparing aqueous suspensions by adding water, provide an active ingredient that can be mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0110] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth; naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, or coloring agents.

[0111] The pharmaceutical compositions of the present invention may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as solutions in 1,3-butanediol), or prepared as lyophilized powders. Acceptable solvents and media are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectable formulations. Acceptable solvents and media are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0112] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 1000 mg of active material, compounded with an appropriate and convenient amount of carrier material, which may vary between approximately 5% to approximately 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosages. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 to 500 µg of active ingredient per milliliter to allow for the infusion of an appropriate volume at a rate of approximately 30 mL / hr.

[0113] Formulations suitable for topical application to the eyes also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly in an aqueous solution of the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w.

[0114] Preparations suitable for topical application in the oral cavity include lozenges containing flavoring active ingredients, typically sucrose and gum arabic or tragacanth; tablets containing inert active ingredients, such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing the active ingredients in a suitable liquid carrier.

[0115] Formulations for rectal administration may be available as suppositories with a suitable matrix, such as cocoa butter or salicylates.

[0116] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or intranasal administration have particle sizes, for example, in the range of 0.1 micrometers to 500 micrometers, such as 0.5 micrometers, 1 micrometer, 30 micrometers, 35 micrometers, etc., and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as dry powders. In some embodiments, the compounds used herein are formulated and administered as nebulized formulations. In some embodiments, the compounds used herein are formulated for delivery via a face mask. In some embodiments, the compounds used herein are formulated for delivery via a face mask inhaler.

[0117] Preparations suitable for vaginal application may be available as pessaries, tampons, creams, gels, pastes, foams or sprays, and contain, in addition to the active ingredient, a suitable carrier known in the art.

[0118] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes to make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0119] The formulation is present in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred single-dose formulations are those containing a daily dose or a sub-daily dose of the active ingredient as described above, or a suitable portion thereof.

[0120] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art related to the type of formulation discussed, such as flavoring agents suitable for oral administration.

[0121] The present invention further provides a veterinary drug composition comprising at least one active ingredient as defined above and its veterinary drug carrier.

[0122] Veterinary drug carriers are materials that can be used to administer compositions and can be solid, liquid, or gaseous materials. They are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary drug compositions can be administered orally, parenterally, or by any other desired route.

[0123] The compounds of the present invention are used to provide controlled-release pharmaceutical formulations (“controlled-release formulations”) containing one or more of the compounds of the present invention as active ingredients, wherein the release of the active ingredient is controlled and regulated to allow administration at a lower frequency or to improve the pharmacokinetic or toxicological characteristics of a given active ingredient.

[0124] V. Reagent Kit This document also provides kits that include the compounds disclosed herein (e.g., compounds of formula I, II, III, IV, V, Va, Vb, VI, VIa, or VIb), their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or tautomers. In some embodiments, the kits described herein may include a label and / or instructions for use to treat a disease or condition in a subject (e.g., a human) in need of the compound. In some embodiments, the disease or condition is a viral infection.

[0125] In some embodiments, the kit may also include instructions for use of one or more additional therapeutic agents and / or instructions for using additional therapeutic agents in combination with compounds of Formula I to treat a disease or condition of a subject in need (e.g., a human).

[0126] In some embodiments, the kits provided herein include individual dose units of the compound described herein or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvation thereof. Examples of individual dose units may include pills, tablets, capsules, pre-filled syringes or syringes, IV bags, inhalers, nebulizers, etc., each comprising a therapeutically effective amount of the compound in question or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvation thereof. In some embodiments, the kit may contain a single dose unit, and in other embodiments, multiple dose units are present, such as the number of dose units required for a specified regimen or cycle.

[0127] Articles are also provided, comprising: a compound of formula I or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof; and a container. In some embodiments, the container for the articles is a vial, can, ampoule, pre-filled syringe, blister pack, can, canister, bottle, box, intravenous bag, inhaler, or nebulizer.

[0128] VI. Application One or more compounds of the present invention may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, local (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). In some embodiments, the compounds disclosed herein are administered by inhalation or intravenous administration. It should be understood that preferred routes may vary depending on, for example, the recipient's condition.

[0129] In the method of treating viral infection of the present invention, the compounds of the present invention can be administered at any time to persons who may be exposed to the virus or who already have a viral infection. In some embodiments, the compounds of the present invention can be administered prophylactically to persons who have been in contact with or are at risk of contact with persons who have been in ...

[0130] In some implementations, the methods disclosed herein include event-driven administration of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject.

[0131] As used herein, the terms “event-driven” or “event-driven administration” mean that a compound of formula I or a pharmaceutically acceptable salt thereof is administered (1) prior to an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more prior to the event); and / or (2) during an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (or more than one repeated event); and / or (3) after an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (or after the final event in a series of repeated events). In some embodiments, event-driven administration is performed before the subject is exposed to the virus. In some embodiments, event-driven administration is performed after the subject is exposed to the virus. In some embodiments, event-driven administration is performed both before and after the subject is exposed to the virus.

[0132] In some embodiments, the methods disclosed herein involve administration, for example as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP), before and / or after an event that will expose an individual to a virus or otherwise increase the individual's risk of acquiring a viral infection. In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0133] In some implementations, a compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject prior to exposure to the virus.

[0134] In some implementations, a compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject before and after exposure to the virus.

[0135] In some implementations, a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject after exposure to the virus.

[0136] Examples of event-driven dosing regimens include administering a compound of Formula I or a pharmaceutically acceptable salt thereof 24 to 2 hours before exposure to the virus, followed by administering a compound of Formula I or a pharmaceutically acceptable salt thereof every 24 hours during exposure, followed by further administration of a compound of Formula I or a pharmaceutically acceptable salt thereof after the last exposure, and a final administration of a compound of Formula I or a pharmaceutically acceptable salt thereof 24 hours later.

[0137] Another example of an event-driven dosing regimen involves administering a compound of Formula I or a pharmaceutically acceptable salt thereof within 24 hours prior to viral exposure, followed by daily administration during exposure, and then a final administration approximately 24 hours after the last exposure (which may be an increased dose, such as a double dose).

[0138] The effective dose of the active ingredient depends at least on the nature of the condition being treated, its toxicity, whether the compound is used prophylactically or against an active viral infection, the delivery method, and the pharmaceutical formulation, and will be determined by clinicians using routine dose-escalation studies. The dose is expected to be from about 0.0001 mg / kg body weight to about 100 mg / kg body weight daily; typically, from about 0.01 mg / kg body weight to about 10 mg / kg body weight daily; more typically, from about 0.01 mg / kg body weight to about 5 mg / kg body weight daily; and most typically, from about 0.05 mg / kg body weight to about 0.5 mg / kg body weight daily. For example, the candidate daily dose range for an adult weighing approximately 70 kg would be from 1 mg to 1000 mg, preferably from 5 mg to 500 mg, and could be in single or multiple doses.

[0139] Any suitable time period for applying the compounds of the present invention has been considered. For example, application may last from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. Application may also last from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer application periods have also been considered.

[0140] In some embodiments, the compound disclosed herein is administered once daily. In some embodiments, the compound disclosed herein is administered every other day. In some embodiments, the compound disclosed herein is administered once weekly. In some embodiments, the compound disclosed herein is administered twice weekly.

[0141] In some embodiments, one or more of the compounds disclosed herein are administered once daily. The once-daily dose may be administered as needed, for example, for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to one month, or longer. In some embodiments, the once-daily dose is administered for up to 20 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6 days, up to 4 days, up to 3 days, up to 2 days, or 1 day.

[0142] In some embodiments, one or more of the compounds disclosed herein are administered once daily for about 6 to 12 days, for example, about 8 to 10 days. In some embodiments, the one or more compounds are administered once daily for about 9 days. In some embodiments, the one or more compounds are administered once daily for about 10 days. In some embodiments, about 50 mg to 150 mg of one or more of the compounds disclosed herein is administered once daily for about 5 to 12 days, for example, about 10 days. In some embodiments, about 100 mg of one or more of the compounds disclosed herein is administered once daily for about 5 to 12 days, for example, about 10 days.

[0143] VII. Instructions for Use This disclosure also provides a method for treating or preventing viral infection in a subject (e.g., a person) in need, the method comprising administering the compound described herein to the subject.

[0144] In some embodiments, this disclosure provides a method for treating a viral infection in a subject (e.g., a person) in need, the method comprising administering the compound described herein to the subject in need.

[0145] In some embodiments, this disclosure provides a method for treating or preventing viral infection in a subject (e.g., a person) in need, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or preventative agent.

[0146] In some embodiments, this disclosure provides a method for treating a viral infection in a subject (e.g., a person) in need, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0147] In some embodiments, this disclosure provides methods for inhibiting viral polymerases in cells, methods comprising contacting virus-infected cells with compounds disclosed herein, thereby inhibiting the viral polymerase.

[0148] In some embodiments, this disclosure provides methods for inhibiting viral polymerases in cells, methods comprising contacting virus-infected cells with the compounds disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0149] This document also provides for the use of the disclosed compounds in treating or preventing viral infections in subjects in need. For example, this document provides for the use of the disclosed compounds in treating viral infections in subjects in need.

[0150] In some embodiments, the viral infection is a paramyxoviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a paramyxoviridae infection in a subject (e.g., a human) of need, comprising administering the disclosed compounds to the subject. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles, mumps, and parainfluenza viruses. In some embodiments, the paramyxoviridae virus is Sosuga virus.

[0151] In some embodiments, the viral infection is a pulmonaviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a pulmonaviridae virus infection, the method comprising administering to the person a compound provided herein. Pulmonaviridae viruses include, but are not limited to, respiratory syncytial virus (RSV) and human metapneumovirus (HMV). In some embodiments, the pulmonaviridae virus infection is a respiratory syncytial virus (RSV) infection. In some embodiments, the pulmonaviridae virus infection is a human metapneumovirus (HMV) infection.

[0152] In some embodiments, this disclosure provides compounds disclosed herein for treating pulmonary viral infections in persons of need. In some embodiments, the pulmonary viral infection is respiratory syncytial virus infection. In some embodiments, the pulmonary viral infection is human metapneumovirus infection.

[0153] In some embodiments, this disclosure provides a method for treating RSV infection in a person of need, the method comprising administering to the person a compound provided herein. In some embodiments, the person has a chronic respiratory syncytial virus infection. In some embodiments, the person is acutely infected with RSV.

[0154] In some embodiments, a method for inhibiting RSV replication is provided, wherein the method includes administering the disclosed compound to a person in need, wherein the administration is by inhalation.

[0155] In some embodiments, this disclosure provides a method for reducing viral load associated with RSV infection, wherein the method includes administering the disclosed compounds to a person infected with RSV.

[0156] In some embodiments, the viral infection is a picornaviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a picornaviridae virus infection, the method comprising administering the disclosed compound to the person. Picornaviridae viruses are heterogeneous enteroviruses that cause a wide range of infections, including herpetic pharyngitis, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), nonparalytic poliomyelitis-like syndrome, epidemic pleuropneumonia (an acute, febrile, infectious disease that typically occurs during epidemics), hand-foot-mouth disease, pancreatitis in children and adults, and severe myocarditis. In some embodiments, the picornaviridae virus infection is a human rhinovirus infection. In some embodiments, the picornaviridae virus infection is an enterovirus infection. In some implementations, piconenoviral infections are selected from the group consisting of: Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

[0157] In some embodiments, this disclosure provides compounds for treating microribonucleoviridae virus infections in people of need. In some embodiments, the microribonucleoviridae virus infection is a human rhinovirus infection.

[0158] In some embodiments, the viral infection is a flaviviridae virus infection. Therefore, in some embodiments, this disclosure provides a method of treating a person in need of a flaviviridae virus infection, the method comprising administering the compound described herein to that person. Representative flaviviridae viruses include, but are not limited to, dengue fever, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the flaviviridae virus infection is dengue virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile virus infection. In some embodiments, the flaviviridae virus infection is Zika virus infection. In some embodiments, the flaviviridae virus infection is Japanese encephalitis virus infection. In some embodiments, the flaviviridae virus infection is hepatitis C virus infection.

[0159] In some embodiments, this disclosure provides the use of the compounds disclosed herein for treating flaviviridae virus infections in persons of need. In some embodiments, the flaviviridae virus infection is dengue virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile virus infection. In some embodiments, the flaviviridae virus infection is Zika virus infection. In some embodiments, the flaviviridae virus infection is hepatitis C virus infection.

[0160] In some embodiments, the viral infection is a filoviridae virus infection. Therefore, in some embodiments, this document provides a method for treating a person in need of a filoviridae virus infection, the method comprising administering to that person a compound disclosed herein. Representative filoviridae viruses include, but are not limited to, Ebola virus (variants Zaire, Bundibugio, Sudan, Tai Forest, or Reston) and Marburg virus. In some embodiments, the filoviridae virus infection is an Ebola virus infection. In some embodiments, the filoviridae virus infection is a Marburg virus infection.

[0161] In some embodiments, this disclosure provides compounds for treating filoviridae virus infections in people of need. In some embodiments, the filoviridae virus infection is Ebola virus infection. In some embodiments, the filoviridae virus infection is Marburg virus infection.

[0162] In some embodiments, the viral infection is a coronavirus infection. Therefore, in some embodiments, this document provides a method for treating a person in need of a coronavirus infection, wherein the method comprises administering to the person a compound provided herein. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus having at least 70% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 80% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 90% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 95% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0163] In some embodiments, this disclosure provides compounds for treating coronavirus infections in people of need. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection (COVID19).

[0164] In some embodiments, the viral infection is an infection of a arenaviridae virus. Therefore, in some embodiments, this disclosure provides a method for treating an arenaviridae virus infection in a person of need, the method comprising administering to the person a compound disclosed herein. In some embodiments, the arenaviridae virus infection is a lassa virus infection or a juniper virus infection.

[0165] In some embodiments, this disclosure provides compounds for treating arenaviridae virus infections in persons in need. In some embodiments, the arenaviridae virus infection is lassa virus infection or Junin virus infection.

[0166] In some implementations, the viral infection is an orthomyxovirus infection, such as an influenza virus infection. In some implementations, the viral infection is an influenza A virus, influenza B virus, or influenza C virus infection.

[0167] In some embodiments, the viral infection is a Nairo virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a Nairo virus infection, the method comprising administering to that person a compound disclosed herein. In some embodiments, the Nairo virus infection is a Crimean-Congo hemorrhagic fever virus infection. In some embodiments, the Nairo virus infection is a Hazara virus infection.

[0168] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a virus, together with one or more adjunctive therapeutic agents. The adjunctive therapeutic agents can be administered to the infected individual simultaneously with, before, or after the administration of the compounds of this disclosure.

[0169] VIII. Combination Therapy The compounds described herein may also be used in combination with one or more additional therapeutic or prophylactic agents. Therefore, this document also provides methods for treating viral infections in subjects of need, wherein these methods include administering to the subject the disclosed compounds and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents. In some embodiments, these methods include administering to the subject the disclosed compounds and a therapeutically effective amount of one or more additional therapeutic agents.

[0170] In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent may be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of: 5-substituted 2'-deoxyuridine analogs, nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogs, acyclic nucleoside phosphonate analogs, HCV NS5A / NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulants, oligonucleotides, antimitotic inhibitors, and combinations thereof.

[0171] In some embodiments, the adjunctive therapeutic agent is a 5-substituted 2'-deoxyuridine analogue. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of iodouridine, trifluorouridine, brovudine [BVDU], and combinations thereof.

[0172] In some embodiments, the adjunctive therapeutic agent is a nucleoside analog. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: vidarabine, entecavir (ETV), telmivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the adjunctive therapeutic agent is favipiravir, ribavirin, galidivir, β-D-N4-hydroxycytidine, or combinations thereof.

[0173] In some embodiments, the adjunctive therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the adjunctive therapeutic agent is phosphonoformic acid or phosphonoacetic acid. In some embodiments, the adjunctive therapeutic agent is phosphonoformic acid.

[0174] In some implementations, the adjunctive therapeutic agent is a nucleoside reverse transcriptase inhibitor. In some implementations, the antiviral agent is zidovudine, didanoxin, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, or combinations thereof.

[0175] In some implementations, the adjunctive therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some implementations, the antiviral agent is selected from the group consisting of: nevirapine, delavudine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0176] In some embodiments, the adjunctive treatment is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, cobistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the adjunctive treatment agent is selected from the group consisting of: voxiprevir, anavipiravir, boprevir, paliprevir, cimetidine, telaprevir, vaniprevir, gzopiclone, ribavirin, danoprevir, fadaprevir, vedoprevir, sovaprevir, deldeprefir, nalaprevir, and combinations thereof. In some embodiments, the adjunctive treatment agent is selected from the group consisting of: voxiprevir, anavipiravir, boprevir, paliprevir, cimetidine, telaprevir, vaniprevir, gzopiclone, and combinations thereof.

[0177] In some embodiments, the adjunctive therapeutic agent is an integrase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: ritagvir, dulutegravir, erteiravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: bicagvir, ritagvir, dulutegravir, cabotevir, erteiravir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: bicagvir, dulutegravir, and cabotevir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is bicagvir.

[0178] In some implementations, the adjunctive therapeutic agent is an entry inhibitor. For example, in some implementations, the adjunctive therapeutic agent is selected from the group consisting of: docosanol, entfuvirtide, maraviro, ipalizumab, fosetexavir, leronlimab, ipalizumab, fosetexavir, leronlimab, palizumab, intravenous respiratory syncytial virus immunoglobulin [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella-zoster immunoglobulin [VZIG], and combinations thereof.

[0179] In some embodiments, the adjunctive therapeutic agent is an acyclovir analogue. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valacyclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0180] In some embodiments, the adjunctive therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, erteiravir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: cidofovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof.

[0181] In some embodiments, the adjunctive therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the adjunctive therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the adjunctive therapeutic agent is an NS5A protease inhibitor. In some embodiments, the adjunctive therapeutic agent is a nucleoside / nucleotide type NS5B polymerase inhibitor. In some embodiments, the adjunctive therapeutic agent is a non-nucleoside type NS5B polymerase inhibitor. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, obbitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, anavipiravir, cimetidine, paliprevir, ritonavir, elbasvir, gzopivir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, obbitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0182] In some embodiments, the adjunctive therapeutic agent is an influenza virus inhibitor. In some embodiments, the adjunctive therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: amantadine, adalimumidine, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: zanamivir, oseltamivir, peramivir, lanimivir caprylate, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: ribavirin, favipiravir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: amantadine, adalimumidine, arbidol (uminovir), baloxavirmabosiform, oseltamivir, peramivir, ingavirin, lanimivir caprylate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some implementations, the adjunctive treatment agent is selected from the group consisting of: amantadine, adalimumab, zanamivir, oseltamivir, peramivir, lanimivir caprylate, ribavirin, favipiravir, and combinations thereof.

[0183] In some embodiments, the adjunctive therapeutic agent is interferon. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon α1b, interferon α2a, interferon α2b, pegylated interferon alfacon 1, pegylated interferon α1b, pegylated interferon α2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon α1b, interferon α2a, interferon α2b, pegylated interferon α2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: interferon alfacon 1, pegylated interferon α2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some implementations, the additional therapeutic agent is pegylated interferon α-2a, pegylated interferon α-2b, or a combination thereof.

[0184] In some embodiments, the adjunctive therapeutic agent is an immunostimulant. In some embodiments, the adjunctive therapeutic agent is an oligonucleotide. In some embodiments, the adjunctive therapeutic agent is an antimitotic inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: fomivirex, prodafiloyl, imiquimod, phenelzine, and combinations thereof.

[0185] In some implementations, the adjunctive treatment agent is selected from the group consisting of: bexifovir, nitrozonide, REGN2222, doravirin, sofosbuvir, velpatasvir, daclatasvir, anavipiravir, becabuvir, FV100, and lemetmovir, as well as combinations thereof.

[0186] In some embodiments, the adjunctive treatment is a pharmaceutical agent used to treat RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or pretovir.

[0187] In some embodiments, the adjunctive therapeutic agent is a drug for treating picornaviruses. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, L-butyrosine sulfoxide, Py-11, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the adjunctive therapeutic agent is rupinetrivir.

[0188] In some implementations, the adjunctive treatment is a drug used to treat malaria. In some implementations, the adjunctive treatment is chloroquine.

[0189] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: hydroxychloroquine, chloroquine, artemether, benzyl fluorene, atovaquinone, chloroguanidine, tafenoxanol, phenazine, artemisinin ester, dihydroartemisinin, piperaquine, artemisinin ester, amodiaquine, phenazine, artemisinin ester, halofantroline, quinine sulfate, mefloquine, sorimycin, pyrimethamine, MMV-390048, ferrocene chloroquine, artemisinin mesylate, ganaplacide, DSM-265, cipargamine, artemisinone, and combinations thereof.

[0190] In some implementations, the adjunctive therapeutic agent is a drug for treating coronavirus. In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: IFX-1, FM-201, CYNK-001, DPP4-Fc, leopard frog enzyme, naftomostat, LB-2, AM-1, antiviral porin, and combinations thereof.

[0191] In some implementations, the adjunctive treatment is an agent used to treat Ebola virus. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: ribavirin, palilizumab, motavizumab, RSV-IGIV (RespiGam). ®MEDI-557, A-60444, MDT-637, BMS-433771, Amiodarone, Dronedarone, Verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), Favipiravir (also known as T-705) Ebola vaccines include, but are not limited to, Avigan, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinoline[8,7-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, bromidedofovir, Vaxart adenovirus vector 5-based Ebola vaccines, Ad26-ZEBOV, FiloVax vaccines, GOVX-E301, GOVX-E302, Ebola virus entry inhibitors (NPC1 inhibitors), rVSV-EBOV, and combinations thereof. In some embodiments, additional therapeutic agents are ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0192] In some embodiments, the adjunctive therapeutic agent is a pharmaceutical agent for treating HCV. In some embodiments, the adjunctive therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, radalbuvir, MK-0608, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: such as GS-9256, vedoprevir, voxiprevir, and combinations thereof.

[0193] In some implementations, the adjunctive therapy is an NS5A inhibitor. For example, in some implementations, the adjunctive therapy is selected from the group consisting of: ledipasvir, velpatasvir, and combinations thereof.

[0194] In some implementations, the adjunctive treatment is an anti-HBV agent. For example, in some implementations, the adjunctive treatment is tenofovir disoproxil fumarate and emtricitabine or a combination thereof. Examples of adjunctive anti-HBV agents include, but are not limited to, α-hydroxytophenone, amadoxovir, duroquinol, β-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, evitabine, ezetimibe, cyclosporine A, gentiopicroside, HH-003, hapratide, JNJ-56136379, nitrozonide, birenapa, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mirtovalidone, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, caryophyllin, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, berberine, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007, sofosbuvir, ledipasvir, UB-551, and ZH-2N, as well as US20150210682 (Roche), US The compounds disclosed in Roche are 2016 / 0122344, WO2015173164, WO2016023877, US2015252057A, WO16128335A1, WO16120186A1, US2016237090A, WO16107833A1, WO16107832A1, US2016176899A, WO16102438A1, WO16012470A1, US2016220586A, and US2015031687A. In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir (HEPSERA). ®), Emtriva ® ), tenofovir disoproxil fumarate (VIREAD) ® Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide diterpenoid, tenofovir alafenamide diterpenoid, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir (BARACLUDE) ® Entecavir maleate, telbivudine (TYZEKA) ® ), fenosvir, pradefovir, clavudine, ribavirin, lamivudine (EPIVIR-HBV) ® The following are listed as additional treatments: zizonidine, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate aspartate, tenofovir disoproxil fumarate orotate, and HS-10234. In some implementations, the additional treatment is an HBV capsid inhibitor.

[0195] In some embodiments, the adjunctive therapeutic agent is a pharmaceutical agent used to treat HIV. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogs, and combinations thereof.

[0196] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), and cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0197] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0198] In some implementations, the adjunctive treatment is an HIV combination drug. Examples of HIV combination drugs include, but are not limited to, ATRIPLA. ® (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); BIKTARVY ® (Bicagvir, Emtricitabine, and Tenofovir Alambutamide); COMPLERA ® (EVIPLERA) ® Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (Ertiravir, Cobistat, Tenofovir Disoproxil Fumarate, and Emtricitabine); TRUVADA ® (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY ® (Tenofovir alafenamide and emtricitabine); ODEFSEEY ® (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA ® (Tenofovir alafenamide, emtricitabine, cobistat, and erteiravir); SYMTUZA ® (Direravir, Tenofovir disoproxil fumarate, Emtricitabine, and Cobistat); SYMFI TM (Efavirenz, Lamivudine, and Tenofovir disoproxil fumarate); CIMDU TM (Lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobistat and ertiravir; COMBIVIR ® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM ® (LIVEXA) ® Abacavir sulfate and lamivudine; ABC+3TC); KALETRA ® (ALUVIA) ®(Lopinavir and ritonavir); TRIUMEQ ® (Drutvir, Abacavir, and Lamivudine); TRIZIVIR ® (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Dermiravir and cobistat; Dulutegravir and rilpivirine; Dulutegravir and rilpivirine hydrochloride; Dulutegravir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Rytegvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Dapivirine + levonorgestrel, Dulutegravir + lamivudine; Durutvir + Emtricitabine + Tenofovir Alamenosamine, Alfavirine + Emtricitabine + Tenofovir Disoproxil Fumarate, Lamivudine + Abacavir + Zidovudine, Lamivudine + Abacavir, Lamivudine + Tenofovir Disoproxil Fumarate, Lamivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine, Tenofovir Disoproxil Fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine, and Lamivudine.

[0199] In some implementations, the adjunctive treatment is an HIV protease inhibitor. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, cobistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, and cobistat. In some implementations, the adjunctive treatment agent is selected from the group consisting of: ampravir, atazanavir, becanavir, deruravir, fossavir, fossavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0200] In some implementations, the adjunctive treatment is an HIV integrase inhibitor. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: retigvir, ertirapvir, dulutegravir, abacavir, lamivudine, bicagvir, and combinations thereof. In some implementations, the adjunctive treatment is bicagvir. In some implementations, the adjunctive treatment is selected from the group consisting of: bicagvir, ertirapvir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine kinase inhibitors, tyrosine kinase inhibitor derivatives, quercetin, quercetin derivatives, retigvir, dulutegravir, JTK-351, bicagvir, AVX-15567, BM. S-986197, Cabotevir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, Cabotevir, and combinations thereof.

[0201] In some implementations, the adjunctive therapy is an HIV entry inhibitor. For example, in some implementations, the adjunctive therapy is selected from the group consisting of entreviride, maraviro, and combinations thereof. Other examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 linker inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include apravirone, vevicvirone, maraviro, cenicriviroc, leronlimab (PRO-140), adatabvir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include praxavir, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0202] In some embodiments, the adjunctive therapeutic agent is an HIV nucleoside reverse transcriptase inhibitor. In some embodiments, the adjunctive therapeutic agent is an HIV non-nucleoside reverse transcriptase inhibitor. In some embodiments, the adjunctive therapeutic agent is an acyclic nucleoside phosphonate analog. In some embodiments, the adjunctive therapeutic agent is an HIV capsid inhibitor.

