Phospholipid compounds and their uses

Abstract

To provide a method for treating a disease. [Solution] Disclosed are a compound for the treatment of viral infections, a method of using the compound alone or in combination with additional agents, and a pharmaceutical composition of the compound (Formula (I)). Surprisingly, remarkable effects are achieved according to the present invention, as described in detail and demonstrated concretely in this specification, and these remarkable effects could not be easily predicted by those skilled in the art from the prior art. JPEG2026086627000413.jpg40133

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 069,449, filed Aug. 24, 2020; U.S. Provisional Patent Application No. 63 / 092,386, filed Oct. 15, 2020; and U.S. Provisional Patent Application No. 63 / 151,509, filed Feb. 19, 2021, each of which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] There is a need for compounds and methods for treating viral infections, such as viral infections of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae families. This disclosure addresses these and other needs.

Summary of the Invention

Means for Solving the Problems

[0003] In one aspect, the disclosure provides a compound of formula (I):

Chemical Formula

[0004] In another embodiment, the 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.

[0005] In another embodiment, the Disclosure provides a method for treating or preventing a viral infection in a person in need thereof, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a person.

[0006] In another embodiment, the disclosure provides a method for producing a pharmaceutical product for treating or preventing a viral infection in a person in need thereof, the method being characterized by using a compound of formula I or a pharmaceutically acceptable salt thereof.

[0007] In another embodiment, the disclosure provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for treating or preventing a viral infection in a person in need thereof. [Modes for carrying out the invention]

[0008] Detailed description of the invention I. Overview The present invention relates more broadly to methods and compounds for the treatment or prevention of viral infections, such as paramyxoviridae virus infections, pneumoviridae virus infections, picornaviridae virus infections, flaviviridae virus infections, filoviridae virus infections, arenaviridae virus infections, orthomyxovirus infections, and coronavirus infections.

[0009] II. Definition Unless otherwise specified, the following terms and phrases, as used herein, are intended to have the following meanings:

[0010] As used herein, “compounds of the disclosure” or “compounds of formula I” means compounds of formula I or pharmaceutically acceptable salts thereof. Similarly, the phrase “compounds of formula (number)” means compounds of that formula and pharmaceutically acceptable salts thereof.

[0011] "Alkyl" refers to a non-branched or branched saturated hydrocarbon chain. For example, an alkyl group consists of 1 to 20 carbon atoms (i.e., C1 to C2). 20 Alkyl, 1-8 carbon atoms (i.e., C1-C8 alkyl), 1-6 carbon atoms (i.e., C1-C6 alkyl) , or may have 1 to 3 carbon atoms (i.e., C1 to C3 alkyl). Suitable examples of alkyl groups include 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, -C H(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 2-methyl-1-butyl(-CH2CH2CH(CH3)2), 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( Examples include, but are not limited to, 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) and 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3).

[0012] "Alkoxy" refers to a group having the formula -O-alkyl, in which the alkyl group defined above is bonded to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group consists of 1 to 20 carbon atoms (i.e., C1 to C20). 20 Alkyl(alkoxy), 1 to 12 carbon atoms (i.e., C1 to C 12The alkoxy group may have alkoxy, 1 to 8 carbon atoms (i.e., C1-C8 alkoxy), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy), or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Suitable examples of alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -OtBu).

[0013] A "haloalkyl" is an alkyl group defined above in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of a haloalkyl group consists of 1 to 20 carbon atoms (i.e., C1 to C2). 20 Haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 The haloalkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include -CF3, -CHF2, -CFH2, and -CH2CF3.

[0014] The term "aryl" refers to an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom in an aromatic ring system. For example, an aryl group may 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, radicals derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracenes, and biphenyls.

[0015] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having monocyclic or polycyclic systems, including condensed ring systems, crosslinked ring systems, and spirocyclic systems. As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C 3~20 Cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 Cycloalkyl), 3-1 It has 0 ring carbon atoms (i.e., C 3~10 Cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 (Cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6 (Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

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

[0017] A “heterocyclic” or “heterocyclic” refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heterocyclil may be monocyclic or polycyclic, and the polycyclic may be condensed, cross-linked, or spiro. As used herein, a heterocyclil has 3 to 20 ring atoms (i.e., a 3 to 20-membered heterocyclil), 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclil), 3 to 10 ring atoms (i.e., a 3 to 10-membered heterocyclil), 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclil), 4 to 12 ring carbon atoms (i.e., a 4 to 12-membered heterocyclil), 4 to 8 ring atoms (i.e., a 4 to 8-membered heterocyclil), or 4 to 6 ring atoms (i.e., a 4 to 6-membered heterocyclil). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. The terms heterocyclic or heterocyclyl do not include, and do not overlap with, heteroaryl groups as defined below.