[0203] In some implementations, the adjunctive therapy is an HIV nucleoside or nucleotide reverse transcriptase inhibitor. For example, the adjunctive therapy is selected from the group consisting of: adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and VIDEX. ® and VIDEX EC ® (Didanoxin, DDL), Abacavir, Abacavir sulfate, Alovudine, Alitabin, Cinovine, Didanoxin, Avtabin, Fetinavivir, Fosalvudine Tidoxil, CMX-157, Dapirine, Doravirine, Etravirine, OCR-5753, Tenofovir disoproxil orotate, Fosalvudine Tidoxil, Islatravir, Lamivudine, Phosphazid, Stavudine, Zacitabine, Zidovudine, Rovafovir-Etalaflavinamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0204] In some implementations, the adjunctive therapy is an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor. For example, the adjunctive therapy is selected from the group consisting of: dapirine, delavudine, delavudine mesylate, doravirine, efavirenz, ectrevirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, favirine rilp (VM-1500), and combinations thereof.

[0205] In some implementations, the additional therapeutic agent is selected from ATRIPLA. ® (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); COMPLERA ® (EVIPLERA) ® Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (Ertiravir, Cobistat, Tenofovir Disoproxil Fumarate, and Emtricitabine); TRUVADA® (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY ® (Tenofovir alafenamide and emtricitabine); ODEFSEEY ® (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA ® (Tenofovir alafenamide, emtricitabine, cobistat, and ertiravir); Adefovir; Adefovir dipivoxil; Cobistat; Emtricitabine; Tenofovir; Tenofovir disoproxil fumarate; Tenofovir disoproxil fumarate; Tenofovir alafenamide hemifumarate; TRIUMEQ ® (Durutexvir, Abacavir, and Lamivudine); Durutvir, Abacavir Sulfate, and Lamivudine; Rettagvir; Rettagvir and Lamivudine; Maraviro; Enfuvir peptide; ALUVIA ® (KALETRA) ® (Lopinavir and ritonavir); COMBIVIR ® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM ® (LIVEXA) ® Abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR ® (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derreravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertirapvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derreravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefernavir; Nefernavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efavirex, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate.

[0206] In some implementation schemes, the adjunctive treatment agent is selected from the group consisting of: colistin, penrubocin, ateband, betasine, epirubocin, epoprosetnol, vaportide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bicagvir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0207] In some implementations, the adjunctive therapeutic agent is an inhibitor of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). For example, in some implementations, the adjunctive therapeutic agent is selected from the group consisting of: (S)-6-amino-9-(1-(but-2-ethynyl)pyrrolidone-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (ibubrutinib (evobr) The adjunctive therapy includes teirabrutinib (ONO-4059), teirabrutinib (ONO-4059), PRN-1008, spetinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, acalabrutinib, danvastatin, and combinations thereof. In some embodiments, the adjunctive therapy is selected from the group consisting of teirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the adjunctive therapy is a tyrosine kinase inhibitor A9 (A9).

[0208] In some embodiments, the adjunctive therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 (Ac-RRRRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0209] In some embodiments, the adjunctive therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is carfilzomib.

[0210] In some embodiments, the adjunctive therapeutic agent is a vaccine. For example, in some embodiments, the adjunctive therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the adjunctive therapeutic agent is mRNA-1273. In some embodiments, the adjunctive therapeutic agent is INO-4800 or INO-4700. In some embodiments, the adjunctive therapeutic agent is the live attenuated RSV vaccine MEDI-559, the anti-RSV human monoclonal antibody REGN2222, palizumab, respiratory syncytial virus immunoglobulin, intravenous respiratory syncytial virus immunoglobulin [RSV-IGIV], and combinations thereof. In some embodiments, the adjunctive therapeutic agent is an HBV vaccine, such as pediarix, engerix-B, and recombivax HB. In some embodiments, the adjunctive therapeutic agent is a VZV vaccine, such as zostavax and varivax. In some embodiments, the adjunctive therapeutic agent is an HPV vaccine, such as cervarix, gardasil9, and gardasil. In some implementations, the adjunctive therapeutic agent is an influenza virus vaccine. For example, (i) a monovalent influenza A vaccine (e.g., a monovalent influenza A [H5N1] virus vaccine and a monovalent influenza A [H1N1] 2009 virus vaccine), (ii) a trivalent influenza A and B virus vaccine (e.g., Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) a quadrivalent influenza A and B virus vaccine (FluMist, Fluarix, Fluzone, and FluLaval). In some implementations, the adjunctive therapeutic agent is a human adenovirus vaccine (e.g., adenovirus type 4 and 7 vaccines, live, orally). In some implementations, the adjunctive therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9 and RotaTeq for rotavirus serotypes G1, G2, G3, or G4). In some embodiments, the adjunctive therapeutic agent is a hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the adjunctive therapeutic agent is a polio virus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the adjunctive therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the adjunctive therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the adjunctive therapeutic agent is a measles vaccine (e.g., MMR II and ProQuad). In some embodiments, the adjunctive therapeutic agent is a mumps vaccine (e.g., MMR II and ProQuad).In some embodiments, the adjunctive therapeutic agent is a rubella vaccine (e.g., MMR II and ProQuad). In some embodiments, the adjunctive therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the adjunctive therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the adjunctive therapeutic agent is a smallpox virus (smallpox) vaccine (ACAM2000). In some embodiments, the adjunctive therapeutic agent is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the adjunctive therapeutic agent is a 2019-nCoV vaccine.

[0211] In some embodiments, the adjunctive therapeutic agent is an antibody, such as a monoclonal antibody. For example, the adjunctive therapeutic agent is an anti-2019-nCoV antibody selected from the group consisting of: Regeneron antibody, Wuxi antibody, Vir Biotechnology antibody, antibody targeting the SARS-CoV-2 spike protein, antibody capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibody), and combinations thereof. In some embodiments, the adjunctive therapeutic agent is the anti-SARS CoV antibody CR-3022. In some embodiments, the adjunctive therapeutic agent is an aPD-1 antibody. In some embodiments, the adjunctive therapeutic agent is REGN-COV2. In some embodiments, the adjunctive therapeutic agent is LY-CoV555.

[0212] In some implementations, the adjunctive therapeutic agent is an injectable protein derived from a recombinant cytokine gene.

[0213] In some embodiments, the adjunctive therapeutic agent is a polymerase inhibitor. In some embodiments, the adjunctive therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is cidofovir. In some embodiments, the adjunctive therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodevir, and combinations thereof.

[0214] In some implementations, the adjunctive treatment agent is selected from the group consisting of: lopinavir, ritonavir, interferon alpha-2b, ritonavir, arbidol, hydroxychloroquine, direravir and cobistat, arbidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir macozide, ruxotetinib, and combinations thereof.

[0215] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: 6'-fluorinated monexin analogues, acyclovir fleximer analogues, disulfiram, thiopurine analogues, ASC09F, GC376, GC813, phenylisoserine derivatives, neuraminidase inhibitor analogues, pyrimethamine derivatives, basilin and 5-hydroxytryptamine derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, ME RS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thiophene-4-azaspiro[4.5]dec-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, arapovir, imatinib mesylate, dasatinib, sumetinib, trametinib, rapamycin, zicatinib, chlorpromazine, trifluprozine, fluphenazine, thiophene, promethazine, cyclophilin inhibitors, K11777, carmostat, K22, teicoplanin derivatives, benzo[a]heterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0216] In some implementations, the adjunctive therapeutic agent is an antibody. In some implementations, the adjunctive therapeutic agent is an antibody that binds to a coronavirus, such as an antibody that binds to SARS or MERS. In some implementations, the adjunctive therapeutic agent is an antibody against the 2019-nCoV virus.

[0217] In some implementations, the adjunctive therapeutic agent is a steroid, such as a corticosteroid. In some implementations, the adjunctive therapeutic agent is dexamethasone.

[0218] The compositions of the present invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infection, preferably, the other active therapeutic agents have anti-coronavirus infection activity, such as anti-2019-nCoV virus infection activity. The compounds and compositions of the present invention are also intended for use in providing general care to patients suffering from 2019-nCoV virus infection, including parenteral fluids (including glucose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory agents (e.g., dry... Interferon, other small molecule or biological antiviral agents targeting 2019-nCoV (such as, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, pain medications, and medications for other common diseases in the patient population, such as antimalarial agents (including artemether and artemisinin-benfluridine combination therapy), typhoid vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or Shigella vaccines. In some implementations, the additional therapeutic agent is dihydroartemisinin / piperaquine.

[0219] In some implementations, the adjunctive therapeutic agent is an immunomodulator. Examples of immunomodulatory therapies include Toll-like receptor modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); prazolam (aldeleukin, IL-2); interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivatives. The ingredients include mycophenolate mofetil (MMF); ribavirin; polymeric polyethyleneimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107; interleukin-15 / Fc fusion protein; AM-0015; ALT-803; NIZ-985; NKTR-255; NKTR-262; NKTR-214; nifedipine; pegylated interferon α-2a; pegylated interferon α-2b; recombinant interleukin-15; Xmab-24306; RPI-MN; STING modulator; RIG-I modulator; NOD2 modulator; SB-9200; and IR-103. In some embodiments, the adjunctive therapeutic agent refers to fingolimod, leflunomide, or a combination thereof. In some embodiments, the adjunctive therapeutic agent is thalidomide.

[0220] In some implementations, the adjunctive treatment is an IL-6 inhibitor, such as tocilizumab, thalidomab, or a combination thereof.

[0221] In some implementations, the adjunctive therapy is an anti-TNF inhibitor. For example, the adjunctive therapy is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0222] In some implementations, the adjunctive therapy is a JAK inhibitor, such as baricitinib, filgortinib, baricitinib, or a combination thereof.

[0223] In some implementations, the additional therapeutic agent is an inflammation inhibitor, such as pirfenidone.

[0224] In some implementations, the adjunctive therapeutic agent is an antibiotic used for secondary bacterial pneumonia. For example, the adjunctive therapeutic agent is a macrolide antibiotic (e.g., azithromycin, clarithromycin, and mycoplasma pneumoniae), a fluoroquinolone (e.g., ciprofloxacin and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof.

[0225] In some implementations, the compounds disclosed herein are used in combination with standards of care for pneumonia (see, for example, Pediatric Community Pneumonia Guidelines, CID 2011:53 (October 1)). Treatment of pneumonia typically involves curing the infection and preventing complications. Specific treatment will depend on several factors, including the type and severity of pneumonia, the individual's age, and overall health. Options include: (i) antibiotics, (ii) cough medicines, and (iii) antipyretics / analgesics (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some implementations, an additional treatment is bromhexine cough suppressant.

[0226] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulins from recovered COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma infusion. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0227] In some implementations, the adjunctive treatment is a TLR agonist. Examples of TLR agonists include, but are not limited to, vesamimod (GS-9620), GS-986, IR-103, lefemod, tilsotolimod, rintatlimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod, and RO-7020531.

[0228] In some implementations, the adjunctive treatment agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, peramisone, clotropone, flucloxacillin, serindole, clovidipine, atorvastatin, sinusizine, clofazimine, fosapiram, and combinations thereof.

[0229] In some implementations, the adjunctive therapeutic agent is azithromycin, suramin, triazolene, dipyridamole, bevacizumab, meperizumab, GD31 (Rhizobium spp.), an NLRP inflammasome inhibitor, or α-ketoamine. In some implementations, the adjunctive therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some implementations, the adjunctive therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0230] In some embodiments, the adjunctive therapeutic agent is an antiviral porin therapeutic agent. For example, the adjunctive therapeutic agent is BIT-314 or BIT-225. In some embodiments, the adjunctive therapeutic agent is a coronavirus E protein inhibitor. For example, the adjunctive therapeutic agent is BIT-009. Other examples of adjunctive therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.

[0231] Any compound of this disclosure may also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0232] Co-administration of the compound disclosed herein with one or more other active therapeutic agents generally means the simultaneous or sequential administration of the compound disclosed herein and one or more other active therapeutic agents such that therapeutically effective amounts of the compound disclosed herein and one or more other active therapeutic agents are present in the patient.

[0233] Co-administration includes administering a unit dose of the compound of the present invention before or after administering a unit dose of one or more other active therapeutic agents, for example, administering the compound of the present invention within seconds, minutes, or hours of administering one or more other active therapeutic agents. For example, a unit dose of the compound of the present disclosure may be administered first, followed by a unit dose of one or more other active therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents may be administered first, followed by a unit dose of the compound of the present disclosure within seconds or minutes. In some cases, it may be necessary to administer a unit dose of the compound of the present disclosure first, followed by a unit dose of one or more other active therapeutic agents several hours (e.g., 1 to 12 hours). In other cases, it may be necessary to administer a unit dose of one or more other active therapeutic agents first, followed by a unit dose of the compound of the present disclosure several hours (e.g., 1 to 12 hours).

[0234] Combination therapy can provide “synergistic” or “synergistic” effects, meaning that the combined effect of active ingredients is greater than the sum of the effects of using the compounds alone. Synergistic effects are achieved when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered alternately or in parallel as individual formulations; or (3) through some other protocol. Synergistic effects are achieved when delivered in alternating therapy, such as when the compounds are administered or delivered in different injection sequences, for example, in separate tablets, pills, or capsules, or by different injection sequences in separate syringes. Typically, in alternating therapy, each active ingredient is administered sequentially (i.e., consecutively), while in combination therapy, two or more active ingredients are administered together in effective doses. A synergistic antiviral effect indicates that the antiviral effect is greater than the predicted additive effect of the individual compounds in the combination.

[0235] 1. Combination therapy for treating pulmonary virology The compounds described herein can also be used in combination with other active therapeutic agents. For the treatment of pulmonary viral infections, preferably, the other active therapeutic agents have activity against pulmonary viral infections, particularly respiratory syncytial virus (RSV) infection and / or metapneumovirus (MRV) infection. Non-limiting examples of these other active therapeutic agents with anti-RSV activity are ribavirin, palilizumab, mavitazumab, and RSV-IGIV (RespiGam). ® MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents with activity against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and pretovir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAb; and viral replication inhibitors such as nitrozonide.

[0236] In some implementations, other active therapeutic agents may be vaccines for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccines.

[0237] Non-limiting examples of other active therapeutic agents that are active against metapneumovirus infection include sialidase modulators, such as DAS-181; RNA polymerase inhibitors, such as ALS-8112; and antibodies for the treatment of metapneumovirus infection, such as EV-046113.

[0238] In some implementations, other active therapeutic agents may be vaccines used to treat or prevent metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines.

[0239] 2. Combination therapy for treating Picornaviridae virus family patients The compounds described herein can also be used in combination with other active therapeutic agents. For the treatment of picornaviridae virus infections, preferably, the other active therapeutic agents have activity against picornaviridae virus infections, particularly enterovirus infections. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors, such as pracinamide, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase proteins, such as DAS-181; capsid protein VP1 inhibitors, such as VVX-003 and AZN-001; viral protease inhibitors, such as CW-33; phosphatidylinositol 4-kinase β inhibitors, such as GSK-480 and GSK-533; and anti-EV71 antibodies.

[0240] In some implementations, other active therapeutic agents may be vaccines for the treatment or prevention of infection with microribonucleoviridae viruses, including but not limited to EV71 vaccines, TAK-021, and vaccines based on EV-D68 adenovirus vectors.

[0241] 3. Combination therapy for respiratory tract infections Infections caused by many viruses of the Pneumoviridae and Picornaviridae families are respiratory infections. Therefore, adjunctive active therapeutic agents for treating respiratory symptoms and post-infectious sequelae can be used in combination with the compounds provided herein. These adjunctive therapeutic agents are preferably administered orally or by direct inhalation. Other preferred adjunctive therapeutic agents, for example, for treating viral respiratory infections in combination with the compounds provided herein include, but are not limited to, bronchodilators and corticosteroids.

[0242] Glucocorticoids First introduced as a treatment for asthma in 1950 (Carryer, Journal of Allergy, Vol. 21, pp. 282-287, 1950), glucocorticoids remain the most effective and consistently effective treatment for this disease, but their mechanisms of action are not fully understood (Morris, J. Allergy Clin. Immunol., Vol. 75 (1 Pt), pp. 1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with serious adverse side effects such as truncal obesity, hypertension, glaucoma, impaired glucose tolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit its use as a long-term treatment (Goodman and Gilman, 10th ed., 2001). A solution to systemic side effects is the direct delivery of steroid medications to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to alleviate the severe side effects of oral steroids. Non-limiting examples of corticosteroids that may be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, flumethonone, flumethonone acetate, clotipreno, clotipreno ecaprate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone acetonide, flunisolone, flucodone-21-butyrate, flumethasone, flumethasone valerate, budesonide, halobetasol propionate, mometasone furoate, fludioxonone, AZD-7594, cyclosporine; or pharmaceutically acceptable salts thereof.

[0243] anti-inflammatory agents Other anti-inflammatory agents that act through an anti-inflammatory cascade mechanism can also be used as adjunctive therapies in combination with the compounds presented herein for the treatment of viral respiratory infections. The application of “anti-inflammatory signal transduction modulators” (referred to herein as AISTMs) such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB via IKK inhibition), or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K, EGFR, or Syk) is a logical approach to interrupting inflammation because these small molecules target a limited number of common intracellular pathways (which are key points of anti-inflammatory therapeutic interventions) (see PJ Barnes’ review, 2006). These non-restrictive adjunctive therapies include: 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38... Map kinase inhibitor ARRY-797); 3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentoxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methanesulfonyl)amino]-1-dibenzofuran carboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indole-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD) 12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentoxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2 -Diethylamino-ethyl ester (the 2-diethyl-ethyl ester prodrug of silostabrine, a PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, an EGFR inhibitor); and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor).

[0244] β2-adrenergic receptor agonists and bronchodilators Combinations of inhaled β2-adrenergic receptor agonists and bronchodilators such as formoterol, salbutamol, or salmeterol with the compounds provided herein are also suitable, but not limiting, combinations for the treatment of respiratory viral infections.

[0245] Inhaled β2-adrenergic receptor agonists and bronchodilators such as formoterol or salmeterol, in combination with ICS, are also used to treat bronchoconstriction and inflammation (symmbicort, respectively). ® and Advair ® Combinations of these ICS and β2-adrenergic receptor agonists, as well as combinations of the compounds presented herein, are also suitable, but not limiting, combinations for the treatment of respiratory viral infections.

[0246] Other examples of β2-adrenergic receptor agonists are bedoradine, vilanterol, indacaterol, olodaterol, tuloterrol, formoterol, abidilol, salbutamol, afortrol, levosalbutamol, fenoterol, and TD-5471.

[0247] Anticholinergic agents Anticholinergic agents have potential use in the treatment or prevention of bronchoconstriction and can therefore be used as adjunctive therapy in combination with the compounds described herein for the treatment of viral respiratory infections.These anticholinergic agents include, but are not limited to, antagonists of muscarinic receptors (especially the M3 subtype), which have been shown to be effective in controlling cholinergic tension in humans for COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)propionyl]pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-aza-onium-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycine ester); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2 1-aza-bicyclo[2.2.2]oct-3-yl formic acid (sofenadine); 1-aza-bicyclo[2.2.2]oct-3-yl 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid (revatropide); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidine-3-yl}-2,2-diphenyl-acetamide (dapoxetine); 4-azacycloheptane-1-yl-2,2-diphenyl-butyramide (Buzepide); 7-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-aza-tricyclo[3.3.1.02,4]nonane (oxotropin- N,N-diethylglycine ester); 7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophene-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-aza-tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycine ester); dimethylaminoacetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycine ester); 3-[4,4-bis-(4-fluorophenyl)-2-oxo-imidazolidine-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidineonium; 1-[1-(3-fluorobenzyl)-piperidin-4-yl]- 4,4-Bis-(4-fluorophenyl)-imidazolidine-2-one; 1-Cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol; 3-[2-(2-diethylamino-acetoxy)-2,2-dithiophene-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-aza-bicyclo[2.2.2]octane (aldecanedinium bromide-N,N-diethylglycine ester); or (2-diethylamino-acetoxy)-dithiophene-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; refenapyridine, ganroammonium bromide, wudiammonium bromide, tiotropium bromide, adicanedinium bromide, benzylquinoline bromide.

[0248] Mucus Dissolving Agent The compounds described herein can also be combined with mucolytics to treat symptoms of infections and respiratory tract infections. A non-limiting example of a mucolytic is ambroxol. Similarly, these compounds can be combined with expectorants to treat symptoms of infections and respiratory tract infections. A non-limiting example of an expectorant is guaiacol.

[0249] Nebulized hypertonic saline is used to improve immediate and long-term airway clearance in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds described herein can also be combined with nebulized hypertonic saline, particularly when viral infection is complicated by bronchiolitis. The combination of the compounds described herein with hypertonic saline may also include any additional agents discussed above. In some embodiments, approximately 3% hypertonic saline is used.

[0250] 4. Combination therapy for treating infections caused by Flaviviridae viruses. The compounds and compositions provided herein can also be used in combination with other active therapeutic agents. For the treatment of flaviviridae virus infections, preferably, the other active therapeutic agents have anti-flaviviridae virus activity.

[0251] Non-limiting examples of other active therapeutic agents for the treatment of dengue virus infection include host cytokine modulators such as GBV-006; fenivel-Amin ABX-220 and BRM-211; α-glucosidase 1 inhibitors such as celgosivir; platelet-activating factor receptor (PAFR) antagonists such as modepapan; cadherin-5 / factor Ia modulators such as FX-06; NS4B inhibitors such as JNJ-8359; viral RNA splicing modulators such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0252] In some implementations, other active therapeutic agents may be vaccines used to treat or prevent dengue fever, including but not limited to TetraVax-DV and Dengvaxia. ® DPIV-001, TAK-003, live attenuated dengue vaccine, quadrivalent dengue vaccine, quadrivalent DNA vaccine, rDEN2delta30-7169 and DENV-1 PIV.

[0253] 5. Combination therapy for treating infections caused by filoviridae viruses. The compounds described herein can also be used in combination with other active therapeutic agents. For the treatment of filoviridae virus infections, preferably, the other active therapeutic agents have activity against filoviridae virus infections, particularly Marburg virus, Ebola virus, and Cuiva virus infections. Non-limiting examples of these other active therapeutic agents are: ribavirin, palilizumab, mavitizumab, and RSV-IGIV (RespiGam). ® MEDI-557, A-60444, MDT-637, BMS-433771, Amiodarone, Dronedarone, Verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7- N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors, such as galidivir, favipiravir (also known as T-705 or Avigan), JK-05; host cytokine modulators, such as GMV-006; cadherin-5 / factor Ia modulators, such as FX-06; and antibodies used to treat Ebola, such as REGN-3470-3471-3479 and ZMapp.

[0254] Other non-restricted active therapeutic agents with anti-Ebola activity include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 grasping integrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cytokine modulators, interferon alpha ligands, neutral alpha-glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0255] In some implementations, other active therapeutic agents may be vaccines used to treat or prevent Ebola, including but not limited to VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccines, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo + Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, recombinant Ebola glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0256] The compounds described herein can also be used in combination with aminophosphate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with translation by forming base-pair duplexes with specific RNA sequences. Examples of PMOs include, but are not limited to, AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0257] The compounds described herein are also intended for use with general care provided to patients with filoviridae virus infections, which include parenteral fluids (including glucose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common illnesses in the patient population, such as antimalarial agents (including artemether and artemisinin-benfluridine combination therapy), typhoid vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or Shigella vaccines.

[0258] IX. Compound Preparation In some embodiments, this disclosure provides methods and intermediates for preparing the compounds provided herein or pharmaceutically acceptable salts thereof.

[0259] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal-phase and reversed-phase, as well as ion exchange resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0260] During any method used to prepare the compounds provided herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved with conventional protecting groups as described in standard works such as TW Greene and PGMUTS, “Protective Groups in Organic Synthesis,” 4th edition, Wiley, New York 2006. Protecting groups can be removed at convenient subsequent stages using methods known in the art.

[0261] Exemplary chemical entities that can be used to implement the methods will now be described with reference to the general preparation described herein and the illustrative synthetic schemes of specific examples below. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, starting materials can be suitably selected such that a reaction scheme, carried out as appropriate or without protection, will produce the desired product by carrying the final desired substituent. Alternatively, it may be necessary or desirable to use a suitable group to replace the final desired substituent, which can be carried out in the reaction scheme and, as appropriate, substituted with the desired substituent. Furthermore, those skilled in the art will recognize that the transformations shown in the following schemes can be carried out in any sequence compatible with the functionality of the particular side groups.

[0262] The methods disclosed herein typically provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer is not determined in all cases. When the stereochemistry of a specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without any stereochemistry being shown at that specific stereocenter, even if the compound may be substantially enantiomerically pure or diastereomerically pure.

[0263] Representative syntheses of the compounds disclosed herein are described in the following schemes and in subsequent specific examples.

[0264] X. Example Intermediate 1-2: (R)-2-(benzyloxy)-3-(octadecyloxy)propyl bis(4-nitrophenyl) phosphate 4-Nitrophenyl dichlorophosphate (1.41 g, 5.52 mmol) was dissolved in DCM (36 mL). The resulting solution was cooled in an ice bath, and a separate solution of 1-O-octadecyl-2-O-benzyl-sn-glycerol (intermediate 1-1, 2 g, 4.6 mmol) in DCM (10 mL) was added. Triethylamine (1.12 g, 11 mmol) was then added dropwise. The ice bath was then removed. After 1 hour and 45 minutes, additional triethylamine (0.239 g, 2.35 mmol) was added, followed by 4-nitrophenol. The reaction progress was monitored by LC / MS and TLC. The reactants were diluted with Et2O, and the resulting solids were removed by filtration. The filtrate was concentrated, and intermediates 1-2 were separated by silica gel column chromatography (25 g loading cartridge, 120 g Combiflash HP Gold column, eluent gradient of 100% hexane to 30% EtOAc / hexane).

[0265] 1 ¹H NMR (400MHz, chloroform-d) δ 8.21 – 8.08 (m, 4H), 7.38 – 7.21 (m, 9H), 4.66 – 4.55 (m, 2H), 4.52 (ddd, J = 10.5, 7.1, 3.2Hz, 1H), 4.38 (ddd, J =10.8, 8.5, 5.5Hz, 1H), 3.83 – 3.76 (m, 1H), 3.57 – 3.46 (m, 2H), 3.39 (t, J =6.6Hz, 2H), 1.57 – 1.46 (m, 2H), 1.33 – 1.17 (m, 30H), 0.90 – 0.80 (m, 3H). 31 P NMR (162MHz, chloroform-d) δ -19.447. Intermediate 1-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6- Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-(benzyloxy)-3- (octadecyloxy)propyl)(4-nitrophenyl)phosphate Intermediates 1-2 (0.503 g, 0.664 mmol) and 1-3 (J. Med. Chem., 2017, Vol. 5, No. 60, p. 1648; 0.2 g, 0.604 mmol) were dissolved in THF. MgCl2 (0.287 g, 3.02 mmol) was added in a single addition at room temperature. The reaction mixture was placed in a 50 °C bath and stirred for 10 min. DIPEA was added dropwise to the resulting mixture. The reaction progress was monitored by LC / MS. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was absorbed into DCM by sonication, and intermediates 1-4 were separated by silica gel column chromatography (12 g loading cartridge, 40 g Combiflash HP Gold column, eluent gradient of 100% hexane to 100% EtOAc).

[0266] 1 H NMR (400MHz, chloroform-d) δ 7.93 – 7.86 (m, 1H), 7.84 – 7.77 (m, 2H), 7.30 – 7.18 (m, 5H), 7.18 – 7.08 (m, 2H), 6.89 (t, J = 4.8Hz, 1H), 6.53 (dd,J = 6.7, 4.6Hz, 1H), 6.01 (brs, 2H), 5.40 (dd,J = 13.8, 6.9Hz, 1H), 4.87(ddd, J = 10.9, 6.9, 4.3Hz, 1H), 4.64 – 4.48 (m, 3H), 4.43 (ddd, J = 10.8,6.8, 4.0Hz, 1H), 4.39 – 2.27 (m, 2H), 4.25 – 4.14 (m, 1H), 3.78 – 3.68 (m,1H), 3.53 – 3.40 (m, 2H), 3.36 (td, J = 6.7, 2.2Hz, 2H), 1.70 (s, 3H), 1.55 –1.42 (m, 2H), 1.33 (d, J = 3.8Hz, 3H), 1.30 – 1.14 (m, 30H), 0.83 (t, J =6.7Hz, 3H). 31 P NMR (162MHz, chloroform-d) δ -7.275 (s), -7.608 (s). MS m / z = 949.10 [M+1] Intermediates 1-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6- Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-(benzyloxy)-3- (octadecyloxy)propyl)hydrogen phosphate Intermediates 1-4 (0.169 g, 0.178 mmol) were dissolved in THF (4 mL). 1N NaOH aqueous solution (0.0249 g, 0.623 mmol) was added dropwise to this solution. After complete addition of NaOH solution, the reaction mixture was placed in a 50°C bath. The reaction progress was monitored by LC / MS. After intermediates 1-4 were consumed, the reaction mixture was cooled in an ice bath. 2N HCl aqueous solution was added until the pH of the reaction mixture reached approximately 4. The reaction mixture was concentrated, and the resulting residue was absorbed into DCM by sonication. Intermediates 1-5 were separated by silica gel column chromatography (12 g loading cartridge, 24 g Combiflash HP Gold column, eluent gradient of 100% DCM to 20% MeOH / DCM).

[0267] 1 H NMR (400MHz, MeOH-d3) δ 7.86 (s, 1H), 7.35 – 7.15 (m, 5H), 6.93 –6.85 (m, 2H), 5.32 (d, J = 6.6Hz, 1H), 5.00 (dd, J = 6.6, 3.1Hz, 1H), 4.64 – 4.51 (m, 3H), 4.03 (t, J = 5.4Hz, 2H), 3.94 – 3.83 (m, 2H), 3.73 – 3.64 (m,1H), 3.53 – 3.40 (m, 2H), 3.37 (td, J = 6.5, 1.6Hz, 2H), 1.69 (s, 3H), 1.51(pent, J = 6.7Hz, 2H), 1.39 (s, 3H), 1.36 – 1.21 (m, 30H), 0.92 – 0.86 (m, 3H). 31 P NMR (162MHz, MeOH-d3) δ 2.852 – -0.151 (brs). MS m / z = 828.69 [M+1], 1656.24 [2M+1] Intermediates 1-6: (R)-2-(benzyloxy)-3-(octadecyloxy)propyl(2-chlorophenyl)triethylammonium phosphate At 0 °C, 1,2,4-triazole (1.33 g, 19.3 mmol) and triethylamine (2.69 mL, 19.3 mmol) were sequentially added to a stirred solution of 2-chlorophenyl dichlorophosphate (1.45 mL, 8.97 mmol) in acetonitrile (30 mL), and the resulting mixture was heated to room temperature. After 40 minutes, a solution of intermediate 1-1 (3.90 g, 8.97 mmol) in pyridine (40 mL) was slowly added via a tube. After 5 hours, triethylamine (5.0 mL) and water (1.5 mL) were added sequentially. After 25 minutes, a saturated aqueous solution of sodium bicarbonate was added. After 10 minutes, a saturated aqueous solution of sodium bicarbonate was added, and the aqueous layer was extracted with dichloromethane (4 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 1-6.

[0268] LCMS: 623.3 [M−C6H 16 N] − . Intermediate 1-7: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6- Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-(benzyloxy)-3- (octadecyloxy)propyl)(2-chlorophenyl)phosphate At room temperature, 1-(trimethylbenzenesulfonyl)-3-nitro-1H-1,2,4-triazole (4.02 g, 13.6 mmol), intermediate 1-3 (3.00 g, 9.05 mmol), and 1-methylimidazole (1.08 mL, 13.6 mmol) were sequentially added to a pyridine-stirred solution of intermediate 1-6 (5.92 g, 8.15 mmol). After 4 hours, the resulting mixture was cooled to 0 °C, and saturated aqueous sodium bicarbonate solution and brine were added sequentially. The aqueous layer was extracted with dichloromethane (2 × 400 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 100% ethyl acetate in hexane) to give intermediate 1-7.

[0269] LCMS: 938.5. Intermediate 1-5—((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-(benzyloxy)- Substitutional Synthesis of 3-(octadecyloxy)propyl)hydrogen phosphate At room temperature, a tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 12.8 mL, 13 mmol) was added via syringe to a stirred mixture of intermediates 1-7 (4.00 g, 4.26 mmol), pyridine (5.0 mL), water (5.0 mL), and tetrahydrofuran (35 mL). After 2 hours, the resulting mixture was cooled to 0 °C. Saturated sodium bicarbonate aqueous solution (15 mL) and water (10 mL) were added sequentially, and the mixture was concentrated under reduced pressure. Dichloromethane and water were added sequentially, followed by hydrogen chloride aqueous solution (2.0 M) until the pH of the aqueous layer reached 3. The aqueous layer was extracted with dichloromethane (4 times). The combined organic layers were washed with a mixture of brine and saturated sodium bicarbonate aqueous solution (pH=8, 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 20% methanol in dichloromethane) to give intermediates 1-5. LCMS: 828.5. Example 1: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyloxy)-3-(octadecyloxy)propyl)hydrogen phosphate (1) Intermediate 1-5 (0.15 g, 0.181 mmol) was dissolved in THF (4 mL). The resulting solution was cooled in an ice bath. Concentrated HCl aqueous solution (1.25 mL, 14.9 mmol) was added dropwise. The cold bath was removed, and the reaction mixture was stirred vigorously. The reaction progress was monitored by LC / MS. After intermediate 1-5 was consumed, the reaction mixture was concentrated. The residue was absorbed in a mixture of MeOH and DCM and concentrated. The resulting residue was absorbed in DCM, and compound 1 was separated by silica gel column chromatography (12 g loading cartridge, 24 g Combiflash HP Gold column, eluent gradient of 100% DCM to 20% MeOH / DCM).

[0270] 1H NMR (400MHz, ACN-d3) δ 7.85 (s, 1H), 7.35 – 7.17 (m, 5H), 6.96 (d,J = 4.6Hz, 1H), 6.90 (d, J = 4.6Hz, 1H), 4.81 (d, J = 5.3Hz, 1H), 4.66 – 4.54(m, 2H), 4.37 – 4.31 (m, 1H), 4.22 (t, J = 5.5Hz, 1H), 4.18 – 4.01 (m, 2H), 3.97 – 3.82 (m, 2H), 3.72 – 3.65 (m ,1H), (qd, J = 10.5, 4.9Hz, 2H), 3.41 –3.34 (m, 2H), 1.50 (pent, J = 7.0Hz, 2H), 1.37 – 1.20 (m, 30H), 0.92 – 0.86 (m, 3H). MS m / z = 786.92 [M-1], 1572.67 [2(M-1)] Intermediate 2-1: (R)-(2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propoxy)(tert-butyl dimethylsilane At 0 °C, a tetrahydrofuran (2.0 mL) solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol (159 mg, 347 µmol) (Bartolmäs, T.; Heyn, T.; Mickeleit, M.; Fischer, A.; Reutter, W.; Danker, KJ Med. Chem., 2005, Vol. 48, p. 6750) was added via a tube to a vigorously stirred mixture of sodium hydride (60 wt% dispersion in mineral oil, 46.6 mg, 1.22 mmol) in tetrahydrofuran (3.0 mL). After 30 minutes, 4-(bromomethyl)-1,1'-biphenyl (300 mg, 1.22 mmol) was added, and the resulting mixture was heated to room temperature. After 21 hours, a saturated aqueous solution of ammonium chloride (3.0 mL) and ethyl acetate (60 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (2:1 v:v, 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 5% ethyl acetate in hexane) to give intermediate 2-1.

[0271] 1H NMR (400MHz, acetonitrile-d3) δ 7.73 – 7.60 (m, 4H), 7.53 – 7.42 (m, 4H), 7.42 – 7.35 (m, 1H), 4.71 (s, 2H), 3.80 – 3.65 (m, 2H), 3.64 – 3.47 (m, 3H), 3.47 – 3.39 (m, 2H), 1.62 – 1.46 (m, 2H), 1.42 – 1.17 (m, 30H), 0.97 – 0.83 (m, 12H), 0.09 (s, 6H). Intermediate 2-2: (S)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecoxy)prop-1-ol At room temperature, a solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 756 µL, 760 µmol) was added via syringe to a stirred solution of intermediate 2-1 (200 mg, 320 µmol) in tetrahydrofuran (3.0 mL). After 85 minutes, saturated aqueous ammonium chloride solution (1.0 mL) and diethyl ether (30 mL) were added sequentially. The organic layer was washed with water (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 30% ethyl acetate in hexane) to give intermediate 2-2.

[0272] LCMS: 533.4 [M+Na] + . Intermediate 2-3: (R)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecoxy)propylbis(4-nitro) Phenyl phosphate At 0 °C, triethylamine (10.8 µL, 77.8 µmol) was added via syringe to a stirred mixture of intermediate 2-2 (33.1 mg, 64.8 µmol), 4-nitrophenyl dichlorophosphate (19.9 mg, 77.8 µmol), and dichloromethane (3.0 mL). After 60 minutes, the resulting mixture was warmed to room temperature. After 30 minutes, 4-nitrophenyl dichlorophosphate (20.0 mg, 78.1 µmol) and triethylamine (20.0 µL, 143 µmol) were added sequentially. After 60 minutes, 4-nitrophenyl dichlorophosphate (60.0 mg, 234 µmol) and triethylamine (50.0 µL, 359 µmol) were added sequentially. After 70 minutes, 4-nitrophenol (150 mg, 1.08 mmol) and triethylamine (200 µL, 1.43 mmol) were added sequentially. After 50 minutes, diethyl ether (60 mL) and citric acid aqueous solution (10 wt%, 10 mL) were added sequentially. The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 30% ethyl acetate in hexane) to give intermediate 2-3.

[0273] LCMS: 855.4 [M+Na] + . Intermediate 2-4: (R)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propyl(((3aR,4R, 6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2,2-dimethyltetrahydrofurano [3,4-d][1,3]dioxacyclopenten-4-yl)methyl)(4-nitrophenyl)phosphate A vigorously stirred mixture of intermediates 2-3 (190 mg, 228 µmol), intermediates 1-3 (75.6 mg, 228 µmol), magnesium chloride (217 mg, 2.28 mmol), and tetrahydrofuran (2.5 mL) was heated to 50 °C. After 5 minutes, N,N-diisopropylethylamine (397 µL, 2.28 mmol) was added via syringe over 1 minute. After 60 minutes, the resulting mixture was cooled to room temperature, and a mixture of citric acid (726 mg), sodium hydroxide aqueous solution (2.0 M, 4 mL), and water (10 mL) was added. Ethyl acetate (60 mL) was added, and the organic layer was washed with a mixture of water and brine (2:1 v:v, 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 4.5% methanol in dichloromethane) to give intermediate 2-4.

[0274] LCMS: 1025.5. Example 2: (R)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propyl(((2R,3S,4R, 5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl (Base) hydrogen phosphate At room temperature, an aqueous solution of sodium hydroxide (2.0 M, 276 µL, 552 µmol) was added via syringe to a vigorously stirred solution of intermediate 2-4 (162 mg, 158 µmol) in tetrahydrofuran (1.8 mL), and the resulting mixture was heated to 50 °C. After 60 minutes, an aqueous solution of sodium hydroxide (2.0 M, 150 µL, 300 µmol) was added via syringe. After 150 minutes, the resulting mixture was cooled to room temperature. An aqueous solution of hydrogen chloride (2.0 M, 400 µL) and a mixture of citric acid (706 mg), an aqueous solution of sodium hydroxide (2.0 M, 3.67 mL), an aqueous solution of hydrogen chloride (2.0 M, 1.83 mL), water (5 mL), and brine (10 mL) were added sequentially. The aqueous layer was extracted with dichloromethane (3 × 30 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2.0 mL) and stirred vigorously at room temperature. Concentrated hydrogen chloride (625 µL, 7.5 mmol) was added via syringe. After 165 minutes, a mixture of citric acid (706 mg), sodium hydroxide aqueous solution (2.0 M, 1.83 mL), water (15 mL), sodium hydroxide aqueous solution (6.0 M, 250 µL), and brine (10 mL) was added. The aqueous layer was extracted sequentially with a mixture of dichloromethane and ethyl acetate (2:5 v:v, 70 mL), ethyl acetate (2 × 50 mL), and tetrahydrofuran (2 × 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (2-propanol / water) to give compound 2.

[0275] 1 H NMR (400MHz, DMSO-d6−methanol-d4) δ 7.92 (s, 1H), 7.63 (d, J = 7.5Hz,2H), 7.59 (d, J = 8.1Hz, 2H), 7.48 – 7.28 (m, 5H), 6.91 (d, J = 4.5Hz, 1H), 6.85 (d, J = 4.8Hz, 1H), 4.68 – 4.52 (m, 3H), 4.39 – 3.25 (m, 11H), 1.54 –0.99 (m, 32H), 0.85 (t, J = 6.6Hz, 3H). LCMS: 864.0. Intermediate 3-1: (S)-2-(cyclohexylmethoxy)-3-(octadecyloxy)prop-1-ol A vigorously stirred mixture of (S)-3-(octadecoxy)propane-1,2-diol (250 mg, 726 µmol), cyclohexaneformaldehyde (92.3 µL, 762 µmol), 4-methylbenzenesulfonic acid monohydrate (13.8 mg, 72.6 µmol), anhydrous magnesium sulfate (162 mg, 1.34 mmol), and dichloromethane (3.0 mL) was heated to 60 °C. After 80 minutes, the resulting mixture was cooled to room temperature, and potassium carbonate (101 mg, 726 µmol) was added. After 10 minutes, the resulting mixture was filtered through diatomaceous earth, and the filter cake was extracted with dichloromethane (8 mL). The combined filtrates were stirred and cooled to -40 °C. Diisobutylaluminum hydride solution (1.0 M in toluene, 5.80 mL, 5.8 mmol) was added via syringe, and the resulting mixture was heated to -10 °C over 145 minutes. The resulting mixture was then heated to room temperature. Twenty-two hours later, methanol (2.0 mL) was slowly added via syringe. Water (50 mL) and aqueous hydrogen chloride solution (2.0 M, 20 mL) were added sequentially, and the aqueous layer was extracted with dichloromethane (2 × 60 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 10% ethyl acetate in hexane) to give intermediate 3-1.

[0276] Example 3: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(cyclohexylmethoxy)-3-(octadecyloxy)propyl)phosphoric acid Hydrogen ester Compound 3 was synthesized in a manner similar to that of Compound 2, using (S)-2-(cyclohexylmethoxy)-3-(octadecoxy)prop-1-ol instead of (S)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecoxy)prop-1-ol.

[0277] 1 ¹H NMR (400MHz, DMSO-d6−methanol-d4) δ 7.94 (s, 1H), 6.93 (d, J = 4.5Hz, 1H), 6.84 (d, J = 4.5Hz, 1H), 4.65 (d, J = 4.9Hz, 1H), 4.31–3.06 (m, 13H), 1.72–1.00 (m, 43H), 0.86 (t, J = 6.7Hz, 3H). 31 P NMR (162MHz, DMSO-d6) δ -1.13 (s, 1P). LCMS: 794.1. Intermediate 4-1: (S)-2-(cyclohexylmethoxy)-3-(octadecyloxy)prop-1-ol Intermediate 4-1 was synthesized in a manner similar to that of intermediate 2-4, using 2-(bromomethyl)naphthalene instead of 4-(bromomethyl)-1,1'-biphenyl.

[0278] Example 4: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(naphth-2-ylmethoxy)-3-(octadecyloxy)propyl)phosphoric acid Hydrogen esters (4) At room temperature, an aqueous solution of sodium hydroxide (2.0 M, 800 µL, 1.6 mmol) was added via syringe to a vigorously stirred solution of intermediate 4-1 (250 mg, 250 µmol) in tetrahydrofuran (1.8 mL), and the resulting mixture was heated to 56 °C. After 186 minutes, the mixture was cooled to room temperature. An aqueous solution of hydrogen chloride (2.0 M, 800 µL) and a mixture of citric acid (706 mg), an aqueous solution of sodium hydroxide (2.0 M, 1.83 mL), water (5 mL), and brine (10 mL) were added sequentially. The aqueous layer was extracted with 2-methyltetrahydrofuran (2 × 30 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1.2 mL) and stirred vigorously at room temperature. Concentrated hydrogen chloride (250 µL, 3.0 mmol) was added via syringe. After 165 minutes, triethylamine (600 µL) was added via syringe, and the resulting mixture was purified by reversed-phase preparative HPLC (2-propanol / water) to obtain compound 4, which is the triethylammonium salt. 1 H NMR (400MHz, methanol-d4) δ 7.86 (s,1H), 7.84 – 7.75 (m, 4H), 7.52 – 7.40 (m, 3H), 7.00 (d, J = 4.6Hz, 1H), 6.88(d, J = 4.6Hz, 1H), 4.86 – 4.71 (m, 3H), 4.35 (t, J = 4.5Hz, 1H), 4.25 (t, J= 5.4Hz, 1H), 4.23 – 4.11 (m, 1H), 4.07 (dt, J = 11.4, 4.6Hz, 1H), 3.92(hept, J = 5.4Hz, 2H), 3.83 – 3.75 (m, 1H), 3.52 (qd, J = 10.7, 5.1Hz, 2H), 3.40 (t, J = 6.5Hz, 2H), 3.22 (q, J = 7.3Hz, 6H), 1.60 – 1.18 (m, 41H), 0.97– 0.86 (m, 3H). LCMS: 838.1. Intermediate 5-1: (R)-3-(hexadecyloxy)-2-hydroxypropyl 4-methylbenzenesulfonate (R)-ethylene oxide-2-ylmethyl-4-methylbenzenesulfonate (507 mg, 2.22 mmol) and 1-hexadecyl alcohol (547 mg, 2.26 mmol) were dissolved in DCM (10 mL) and treated with a few drops of trifluoroborane ether compound. The resulting solution was stirred for 18 hours, during which time the solvent was removed under reduced pressure, and the resulting residue was precipitated with hexane to give intermediate 5-1.

[0279] 1 ¹H NMR (400MHz, chloroform-d) δ. 7.83 (d, J = 8.0Hz, 2H), 7.38 (d, J = 8.0Hz, 2H), 4.21 – 3.90 (m, 2H), 3.55 – 3.26 (m, 3H), 2.48 (s, 3H), 1.53 (s, 3H), 1.28 (s, 28H), 0.90 (t, J = 6.6Hz, 3H). MS m / z = 471.0 Intermediate 5-2: (R)-2-(benzyloxy)-3-(hexadecyloxy)propyl 4-methylbenzenesulfonate Intermediate 5-1 (216 mg, 0.459 mmol) was dissolved in dioxane (4 mL) and treated with benzyl 2,2,2-trichloroacetilimate (0.175 mL, 0.942 mmol), followed by a few drops of trifluoromethanesulfonic acid. The reaction mixture was stirred for 90 min, at which point another benzyl 2,2,2-trichloroacetilimate (0.1 mL, 0.538 mol) and a few drops of trifluoromethanesulfonic acid were added. The reaction mixture was stirred for 18 h, at which point another benzyl 2,2,2-trichloroacetilimate (0.2 mL, 1.08 mmol) and a few drops of trifluoromethanesulfonic acid were added. The reaction mixture was stirred for 90 min, at which point the reaction mixture was diluted with dichloromethane, washed successively with saturated sodium bicarbonate solution and water, dried over sodium sulfate, filtered, and evaporated under reduced pressure. Intermediate 5-2 was separated from the residue by silica gel column chromatography (elution gradient 0-20% EtOAc:hexane).

[0280] 1H NMR (400MHz, chloroform-d) δ. 7.81 (d, J = 8.3Hz, 2H), 7.45 – 7.24 (m,7H), 4.22 (dd, J = 10.4, 4.1Hz, 1H), 4.11 (dd, J = 10.4, 5.8Hz, 1H), 3.78(qd, J = 5.5, 4.1Hz, 1H), 3.48 (dd, J = 5.3, 4.1Hz, 2H), 3.38 (t, J = 6.7Hz,2H), 2.46 (s, 3H), 1.51 (t, J = 6.7Hz, 2H), 1.29 (s, 28H), 0.91 (t, J =6.7Hz, 3H). Intermediate 5-3: (S)-2-(benzyloxy)-3-(hexadecyloxy)prop-1-ol Intermediate 5-2 (257 mg, 0.458 mmol) was dissolved in DMSO (10 mL) and treated with sodium nitrite (976 mg, 14.1 mmol). The mixture was then heated to 40 °C for 18 hours. During this process, the reaction mixture was diluted with water, extracted to dichloromethane, dried over sodium sulfate, filtered, and evaporated under reduced pressure. Intermediate 5-3 was separated from the residue by silica gel column chromatography (elution gradient of 0-25% EtOAc:hexane).

[0281] 1 H NMR (400MHz, chloroform-d) δ. 7.47 – 7.22 (m, 5H), 4.74 (d, J = 11.8Hz, 1H), 4.65 (d, J = 11.8Hz, 1H), 3.78 (q, J = 6.2Hz, 1H), 3.69 (dq, J = 6.4,4.8Hz, 2H), 3.62 (dd, J = 10.0, 4.7Hz, 1H), 3.56 (dd, J = 10.0, 5.2Hz, 1H), 3.46 (td, J = 6.7, 1.6Hz, 2H), 2.22 (d, J = 20.1Hz, 1H), 1.59 (p, J = 6.7Hz,2H), 1.28 (s, 28H), 0.94 – 0.87 (m, 3H). MS m / z = 406.9 Intermediate 5-4: (R)-2-(benzyloxy)-3-(hexadecyloxy)propyl bis(4-nitrophenyl) phosphate Intermediate 5-3 (21.0 mg, 0.0516 mmol) was dissolved in DCM (2 mL) and treated with triethylamine (0.0300 mL, 0.215 mmol) and 4-nitrophenyl dichlorophosphate (46.0 mg, 0.180 mmol). The reaction mixture was stirred for 30 min, at which point additional triethylamine (0.0500 mL, 0.359 mmol) and 4-nitrophenyl dichlorophosphate (100 mg, 0.391 mmol) were added, and stirring was continued for 1 h. Triethylamine (0.100 mL, 0.717 mmol) and 4-nitrophenol (160 mg, 1.15 mmol) were added sequentially, and stirring was continued for 20 min. The reaction mixture was then diluted with diethyl ether, filtered to remove solids, and the filtrate was evaporated under reduced pressure. Intermediate 5-4 was separated from the residue by silica gel column chromatography (elution gradient of 0-20% EtOAc:hexane).

[0282] 1 H NMR (400MHz, chloroform-d) δ. 8.26 – 8.10 (m, 4H), 7.45 – 7.21 (m, 9H), 4.68 (d, J = 11.5Hz, 1H), 4.64 – 4.53 (m, 2H), 4.45 (ddd, J = 10.8, 8.4,5.5Hz, 1H), 3.86 (ddt, J = 5.0, 3.3, 1.7Hz, 1H), 3.60 (dd, J = 10.1, 4.9Hz,1H), 3.54 (dd, J = 10.1, 6.5Hz, 1H), 3.44 (t, J = 6.7Hz, 2H), 1.56 (t, J =7.0Hz, 2H), 1.27 (d, J = 2.9Hz, 28H), 0.90 (t, J = 6.8Hz, 3H). 31 P NMR (162MHz, chloroform-d) δ .13.36 (t, J = 7.9Hz). Intermediate 5-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6- Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)((R)-2-(benzyloxy)-3-(deca-) (Hexaalkoxy)propyl)(4-nitrophenyl)phosphate Intermediate 5-4 (39.0 mg, 0.0545 mmol) and intermediate 1-3 (19.5 mg, 0.0589 mmol) were dissolved in THF (2 mL) and treated with magnesium chloride (28.0 mg, 0.294 mmol). The resulting solution was stirred at 50 °C for 15 min, at which point N,N-diisopropylethylamine (0.0500 mL, 0.287 mmol) was added, and stirring was continued at 50 °C for another 2 h. The solvent was removed under reduced pressure, and intermediate 5-5 was separated from the residue by silica gel column chromatography (elution gradient of 0-5% MeOH:DCM).

[0283] 1 H NMR (400MHz, chloroform-d) δ. 8.00 – 7.81 (m, 3H), 7.37 – 7.26 (m, 5H), 7.19 (dd, J = 15.2, 9.0Hz, 2H), 6.99 (dd, J = 7.6, 4.6Hz, 1H), 6.60 (t, J =4.9Hz, 1H), 5.77 (s, 2H), 5.46 (dd, J = 15.5, 6.9Hz, 1H), 4.94 (ddd, J =11.3, 6.9, 4.3Hz, 1H), 4.72 – 4.30 (m, 6H), 4.31 – 4.19 (m, 1H), 3.86 – 3.72(m, 1H), 3.61 – 3.45 (m, 2H), 3.42 (t, J = 6.7Hz, 2H), 1.77 (s, 3H), 1.55 (t,J = 6.9Hz, 2H), 1.40 (d, J = 3.8Hz, 3H), 1.27 (s, 28H), 0.90 (t, J = 6.7Hz,3H). 31 P NMR (162MHz, chloroform-d) δ .7.24 (q, J = 7.2Hz), -7.60 (q, J = 7.4Hz). MS m / z = 921.6 Example 5: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyloxy)-3-(hexadecyloxy)propyl)hydrogen phosphate (5) Intermediate 5-5 (13.0 mg, 0.0141 mmol) was dissolved in THF (1 mL THF), treated with 2 M NaOH aqueous solution (0.075 mL, 0.15 mmol), and heated to 50 °C. The reaction solution was stirred for 2 hours, during which time the reaction flask was placed in an ice bath and acidified with concentrated HCl aqueous solution. The reaction solution was heated to room temperature and stirred for 18 hours, during which time triethylamine was titrated until a persistent yellow color was obtained, at which point the solvent was removed under reduced pressure. The resulting residue was absorbed in a 4:1 MeOH:dioxane mixture, and compound 5 was separated as triethylammonium salt by preparative HPLC (elution gradient of 60%-100% water:i-PrOH).

[0284] 1 H NMR (400MHz, chloroform-d) δ. 7.91 (s, 1H), 7.35 – 7.19 (m, 5H), 6.90 (d, J = 4.5Hz, 1H), 6.85 (d, J = 4.6Hz, 1H), 4.65 – 4.51 (m, 3H), 3.95 (dd, J= 6.4, 4.9Hz, 1H), 3.75 (s, 2H), 3.64 (dd, J = 5.8, 4.1Hz, 1H), 3.49 – 3.26(m, 6H), 3.17 – 3.04 (m, 7H), 1.45 (t, J = 6.8Hz, 2H), 1.31 – 1.14 (m, 34H), 0.89 – 0.81 (m, 3H). MS m / z = 760.2 Example 6: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyloxy)-3-(heptadecanoxy)propyl)hydrogen phosphate Compound 6 was synthesized as a triethylammonium salt by replacing 1-heptadecanool with 1-heptadecanool in a manner similar to that of compound 5.

[0285] 1H NMR (400MHz, DMSO-d6) δ 7.91 (s, 1H), 7.35 – 7.18 (m, 5H), 6.90 (d,J = 4.6Hz, 1H), 6.84 (d, J = 4.4Hz, 1H), 4.57 (d, J = 7.5Hz, 1H), 4.18 – 3.12(m, 13H), 3.09 (q, J = 7.3Hz, 6H), 1.45 (p, J = 6.9Hz, 2H), 1.32 – 1.13 (m,37H), 0.85 (t, J = 6.6Hz, 3H). MS m / z = 774.0. Example 7: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyloxy)-3-(nonadecanoxy)propyl)hydrogen phosphate (7) Compound 7 was synthesized as a triethylammonium salt by replacing 1-hexadecaneol with 1-nonadecanol in a manner similar to that of compound 5.

[0286] 1 H NMR (400MHz, chloroform-d) δ. 7.91 (s, 1H), 7.36 – 7.20 (m, 5H), 6.90 (d, J = 4.5Hz, 1H), 6.84 (d, J = 4.5Hz, 1H), 4.64 – 4.50 (m, 3H), 3.94 (dd, J= 6.5, 4.9Hz, 1H), 3.83 (q, J = 5.9Hz, 1H), 3.72 (t, J = 5.7Hz, 2H), 3.67 –3.59 (m, 1H), 3.49 – 3.28 (m, 8H), 3.16 – 3.02 (m, 5H), 1.44 (q, J = 6.7Hz,2H), 1.23 (d, J = 5.8Hz, 32H), 1.17 (t, J = 7.3Hz, 9H), 0.89 – 0.81 (m, 3H). MS m / z = 802.2 Example 8: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyloxy)-3-(eicosyloxy)propyl)hydrogen phosphate Compound 8 was synthesized as a triethylammonium salt by replacing 1-hexadecaneol with 1-eicosanol in a manner similar to that of compound 5.

[0287] 1H NMR (400MHz, chloroform-d) δ. 7.91 (s, 1H), 7.35 – 7.18 (m, 5H), 6.90 (d, J = 4.5Hz, 1H), 6.85 (d, J = 4.5Hz, 1H), 4.64 – 4.51 (m, 3H), 4.15 (t, J= 5.2Hz, 1H), 3.94 (dd, J = 6.5, 4.9Hz, 1H), 3.85 (d, J = 5.7Hz, 1H), 3.74(d, J = 6.1Hz, 2H), 3.66 – 3.27 (m, 7H), 3.13 (td, J = 3.2, 1.6Hz, 2H), 3.08(t, J = 7.3Hz, 3H), 1.31 – 1.14 (m, 45H), 0.89 – 0.81 (m, 3H). MS m / z = 816.2 Intermediate 9-1: (S)-3-(octadecyloxy)propane-1,2-diol [1-O-octadecyl-sn-glycerol] A mixture of (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (6.68 g, 50.6 mmol), powdered potassium hydroxide (10 g, 178 mmol), and 1-bromooctadecane (16.9 g, 50.6 mmol) in benzene (100 mL) was stirred under reflux for 15 hours while removing the water formed by azeotropic distillation. The reaction mixture was then cooled to room temperature, filtered, and the volume of solvent was reduced by half. Water (100 mL) was added, and the mixture was extracted with diethyl ether (3 × 100 mL). The combined organic phases were combined, dried over Na₂SO₄, filtered, and the solvent was removed under reduced pressure to give the intermediate.

[0288] 1 ¹H NMR (400MHz, chloroform-d) δ 4.29 (p, J = 6.0Hz, 1H), 4.08 (dd, J = 8.3, 6.4Hz, 1H), 3.75 (dd, J = 8.2, 6.4Hz, 1H), 3.60 – 3.37 (m, 4H), 1.58 (q, J = 7.1Hz, 2H), 1.45 (s, 3H), 1.39 (s, 3H), 1.27 (s, 30H), 0.90 (t, J = 6.7Hz, 3H). Add 2M HCl solution (13 mL, 26 mmol) to a methanol (80 mL) solution of the above crude intermediate (5 g, 13 mmol), and heat the solution to reflux for 4 hours. After cooling to room temperature, pour the mixture into water, extract the organic layer with diethyl ether, dry with Na2SO4 and remove the solvent under vacuum to obtain a small volume, precipitate the product from hexane to give intermediate 9-1.

[0289] 1 ¹H NMR (400MHz, chloroform-d) δ 3.93 – 3.84 (m, 1H), 3.79 – 3.64 (m, 2H), 3.61 – 3.42 (m, 4H), 1.59 (q, J = 6.9Hz, 2H), 1.28 (s, 30H), 0.96 – 0.84 (m, 3H). Intermediate 9-2: 1-O-octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol At 0 °C, tert-butylchlorodimethylsilane (1.44 g, 9.58 mmol) was added to a solution of (S)-3-(octadecoxy)propane-1,2-diol (3 g, 8.71 mmol) and imidazole (120 mg, 0.75 mmol) in a mixture of pyridine (45 mL), CH2Cl2 (5 mL), and DMF (5 mL). After stirring at room temperature for 5 hours, the reaction mixture was diluted with water (10 mL), extracted with CH2Cl2, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by rapid chromatography (0-30% EtOAc in hexane) to give the product.

[0290] 1 ¹H NMR (400MHz, chloroform-d) δ 3.93 – 3.77 (m, 1H), 3.73 – 3.60 (m, 2H), 3.53 – 3.38 (m, 4H), 1.72 – 1.48 (m, 2H), 1.27 (s, 30H), 1.01 – 0.83 (m, 12H), 0.11 (d, J = 11.7Hz, 6H). Intermediate 9-3: (R)-4-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2- (Benzyl)oxymethyl)benzyl nitrile NaH (60% oily dispersion, 143 mg, 3.74 mmol) was suspended in THF (8 mL) and cooled to 0 °C. A solution of 1-O-octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol (350 mg, 0.763 mmol) in THF (3 mL) was added over 30 seconds. After 30 minutes, a solution of 4-(bromomethyl)benzyl nitrile (493 mg, 2.52 mmol) in THF (3 mL) was added at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (15 mL). The mixture was extracted with EtOAC. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by rapid chromatography (0-30% EtOAc in hexane) to give the product.

[0291] 1 ¹H NMR (400MHz, chloroform-d) δ 7.77 – 7.58 (m, 2H), 7.58 – 7.42 (m, 2H), 4.79 (s, 1H), 4.50 (m, 2H), 3.86 – 3.34 (m, 6H), 1.58 (m, 2H), 1.27 (m, 30H), 0.91 (m, 12H), 0.07 (s, 6H). Intermediate 9-4: (S)-4-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)benzylnitrile At 0 °C, a solution of 1 M TBAF in THF (1 mL, 1 mmol) was added to a THF (3.6 mL) solution of silyl-protected compound 9-3 (480 mg, 0.836 mmol) and stirred for 1 hour. The solution was diluted with water (3 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (2 × 5 mL) and brine, dried over Na₂SO₄, evaporated, and the residue was purified by column chromatography (silica gel, 0-60% ethyl acetate in hexane) to give the product.

[0292] 1 H NMR (400MHz, DMSO-d6) δ 7.81 (d, J = 1.8Hz, 1H), 7.79 (d, J =1.9Hz, 1H), 7.54 (q, J = 8.1Hz, 2H), 4.81 – 4.62 (m, 3H), 3.60 – 3.39 (m,6H), 1.46 (q, J = 6.7Hz, 2H), 1.23 (m, 30H), 0.95 – 0.72 (m, 3H). Intermediate 9-5: (7-((3aR,4R,6R,6aR)-6-((((2-chlorophenoxy)((R)-2-((4-cyanobenzyl)oxy) 3-(octadecyloxy)propoxy)phosphoyl)oxy)methyl)-4-cyano-2,2-dimethyltetrahydrofurano[3,4-d] [1,3]dioxacyclopenten-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)tert-butyl carbamate A solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL) was added to an anhydrous THF (0.4 mL) solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 µL, 0.62 mmol). The mixture was stirred for 30 minutes and then filtered. Additional THF (1.2 mL), nucleoside (100 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol) were added sequentially to the filtrate. After 1 hour, (S)-4-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)benzyl nitrile (107 mg, 0.232 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by silica gel rapid chromatography (0–15% MeOH in CH2Cl2) to give the compound (136 mg, 55%).

[0293] 1 ¹H NMR (400MHz, chloroform-d) δ 8.35 – 8.10 (m, 1H), 7.65 (d, 2H), 7.58 (m, 1H), 7.49 (d, J = 8.0Hz, 2H), 7.46 – 7.31 (m, 2H), 7.23 – 7.00 (m, 3H), 5.53– 5.23 (m, 1H), 5.06 – 4.10 (m, 6H), 3.91 – 3.26 (m, 5H), 1.77 (m, 2H), 1.59 (s, 6H), 1.47 (s, 9H), 1.27 (s, 30H), 0.89 (t, J = 6.7Hz, 3H). 31 P NMR (162MHz, chloroform-d) δ -6.94 (m). Example 9: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((4-cyanobenzyl)oxy)-3-(octadecyloxy)propyl) hydrogen phosphate (9) The intermediate (130 mg, 0.122 mmol) was dissolved in 2.5 mL of THF, and 0.5 N NaOH (0.9 mL, 3.6 equivalents) was added. The mixture was stirred at 50 °C for 4 hours. The reaction progress was monitored by TLC. After the intermediate was consumed, the mixture was neutralized with 1 N HCl at 0 °C. The mixture was diluted with a buffer solution (pH 3) and brine, and extracted twice with a mixture of DCM and MeOH. The combined organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the residue.

[0294] The residue was dissolved in THF (0.6 mL). The resulting solution was cooled in an ice bath. Concentrated HCl aqueous solution (0.12 mL) was added. The cold bath was removed, and the reaction mixture was stirred vigorously for 3 hours. The mixture was neutralized with Na₂CO₃, diluted with MeOH, and filtered. The filtrate was evaporated to obtain the residue, which was purified by preparative HPLC (Gemini column, 50%-100% isopropanol in H₂O) to give compound 9.

[0295] 1 H NMR (400MHz, methanol-d4) δ 8.07-8.21 (d, 1H), 7.63 (dd, J = 8.2,1.7Hz, 2H), 7.53 (dd, J = 10.5, 8.2Hz, 2H), 7.31 (dd, J = 7.4, 4.8Hz, 1H),7.21 (dd, J = 14.6, 4.8Hz, 1H), 4.85 – 4.65 (m, 3H), 4.44 – 4.31 (m, 1H),4.29 – 4.18 (m, 2H), 4.18 – 3.86 (m, 4H), 3.85 – 3.37 (m, 5H), 1.62 (s, 4H), 1.59 – 1.48 (m, 2H), 1.42 – 1.20 (m, 30H), 0.92 (t, J = 6.8Hz, 3H). 31 P NMR (162MHz, methanol-d4) δ 0.16. Example 10: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((4-methoxybenzyl)oxy)-3-(octadecyloxy)propane (10) Hydrogen phosphate Compound 10 was synthesized in a manner similar to that of Compound 9, using 4-methoxybenzyl bromide instead of 4-cyanobenzyl bromide.

[0296] 1H NMR (400MHz, DMSO-d6) δ 7.93 (m, 2H, 1 proton D2O exchangeable),7.26 – 7.18 (m, 2H), 6.90 (d, J = 4.5Hz, 1H), 6.85 (m, 3H), 6.34 (d, J =6.1Hz, 1H, D2O exchangeable), 4.64 (t, J = 5.3Hz, 1H), 4.55 – 4.41 (m, 2H), 4.30 – 4.05 (m, 2H), 4.06 – 3.78 (m, 5H), 3.72 (s, 3H), 3.70 – 3.59 (m, 1H), 1.43 (t, J = 6.9Hz, 2H), 1.22 (d, J = 7.9Hz, 30H), 0.93 – 0.78 (m, 3H). 31 P NMR (162MHz, DMSO-d6) δ -1.09. Example 11: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-3-(octadecyloxy)-2-((4-(trifluoromethyl)benzyl)oxy) Propyl) hydrogen phosphate (11) Compound 11 was synthesized in a manner similar to that of Compound 9, using 4-trifluoromethylbenzyl bromide instead of 4-cyanobenzyl bromide.

[0297] 1 H NMR (400MHz, DMSO-d6) δ 7.92 (m, 3H, 2 proton D2O exchangeable), 7.66 (d, J = 8.1Hz, 2H), 7.54 (d, J = 8.0Hz, 2H), 6.90 (d, J = 4.5Hz, 1H), 6.84 (d, J = 4.5Hz, 1H), 6.35 (d, J = 6.0Hz, 1H, D2O exchangeable), 4.75 –4.59 (m, 3H), 4.17 (m, 2H), 3.94 (m, 4H), 3.70 (m, 1H), 3.44 (m, 4H), 1.42(m, 2H), 1.21 (m, 30H), 0.93 – 0.79 (m, 3H). 31 P NMR (162MHz, DMSO-d6) δ -1.10 (m). Intermediate 12-1: (R)-2-(benzyloxy)-3-(octadecyloxy)propyl(2-chlorophenyl)triethylammonium phosphate 2-Chlorophenyl dichlorophosphate (2.2 g, 8.97 mmol) was dissolved in acetonitrile (30 mL) and cooled to 0 °C. 1,2,4-triazole (1.33 g, 19.3 mmol) was added to this solution, followed by slow addition of TEA (2.69 mL, 19.3 mmol). The cold bath was removed and the mixture was stirred at room temperature for 45 min. A solution of (S)-2-(benzyloxy)-3-(octadecyloxy)prop-1-ol (3.9 g, 8.97 mmol) in pyridine (40 mL) was slowly added to the stirred mixture, and the mixture was stirred at room temperature for 4 h. TEA (2.69 mL) was added to the mixture, followed by water (1.5 mL), and the mixture was stirred for 25 min. Saturated NaHCO3 (20 mL) was then added and the mixture was stirred for another 10 min. The mixture was diluted with more saturated NaHCO3 and then extracted with DCM (2 × 100 mL). The combined organic layers were washed with a 1:1:1 mixture of water, brine, and saturated NaHCO3 (180 mL). The combined organic layers were dried over Na2SO4, concentrated, co-evaporated with toluene (50 mL × 2), and dried under high vacuum. The crude product was dissolved in 5% MeOH / DCM, loaded onto a 220 g gold column, and eluted with 0-40% MeOH. The product was then eluted with 20% MeOH / DCM, showing two broad peaks (elongated peaks). The pure fractions (verified by TLC / LCMS) were combined and concentrated to give intermediate 12-1.

[0298] MS m / z = 625.4 [M+1] 1H NMR (400MHz, DMSO-d6) δ 9.90 (s, 1H), 7.62 (dd, J = 8.4, 1.4Hz, 1H), 7.39 – 7.22 (m, 6H), 7.15 (td, J = 8.3, 7.8, 1.7Hz, 1H), 6.94 (td, J =7.7, 1.5Hz, 1H), 4.56 (d, J = 2.4Hz, 2H), 4.17 – 4.05 (m, 1H), 3.89 – 3.74(m, 2H), 3.69 – 3.59 (m, 1H), 3.47 – 3.26 (m, 6H), 3.04 (qd, J = 7.2, 4.5Hz,5H), 1.43 (q, J = 6.6Hz, 2H), 1.23 (d, J = 2.6Hz, 32H), 1.16 (t, J = 7.3Hz, 9H), 0.90 – 0.81 (m, 3H). 31 P NMR (162MHz, DMSO-d6) δ -5.82. Intermediate 12-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-(benzyloxy)- 3-(octadecyloxy)propyl)(2-chlorophenyl)phosphate Intermediate 12-1 (3.0 g, 9.05 mmol) was dissolved in pyridine (80 mL). 1-(trimethylbenzene-2-sulfonyl)-3-nitro-1,2,4-triazole (4.02 g, 13.6 mmol) was added to this solution, followed by intermediate 1-3 (3.0 g, 9.05 mmol). NMI (1.12 mL, 13.6 mmol) was added to this solution, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled in an ice bath and quenched by the slow addition of a saturated aqueous solution of NaHCO3. The aqueous layer was diluted with a 1:1:1 mixture of water, saturated aqueous solution of NaHCO3, and brine. The aqueous layer was extracted with DCM (2 × 400 mL), and the combined organic matter was dried over Na2SO4 and removed by filtration. The filtrate was concentrated, and intermediate 12-2 was separated by silica gel column chromatography (220g, Combi flash HP Gold column, eluent gradient of 0-100% EtOAc / hexane).

[0299] MS m / z = 938.3 [M+1] Intermediate 12-3: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5- Cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyloxy)-3-(octadecyloxy)propyl)(2-chlorobenzene Phosphate ester. Intermediate 12-2 (0.5 g, 0.533 mmol) was dissolved in THF (20 mL). Concentrated HCl (3.32 mL, 50.6 mmol) was added dropwise to this solution at 0 °C. The reaction mixture was heated and stirred at room temperature for at least 4 hours. After completion, the reaction mixture was concentrated, and the residue was co-evaporated with THF (2 × 30 mL) and DCM (2 × 30 mL). The resulting residue was absorbed into DCM, and intermediate 12-3 was separated by silica gel column chromatography (40 g Combi flash HP Gold column, eluent gradient 0-40% MeOH / DCM).

[0300] MS m / z = 898.4 [M+1] Intermediate 12-4: (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-(((((R)-2-(benzyloxy)-3-(octadecyloxy)propoxy)(2-chlorophenoxy)phosphoryl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofuran-3-yl isobutyrate.

[0301] Intermediate 13-4: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((((R)-2-(benzyloxy)-3-(octadecyloxy)propoxy)(2-chlorophenoxy)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-dimethylbis(2-methylpropionate). DMAP (0.272 mg, 2.23 mmol) was added in a single batch to a mixture of intermediate 12-3 (0.5 g, 0.557 mmol), 2-methylpropionic acid (98.1 mg, 1.11 mmol), and EDCI (0.427 mg, 2.23 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1.2 h. The reactants were diluted with DCM, washed with water, then washed with a saturated ammonium chloride solution, dried over sodium sulfate, concentrated, and dried under high vacuum. The resulting crude residue contained intermediates 12-4 and 13-4 as confirmed by LCMS and was used in the next step.

[0302] Intermediate 12-4: MS m / z = 968.5 [M+1] Intermediate 13-4: MS m / z = 1038.7 [M+1] Example 12: (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-(((((R)-2-(benzyloxy)-3-(octadecyloxy)propoxy)(hydroxy)phosphoryl)oxy)methyl)-5-cyano-4-hydroxytetrahydrofuran-3-yl isobutyrate (12) Example 13: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((((R)-2-(benzyloxy)-3-(octadecyloxy)propoxy)(hydroxy)phosphoryl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-dimethylbis(2-methylpropionate) (13) A crude mixture of intermediates 12-4 and 13-4 (0.5 g, 0.451 mmol) was dissolved in THF (10.2 mL), and pyridine (1.25 mL) was added, followed by water (1.25 mL). A 1 M solution of TBAF in THF (1.8 mL, 0.43 mmol) was added to the resulting clear, homogeneous solution. The reaction mixture was stirred at room temperature for more than 3 hours. After confirming the completion of the reaction by LCMS, the reaction mixture was cooled in an ice bath and quenched with a saturated aqueous solution of NaHCO3 (5 mL). The reaction mixture was concentrated to remove most of the volatiles and partitioned between DCM and water. 2N HCl was added dropwise to the stirred solution to adjust the pH to approximately 3, and the mixture was extracted with DCM (2 × 100 mL). The combined organic phases were washed once with brine (adjusted to pH 8 with a saturated aqueous solution of NaHCO3), dried over Na2SO4, and removed by filtration. The filtrate was concentrated, and the crude product was dissolved in a mixture of MeOH / dioxane / water (approximately 6:1:0.1 mL), sonicated to complete dissolution, filtered, and purified by preparative HPLC (Gemini, 10 µM, NX-C18, 110 Å, 250 mm × 30 mm column, gradient 60%–100%, 16 min, acetonitrile / water, and 100% acetonitrile, 16 min, to give compounds 12 and 13).

[0303] Compound 12 MS m / z = 858.5 [M+1] 11H NMR (400 MHz, chloroform-d) δ 8.05 (s, 1H), 7.28 (s, 5H), 6.94 (d, J = 4.6 Hz, 1H), 6.64 (d, J = 4.7 Hz, 1H), 6.27 (d, J = 5.9 Hz, 1H), 5.61 (s, 2H), 5.53 (dd, J = 5.9, 4.2 Hz, 1H), 4.65 (q, J = 4.1 Hz, 1H), 4.41 (qd, J = 12.3, 4.1 Hz, 2H), 4.28 – 4.03 (m, 1H), 4.02 – 3.84 (m, 1H), 3.87 – 3.59 (m, 2H), 3.58 – 3.22 (m, 1H), 2.80 – 2.48 (m, 3H), 1.48 (d, J = 32.7 Hz, 2H), 1.39 – 1.04 (m, 38H), 0.93 (dt, J = 23.4, 7.1 Hz, 3H). Compound 13 MS m / z = 928.5 [M+1] 1H NMR (400MHz, chloroformd) δ 7.87 (s, 1H), 7.34 – 7.17 (m, 5H), 6.92 (s,2H), 6.90 (d, J = 4.8Hz,1H), 6.68 (d, J = 4.7Hz, 1H), 6.23 (d, J = 6.0Hz,1H), 5.46 (dd, J = 6.0, 4.2Hz, 1H), 5.08 (t, J = 2.8Hz, 1H), 4.72 – 4.49 (m,2H), 4.30 (qd, J = 10.9, 4.5Hz, 1H), 4.19 (ddd, J = 11.9, 7.8, 4.2Hz, 1H),4.06 (dq, J = 12.9, 6.7Hz, 1H), 3.75 (td, J = 8.7, 8.1, 3.2Hz, 2H), 3.65 (dt,J = 11.6, 3.0Hz, 1H), 3.57 – 3.41 (m, 1H), 3.40 – 3.25 (m, 1H), 3.24 – 3.13(m, 1H), 2.74 – 2.58 (m, 2H), 1.53 – 1.35 (m, 3H), 1.32 – 1.21 (m, 36H), 1.21– 1.15 (m, 7H), 0.90 (t, J = 6.7Hz, 3H). Intermediate 14-0: (2R)-1-[tert-butyl(dimethyl)silyl]oxy-3-octadecyloxy-prop-2-ol At 0 °C, a solution of tert-butyldimethylsilyl chloride (350 mg, 2.32 mmol) in dichloromethane (2 mL) was added over 1 minute to a solution of (2S)-3-octadecoxypropane-1,2-diol (500 mg, 1.45 mmol) and imidazole (198 mg, 2.90 mmol) in dichloromethane (5 mL). After 2 hours, the ice bath was removed. After 3 hours, the reaction mixture was washed with water (5 mL). The aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to rapid chromatography (0-30% ethyl acetate / hexane). The fractions containing the product were combined and the solvent was removed under reduced pressure to give intermediate 14-0.

[0304] 1¹H NMR (400MHz, chloroform-d) δ 3.83 (p, J = 5.4Hz, 1H), 3.74 – 3.62 (m, 2H), 3.50 – 3.42 (m, 4H), 1.58 (q, J = 7.0Hz, 2H), 1.27 (m, 30H), 0.91 (m, 12H), 0.09 (s, 6H). Intermediate 14-1: tert-butyl-[(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy-propoxy [B-dimethylsilane] A 60% dispersion of sodium hydride in mineral oil (53.4 mg, 1.39 mmol) was suspended in tetrahydrofuran (5 mL) and cooled to 0 °C. A solution of 14-0 (320 mg, 0.697 mmol) in tetrahydrofuran (2 mL) was added over 30 seconds. After 30 minutes, a solution of 4-(bromomethyl)-1,2-difluorobenzene (178 µL, 1.39 mmol) in tetrahydrofuran (2 mL) was added. The ice bath was removed. After 16 hours, the reaction was determined to be complete by TLC (15% ethyl acetate / hexane). The reactants were quenched with water (10 mL) at 0 °C. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to rapid chromatography (0–20% ethyl acetate / hexane, detected using ELSD). Fractions containing the product were combined and the solvent was removed under reduced pressure to give intermediate 14-1.

[0305] 1 H NMR (400MHz, chloroform-d) δ 7.25 (dd, J = 7.4, 4.8Hz, 1H), 7.18 – 7.03(m, 2H), 4.67 (s, 2H), 3.71 (d, J = 6.0Hz, 2H), 3.63 (p, J = 5.3Hz, 1H), 3.56(dd, J = 10.3, 4.2Hz, 1H), 3.50 (dd, J = 10.3, 5.8Hz, 1H), 3.45 (t, J =6.8Hz, 2H), 1.58 (q, J = 7.2Hz, 2H), 1.27 (s, 30H), 0.91 (d, J = 5.7Hz, 12H),0.08 (s, 6H). 19 F NMR (376MHz, chloroform-d) δ -138.62 – -138.83 (m), -140.54 – -140.77 (m). Intermediate 14-2: (2S)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy-prop-1-ol A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.995 mL, 0.995 mmol) was added to a solution of intermediate 14-1 (194 mg, 0.332 mmol) in tetrahydrofuran (5 mL). After 45 minutes, the reaction mixture was diluted with ethyl acetate (20 mL). The organic phase was washed with water (3 × 5 mL) and brine (5 mL). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to rapid chromatography (0–20% ethyl acetate / hexane, using ELSD). Fractions containing the product were combined and the solvent was removed under reduced pressure to give intermediate 14-2.

[0306] Intermediate 14-3: [(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy-propyl]bis(4-nitro] Phenyl phosphate At 0 °C, a solution of intermediate 14-2 (143 mg, 0.304 mmol) in dichloromethane (2 mL) was added to a solution of 4-nitrophenyl dichlorophosphate (93.5 mg, 0.365 mmol) in dichloromethane (5 mL). Triethylamine (106 µL, 0.761 mmol) was added. After 5 minutes, the bath was removed. After 2 hours, 4-nitrophenol (59.3 mg, 0.426 mmol) was added. After 1 hour, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 × 5 mL) and brine (5 mL). The residue was subjected to rapid chromatography (0-50% ethyl acetate / hexane). Fractions containing the product were combined and the solvent was removed under reduced pressure to give intermediate 14-3.

[0307] 1 H NMR (400MHz, chloroform-d) δ 8.30 – 8.19 (m, 4H), 8.13 (d, J = 9.1Hz,0.41H), 7.46 – 7.35 (m, 4H), 7.23 – 7.14 (m, 1H), 7.10 (dt, J = 10.1, 8.1Hz,1H), 7.04 – 6.95 (m, 1H), 4.63 – 4.51 (m, 3H), 4.42 (m, 1H), 3.83 (m, 1H), 3.55 (m, 2H), 3.43 (t, J = 6.6Hz, 2H), 1.55 (q, J = 6.8Hz, 2H), 1.26 (m,30H), 0.89 (t, J = 6.7Hz, 3H). 19F NMR (376MHz, chloroform-d) δ -137.88 (ddd, J = 21.0, 11.1, 8.0Hz), -139.15 – -139.37 (m). 31 P NMR (162MHz, chloroform-d) δ -13.10 (t, J = 8.0Hz). Intermediate 14-4: [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 4-Cyano-2,2-dimethyl-6,6a-dihydro-3aH-furano[3,4-d][1,3]dioxacyclopenten-6-yl]methyl [(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxypropyl](4-nitrophenyl)phosphate Magnesium chloride (31.3 mg, 0.329 mmol) was added to a tetrahydrofuran (5 mL) solution of intermediate 14-3 (52.2 mg, 0.0658 mmol) and intermediate 1-3 (20.7 mg, 0.0625 mmol). The mixture was stirred at 50 °C for 15 min. The mixture was briefly cooled and N,N-diisopropylethylamine (0.057 mL, 0.329 mmol) was added. After 2 hours, the reaction mixture was quenched with water (5 mL) and brine (5 mL). The mixture was extracted with 2-methyltetrahydrofuran (3 × 10 mL). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to rapid chromatography (0-10% methanol / dichloromethane). The fractions containing the product were combined and the solvent was removed under reduced pressure to give intermediate 14-4.

[0308] 1H NMR (400MHz, chloroform-d) δ 8.01 (d, J = 9.1Hz, 1H), 7.91 – 7.85 (m,2H), 7.31 – 7.18 (m, 3H), 7.17 – 7.00 (m, 3H), 6.98 (dd, J = 6.9, 4.6Hz, 1H), 6.59 (t, J = 4.6Hz, 1H), 5.85 (m, 2H), 5.48 (dd, J = 9.2, 6.9Hz, 1H), 4.95(m, 1H), 4.65 – 4.55 (m, 3H), 4.52 (m, 1H), 4.48 – 4.42 (m, 1H), 4.42 – 4.31(m, 1H), 4.25 (m, 1H), 3.83 – 3.71 (m, 1H), 3.50 (m, 2H), 3.42 (td, J = 6.7,3.6Hz, 2H), 1.76 (s, 3H), 1.54 (q, J = 6.8Hz, 2H), 1.40 (d, J = 3.9Hz, 3H), 1.37 – 1.20 (m, 30H), 0.95 – 0.86 (m, 3H). MS m / z [M+1] = 985.35 19 F NMR (377MHz, chloroform-d) δ -137.94 – -138.19 (m), -139.46 – -139.82 (m). 31 P NMR (162MHz, chloroform-d) δ -7.15 (p, J = 7.4Hz), -7.51 (p, J = 7.4Hz). Example 14: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3,4-difluorobenzyl)oxy)-3-(octadecyloxy)propane (14) Hydrogen phosphate A sodium hydroxide solution (1N, 0.14 mL, 0.14 mmol) was added to a tetrahydrofuran (5 mL) solution of intermediate 14-4 (34.4 mg, 0.0349 mmol), and the mixture was heated at 50 °C. After 2 hours, the residual starting material was collected. After 5 hours, the reaction mixture was cooled and diluted with 2-methyltetrahydrofuran (10 mL) and hydrochloric acid (1N, 0.3 mL, 0.3 mmol). The aqueous phase was extracted with 2-methyltetrahydrofuran (2 × 10 mL). The combined organic phases were washed with brine (10 mL) and dried over sodium sulfate. The residue was subjected to rapid chromatography (0-20% methanol / dichloromethane). The fractions containing the product were combined and the solvent was removed under reduced pressure to obtain [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furano[3,4-d][1,3]dioxacyclopenten-6-yl]methyl[(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy-propyl]hydrogen phosphate.

[0309] MS m / z [M+1] = 864.28 Concentrated hydrochloric acid (12N, 0.30 mL, 3.69 mmol) was added to a solution of [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furano[3,4-d][1,3]dioxacyclopenten-6-yl]methyl[(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy-propyl]hydrogen phosphate (24.5 mg, 0.0295 mmol). After 2 hours, triethylamine (0.51 mL, 3.69 mmol) was added. A minimum amount of methanol was added to the mixture to dissolve any solids. The solution was subjected to preparative HPLC (50%–100% isopropanol / water, within 20 minutes). The fractions containing the product were combined, and isopropanol was removed under reduced pressure. The residue was absorbed in 1,4-dioxane (5 mL) and lyophilized. Further purification was required. The product was subjected to preparative HPLC (50%–100% isopropanol / water, over 20 minutes). The fractions containing the product were combined, and isopropanol was removed under reduced pressure. The residue was absorbed in 1,4-dioxane (5 mL) and lyophilized to give compound 14.

[0310] 1H NMR (400MHz, DMSO-d6) δ 12.13 – 12.04 (m, 0.15H), 8.12 – 7.67 (m,3H), 7.42 – 7.24 (m, 2H), 7.18 – 7.10 (m, 1H), 6.94 – 6.74 (m, 2H), 6.27 – 6.20 (m, 1H), 5.92 – 5.83 (m, 1H), 4.67 – 4.48 (m, 3H), 4.24 – 4.10 (m, 1H), 4.03 – 3.89 (m, 1H), 3.89 – 3.77 (m, 1H), 3.72 (q, J = 4.9Hz, 1H), 3.68 –3.57 (m, 3H), 3.57 – 3.40 (m, 2H), 3.40 – 3.27* (m, 2H / 7H), 1.45 (p, J =6.7Hz, 2H), 1.22 (d, J = 7.6Hz, 30H), 0.90 – 0.81 (m, 3H). *Peaks overlap with water.

[0311] 19 F NMR (376MHz, DMSO-d6) δ -139.77 (dddd, J = 33.5, 25.3, 11.7, 8.2Hz), -141.80 (dddt, J = 37.3, 23.1, 11.8, 4.8Hz). 31 P NMR (162MHz, DMSO-d6) δ 0.26 – -0.34 (m). MS m / z [M+1] = 824.18 Example 15: [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano [(2R)-2-[(3,5-difluorophenyl)methoxy]-3-octadecyloxy- [Propyl] hydrogen phosphate (15) Compound 15 was synthesized in a manner similar to that of Compound 14, using 5-(bromomethyl)-1,3-difluorobenzene instead of 4-(bromomethyl)-1,2-difluorobenzene.

[0312] 1H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 6.98 (d, J = 4.6Hz, 1H), 6.96 – 6.91 (m, 2H), 6.89 (d, J = 4.6Hz, 1H), 6.75 (tt, J = 9.2, 2.5Hz, 1H), 4.84 (d, J = 5.4Hz, 1H), 4.72 – 4.55 (m, 2H), 4.44 – 4.36 (m, 1H), 4.27 (t, J= 5.5Hz, 1H), 4.25 – 4.14 (m, 1H), 4.14 – 4.04 (m, 1H), 3.97 – 3.84 (m, 2H), 3.77 – 3.66 (m, 2H), 3.59 – 3.43 (m, 2H), 3.43 – 3.37 (m, 2H), 1.59 – 1.48(m, 2H), 1.40 – 1.21 (m, 30H), 0.91 (t, J = 6.6Hz, 3H). 19 F NMR (377MHz, methanol-d4) δ -112.53 (t, J = 8.3Hz). 31 P NMR (162MHz, methanol-d4) δ -0.65. MS m / z [M+1] = 824.17 Example 16: [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano [(2R)-2-[(3-cyano-5-fluoro-phenyl)methoxy]-3-octadecyloxy]

[16] Hydrogen phosphate (16) Compound 16 was synthesized in a manner similar to that of Compound 14, using 5-(bromomethyl)-1-cyano-3-fluorobenzene instead of 4-(bromomethyl)-1,2-difluorobenzene.

[0313] 1H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.52 (s, 1H), 7.44 (dd, J =9.6, 2.5Hz, 1H), 7.36 (d, J = 8.3, 2.5Hz, 1H), 6.98 (d, J = 4.6Hz, 1H), 6.88(d, J = 4.6Hz, 1H), 4.85 (d, J = 5.5Hz, 1H), 4.78 – 4.60 (m, 2H), 4.42 – 4.33(m, 1H), 4.27 (t, J = 5.5Hz, 1H), 4.22 – 4.13 (m, 1H), 4.13 – 4.03 (m, 1H),4.00 0.91 (t, J = 6.6Hz, 3H). 19 F NMR (377MHz, methanol-d4) δ -112.78 (t, J = 8.8Hz). 31 P NMR (162MHz, methanol-d4) δ -0.47. MS m / z [M+1] = 831.21. Example 17: [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano [(2R)-2-[(3-cyano-5-fluoro-phenyl)methoxy]-3-octadecyloxy]

[17] Hydrogen phosphate (17) Compound 17 was synthesized in a manner similar to that of Compound 14, using 4-(bromomethyl)-2-chloro-1-fluoro-benzene instead of 4-(bromomethyl)-1,2-difluoro-benzene.

[0314] 1H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.44 (dd, J = 7.2, 2.1Hz,1H), 7.30 – 7.22 (m, 1H), 7.12 (t, J = 8.8Hz, 1H), 6.99 (d, J = 4.6Hz, 1H), 6.89 (d, J = 4.6Hz, 1H), 4.85 (d, J = 5.4Hz, 1H), 4.68 – 4.50 (m, 2H), 4.41 –4.34 (m, 1H), 4.27 (t, J = 5.4Hz, 1H), 4.24 – 4.13 (m, 1H), 4.13 – 4.03 (m,1H), 3.97 – 3.83 (m, 2H), 3.77 – 3.62 (m, 2H), 3.59 – 3.42 (m, 2H), 3.39 (td,J = 6.5, 2.4Hz, 2H), 1.59 – 1.47 (m, 2H), 1.39 – 1.20 (m, 30H), 0.91 (t, J =6.7Hz, 3H). 19 F NMR (377MHz, methanol-d4) δ -120.49 (td, J = 8.4, 4.9Hz). 31 P NMR (162MHz, methanol-d4) δ -0.26. MS m / z [M+1] = 840.18 Intermediate 18-1: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol At 0 °C, a solution of octadecane-1-ol (10.1 g, 37.4 mmol) in tetrahydrofuran (30 mL) was added via a syringe to a vigorously stirred mixture of sodium hydride (1.50 g, 39.1 mmol). The reaction mixture was fitted with a reflux condenser and heated to 80 °C. After 2 hours, tert-butyl-dimethyl-[[(2S)-epoxyethylene-2-yl]methoxy]silane (4.70 g, 25.0 mmol) was added via syringe. After 17 hours, the reaction mixture was cooled to room temperature. A saturated aqueous solution of ammonium chloride (50 mL), water (100 mL), and diethyl ether (200 mL) were added sequentially. The organic layer was extracted with water, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 10% ethyl acetate in hexane) to give intermediate 18-1.

[0315] Intermediate 18-2: [(2S)-2-benzyloxy-3-octadecyloxy-propoxy]-tert-butyl-dimethyl-silane At 0 °C, a solution of intermediate 18-1 (300 mg, 650 µmol) in tetrahydrofuran (3.0 mL) was added via syringe to a vigorously stirred mixture of sodium hydride (50 mg, 1.3 mmol) in tetrahydrofuran (6.0 mL). After 45 minutes, a solution of bromomethylbenzene (280 mg, 1.6 mmol) in tetrahydrofuran (3.0 mL) was added via syringe. The reaction mixture was heated to room temperature. After 16 hours, the reaction mixture was cooled to 0 °C. Water (30 mL), ethyl acetate (50 mL), and brine (20 mL) were added sequentially. The aqueous layer was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 20% ethyl acetate in hexane) to give intermediate 18-2.

[0316] Intermediate 18-3: (2R)-2-benzyloxy-3-octadecyloxy-prop-1-ol A solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 623 µL, 623 µmol) was added via syringe to a stirred solution of intermediate 18-2 (114 mg, 208 µmol) in tetrahydrofuran (3.0 mL). After 45 minutes, ethyl acetate (10 mL) and water (10 mL) were added sequentially. The organic layer was washed with water (10 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate in hexane) to give intermediate 18-3.

[0317] Intermediate 18-4: [(2S)-2-benzyloxy-3-octadecyloxy-propyl]bis(4-nitrophenyl)phosphate Intermediate 18-4 was prepared in a manner similar to that of intermediate 2-3, using intermediate 18-3 instead of intermediate 2-2.

[0318] Intermediate 18-5: [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 4-Cyano-2,2-dimethyl-6,6a-dihydro-3aH-furano[3,4-d][1,3]dioxacyclopenten-6-yl]methyl [(2S)-2-benzyloxy-3-octadecyloxy-propyl](4-nitrophenyl)phosphate Intermediate 18-5 was prepared in a manner similar to that of intermediate 2-4, using intermediate 18-4 instead of intermediate 2-3.

[0319] Example 18: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((S)-2-(benzyloxy)-3-(octadecyloxy)propyl)hydrogen phosphate （18） At 50 °C, an aqueous solution of sodium hydroxide (2.0 M, 62 µL, 130 µmol) was added to a vigorously stirred solution of intermediate 18-5 (12 mg, 13 µmol) in tetrahydrofuran (2.0 mL). After 90 minutes, the resulting mixture was cooled to room temperature. A few drops of concentrated hydrochloric acid were added until the resulting mixture had a pH < 1. After 16 hours, triethylamine was added until the mixture had a pH > 7, as indicated by a persistent yellow color. The mixture was purified by reversed-phase preparative HPLC (2-propanol / water) to give compound 18, which forms a complex with triethylamine.

[0320] 1 H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.34 (d, J = 7.5Hz, 2H), 7.28(t, J = 7.4Hz, 2H), 7.23 (d, J = 7.2Hz, 1H), 7.01 (d, J = 4.6Hz, 1H), 6.89(d, J = 4.6Hz, 1H), 4.83 (d, J = 5.2Hz, 2H), 4.66 (d, J = 11.8Hz, 1H), 4.62 –4.52 (m, 2H), 4.34 (s, 1H), 4.26 (t, J = 5.3Hz, 1H), 4.17 – 3.98 (m, 2H),3.87 (t, J = 5.6Hz, 2H), 3.71 (d, J = 6.2Hz, 1H), 3.47 – 3.42 (m, 1H), 3.39(d, J = 2.1Hz, 1H), 1.51 (d, J = 6.8Hz, 2H), 1.29 (d, J = 7.3Hz, 30H), 0.92(t, J = 6.7Hz, 3H). LCMS: 788.305. Intermediate 19-0: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2, 2-Dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-6-(prop-1-en-2-yl)-2-sulfonylhexahydrobenzo[d][1,3, 2]Oxathiaphosphatidyl-2-yl)oxy)methyl)tetrahydrofurano[3,4-d][1,3]dioxacyclopentene-4-carboxynitrile At room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (609 µL, 4.07 mmol) was added via syringe over 2 minutes to a vigorously stirred mixture of intermediates 1-3 (1.00 g, 3.02 mmol), (2R,3aR,6S,7aR)-3a-methyl-2-((perfluorophenyl)thio)-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphonyl 2-sulfide (1.75 g, 3.92 mmol), and acetonitrile (24.0 mL). After 10 minutes, saturated ammonium chloride aqueous solution (10 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with water (70 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 10% methanol in dichloromethane) to give intermediate 19-0. LCMS: 578.2. Intermediate 19-1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-2-oxo-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphatidyl-2-yl)oxy)methyl)tetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-carboxynitrile Selenium dioxide (316 mg, 2.84 mmol) was added to a vigorously stirred solution of intermediate 19-0 (1.57 g, 2.71 mmol) in acetonitrile (23.5 mL) and water (8.9 mL) at room temperature. After 60 minutes, ethyl acetate (250 mL) was added, and the resulting suspension was filtered through diatomaceous earth. The organic layer of the filtrate was washed with a mixture of water and brine (1:1 v:v, 120 mL), and the aqueous layer was extracted with ethyl acetate (75 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give intermediate 19-1. LCMS: 562.2. Intermediate 19-2: (S)-2-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)-3-(octadecoxy)prop-1-ol At 0°C, a solution of potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 382 µL, 380 µmol) was added via syringe to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol (159 mg, 347 µmol) in tetrahydrofuran (1.0 mL) over 1 minute. After 10 minutes, 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (223 mg, 869 µmol) was added, and the resulting mixture was heated to room temperature. After 50 minutes, concentrated hydrochloric acid (300 µL, 3.60 mmol) and methanol (0.3 mL) were added sequentially, and the resulting biphasic mixture was stirred vigorously. After 60 minutes, saturated sodium bicarbonate aqueous solution (15 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in hexane) to give intermediate 19-2. LCMS: 543.4 [M+Na] + . Example 19: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)-3-(octadecane) (19)Oxypropyl)hydrogen phosphate At room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (10.7 µL, 71.2 µmol) was added via syringe over 1 minute to a vigorously stirred mixture of intermediate 19-2 (18.5 g, 35.6 µmol), intermediate 19-1 (20.0 mg, 35.6 µmol), and tetrahydrofuran (0.7 mL). After 18 minutes, water (50 µL) and concentrated hydrochloric acid (300 µL, 3.60 mmol) were added sequentially. After 120 minutes, the resulting mixture was purified by reversed-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 19. 1H NMR (400MHz, methanol-d4) δ 8.06 (s, 1H), 7.49 (s, 1H), 7.43(d, J = 9.3Hz, 1H), 7.33 – 7.25 (m, 2H), 7.20 (d, J = 4.8Hz, 1H), 4.97 – 4.68(m, 3H), 4.40 – 4.31 (m, 1H), 4.25 (t, J = 5.5Hz, 1H), 4.23 – 4.15 (m, 1H), 4.14 – 4.05 (m, 1H), 4.04 – 3.90 (m, 2H), 3.86 – 3.79 (m, 1H), 3.63 – 3.31 (m, 4H), 1.63 – 1.49 (m, 2H), 1.40 – 1.20 (m, 30H), 0.92 (t, J = 6.6Hz, 3H). 31 P NMR (162 MHz, methanol-d4) δ 0.19. LCMS: 872.4 [M−H] − . Example 20: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-3-(octadecyloxy)-2-(thiophene-3-ylmethoxy)propyl)phosphine Hydrogen ester (20) Compound 20 was synthesized in a manner similar to that of Compound 4, using 3-(bromomethyl)thiophene instead of 2-(bromomethyl)naphthalene. 1H NMR (400MHz, methanol-d4) δ 7.91 (s, 1H), 7.34 – 7.27 (m, 2H), 7.07 (dd, J= 4.9, 1.4Hz, 1H), 7.04 (d, J = 4.6Hz, 1H), 6.96 (d, J = 4.6Hz, 1H), 4.83 –4.79 (m, 1H), 4.69 – 4.57 (m, 2H), 4.39 – 4.31 (m, 1H), 4.26 (t, J = 5.4Hz, 1H), 4.14 (dt, J = 11.5, 4.3Hz, 1H), 4.09 – 4.02 (m, 1H), 3.94 – 3.79 (m, 2H), 3.74 – 3.65 (m, 1H), 3.56 – 3.36 (m, 4H), 3.23 (q, J = 7.3Hz, 6H), 1.61 – 1.42 (m, 2H), 1.38 – 1.19 (m, 39H), 0.94 – 0.86 (m, 3H). LCMS: 794.1. Intermediate 21-1: (R)-Triisopropyl((2-methylepoxyethylene-2-yl)methoxy)silane At 0 °C, triisopropylchlorosilane (5.38 mL, 25.2 mmol) was added via syringe over 2 minutes to a stirred mixture of (S)-(2-methylethyleneoxy-2-yl)methanol (1.81 mL, 22.6 mmol), triethylamine (5.49 mL, 39.4 mmol), 4-(dimethylamino)pyridine (208 mg, 1.70 mmol), and dichloromethane (30 mL). After 8 minutes, the resulting mixture was heated to room temperature. After 20 hours, the resulting mixture was poured into a two-phase mixture of 0 °C ether (100 mL), citric acid aqueous solution (10% wt / v, 10 mL), and water (80 mL). The mixture was stirred, and the layers were separated. The organic layer was washed with a mixture of water and saturated sodium bicarbonate aqueous solution (10:1 v:v, 90 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 4% ethyl acetate in hexane) to give intermediate 21-1. LCMS: 245.2. Intermediate 21-2: (R)-2-methyl-1-(octadecyloxy)-3-((triisopropylsilyl)oxy)prop-2- alcohol At room temperature, 1-octadecanol (2.13 g, 7.88 mmol) was added to a vigorously stirred mixture of sodium hydride (60 wt% dispersion in mineral oil, 311 mg, 8.12 mmol) in 2-methyltetrahydrofuran (20 mL), and the resulting mixture was heated to 85 °C. After 80 minutes, a solution of intermediate 21-1 (1.47 g, 6.01 mmol) in N,N-dimethylformamide (10 mL) was added via a tube, and the resulting mixture was heated to 90 °C. After 17 hours, the resulting mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution (10 mL) and diethyl ether (500 mL) were added sequentially. The organic layer was washed with water (2 × 500 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 100% dichloromethane in hexane, then 0 to 2% ethyl acetate in dichloromethane) to give intermediate 21-2. LCMS: 515.5. Example 21: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyloxy)-2-methyl-3-(octadecyloxy)propyl)phosphoric acid Hydrogen esters (21) Compound 21 was synthesized in a manner similar to that of Compound 4, using benzyl bromide instead of 2-(bromomethyl)naphthalene and intermediate 21-2 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol. 11H NMR (400 MHz, methanol-d4) δ 7.93 (s, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.29 – 7.23 (m, 2H), 7.23 – 7.16 (m, 1H), 7.07 (d, J = 4.7 Hz, 1H), 7.03 (d, J = 4.7 Hz, 1H), 4.80 (d, J = 5.3 Hz, 1H), 4.56 (s, 2H), 4.34 (d, J = 4.8 Hz, 1H), 4.26 (t, J = 5.4 Hz, 1H), 4.16 (dt, J = 11.6, 4.2 Hz, 1H), 4.07 (dt, J = 10.3, 4.1 Hz, 1H), 3.93 (dd, J = 10.3, 3.9 Hz, 1H), 3.85 (dd, J = 10.3, 4.1 Hz, 1H), 3.56 – 3.37 (m, 3H), 3.23 (q, J = 7.3 Hz, 6H), 1.62 – 1.49 (m, 2H), 1.45 – 1.08 (m, 42H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 800.3 [M−H] − . Intermediate 22-1: (R)-(4-(benzyloxy)-3-((octadecyloxy)methyl)butyl)benzene Sodium hydride (60 wt% dispersion in mineral oil, 186 mg, 4.64 mmol) was added to a vigorously stirred solution of (R)-2-((benzyloxy)methyl)-4-phenylbut-1-ol (419 mg, 1.55 mmol) in N,N-dimethylformamide (2.5 mL) at room temperature. After 40 minutes, 1-bromooctadecane (1.32 mL, 3.87 mmol) and tetrahydrofuran (1.0 mL) were added sequentially. After 140 minutes, the resulting mixture was heated to 80 °C. After 16.5 hours, the resulting mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution (5.0 mL) and diethyl ether (100 mL) were added sequentially. The organic layer was washed with water (2 × 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% ethyl acetate in hexane) to give intermediate 22-1. LCMS: 545.4 [M + Na] + . Intermediate 22-2: (S)-2-((octadecoxy)methyl)-4-phenylbut-1-ol At room temperature, a vigorously stirred mixture of intermediate 22-1 (535 mg, 1.02 mmol), palladium (10 wt% on carbon, 109 mg, 102 µmol), tetrahydrofuran (3.0 mL), and ethanol (3.0 mL) was placed under a hydrogen atmosphere (balloon). After 13 hours, the resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give intermediate 22-2. LCMS: 455.4 [M+Na] + . Example 22: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((octadecyloxy)methyl)-4-phenylbutyl)hydrogen phosphate （22） Compound 22 was synthesized in a manner similar to that of Compound 2, using intermediate 22-2 instead of intermediate 2-2. 1HNMR (400MHz, methanol-d4) δ 7.95 (s, 1H), 7.27 – 7.06 (m, 7H), 4.82 (d, J =5.2Hz, 1H), 4.37 (d, J = 4.6Hz, 1H), 4.28 (t, J = 5.4Hz, 1H), 4.16 (dt, J =11.5, 4.3Hz, 1H), 4.11 – 3.74 (m, 3H), 3.53 – 3.28 (m, 4H), 3.23 (q, J =7.3Hz, 6H), 2.73 – 2.53 (m, 2H), 1.83 (h, J = 6.6Hz, 1H), 1.66 (dd, J = 14.3,7.4Hz, 2H), 1.59 – 1.41 (m, 2H), 1.41 – 1.09 (m, 39H), 0.92 (t, J = 6.7Hz,3H). LCMS: 784.3 [M−H] − . Intermediate 23-1: (S)-2-chloro-4-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)benzylnitrile Intermediate 23-1 was synthesized in a manner similar to intermediate 2-2, using 4-(bromomethyl)-2-chlorobenzyl nitrile instead of 4-(bromomethyl)-1,1'-biphenyl. LCMS: 516.3 [M+Na] + . Intermediate 23-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-((3-chloro-4-) cyanobenzyl)oxy)-3-(octadecyloxy)propyl)(2-chlorophenyl)phosphate At room temperature, 2-chlorophenyl dichlorophosphate (33.3 µL, 206 µmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (28.6 mg, 414 µmol), triethylamine (57.8 µL, 414 µmol), and tetrahydrofuran (0.4 mL). After 40 minutes, intermediate 1-3 (59.1 mg, 178 µmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (16.5 µL, 206 µmol) were added sequentially. After 60 minutes, a solution of intermediate 23-1 (76.7 mg, 155 µmol) in tetrahydrofuran (0.7 mL) was added via tubing. 1-Methylimidazole (20 µL, 250 µmol) was then added. After 15 hours, saturated sodium bicarbonate aqueous solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 5% methanol in dichloromethane) to give intermediate 23-2. LCMS: 997.4. Example 23: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-chloro-4-cyanobenzyl)oxy)-3-(octadecyloxy) Propyl) hydrogen phosphate (23) At room temperature, a tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 457 µL, 460 µmol) was added via syringe to a vigorously stirred mixture of intermediate 23-2 (152 mg, 152 µmol), pyridine (61.6 µL, 762 µmol), water (54.9 µL, 3.05 mmol), and tetrahydrofuran (0.1 mL). After 4 hours, trimethylchlorosilane (58.0 µL, 457 µmol) and concentrated hydrochloric acid (300 µL, 3.60 mmol) were added sequentially. After 150 minutes, the resulting mixture was purified by reversed-phase preparative HPLC (0.1% trifluoroacetic acid in 2-propanol / water) to give compound 23. 1¹H NMR (400MHz, methanol-d⁴) δ 8.08 (s, 1H), 7.70 (d, J = 8.0Hz, 1H), 7.63 (d, J = 1.4Hz, 1H), 7.49 – 7.43 (m, 1H), 7.30 (d, J = 4.8Hz, 1H), 7.19 (d, J = 4.8Hz, 1H), 4.91 – 4.69 (m, 3H), 4.39 – 4.31 (m, 1H), 4.28 – 4.16 (m, 2H), 4.15 – 4.06 (m, 1H), 4.06 – 3.91 (m, 2H), 3.81 (p, J = 5.2Hz, 1H), 3.64 – 3.41 (m, 4H), 1.63 – 1.49 (m, 2H), 1.39 – 1.22 (m,30H), 0.94 – 0.89 (m, 3H). LCMS: 845.6 [M−H] − . Intermediate 24-1: (S)-2-(benzyloxy)-3-((15-methylhexadecyl)oxy)prop-1-ol Intermediate 24-1 was synthesized in a manner similar to intermediate 9-4, using benzyl bromide instead of 4-(bromomethyl)benzyl nitrile and 1-bromo-15-methylhexadecane instead of 1-bromooctadecane. LCMS: 443.4 [M+Na] + . Example 24: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyloxy)-3-((15-methylhexadecyl)oxy)propyl) hydrogen phosphate (24) Compound 24 was synthesized in a manner similar to that of Compound 19, using intermediate 24-1 instead of intermediate 19-2. 1HNMR (400MHz, methanol-d4) δ 8.01 (s, 1H), 7.36 – 7.32 (m, 2H), 7.32 – 7.26 (m,2H), 7.26 – 7.19 (m, 2H), 7.17 (d, J = 4.8Hz, 1H), 4.78 (d, J = 5.2Hz, 1H), 4.66 (d, J = 11.9Hz, 1H), 4.61 (d, J = 11.9Hz, 1H), 4.39 – 4.31 (m, 1H), 4.26(t, J = 5.4Hz, 1H), 4.17 (dq, J = 12.8, 4.4Hz, 1H), 4.13 – 4.02 (m, 1H), 4.01– 3.86 (m, 2H), 3.75 (q, J = 5.2Hz, 1H), 3.61 – 3.38 (m, 4H), 1.69 – 1.47 (m,3H), 1.40 – 1.08 (m, 24H), 0.98 – 0.81 (m, 6H). LCMS: 772.4 [M−H] − . Example 25: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl(4-(hexadecyloxy)butyl)hydrogen phosphate (25) Compound 25 was synthesized in a manner similar to that of Compound 55, using 1,4-butanediol instead of 1,3-propanediol and 1-bromohexadecane instead of 1-bromoheptadecane. 1 H NMR (400MHz, methanol-d4) δ 7.89 (s, 1H), 6.98 (d, J = 4.6Hz, 1H), 6.93 (d, J = 4.6Hz, 1H), 4.95 – 4.83 (m, 1H), 4.38 (t, J= 4.4Hz, 1H), 4.28 (t, J = 5.4Hz, 1H), 4.19 – 3.96 (m, 2H), 3.86 – 3.73 (m,2H), 3.47 – 3.34 (m, 4H), 1.72 – 1.44 (m, 6H), 1.29 (s, 27H), 1.00 – 0.81 (m,3H). LCMS: 668.2. Intermediate 26-1: (R)-5-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop- 2-yl)oxy)methyl)isophthalonitrile At 0 °C, a solution of potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 490 µL, 490 µmol) was added via syringe to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol (150 mg, 327 µmol) in tetrahydrofuran (0.5 mL). After 5 minutes, a solution of 5-(iodomethyl)isophthalonitrile (437 mg, 1.63 mmol) in tetrahydrofuran (2.0 mL) was added via syringe, and the resulting mixture was heated to room temperature. After 16 hours, saturated ammonium chloride aqueous solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 10% ethyl acetate in hexane) to give intermediate 26-1. LCMS: 621.5 [M+Na] + . Intermediate 26-2: (S)-5-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)isophthalonitrile Intermediate 26-2 was synthesized using intermediate 26-1 in place of intermediate 2-1, similar to how intermediate 2-2 was synthesized. LCMS: 507.4 [M+Na] + . Intermediate 26-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)((R)- 2-((3,5-dicyanobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate Intermediate 26-3 is synthesized in a manner similar to that of intermediate 23-2, using intermediate 26-2 instead of intermediate 23-1. LCMS: 988.4. Example 26: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3,5-dicyanobenzyl)oxy)-3-(octadecyloxy)propane (26) Hydrogen phosphate (26) At room temperature, a tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 300 µL, 300 µmol) was added via syringe to a vigorously stirred mixture of intermediate 26-3 (23.6 mg, 23.9 µmol), 4-(dimethylamino)pyridine (29.2 mg, 239 µmol), water (45.0 µL, 2.50 mmol), and tetrahydrofuran (0.1 mL). After 82 minutes, trimethylchlorosilane (38.2 µL, 301 µmol) and concentrated hydrochloric acid (300 µL, 3.60 mmol) were added sequentially. After 140 minutes, the resulting mixture was purified by reversed-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 26. 1¹H NMR (400MHz, methanol-d⁴) δ 8.07 (s, 1H), 8.01 (s, 3H), 7.31 (d, J = 4.8Hz, 1H), 7.20 (d, J = 4.8Hz, 1H), 4.93 – 4.70 (m, 3H), 4.38 – 4.28 (m, 1H), 4.25 – 4.16 (m, 2H), 4.16 – 4.05 (m, 1H), 4.06 – 3.90 (m, 2H), 3.82 (p, J = 5.0Hz, 1H), 3.63 – 3.41 (m, 4H), 1.65 – 1.51 (m, 2H), 1.38 – 1.22 (m, 30H). 0.95 – 0.86 (m, 3H). LCMS: 836.4[M−H] − . Intermediate 27-1: tert-butyldimethyl((2R)-3-(octadecyloxy)-2-(1-phenylethoxy)propoxy)silyl alkyl Intermediate 27-1 was synthesized as a diastereomeric 1:1 mixture by replacing intermediate 5-1 with (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol and (R)-1-phenylethyl 2,2,2-trichloroacetylimine ester (WO 2011059021) instead of benzyl 2,2,2-trichloroacetylimine ester, in a manner similar to that of intermediate 5-2. LCMS: 585.6 [M+Na] + . Intermediate 27-2: (2S)-3-(octadecyloxy)-2-(1-phenylethoxy)prop-1-ol (washes faster on silica gel) (de-diastere) Intermediate 28-1: (2S)-3-(octadecyloxy)-2-(1-phenylethoxy)prop-1-ol (washes slowly on silica gel) (de-diastere) Intermediates 27-2 and 28-1 were synthesized in a manner similar to that of intermediate 2-2, using intermediate 27-1 instead of intermediate 2-1. The diastereomers were separated by silica gel rapid column chromatography (0 to 9% ethyl acetate in hexane) to give intermediate 27-2 (the faster-eluting diastereomer) and intermediate 28-1 (the slower-eluting diastereomer). Intermediate 27-2: LCMS: 471.4 [M+Na] + Intermediate 28-1: LCMS: 471.4 [M+Na] + .

[0321] Example 27: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((2R)-3-(octadecyloxy)-2-(1-phenylethoxy)propyl)phosphoric acid Hydrogen esters (27) Compound 27 was synthesized in a manner similar to that of Compound 26, using intermediate 27-2 instead of intermediate 26-2. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.06 (s, 1H), 7.40 – 7.19 (m, 6H), 7.17 (d, J = 4.8 Hz, 1H), 4.83 – 4.69 (m, 2H), 4.36 – 4.28 (m, 1H), 4.22 (t, J = 5.4 Hz, 1H), 4.16 – 4.05 (m, 1H), 4.05 – 3.94 (m, 1H), 3.83 – 3.76 (m, 2H), 3.75 – 3.43 (m, 5H), 1.66 – 1.50 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H), 1.37 – 1.21 (m,30H), 0.92 (t, J = 6.7Hz, 3H). LCMS: 800.3 [M−H] − . Example 28: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((2R)-3-(octadecyloxy)-2-(1-phenylethoxy)propyl)phosphoric acid Hydrogen esters (28) Compound 28 was synthesized in a manner similar to that of Compound 26, using intermediate 28-1 instead of intermediate 26-2. 1 HNMR (400MHz, methanol-d4) δ 8.07 (s, 1H), 7.40 – 7.34 (m, 2H), 7.34 – 7.28 (m, 3H), 7.25 (d, J = 7.1Hz, 1H), 7.21 (d, J = 4.8Hz, 1H), 4.81 – 4.70 (m, 2H), 4.41 – 4.33 (m, 1H), 4.30 – 4.16 (m, 2H), 4.16 – 4.06 (m, 1H), 4.05 – 3.85 (m, 2H), 3.62 – 3.53 (m, 1H), 3.42 – 3.22 (m, 4H), 1.51 – 1.40 (m, 2H), 1.38(d, J = 6.5Hz, 3H), 1.35 – 1.21 (m, 30H), 0.91 (t, J = 6.8Hz, 3H). LCMS:800.3 [M−H] − . Intermediate 29-1: 2,2-Dimethyl-5-(phenoxymethyl)-1,3-dioxane At 0 °C, methanesulfonyl chloride (1.53 mL, 19.8 mmol) was added via syringe over 3 minutes to a stirred mixture of (2,2-dimethyl-1,3-dioxane-5-yl)methanol (2.41 g, 16.5 mmol), triethylamine (3.21 mL, 23.1 mmol), and dichloromethane (35 mL), and the resulting mixture was heated to room temperature. After 4 hours, diethyl ether (200 mL) was added. The organic layer was washed sequentially with a mixture of aqueous phosphoric acid (85% wt / wt, 1.13 mL) in water (100 mL) and a mixture of water and saturated sodium bicarbonate aqueous solution (5:1 v:v, 60 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. At room temperature, the residue was dissolved in N,N-dimethylformamide (25 mL), and the resulting solution was stirred vigorously. Phenol (2.47 g, 26.2 mmol) and potassium carbonate (6.39 g, 45.9 mmol) were added sequentially, and the resulting mixture was heated to 95 °C. After 18.5 hours, the mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution (25 mL) and diethyl ether (500 mL) were added sequentially. The organic layer was washed with water (2 × 500 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 100% ethyl acetate in hexane) to give intermediate 29-1. LCMS: 245.1 [M + Na] + . Intermediate 29-2: 2-(phenoxymethyl)propane-1,3-diol At room temperature, concentrated hydrochloric acid (387 µL, 4.64 mmol) was added via syringe to a stirred solution of intermediate 29-1 (2.69 g, 12.1 mmol) in methanol (12 mL) and water (1.2 mL). After 4.5 hours, sodium bicarbonate (1.02 g, 12.1 mmol) was added, and the mixture was stirred vigorously. After 10 minutes, ethyl acetate (100 mL) and anhydrous magnesium sulfate were added, and the suspension was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel rapid column chromatography (0 to 100% ethyl acetate in hexane) to give intermediate 29-2. LCMS: 183.0. Intermediate 29-3: 3-(octadecoxy)-2-(phenoxymethyl)prop-1-ol At 0 °C, a solution of potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 2.63 mL, 2.6 mmol) was added via syringe over 1 minute to a vigorously stirred solution of intermediate 29-2 (400 mg, 2.20 mmol) in N,N-dimethylformamide (6.0 mL), and the resulting mixture was heated to room temperature. After 5 minutes, 1-bromooctadecane (732 mg, 2.20 mmol) and tetrahydrofuran (2.0 mL) were added sequentially, and the resulting mixture was heated to 80 °C. After 18 hours, the resulting mixture was cooled to room temperature over 40 minutes. Methanol (8.0 mL) and concentrated hydrochloric acid (723 µL, 8.78 mmol) were added sequentially. After 180 minutes, diethyl ether (125 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 120 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 25% ethyl acetate in hexane) to give intermediate 29-3. LCMS: 435.1. Example 29: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl(3-(octadecoxy)-2-(phenoxymethyl)propyl)hydrogen phosphate （29） Compound 29 was synthesized as a 1:1 mixture of diastereomers by using intermediate 29-3 instead of intermediate 26-2 in a manner similar to that of compound 26. 1 ¹H NMR (400MHz, methanol-d⁴) δ 8.00 (s, 0.5H), 7.99 (s, 0.5H), 7.24 (d, J = 4.8Hz, 1H), 7.22 – 7.14 (m, 3H), 6.89 – 6.80 (m, 3H), 4.73 (d, J = 5.1Hz, 1H), 4.35 – 4.26 (m, 1H), 4.22 (t, J = 5.5Hz, 1H), 4.19 – 4.09 (m, 1H), 4.10 – 3.91 (m, 5H), 3.57 – 3.48 (m, 2H), 3.39 (t, J = 6.4Hz, 2H), 2.37– 2.22 (m, 1H), 1.57 – 1.45 (m, 2H), 1.36 – 1.17 (m, 30H), 0.88 (t, J =6.6Hz, 3H).. LCMS: 786.4 [M−H] − . Intermediate 30-1: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propyl-2-yl-4- Methylbenzenesulfonate At 0 °C, 4-toluenesulfonyl chloride (929 mg, 4.87 mmol) was added to a stirred mixture of intermediate 18-1 (1.40 g, 3.04 mmol), N,N-diisopropylethylamine (848 µL, 4.87 mmol), 4-(dimethylamino)pyridine (37.2 mg, 304 µmol), and dichloromethane (7.0 mL). After 2 minutes, the mixture was heated to room temperature. After 170 minutes, 4-(dimethylamino)pyridine (67.0 mg, 548 µmol) was added. After 30 minutes, the mixture was heated to 65 °C. After 17 hours, the mixture was cooled to room temperature, and diethyl ether (120 mL), ethyl acetate (20 mL), and aqueous hydrogen chloride solution (2.0 M, 5 mL) were added sequentially. The organic layer was washed sequentially with water (100 mL) and then with a mixture of water and saturated sodium bicarbonate solution (5:1 v:v, 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% dichloromethane in hexane) to give intermediate 30-1. LCMS: 635.4 [M+Na] + . Intermediate 30-2: (S)-3-((1-hydroxy-3-(octadecyloxy)prop-2-yl)oxy)benzylnitrile At 0 °C, potassium tert-amyl alcohol solution (1.7 M in toluene, 461 µL, 783 µmol) was added via syringe over 1 minute to a vigorously stirred mixture of intermediate 30-1 (160 mg, 261 µmol), 3-hydroxybenzyl nitrile (103 mg, 861 µmol), and N-,N-dimethylformamide (0.6 mL), and the resulting mixture was heated to 90 °C. After 55 minutes, the mixture was heated to 130 °C. After 1 hour, the mixture was cooled to room temperature. After 14 hours, diethyl ether (40 mL), saturated ammonium chloride aqueous solution (10 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.5 mL), and the resulting solution was stirred at room temperature. Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 1.07 mL, 1.1 mmol) was added via syringe. After 60 minutes, saturated ammonium chloride aqueous solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 30% ethyl acetate in hexane) to give a mixture of intermediates 30-2. The mixture was further purified by basic alumina rapid column chromatography (0 to 15% ethyl acetate in hexane) to give intermediate 30-2. LCMS: 468.4 [M+Na] + . Example 30: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(3-cyanophenoxy)-3-(octadecoxy)propyl)phosphoric acid Hydrogen ester (30) Compound 30 was synthesized in a manner similar to that of Compound 19, using intermediate 30-2 instead of intermediate 19-2. 1 HNMR (400MHz, methanol-d4) δ 8.06 (s, 1H), 7.40 (dd, J = 9.3, 7.5Hz, 1H), 7.35 –7.30 (m, 2H), 7.29 (d, J = 4.7Hz, 1H), 7.25 (dd, J = 7.5, 1.4Hz, 1H), 7.18(d, J = 4.8Hz, 1H), 4.78 (d, J = 5.2Hz, 1H), 4.73 – 4.62 (m, 1H), 4.39 – 4.30(m, 1H), 4.24 (t, J = 5.4Hz, 1H), 4.22 – 4.12 (m, 1H), 4.12 – 3.97 (m, 3H), 3.70 (dd, J = 10.7, 3.8Hz, 1H), 3.63 (dd, J = 10.8, 6.1Hz, 1H), 3.53 – 3.41(m, 2H), 1.58 – 1.46 (m, 2H), 1.40 – 1.20 (m, 30H), 0.92 (t, J = 6.8Hz, 3H).LCMS: 797.4 [M−H] − . Example 31: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano (R)-2-(3-cyano-5-fluorophenoxy)-3-(octadecyloxy)propyl hydrogen phosphate (31) Compound 31 was synthesized in a manner similar to that of Compound 30, using 3-fluoro-5-hydroxybenzyl nitrile instead of 3-hydroxybenzyl nitrile. 1¹H NMR (400MHz, methanol-d⁴) δ 8.09 (s, 1H), 7.33 (d, J = 4.7Hz, 1H), 7.20 (d, J = 4.3Hz, 2H), 7.14 (dt, J = 10.7, 2.4Hz, 1H), 7.09 – 7.03 (m, 1H), 4.79 – 4.68 (m, 2H), 4.39 – 4.32 (m, 1H), 4.27 – 4.14 (m, 2H), 4.14 – 3.92 (m, 3H), 3.84 – 3.40 (m, 4H), 1.64 – 1.45 (m, 2H), 1.44 – 1.19 (m, 30H), 1.00 – 0.85(m, 3H). LCMS: 815.4 [M−H] − . Example 32: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-(difluoromethyl)benzyl)oxy)-3-(octadecyloxy) Propyl) hydrogen phosphate (32) Compound 32 was synthesized in a manner similar to that of Compound 19, using 1-(bromomethyl)-3-(difluoromethyl)benzene instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene. 1 H NMR (400MHz, DMSO-d6) δ 7.94 (s, 1H),7.53 – 7.41 (m, 4H), 7.18 – 6.74 (m, 3H), 4.73 – 4.54 (m, 3H), 4.18 (ddt, J =30.5, 6.1, 3.0Hz, 2H), 4.08 – 3.85 (m, 4H), 3.77 – 3.66 (m, 1H), 1.44 (q, J =6.7Hz, 2H), 1.22 (d, J = 9.8Hz, 28H), 0.93 – 0.79 (m, 3H). LCMS: 838.2. Example 33: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((4-(difluoromethyl)benzyl)oxy)-3-(octadecyloxy) Propyl) hydrogen phosphate (33) Compound 33 was synthesized in a manner similar to that of Compound 19, using 1-(bromomethyl)-4-(difluoromethyl)benzene instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene. 1H NMR (400MHz, DMSO-d6) δ 7.95 (s, 1H), 7.51 (d, J = 8.0Hz, 2H), 7.45 (d, J = 8.1Hz, 2H), 7.17 – 6.81 (m, 3H), 4.71 –4.57 (m, 3H), 3.78 – 3.64 (m, 1H), 3.44 (dd, J = 5.2, 1.9Hz, 2H), 3.34 (t, J= 6.5Hz, 2H), 3.13 (p, J = 1.6Hz, 1H), 1.44 (t, J = 6.8Hz, 2H), 1.22 (d, J =8.0Hz, 32H), 0.96 – 0.78 (m, 3H). LCMS: 838.2. Intermediate 34-1: (R)-1-((tert-butyldimethylsilyl)oxy)-3-(heptadecanoxy)prop-2-ol Intermediate 34-1 was synthesized in a manner similar to that of intermediate 9-2, using (S)-3-(heptadecoxy)propane-1,2-diol instead of (S)-3-(octadecoxy)propane-1,2-diol. 1 ¹H NMR (400MHz, chloroform-d) δ 3.82 (q, J = 5.3Hz, 1H), 3.72 – 3.61 (m, 2H), 3.47 (td, J = 6.7, 6.3, 1.4Hz, 4H), 1.59 (t, J = 7.1Hz, 2H), 1.28 (s, 30H), 0.92 (s, 9H), 0.10 (s, 6H). Example 34: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-cyanobenzyl)oxy)-3-(heptadecanoxy)propyl) hydrogen phosphate (34) Compound 34 was synthesized in a manner similar to that of Compound 19, using 3-(bromomethyl)benzylnitrile instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene and using intermediate 34-1 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol. 1H NMR (400MHz, DMSO-d6, drop CD3OD) δ 7.96 (s, 1H),7.75 (s, 1H), 7.71 (d, J = 7.8Hz, 1H), 7.65 (d, J = 8.0Hz, 1H), 7.52 (t, J =7.8Hz, 1H), 6.97 (d, J = 4.5Hz, 1H), 6.86 (t, J = 3.5Hz, 1H), 4.66 (t, J =10.0Hz, 4H), 4.23 (s, 2H), 3.76 – 3.55 (m, 4H), 3.44 (t, J = 3.2Hz, 2H), 3.36(d, J = 13.3Hz, 5H), 3.08 (dd, J = 25.4, 13.0Hz, 3H), 2.80 (s, 4H), 1.45 (t,J = 6.8Hz, 3H), 1.22 (d, J = 8.1Hz, 33H), 0.85 (t, J = 6.5Hz, 3H). LCMS:799.3. Example 35: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(heptadecyloxy) Propyl) hydrogen phosphate (35) Compound 35 was synthesized in a manner similar to that of Compound 19, using 3-(bromomethyl)-5-fluorobenzyl nitrile instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene and using intermediate 34-1 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol. 1 H NMR (400MHz, DMSO-d6, drop CD3OD) δ 7.92 (s,1H), 7.71 (d, J = 8.7Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 9.7Hz, 1H), 6.91 (d,J = 4.8Hz, 1H), 6.84 (d, J = 3.5Hz, 1H), 4.72 – 4.56 (m, 2H), 3.71 (s, 1H), 3.47 – 3.38 (m, 2H), 3.33 (d, J = 7.2Hz, 2H), 3.13 (s, 2H), 1.45 (t, J =6.9Hz, 2H), 1.22 (d, J = 9.0Hz, 29H), 0.85 (t, J = 6.7Hz, 3H). LCMS: 817.3. Example 36: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((4-cyanobenzyl)oxy)-3-(heptadecanoxy)propyl) Hydrogen phosphate (36) Compound 36 was synthesized in a manner similar to that of Compound 19, using 4-(bromomethyl)benzylnitrile instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene and using intermediate 34-1 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol. 1 H NMR (400MHz, DMSO-d6) δ7.93 (d, J = 2.6Hz, 1H), 7.76 (d, J = 8.1Hz, 2H), 7.51 (d, J = 7.7Hz, 2H), 6.91 (d, J = 3.4Hz, 1H), 6.85 (d, J = 3.7Hz, 1H), 4.66 (dt, J = 9.0, 3.5Hz, 3H), 3.77 – 3.66 (m, 1H), 3.62 (d, J = 12.3Hz, 1H), 3.49 – 3.40 (m, 2H), 3.35 (q, J = 9.5, 7.5Hz, 3H),3.10 (d, J = 24.5Hz, 1H), 2.81 (d, J = 2.7Hz, 1H), 1.43 (d, J = 7.3Hz, 2H), 1.22 (d, J = 9.3Hz, 26H), 0.85 (t, J = 6.1Hz, 3H). LCMS: 799.3. Example 37: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-3-(heptadecyloxy)-2-((4-methoxybenzyl)oxy)propane (37) Hydrogen phosphate (37) Compound 37 was synthesized in a manner similar to that of Compound 19, using 1-(bromomethyl)-4-methoxybenzene instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene and using intermediate 34-1 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol. 1H NMR (400MHz, DMSO-d6, drop CD3OD) δ 7.93(d, J = 2.8Hz, 1H), 7.23 (d, J = 8.2Hz, 2H), 6.98 – 6.74 (m, 4H), 4.66 (d, J= 4.6Hz, 1H), 4.49 (d, J = 4.8Hz, 2H), 4.22 (s, 2H), 3.78 – 3.55 (m, 4H), 3.48 – 3.25 (m, 4H), 3.13 (s, 2H), 1.43 (s, 2H), 1.23 (d, J = 5.5Hz, 29H), 0.85 (d, J = 7.5Hz, 3H). LCMS: 804.2. Intermediate 38-1: (R)-3-(octadecoxy)-2-phenoxyprop-1-ol Triphenylphosphine (80.0 mg, 0.305 mmol) was added to (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol (109 mg, 0.237 mmol), phenol (41.0 mg, 0.436 mmol), and diisopropyl azodicarbonate (0.0750 mL, 0.359 mmol) in a 0°C cooled solution of tetrahydrofuran (2 mL), i.e., THF. The reaction mixture was gradually heated to room temperature and stirred for 24 hours. During this time, the solvent was removed under reduced pressure, and the crude product was adsorbed onto silica gel. The crude product was purified by rapid silica gel column chromatography (0 to 10% ethyl acetate in hexane) to give (S)-tert-butyldimethyl(3-(octadecyloxy)-2-phenoxypropoxy)silane. 1 H NMR (400MHz, chloroform-d) δ 7.33 – 7.22 (m, 2H), 7.03– 6.90 (m, 3H), 4.43 (q, J = 5.1Hz, 1H), 3.89 – 3.79 (m, 2H), 3.67 (qd, J =10.4, 4.9Hz, 2H), 3.49 (td, J = 6.5, 1.9Hz, 2H), 1.63 – 1.53 (m, 2H), 1.27(s, 30H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H). A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.500 mL, 0.500 mmol) was added to a 2 mL solution of (S)-tert-butyldimethyl(3-(octadecyloxy)-2-phenoxypropoxy)silane (84.0 mg, 0.157 mmol) in tetrahydrofuran. The reaction mixture was stirred for one hour, during which time it was diluted with ethyl acetate and washed successively with 3% water, followed by a saturated sodium chloride aqueous solution. The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 20% ethyl acetate in hexane) to give intermediate 38-1. 1 ¹H NMR (400MHz, chloroform-d) δ 7.38 – 7.29 (m, 2H), 7.04 – 6.86 (m, 3H), 4.19 (s, 1H), 4.05 (dd, J = 5.5, 2.8Hz, 2H), 3.62 (qd, J = 9.7, 5.2Hz, 2H), 3.51 (td, J = 6.6, 1.8Hz, 2H), 1.59 (d, J = 12.7Hz, 2H), 1.28 (s, 30H), 0.96 – 0.85 (m, 3H). Example 38: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((S)-3-(octadecoxy)-2-phenoxypropyl)hydrogen phosphate (38) Compound 38 was synthesized in a manner similar to that of Compound 2, using intermediate 38-1 instead of intermediate 2-2. 1 HNMR (400MHz, methanol-d4) δ 7.93 (d, J = 2.4Hz, 1H), 7.20 (t, J = 8.0Hz, 2H), 7.07 (d, J = 10.6Hz, 2H), 6.85 (d, J = 8.5Hz, 3H), 4.52 – 3.98 (m, 7H), 3.82– 3.38 (m, 6H), 3.15 (s, 1H), 1.51 (s, 2H), 1.27 (d, J = 25.3Hz, 44H), 0.91(d, J = 7.4Hz, 3H). LCMS: 774.1. Example 39: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-cyanobenzyl)oxy)-3-(octadecyloxy)propyl) hydrogen phosphate (39) Compound 39 was synthesized as a 1:1 mixture of diastereomers by replacing 3-(bromomethyl)-5-fluorobenzyl nitrile with 3-(bromomethyl)benzyl nitrile in a manner similar to that of Compound 16.1 H NMR (400MHz, methanol-d4) δ 7.89 (s, 1H), 7.70(d, J = 1.9Hz, 1H), 7.62 (d, J = 7.7Hz, 1H), 7.57 (d, J = 7.7Hz, 1H), 7.45(t, J = 7.7Hz, 1H), 7.00 (d, J = 4.6Hz, 1H), 6.93 (d, J = 4.6Hz, 1H), 4.83(d, J = 5.4Hz, 1H), 4.76 – 4.62 (m, 2H), 4.40 – 4.33 (m, 1H), 4.25 (t, J =5.5Hz, 1H), 4.23 – 4.14 (m, 1H), 4.14 – 4.05 (m, 1H), 4.00 – 3.85 (m, 2H), 3.79 – 3.70 (m, 1H), 3.57 – 3.44 (m, 2H), 3.44 – 3.37 (m, 2H), 3.18 (q, J =7.3Hz, 2H), 1.59 – 1.49 (m, 2H), 1.39 – 1.20 (m, 30H), 0.91 (t, J = 6.7Hz, 3H). 31 P NMR (162MHz, methanol-d4) δ -0.41. LCMS: 813.25 [M+H] + Example 40: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((4-methylbenzyl)oxy)-3-(octadecyloxy)propyl) hydrogen phosphate (40) Compound 40 was synthesized as a 1:1 mixture of diastereomers by replacing 3-(bromomethyl)-5-fluorobenzyl nitrile with 1-(bromomethyl)-4-methylbenzene in a manner similar to that of Compound 16. 1H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H),7.19 (d, J = 7.7Hz, 2H), 7.07 (d, J = 7.7Hz, 2H), 6.98 (d, J = 4.6Hz, 1H), 6.89 (d, J = 4.6Hz, 1H), 4.83 (d, J = 5.3Hz, 1H), 4.62 – 4.52 (m, 2H), 4.42 –4.35 (m, 1H), 4.27 (t, J = 5.5Hz, 1H), 4.24 – 4.13 (m, 1H), 4.13 – 4.04 (m,1H), 3.98 – 3.85 (m, 2H), 3.76 – 3.66 (m, 1H), 3.58 – 3.42 (m, 2H), 3.38 (t,J = 6.6Hz, 2H), 2.29 (s, 3H), 1.57 – 1.45 (m, 2H), 1.42 – 1.17 (m, 30H), 0.91(t, J = 6.7Hz, 3H). 31 P NMR (162MHz, methanol-d4) δ -0.57. LCMS: 802.12 [M+H] + Example 41: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((4-chlorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphine Hydrogen ester (41) Compound 41 was synthesized as a 1:1 mixture of diastereomers by replacing 3-(bromomethyl)-5-fluorobenzyl nitrile with 1-(bromomethyl)-4-chlorobenzene in a manner similar to that of compound 16. 1H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.30(d, J = 8.3Hz, 2H), 7.25 (d, J = 8.3Hz, 2H), 6.98 (d, J = 4.6Hz, 1H), 6.89(d, J = 4.6Hz, 1H), 4.84 (d, J = 5.4Hz, 1H), 4.67 – 4.53 (m, 2H), 4.42 – 4.34(m, 1H), 4.27 (t, J = 5.5Hz, 1H), 4.23 – 4.13 (m, 1H), 4.13 – 4.03 (m, 1H),3.99 – 3.83 (m, 2H), 3.78 – 3.64 (m, 1H), 3.57 – 3.42 (m, 2H), 3.38 (t, J =6.5, 1.9Hz, 2H), 1.59 – 1.46 (m, 2H), 1.41 – 1.17 (m, 30H), 0.91 (t, J =6.7Hz, 3H). 31 P NMR (162MHz, methanol-d4) δ -0.62. LCMS: 822.16 [M+H] + Example 42: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphine Hydrogen ester (42) Compound 42 was synthesized as a 1:1 mixture of diastereomers by replacing 3-(bromomethyl)-5-fluorobenzyl nitrile with 1-(bromomethyl)-2-fluorobenzene in a manner similar to that of Compound 16. 1H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.52– 7.45 (m, 1H), 7.30 – 7.22 (m, 1H), 7.11 (t, J = 7.5Hz, 1H), 7.07 – 7.01 (m,1H), 6.99 (d, J = 4.4Hz, 1H), 6.89 (d, J = 4.6Hz, 1H), 4.84 (d, J = 5.3Hz,1H), 4.76 – 4.67 (m, 2H), 4.41 – 4.33 (m, 1H), 4.27 (t, J = 5.4Hz, 1H), 4.19– 4.11 (m, 1H), 4.11 – 4.04 (m, 1H), 3.98 – 3.86 (m, 2H), 3.79 – 3.62 (m,2H), 3.60 – 3.51 (m, 1H), 3.51 – 3.43 (m, 1H), 3.39 (td, J = 6.6, 2.5Hz, 2H),1.58 – 1.47 (m, 2H), 1.39 – 1.22 (m, 30H), 0.91 (t, J = 6.7Hz, 3H). 31 P NMR (162MHz, methanol-d4) δ -0.01. 19 F NMR (376MHz, methanol-d4) δ -121.40 (dt, J = 12.1, 6.1Hz). LCMS: 806.19 [M+H] + Example 43: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((2,6-difluorobenzyl)oxy)-3-(octadecyloxy)propane (43) Hydrogen phosphate (43) Compound 43 was synthesized as a 1:1 mixture of diastereomers by replacing 3-(bromomethyl)-5-fluorobenzyl nitrile with 2-(bromomethyl)-1,3-difluorobenzene in a manner similar to that of compound 16. 1¹H NMR (400MHz, methanol-d⁴) δ 7.87 (s, 1H), 7.41 – 7.27 (m, 1H), 7.03 – 6.97 (m, 1H), 6.96 – 6.82 (m, 3H), 4.86 – 4.82 (m, 1H), 4.69 (s, 2H), 4.41 – 4.35 (m, 1H), 4.32 – 4.25 (m, 1H), 4.23 – 4.13 (m, 1H), 4.13 – 4.03 (m, 1H), 3.97 – 3.84 (m, 2H), 3.80 – 3.63 (m, 2H), 3.62– 3.49 (m, 1H), 3.49 – 3.42 (m, 1H), 3.38 (t, J = 6.6Hz, 1H), 1.59 – 1.40 (m,2H), 1.40 – 1.13 (m, 30H), 0.91 (t, J = 6.6Hz, 3H). 31 P NMR (162MHz, methanol-d4) δ -0.93. 19 F NMR (376MHz, methanol-d4) δ -117.21 (t, J = 6.9Hz). LCMS: 824.19 [M+H] + Example 44: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-methoxy-3-(octadecoxy)propyl)hydrogen phosphate (44) Compound 44 was synthesized as a 1:1 mixture of diastereomers by replacing 3-(bromomethyl)-5-fluorobenzyl nitrile with iodomethane in a manner similar to that of compound 16. 1H NMR (400MHz, methanol-d4) δ 7.90 (s, 1H), 7.00 (d, J =4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 4.88 – 4.79 (m, 1H), 4.42 – 4.35 (m,1H), 4.28 (t, J = 5.3Hz, 1H), 4.24 – 4.11 (m, 1H), 4.11 – 4.02 (m, 1H), 3.92– 3.76 (m, 2H), 3.77 – 3.63 (m, 1H), 3.63 – 3.45 (m, 2H), 3.44 – 3.37 (m,5H), 1.61 – 1.48 (m, 2H), 1.41 – 1.22 (m, 30H), 0.91 (t, J = 6.8Hz, 3H). 31 P NMR (162MHz, methanol-d4) δ -0.09. LCMS: 712.16 [M+H] + Example 45: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphine Hydrogen ester (45) Compound 45 was synthesized as a 1:1 mixture of diastereomers by replacing 3-(bromomethyl)-5-fluorobenzyl nitrile with 1-(bromomethyl)-3-fluorobenzene in a manner similar to that of Compound 16. 1H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.28(td, J = 8.0, 5.7Hz, 1H), 7.15 – 7.05 (m, 2H), 6.99 (d, J = 4.6Hz, 1H), 6.94(td, J = 8.5, 2.6Hz, 1H), 6.89 (d, J = 4.6Hz, 1H), 4.84 (d, J = 5.4Hz, 1H), 4.72 – 4.54 (m, 2H), 4.45 – 4.33 (m, 1H), 4.27 (t, J = 5.4Hz, 1H), 4.21 –4.12 (m, 1H), 4.12 – 4.04 (m, 1H), 3.98 – 3.84 (m, 2H), 3.77 – 3.64 (m, 1H), 3.55 – 3.44 (m, 2H), 3.44 – 3.36 (m, 2H), 1.59 – 1.47 (m, 2H), 1.40 – 1.18(m, 30H), 0.91 (t, J = 6.7Hz, 3H). 31 P NMR (162MHz, methanol-d4) δ 0.17. 19 F NMR (377MHz, methanol-d4) δ -116.09 (td, J = 9.3, 5.7Hz). LCMS: 806.20 [M+H] + Intermediate 46-1: (R)-tert-butyldimethyl(2-((2-methylallyl)oxy)-3-(octadecyloxy)propoxy silylan Intermediate 46-1 was prepared in a manner similar to that of intermediate 2-1, using 3-bromo-2-methylpropene instead of 4-(bromomethyl)-1,1'-biphenyl. 1 ¹H NMR (400MHz, chloroform-d) δ 5.02 – 4.98 (m, 1H), 4.89 (m, 1H), 4.06 (s, 2H), 3.69 (dd, J = 5.1, 1.6Hz, 1H), 3.58 – 3.51 (m, 2H), 3.50 – 3.40 (m, 4H), 1.77 (s, 3H), 1.56 (m, 2H), 1.28 (s, 30H), 0.91 (m, 12H), 0.09 (m, 6H). Intermediate 46-2: (S)-2-((2-methylallyl)oxy)-3-(octadecoxy)prop-1-ol At room temperature, a solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.05 mL, 1.05 mmol) was added via syringe to a stirred solution of 46-1 (179 mg, 359 µmol) in tetrahydrofuran (10 mL). After 150 minutes, an aqueous solution of ammonium chloride (25 mL), diethyl ether (50 mL), and water (25 mL) were added sequentially. The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate in hexane) to give intermediate 46-2. 1 ¹H NMR (400MHz, chloroform-d) δ 5.00 (m, 1H), 4.92 – 4.86 (m, 1H), 4.06 (s, 2H), 3.69 (dd, J = 5.1, 1.6Hz, 1H), 3.55 (m, 2H), 3.52 – 3.41 (m, 4H), 1.80 – 1.72 (s, 3H), 1.57 (m, 2H), 1.28 (s, 30H). Intermediate 46-3: (S)-2-isobutoxy-3-(octadecoxy)prop-1-ol At room temperature, a vigorously stirred mixture of intermediate 46-2 (140 mg, 351 µmol), platinum (10 wt% on carbon, 193 mg, 98.0 µmol), tetrahydrofuran (1.5 mL), and ethanol (4.5 mL) was placed under a hydrogen atmosphere (balloon). After 16 hours, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give intermediate 46-3. 1 H NMR (400MHz, chloroform-d) δ 3.80 – 3.72 (m, 1H), 3.65 (dd, J = 11.4, 4.9Hz, 1H), 3.59 – 3.38(m, 4H), 3.31 (dd, J = 9.1, 6.6Hz, 1H), 1.88 (p, J = 6.7Hz, 1H), 1.63 – 1.52 (m, 2H), 1.28 (s, 30H), 0.99 – 0.83 (m, 6H). Intermediate 46-4: (R)-2-isobutoxy-3-(octadecoxy)propyl bis(4-nitrophenyl) phosphate Intermediate 46-4 was prepared in a manner similar to that of intermediate 2-3, using 46-3 instead of intermediate 2-2. LCMS: 722.9. Intermediate 46-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-isobutoxy- 3-(octadecyloxy)propyl)(4-nitrophenyl)phosphate Intermediate 46-5 was prepared in a manner similar to that of intermediate 2-4, using 46-4 instead of intermediate 2-3. LCMS: 915.3. Example 46: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-isobutoxy-3-(octadecoxy)propyl)hydrogen phosphate （46） Compound 46 was prepared in a manner similar to that of compound 18, using 46-5 instead of intermediate 18-5. 1 H NMR (400MHz, methanol-d4) δ 7.89 (s, 1H), 7.01 (d, J = 4.6Hz, 1H), 6.94 (d, J =4.6Hz, 1H), 5.08 (m, 1H), 4.59 (s, 1H), 4.27 (t, J = 5.3Hz, 1H), 4.20 – 4.11(m, 1H), 4.11 – 3.97 (m, 1H), 3.82 (t, J = 5.5Hz, 2H), 3.74 – 3.63 (m, 2H), 3.41 (m, 2H), 3.23 (m, 2H), 2.31 (m, 2H), 1.54 (m, 2H), 1.32 (m, 30H), 0.94 –0.89 (m, 9H). LCMS: 754.1. Intermediate 47-1: (R)-2,2-dimethyl-4-((octadecyloxy)methyl)-1,3-dioxolane At room temperature, acetone (458 µL, 6.18 mmol) was added via syringe to a rapidly stirred mixture of p-toluenesulfonic acid monohydrate (11.8 mg, 61.8 µmol) and (S)-3-(octadecyloxy)propane-1,2-diol (213 mg, 618 µmol) in dichloromethane (10 mL). After 90 minutes, the reaction mixture was heated to 50 °C. After 30 minutes, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (0 to 30% ethyl acetate in hexane) to give intermediate 47-1. 1¹H NMR (400MHz, chloroform-d) δ 4.33 – 4.23 (m, 1H), 4.08 (dd, J = 8.3, 6.4Hz, 1H), 3.75 (dd, J = 8.2, 6.4Hz, 1H), 3.59 – 3.38 (m, 4H), 1.63– 1.50 (m, 2H), 1.45 (s, 3H), 1.39 (s, 3H), 1.28 (s, 30H), 0.94 – 0.86 (m, 3H). Intermediate 47-2: (S)-2-isopropoxy-3-(octadecoxy)prop-1-ol At -60°C, the dichloroborane dimethyl sulfide complex (52 µL, 380 µmol) was added via syringe to a rapidly stirred mixture of intermediate 47-1 (149 mg, 387 µmol) in tetrahydrofuran (750 µL). The reaction mixture was heated to room temperature over 15 minutes. After 16 hours, ammonium chloride aqueous solution (10 mL) and diethyl ether (10 mL) were added sequentially. The organic layer was washed with water (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (0 to 30% ethyl acetate in hexane) to give intermediate 47-2. 1 H NMR (400MHz, chloroform-d) δ 3.80 (p, J = 6.1Hz,1H), 3.71 (dd, J = 10.1, 3.4Hz, 1H), 3.67 – 3.56 (m, 2H), 3.52 (dd, J = 9.8,4.8Hz, 1H), 3.49 – 3.41 (m, 3H), 1.58 (m, 2H), 1.28 (d, J = 1.9Hz, 30H), 1.20 (dd, J = 6.1, 0.9Hz, 6H), 0.94 – 0.85 (m, 3H). Intermediate 47-3: (R)-2-isopropoxy-3-(octadecoxy)propyl bis(4-nitrophenyl) phosphate Intermediate 47-3 was prepared in a similar manner to 46-4, using 47-2 instead of 46-3. LCMS: 731.2 [M+Na] + . Intermediate 47-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-isopropoxy- 3-(octadecyloxy)propyl)(4-nitrophenyl)phosphate Intermediate 47-4 was prepared in a similar manner to 46-5, using 47-3 instead of 46-4. LCMS: 923.4 [M+Na] + . Example 47: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-isopropoxy-3-(octadecoxy)propyl)hydrogen phosphate （47） At room temperature, potassium trimethylsilanolate (9.8 mg, 77 µmol) was added to a rapidly stirred mixture of 47-4 (23.0 mg, 25.5 µmol) in tetrahydrofuran (800 µL). After 45 minutes, potassium trimethylsilanolate (27 mg, 210 µmol) was added. After 45 minutes, concentrated hydrochloric acid (200 µL) was added. After 90 minutes, triethylamine was added until the mixture had a pH > 7, as indicated by a persistent yellow color. The mixture was purified by reversed-phase preparative HPLC (2-propanol / water) to give compound 47, which forms a salt with triethylamine. 1 HNMR (400MHz, methanol-d4) δ 7.98 (s, 1H), 7.11 (s, 2H), 4.82 (d, J = 5.3Hz, 1H), 4.36 (d, J = 4.7Hz, 1H), 4.27 (t, J = 5.4Hz, 1H), 4.22 – 4.13 (m, 1H), 4.12 –4.03 (m, 1H), 3.86 – 3.74 (m, 3H), 3.74 – 3.63 (m, 1H), 3.59 (dd, J = 11.2,4.9Hz, 1H), 3.54 (d, J = 6.0Hz, 1H), 3.47 – 3.39 (m, 2H), 1.56 (m, 2H), 1.30(m, 30H), 1.12 (dd, J = 6.1, 1.7Hz, 6H), 0.96 – 0.88 (m, 3H). LCMS: 738.4 [MH] - . Intermediate 48-1: (R)-tert-butyl(2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propoxy)di Methylsilane Sodium hydride (60 wt% dispersion in mineral oil, 74 mg, 1.94 mmol) was added to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol (335 mg, 730 µmol) in tetrahydrofuran (6 mL). After 30 minutes, 4-(bromomethyl)-1,2-dichlorobenzene (438 mg, 1.83 mmol) was added, and the resulting mixture was heated to room temperature and stirred overnight. The suspension was then cooled to 0 °C, quenched with water (5 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic fractions were then washed with brine (25 mL) and dried over magnesium sulfate. The mixture was then filtered and concentrated, and the crude residue was purified by silica gel rapid column chromatography (0 to 20% ethyl acetate in hexane) to give intermediate 48-1. 1 H NMR (400MHz, chloroform-d) δ 7.51 (d, J = 1.9Hz, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.21 (dd, J = 8.2, 2.0Hz, 1H), 4.68 (s, 2H), 3.71 (d, J = 5.9Hz, 2H), 3.67 –3.60 (m, 1H), 3.60 – 3.39 (m, 4H), 1.66 – 1.49 (m, 2H), 1.39 – 1.20 (m, 30H), 1.00 – 0.84 (m, 12H), 0.08 (s, 6H). Intermediate 48-2: (S)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)prop-1-ol At 0 °C, tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.63 mL, 0.63 mmol) was added to a stirred solution of intermediate 48-1 (323 mg, 523 µmol) in tetrahydrofuran (5 mL). After 1 hour, water (5 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic fractions were then washed with brine (25 mL) and dried over magnesium sulfate. The mixture was then filtered and concentrated, and the crude residue was purified by silica gel rapid column chromatography (0 to 50% ethyl acetate in hexane) to give intermediate 48-2. 1H NMR (400MHz, chloroform-d) δ 7.49 (d, J = 1.9Hz, 1H), 7.43 (d, J= 8.2Hz, 1H), 7.20 (dd, J = 8.2, 2.0Hz, 1H), 4.66 (q, J = 12.3Hz, 2H), 3.83 –3.64 (m, 3H), 3.59 (qd, J = 10.0, 5.0Hz, 2H), 3.46 (td, J = 6.7, 1.9Hz, 2H), 2.11 (t, J = 6.0Hz, 1H), 1.65 – 1.55 (m, 2H), 1.28 (s, 30H), 0.90 (t, J =6.7Hz, 3H). Intermediate 48-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)((R)- 2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate At room temperature, 2-chlorophenyl dichlorophosphate (64.6 µL, 392 µmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (54.3 mg, 786 µmol), triethylamine (110 µL, 786 µmol), and tetrahydrofuran (0.6 mL). After 40 minutes, intermediate 1-3 (97.5 mg, 294 µmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (31.3 µL, 313 µmol) were added sequentially. After 60 minutes, a solution of intermediate 48-2 (148 mg, 294 µmol) in tetrahydrofuran (0.7 mL) was added via tubing. 1-Methylimidazole (20 µL, 392 µmol) was then added. After 15 hours, saturated sodium bicarbonate aqueous solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 10% methanol in dichloromethane) to give intermediate 48-3. 1HNMR (400MHz, chloroform-d) δ 8.01 (d, J = 1.6Hz, 1H), 7.45 – 7.34 (m, 4H), 7.21 –7.06 (m, 3H), 7.01 (t, J = 4.6Hz, 1H), 6.61 (dd, J = 10.3, 4.7Hz, 1H), 5.62(s, 2H), 5.44 (dd, J = 17.1, 6.8Hz, 1H), 4.99 (ddd, J = 9.2, 6.8, 4.0Hz, 1H), 4.69 – 4.19 (m, 7H), 3.82 – 3.73 (m, 1H), 3.53 – 3.46 (m, 2H), 3.45 – 3.37(m, 2H), 1.91 – 1.38 (m, 8H), 1.27 (d, J = 2.7Hz, 30H), 0.90 (t, J = 6.7Hz, 3H). Intermediate 48-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-((3,4-di) chlorobenzyl)oxy)-3-(octadecyloxy)propyl)hydrogen phosphate Sodium hydroxide (0.5 N, 715 µL, 357 µmol) was added to a tetrahydrofuran (4 mL) solution of 48-3 (100 mg, 99.3 µmol), and the mixture was heated to 50 °C. After 3 hours, concentrated hydrochloric acid (30 µL, 357 µmol) was added. The residue was then concentrated and purified by silica gel rapid column chromatography (0 to 30% methanol in dichloromethane) to give intermediate 48-4. 1HNMR (400MHz, methanol-d4) δ 7.88 (s, 1H), 7.50 (d, J = 2.0Hz, 1H), 7.41 (d, J =8.3Hz, 1H), 7.24 (dd, J = 8.2, 1.9Hz, 1H), 6.93 (d, J = 4.6Hz, 1H), 6.88 (d,J = 4.6Hz, 1H), 5.40 (d, J = 6.4Hz, 1H), 5.03 (dd, J = 6.5, 3.2Hz, 1H), 4.65– 4.50 (m, 3H), 4.06 (d, J = 5.7Hz, 2H), 3.95 – 3.84 (m, 2H), 3.78 – 3.66 (m,1H), 3.56 – 3.34 (m, 4H), 1.72 (s, 3H), 1.60 – 1.47 (m, 2H), 1.42 (s, 3H), 1.38 – 1.12 (m, 30H), 1.02 – 0.84 (m, 3H). Example 48: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propane (48) Hydrogen phosphate (48) Concentrated hydrochloric acid (52.4 µL, 629 µmol) was added to a solution of 48-4 (47 mg, 52.4 µmol) in tetrahydrofuran (0.5 mL). After 3 hours, sodium carbonate (67 mg, 629 µmol), methanol (10 mL), and magnesium sulfate were added sequentially, and the mixture was stirred at room temperature for 10 minutes. The mixture was then filtered and concentrated, and the residue was purified by silica gel rapid column chromatography (0 to 50% methanol in dichloromethane) to give compound 48. 1H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.50 (s, 1H), 7.44 (d,J = 8.2Hz, 1H), 7.24 (d, J = 9.1Hz, 1H), 6.96 (d, J = 4.5Hz, 1H), 6.89 (d, J= 4.6Hz, 1H), 4.95 – 4.75 (m, 1H), 4.60 (s, 2H), 4.39 – 4.33 (m, 1H), 4.20(t, J = 5.8Hz, 2H), 4.14 – 4.08 (m, 1H), 4.05 – 3.86 (m, 2H), 3.76 – 3.68 (m,1H), 3.52 – 3.25 (m, 4H), 1.57 – 1.50 (m, 2H), 1.39 – 1.25 (m, 30H), 0.92 (t,J = 6.7Hz, 3H). Intermediate 49-1: (R)-tert-butyl(2-((3-chloro-4-methoxybenzyl)oxy)-3-(octadecyloxy)propoxy dimethylsilane Intermediate 49-1 was prepared in a manner similar to intermediate 2-1, using 4-(bromomethyl)-2-chloro-1-methoxybenzene instead of 4-(bromomethyl)-1,1'-biphenyl. LCMS: 635.5 [M+Na] + . Intermediate 49-2: (S)-2-((3-chloro-4-methoxybenzyl)oxy)-3-(octadecyloxy)prop-1-ol Intermediate 49-2 was prepared in a manner similar to that of intermediate 18-3, using 49-1 instead of intermediate 18-2. LCMS: 522.1 [M+Na] + . Intermediate 49-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl((R)-2-((3-chloro-4-) Methoxybenzyl)oxy)-3-(octadecyloxy)propyl)(2-chlorophenyl)phosphate Intermediate 49-3 was prepared in a similar manner to 23-2, using 49-2 instead of 23-1. LCMS: 1024.5 [M+Na] + . Example 49: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-chloro-4-methoxybenzyl)oxy)-3-(octadecyloxy) propyl phosphate (49) Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 25 µL, 25 µmol) was added via syringe to a vigorously stirred mixture of intermediate 49-3, pyridine (3 µL, 40 µmol), water (3 µL, 200 µmol), and tetrahydrofuran (100 µL). After 4 hours, another 25 µL (25 µmol) of tetrabutylammonium fluoride was added via syringe. After 16 hours, trimethylchlorosilane (6 µL, 50 µmol) and concentrated hydrochloric acid (200 µL, 2.40 mmol) were added sequentially. The resulting mixture was purified by reversed-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 49. 1 H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.34(d, J = 2.2Hz, 1H), 7.22 (d, J = 7.3Hz, 1H), 7.00 (d, J = 4.5Hz, 1H), 6.98(s, 1H), 6.88 (d, J = 4.6Hz, 1H), 5.19 (s, 1H), 4.59 (d, J = 4.7Hz, 2H), 4.56(s, 1H), 4.51 (s, 1H), 4.48 (s, 1H), 4.35 (s, 2H), 4.26 (t, J = 5.4Hz, 1H),4.08 (s, 1H), 3.87 (s, 3H), 3.78 – 3.63 (m, 2H), 3.59 (s, 1H), 1.53 (s, 2H), 1.30 (d, J = 10.7Hz, 30H), 1.00 – 0.81 (m, 3H).LCMS: 850.5 [MH] - . Intermediate 50-1: (R)-2-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop- 2-yl)oxy)methyl)benzylnitrile Intermediate 50-1 was prepared in a manner similar to intermediate 2-1, using 2-(bromomethyl)benzylnitrile instead of 4-(bromomethyl)-1,1'-biphenyl. 1H NMR (400MHz, chloroform-d) δ 7.71 (d, J = 7.8Hz, 1H), 7.65 (dd,J = 7.6, 1.2Hz, 1H), 7.59 (td, J = 7.7, 1.3Hz, 1H), 7.38 (td, J = 7.6, 1.2Hz,1H), 4.93 (s, 2H), 3.77 (d, J = 5.4Hz, 2H), 3.71 (tt, J = 5.7, 4.4Hz, 1H), 3.60 (qd, J = 10.3, 4.9Hz, 2H), 3.46 (td, J = 6.6, 1.6Hz, 2H), 1.58 (q, J =7.1Hz, 2H), 1.27 (s, 30H), 0.91 (d, J = 6.6Hz, 12H), 0.09 (s, 6H). Intermediate 50-2: (S)-2-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)benzylnitrile Intermediate 50-2 was prepared in a manner similar to that of intermediate 18-3, using 50-1 instead of intermediate 18-2. 1 ¹H NMR (400MHz, chloroform-d) δ 7.72 – 7.66 (m, 1H), 7.65 – 7.57 (m, 2H), 7.42 (ddd, J = 7.7, 6.0, 2.8Hz, 1H), 4.91 (d, J = 12.2Hz, 1H), 4.86 (d, J = 12.2Hz, 1H), 3.90 – 3.81 (m, 1H), 3.81 – 3.72 (m, 2H), 3.71 – 3.58 (m, 2H), 3.48 (td, J = 6.6, 1.1Hz, 2H), 1.67 – 1.49 (m, 2H), 1.28 (s, 30H), 0.90 (t, J = 6.7Hz, 3H). Intermediate 50-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)((R)- 2-((2-cyanobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate Intermediate 50-3 was prepared in a similar manner to 23-2, using 50-2 instead of 23-1. LCMS: 963.3. Example 50: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((2-cyanobenzyl)oxy)-3-(octadecyloxy)propyl) Hydrogen phosphate (50) Compound 50 was prepared in a manner similar to that of 49, using intermediate 50-3 instead of 49-3. 1 H NMR (400MHz, methanol-d4) δ 8.06 (s, 1H), 7.69 (d, J = 8.2Hz, 2H), 7.63 (t, J =7.7Hz, 1H), 7.48 – 7.38 (m, 1H), 7.37 – 7.26 (m, 1H), 7.20 (d, J = 4.8Hz, 1H), 4.78 (d, J = 5.1Hz, 2H), 4.64 (d, J = 11.5Hz, 1H), 4.35 (s, 2H), 4.26 (t, J = 5.4Hz, 1H), 4.23 – 4.14 (m, 1H), 4.14 – 4.06 (m, 1H), 3.98 (qt, J =11.1, 5.6Hz, 2H), 3.83 (t, J = 5.1Hz, 1H), 3.58 (qd, J = 10.6, 5.1Hz, 2H), 3.45 (td, J = 6.5, 2.4Hz, 1H), 1.54 (t, J = 7.0Hz, 2H), 1.29 (d, J = 7.9Hz, 30H), 0.92 (t, J = 6.5Hz, 3H). LCMS: 813.2. Intermediate 51-1: (R)-2-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop- 2-yl)oxy)methyl)-4-fluorobenzyl nitrile Intermediate 51-1 was prepared in a manner similar to intermediate 2-1, using 2-(bromomethyl)-4-fluorobenzyl nitrile instead of 4-(bromomethyl)-1,1'-biphenyl. 1 H NMR (400MHz, chloroform-d) δ 7.64 (dd, J = 8.6, 5.3Hz,1H), 7.52 (dd, J = 9.5, 2.6Hz, 1H), 7.06 (td, J = 8.2, 2.6Hz, 1H), 4.94 (s,2H), 3.77 (d, J = 4.9Hz, 2H), 3.72 (tt, J = 6.2, 4.5Hz, 1H), 3.63 – 3.54 (m,2H), 3.47 (tt, J = 5.6, 1.9Hz, 2H), 1.65 – 1.52 (m, 2H), 1.40 – 1.19 (m,30H), 0.96 – 0.84 (m, 12H), 0.09 (s, 6H). Intermediate 51-2: (S)-4-fluoro-2-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)benzylnitrile Intermediate 51-2 was prepared in a manner similar to that of intermediate 18-3, using 51-1 instead of intermediate 18-2. 1 HNMR (400MHz, chloroform-d) δ 7.69 (dd, J = 8.6, 5.3Hz, 1H), 7.39 (dd, J = 9.2,2.6Hz, 1H), 7.11 (td, J = 8.2, 2.6Hz, 1H), 4.90 (d, J = 3.4Hz, 2H), 3.85 (d,J = 9.0Hz, 1H), 3.81 – 3.72 (m, 2H), 3.70 – 3.59 (m, 2H), 3.48 (td, J = 6.6,1.5Hz, 2H), 2.22 (s, 1H), 1.58 (d, J = 14.8Hz, 2H), 1.28 (s, 30H), 0.94 –0.86 (m, 3H). Example 51: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((2-cyano-5-fluorobenzyl)oxy)-3-(octadecyloxy) Propyl) hydrogen phosphate (51) Compound 51 was prepared in a manner similar to that of compound 19, using 51-2 instead of 19-2. 1 H NMR(400MHz, methanol-d4) δ 7.87 (s, 1H), 7.73 (s, 1H), 7.48 (d, J = 9.0Hz, 1H), 7.19(d, J = 25.2Hz, 1H), 7.00 (s, 1H), 6.90 (m, 1H), 4.36 (s, 2H), 4.28 (s, 2H), 4.14 (s, 1H), 3.89 (s, 2H), 3.78 (s, 1H), 3.71 (s, 4H), 3.61 (d, J = 10.2Hz,2H), 1.56 (m, 2H), 1.30 (s, 30H), 0.91 (m, 3H). LCMS: 829.5 [MH] - . Example 52: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((2,3-dihydro-1H-inden-5-yl)methoxy)-3-(octadecane) (52)Oxypropyl)hydrogen phosphate Compound 52 was prepared in a manner similar to that of compound 19, using 5-(bromomethyl)-2,3-dihydro-1H-indene instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene. 1 H NMR (400MHz, methanol-d4) δ 7.87 (s, 1H), 7.18 (s, 1H), 7.12 – 7.04 (m, 2H), 7.00 (d, J = 4.6Hz, 1H), 6.89 (d, J =4.6Hz, 1H), 4.80 (d, J = 5.3Hz, 2H), 4.63 – 4.50 (m, 2H), 4.41 – 4.31 (m,2H), 4.26 (t, J = 5.3Hz, 1H), 4.17 – 4.02 (m, 2H), 3.92 – 3.83 (m, 2H), 3.76– 3.66 (m, 1H), 3.42 – 3.36 (m, 2H), 2.86 (t, J = 7.4Hz, 4H), 2.13 – 1.96 (m,2H), 1.52 (t, J = 6.8Hz, 2H), 1.38 – 1.24 (m, 30H), 0.92 (t, J = 6.7Hz, 3H).LCMS: 828.2. Intermediate 53-1: (R)-4-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop- 2-yl)oxy)methyl)-3-fluorobenzyl nitrile : NaH (60% oily dispersion, 88 mg, 2.29 mmol, 3.5 equivalents) was suspended in THF (6 mL) and cooled to 0 °C. A solution of 1-O-octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol (300 mg, 0.654 mmol, 1 equivalent) in THF (2.5 mL) was added over 30 seconds. After 30 minutes, a solution of alkyl bromide (560 mg, 2.62 mmol) in THF (2.5 mL) was added at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (15 mL). The mixture was extracted with EtOAc. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by rapid chromatography (0-30% EtOAc in hexane) to give the product.

[0322] Intermediate 53-2: (S)-3-fluoro-4-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)benzylnitrile : At 0 °C, a solution of 1 M TBAF in THF (1 mL, 1 mmol) was added to a THF (3.3 mL) solution of the silyl-protected compound (342 mg, 0.578 mmol) and stirred for 1 hour. The solution was diluted with water (3 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (2 × 5 mL) and brine, dried over Na₂SO₄, evaporated, and the residue was purified by silica gel column chromatography (0-60% ethyl acetate in hexane) to give the product. 1 ¹H NMR (400MHz, chloroform-d) δ 7.66 (t, 1H), 7.47 (dd, 1H), 7.34 (dd, 1H), 4.92 – 4.73 (m, 2H), 3.90 – 3.66 (m, 3H), 3.61 (m, 2H), 3.45 (m, 2H), 2.21 (s, 1H), 1.57 (m, 2H), 1.26 (s, 26H), 0.94 –0.81 (m, 3H). Intermediate 53-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)((R)- 2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate : A solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL) was added to an anhydrous THF (0.4 mL) solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 µL, 0.62 mmol). The mixture was stirred for 30 minutes and then filtered. Additional THF (1.2 mL), nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol) were added sequentially to the filtrate. After 1 hour, (S)-3-fluoro-4-(((1-hydroxy-3-(octadecyloxy)prop-2-yl)oxy)methyl)benzyl nitrile (107 mg, 0.232 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. The solvent was removed, and the residue was purified by silica gel rapid chromatography (0-15% MeOH in CH2Cl2) to give the compound.

[0323] Example 53: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy) Propyl) hydrogen phosphate (53) Intermediate 53-3 (250 mg, 0.255 mmol) was dissolved in THF (5 mL), and 0.5 N NaOH (1.9 mL) was added at 0 °C. The mixture was stirred at 50 °C for 4 hours. The reaction progress was monitored by TLC. After the intermediate was almost completely consumed, the mixture was neutralized with 4 N HCl at 0 °C. The mixture was diluted with methanol, and Na₂SO₄ was added. The mixture was filtered, and the filtrate was evaporated to obtain the residue.

[0324] The residue was dissolved in THF (1.5 mL). The resulting solution was cooled in an ice bath. Concentrated HCl aqueous solution (0.3 mL) was added. The cold bath was removed, and the reaction mixture was stirred vigorously for 3 hours. The mixture was neutralized with Na₂CO₃, diluted with MeOH, and filtered. The filtrate was evaporated to obtain the residue, which was purified by silica gel column chromatography (0-40% MeOH in DCM) to obtain the product. 1 H NMR (400MHz, methanol-d4) δ 7.91 (s, 1H), 7.74 (t, J = 7.5Hz, 1H), 7.54 –7.39 (m, 2H), 7.04 (d, J = 4.7Hz, 1H), 6.98 (d, J = 4.6Hz, 1H), 4.85 – 4.72(m, 2H), 4.36 (m, 1H), 4.27 (m, 1H), 4.18 (m, 1H), 4.09 (m, 1H), 3.92 (m,1H), 3.78 (t, 1H), 3.63 – 3.35 (m, 4H), 1.51 (m, 2H), 1.28 (d, 30H), 1.01 –0.84 (m, 3H). 31 P NMR (162MHz, methanol-d4) δ 0.28. MS: 831.22 (M+1). Intermediate 54-1: (R)-4-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop- 2-yl)oxy)methyl)-2-methoxybenzyl nitrile : Intermediate 54-1 was synthesized in a manner similar to that of 53-1.

[0325] Intermediate 54-2: (S)-4-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)-2-methoxy benzyl nitrile Intermediate 54-2 was synthesized in a manner similar to that of 53-2. 1H NMR (400MHz, chloroform-d) δ 7.50(d, J = 7.9Hz, 1H), 7.04 (s, 1H), 6.98 (d, J = 8.0Hz, 1H), 4.82 – 4.63 (m,2H), 3.94 (s, 3H), 3.83 – 3.53 (m, 4H), 3.45 (m, 2H), 2.25 (s, 1H), 1.56 (q,J = 6.9Hz, 2H), 1.26 (s, 30H), 0.88 (t, J = 6.7Hz, 3H). Intermediate 54-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)((R)- 2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate : A solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL) was added to an anhydrous THF (0.4 mL) solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 µL, 0.62 mmol). The mixture was stirred for 30 minutes and then filtered. Additional THF (1.2 mL), nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol) were added sequentially to the filtrate. After 1 hour, (S)-4-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)-2-methoxybenzyl nitrile (115 mg, 0.235 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. The solvent was removed, and the residue was purified by silica gel rapid chromatography (0-15% MeOH in CH2Cl2) to give the compound.

[0326] Example 54: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((4-cyano-3-methoxybenzyl)oxy)-3-(octadecyloxy) propyl phosphate (54) The intermediate (222 mg, 0.223 mmol) was dissolved in THF (4.5 mL), and 0.5 N NaOH (1.6 mL) was added at 50 °C. The mixture was stirred at 50 °C for 3 hours. The reaction progress was monitored by TLC. After the intermediate was almost completely consumed, the mixture was neutralized with 4 N HCl at 0 °C. The mixture was diluted with methanol, and Na₂SO₄ was added. The mixture was filtered, and the filtrate was evaporated to obtain the residue.

[0327] The residue was dissolved in THF (1.5 mL). The resulting solution was cooled in an ice bath. Concentrated HCl aqueous solution (0.3 mL) was added. The cold bath was removed, and the reaction mixture was stirred vigorously for 3 hours. The mixture was neutralized with Na₂CO₃, diluted with MeOH, and filtered. The filtrate was evaporated to obtain the residue, which was purified by silica gel column chromatography (0-40% MeOH in DCM) to obtain the product. 1 H NMR (400MHz, DMSO-d6) δ 7.94 (s, 1H), 7.64 (d, J = 7.9Hz, 1H), 7.19 (s,1H), 7.03 (d, J = 7.9Hz, 1H), 6.93 (d, J = 4.6Hz, 1H), 6.85 (d, 1H), 4.65 (d,3H), 4.30 – 4.09 (m, 2H), 4.07 – 3.96 (m, 2H), 3.91 (d, 4H), 1.43 (d, 2H), 1.22 (d, 30H), 0.86 (t, 3H). 31 P NMR (162MHz, DMSO-d6) δ -1.11. MS: 843.28 (M+1). Preparation of intermediate 55-1: 3-(heptadecanoxy)prop-1-ol : At 0 °C, NaH (60% oily dispersion; 0.172 g, 4.5 mmol) was added fractionally to an anhydrous DMF (6 mL) solution of 1,3-propanediol (1.03 g, 13.5 mmol), and the mixture was stirred at room temperature for 10 min. 1-Bromoheptadecane (0.958 g, 3 mmol) and KI (498 mg, 3 mmol) were added, and the mixture was heated at 95 °C for 4 h. After cooling, the mixture was poured into ice water and extracted with DCM. The extract was washed with brine, dried over Na₂SO₄, and evaporated. The resulting residue was purified by rapid column chromatography (silica gel; AcOEt / hexane, 1:2) to give the product as a solid. 1 ¹H NMR (400MHz, chloroform-d) δ 3.87 – 3.77 (m, 2H), 3.64 (t, J = 5.7Hz, 2H), 3.45 (t, J = 6.6Hz, 2H), 1.86 (m, 2H), 1.65 – 1.51 (m, 2H), 1.28 (s, 30H), 0.98 – 0.85 (m, 3H). Intermediate 55-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)((R)- 2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate : A solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL) was added to an anhydrous THF (0.4 mL) solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 µL, 0.62 mmol). The mixture was stirred for 30 minutes and then filtered. Additional THF (1.2 mL), nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol) were added sequentially to the filtrate. After 1 hour, 3-(heptadecanoxy)prop-1-ol (74 mg, 0.235 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. The solvent was removed, and the residue was purified by silica gel rapid chromatography (0-15% MeOH in CH2Cl2) to give the compound.

[0328] Example 55: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl(3-(heptadecyloxy)propyl)hydrogen phosphate (55) Intermediate 55-2 (100 mg, 0.122 mmol) was dissolved in THF (1.2 mL), and 1 N TBAF (1.5 mL), DMAP (149 mg, 1.22 mmol), and water (45 mg) were added. The reaction mixture was stirred at room temperature for 2 hours. TMSCl (0.19 mL, 1.47 mmol) was added to the mixture, followed by concentrated HCl (1.4 mL). The mixture was stirred at room temperature for 2.5 hours. Then 4-methylmorpholine (1.98 g) was added and diluted with MeOH. The mixture was filtered and purified by HPLC (60%–100% ACN aqueous solution containing 0.1% TFA) to give the product. 1 H NMR (400MHz, methanol-d4) δ 8.10 (s, 1H),7.37 (d, J = 4.8Hz, 1H), 7.20 (d, J = 4.8Hz, 1H), 4.77 (d, J = 5.2Hz, 1H),4.44 – 4.34 (m, 1H), 4.31 – 4.19 (m, 2H), 4.14 (m, 1H), 4.00 (m, 2H), 3.51(t, 2H), 3.42 (m, 2H), 1.88 (m, 2H), 1.55 (m, 2H), 1.40 – 1.22 (m, 30H), 0.98– 0.85 (m, 3H). 31P NMR (162MHz, methanol-d4) δ -0.01. MS 668.24 (M+1). Intermediate 56-1: 3-decoxyprop-1-ol : 56-1 was synthesized using 1-bromodecane as an alkylating agent in a manner similar to that of 55-1. 1 H NMR (400MHz, DMSO-d6) δ 4.36 (t, J = 5.1Hz, 1H), 3.49 – 3.35 (m, 4H), 1.63 (p, J = 6.4Hz, 2H), 1.47 (t, J = 6.7Hz, 2H), 1.25 (s, 14H), 0.93 – 0.79 (m, 3H). Intermediate 56-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)(3-(decyl) oxypropyl phosphate : Intermediate 56-2 was synthesized using intermediate 3-decoxyprop-1-ol in a manner similar to that of 55-2.

[0329] Example 56: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl(3-(decoxy)propyl)hydrogen phosphate (56) A THF solution (1 mL) of 1,1,3,3-tetramethylguanidine (61 mg, 0.53 mmol) and cis-2-pyridinaldehyde oxime (0.11 g, 0.88 mmol) was added to a THF solution (1.8 mL) of 56-2 (63 mg, 0.088 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by rapid chromatography using 0–50% MeOH in DCM solution to obtain the product. MS: 610.20 (M+1). The product was dissolved in THF (0.5 mL). The resulting solution was cooled in an ice bath. Concentrated HCl aqueous solution (0.1 mL) was added. The cold bath was removed, and the reaction mixture was stirred vigorously for 3 hours. The mixture was neutralized with Na2CO3, diluted with MeOH, and filtered. The solution was purified by preparative HPLC using a Gilson preparative HPLC (Gemini column, 40%-100% CH3CN in H2O solution, containing 0.1% TFA) to obtain the product. 1H NMR (400MHz, methanol-d4) δ 8.07 (s, 1H), 7.32 (d, J= 4.8Hz, 1H), 7.17 (d, J = 4.8Hz, 1H), 4.78 (m, 1H), 4.38 (m, 1H), 4.24 (m,2H), 4.21 – 4.08 (m, 1H), 3.98 (m, 2H), 3.51 (m, 2H), 3.41 (m, 2H), 1.87 (m,2H), 1.54 (t, 2H), 1.30 (d, 14H), 0.91 (t, 3H). 31 P NMR (162MHz, methanol-d4) δ 0.18. MS: 570.16 (M+1). Intermediate 57-1: Preparation of 3-dodecyloxyprop-1-ol : Intermediate 57-1 was synthesized using 1-bromodecane as an alkylating agent in a manner similar to that of 55-1. 1 H NMR(400MHz, DMSO-d6) δ 4.36 (t, J = 5.1Hz, 1H), 3.48 – 3.36 (m, 6H), 1.63 (m,2H), 1.47 (m, 2H), 1.25 (s, 18H), 0.92 – 0.80 (m, 3H). Intermediate 57-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)(3-(deca-) Dialkoxypropyl phosphate Intermediate 57-2 was synthesized using intermediate 3-dodecoxyprop-1-ol in a manner similar to that of 55-2.

[0330] Example 57: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl(3-(dodecyloxy)propyl)hydrogen phosphate (57) Compound 57 was synthesized in a manner similar to that of compound 56. 1H NMR (400MHz, methanol-d4) δ8.07 (s, 1H), 7.33 (d, J = 4.8Hz, 1H), 7.18 (d, J = 4.8Hz, 1H), 4.78 (d, J =5.2Hz, 1H), 4.38 (dt, J = 6.5, 3.4Hz, 1H), 4.29 – 4.20 (m, 2H), 4.13 (m, 1H), 3.98 (m, 2H), 3.51 (m, 2H), 3.41 (m, 2H), 1.87 (m, 2H), 1.53 (m, 2H), 1.29(s, 18H), 0.99 – 0.84 (m, 3H). 31 P NMR (162MHz, methanol-d4) δ 0.22. MS: 596.18 (M+1). Intermediate 58-1: Preparation of 3-(tetradecoxy)prop-1-ol : Intermediate 58-1 was synthesized using 1-bromotetradecane as an alkylating agent in a manner similar to that of 55-1. 1 H NMR(400MHz, DMSO-d6) δ 4.36 (t, J = 5.2Hz, 1H), 3.49 – 3.35 (m, 5H), 1.63 (t, J= 6.4Hz, 2H), 1.47 (t, J = 6.7Hz, 2H), 1.25 (s, 22H), 0.94 – 0.79 (m, 3H). Intermediate 58-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)(3-(deca-) Tetraalkoxypropyl phosphate : Intermediate 58-2 was synthesized using intermediate 3-(tetradecoxy)prop-1-ol in a manner similar to that of 55-2.

[0331] Example 58: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl(3-(tetradecoxy)propyl)hydrogen phosphate (58) Compound 58 was synthesized in a manner similar to that of compound 56. 1H NMR (400MHz, methanol-d4) δ8.09 (s, 1H), 7.35 (d, J = 4.8Hz, 1H), 7.19 (d, J = 4.8Hz, 1H), 4.77 (d, J =5.2Hz, 1H), 4.43 – 4.32 (m, 1H), 4.24 (m, 2H), 4.13 (m, 1H), 3.99 (m, 2H), 3.51 m, 2H), 3.41 (m, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.30 (s, 22H), 0.98 –0.86 (m, 3H). 31 P NMR (162MHz, methanol-d4) δ 0.09. MS: 626.19 (M+1). Intermediate 59-1: Preparation of 3-octadecyloxyprop-1-ol : Intermediate 59-1 was synthesized using 1-bromooctadecane as an alkylating agent in a manner similar to that of 55-1. 1 H NMR (400MHz, DMSO-d6) δ 4.36 (t, J = 5.1Hz, 1H), 3.48 – 3.36 (m, 4H), 3.30 (s, 2H), 1.63 (m, 2H), 1.47 (m, 2H), 1.24 (s, 32H), 0.91 – 0.81 (m, 3H). Intermediate 59-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)(3-(deca-) Octaalkoxypropyl phosphate : Intermediate 59-2 was synthesized using intermediate 3-octadecoxyprop-1-ol in a manner similar to that of 55-2.

[0332] Example 59: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,...

Claims

1. A compound of formula I: ， Formula I Or its pharmaceutically acceptable salt, wherein: Z 1 It is -CH2- or –CH2-CH2-; Z 2 It is -CH2- or –CH2-CH2-; X represents a chemical bond, -O-, or -(CR). 12A R 12B ) q -、-O(CR 12A R 12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-;in Each R 12A Independently, it is H, C1-C6 alkyl, or phenyl; Each R 12B Independently H or C1-C6 alkyl; or R on the same carbon 12A and R 12B They are linked together to form C3-C6 cycloalkylene groups; R 13 It is H, C1-C6 alkyl or phenyl; R 14 It is H, C1-C6 alkyl or phenyl; and q is 1 or 2; R 1 For H, C1-C 20 Alkyl, C3-C 10 Cycloalkyl groups, containing one, two, or three heteroatoms selected from N, O, and S, consisting of 4 to 6-membered heterocyclic groups, C6-C. 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein when R 1 When R is not H, 1 The group is optionally surrounded by one or two R groups. 1A Group substitution; Each R 1A Independently, it is a C1-C3 alkyl, phenyl, haloyl, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; or two Rs on the same or adjacent carbons thereon. 1A They are linked together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclic ring containing one, two, or three heteroatoms selected from N, S, and O; R 2 It is H or C1-C3 alkyl; Y is absent, or is a phenylene or a C3-C6 cycloalkylene group; R 3 It can be H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; Each R 4 Independently, it is H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R 4 The group and the R of an adjacent carbon atom 4 The groups together form a double bond; Each R 5 It can be independently H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; R 6 It is H or -C(O)C1-C6 alkyl; R 7 It is H or -C(O)C1-C6 alkyl; and m is an integer from 10 to 21.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond, -O-, -(CR) 12A R 12B ) q -or-O(CR) 12A R 12B ) q - 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond, -O-, -OCH2 or -CH2CH2.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is -O-, -(CR) 12A R 12B ) q -、-O(CR 12A R 12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-.

6. The compound according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, wherein X is -O-, -O(CR) 12A R 12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X is -O-, -O(CR) 12A R 12B - or - OCR 12A R 12B -(CR 13 =CR 14 )-.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein X is -O-, -OCH2- or -OCH2-(CH=CH)-.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein X is -O-.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein X is -OCH2-.

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