[0018] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic structure with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having 1 to 20 ring atoms (i.e., C1~20 Heteroaryl), 3 to 12 ring atoms (i.e., C 3~12 Heteroaryl), or 3 to 8 ring atoms (i.e., C 3~8 Heteroaryl groups include one to five ring heteroatoms, one to four ring heteroatoms, one to three ring heteroatoms, one to two ring heteroatoms, or one ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, prinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl groups do not contain aryl as defined above, and do not overlap with aryl groups.

[0019] The term "optionally substituted" (e.g., an optionally substituted aryl group) with respect to a particular part of a compound of formula I means that all substituents are hydrogen atoms, or that one or more of the hydrogen atoms of the part are listed substituents.

[0020] Unless otherwise specified, the carbon atoms in compounds of formula I are intended to have a valency of 4. In some chemical structural representations where there are not enough variables for the carbon atom to produce a valency of 4, it should be assumed that the remaining carbon substituent needed to provide a valency of 4 is hydrogen.

[0021] As used herein, the term “to treat” means, unless otherwise indicated, to reverse, alleviate, inhibit the progression of, or prevent one or more symptoms of the disorder or condition to which such term applies. As used herein, the term “treatment” means the act of treating, as “to treat” is defined immediately before it.

[0022] As used herein, the term “therapeutic dose” means the amount of the compound of Formula I used herein required to deliver a desired level of the drug to the secretions and airway and lung tissues of the subject, or alternatively, to the bloodstream of the subject being treated, thereby producing an expected physiological response or desired biological effect when such a composition is administered via a selected route of administration. The exact amount depends on a number of 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, its intended use, and patient considerations such as the severity of the disease state and patient collaboration, and can be readily determined by a person skilled in the art based on the information provided herein.

[0023] As used herein, the term “adjacent carbons” refers to a sequence of carbon atoms that are directly bonded to one another. For example, [ka] Then, 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, [ka] Therefore, C1 and C2 are adjacent carbon atoms, C2 and C3 are adjacent carbon atoms, C3 and C4 are adjacent carbon atoms, C4 and C5 are adjacent carbon atoms, C5 and C6 are adjacent carbon atoms, and C6 and C1 are adjacent carbon atoms.

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

[0025] III.Compound Formula I: [ka] (In the formula, Z 1 is -CH2- or -CH2-CH2-, Z 2 is -CH2- or -CH2-CH2-, X is a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, or -OCR 12A R 12B -(CR 13 =CR 14 )- and, Each R 12A These are independently H, C1-C6 alkyl, or phenyl. Each R 12B These are independently H or C1-C6 alkyl, or R on the same carbon 12A and R 12B These bonds integrally to form a C3-C6 cycloalkylene. R 13 is H, C1-C6 alkyl or phenyl, R 14 is H, C1-C6 alkyl, or phenyl, q is either 1 or 2. R 1 H, C1~C 20 Alkyl, C3~C 10 A 4-6 membered heterocycline containing one, two, or three heteroatoms selected from cycloalkyl, N, O, and S, C6-C 10 A 5-10 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, S, and O, R 1 If it is not H, then R 1 The base can optionally consist of one or two R 1A Substituted by the group, Each R 1Ais independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl, or two Rs on the same or adjacent carbons 1A are joined together to form a 3-6 member cycloalkyl or 4-6 member heterocyclyl ring containing one, two, or three heteroatoms selected from N, S, and O, R 2 is H or C1-C3 alkyl, Y is absent or phenylene or C3-C6 cycloalkylene, R 3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl, each R 4 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl, or the R 4 groups together with the R 4 groups on one adjacent carbon atom form a double bond, each R 5 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl, R 6 is H or -C(O)C1-C6 alkyl, R 7 is H or -C(O)C1-C6 alkyl, m is an integer from 10 to 21), or a pharmaceutically acceptable salt thereof, are provided herein.

[0026] In some embodiments of the compounds of formula I, Z 1 is -CH2-, and Z 2 is -CH2-. In some embodiments, at least one of Z 1 and Z 2 is -CH2-CH2-. In some embodiments, both Z 1 and Z 2 are -CH2-CH2-. In some embodiments, Z 1is -CH2-CH2-, and Z2 is -CH2-. In some embodiments, Z 1 is -CH2-, and Z2 is -CH2-CH2-.

[0027] In some embodiments, the compound of formula I is of formula II: [Chemical formula] (wherein, R 8 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl, R 9 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl, w and v are independently integers from 10 to 21, u is 0 or 1, and w + u + v is an integer from 10 to 21).

[0028] In some embodiments of the compound of formula II, u is 0. In some embodiments, u is 1. In some embodiments, u is 1 and R 8 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl, and R 9 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, u is 1 and R 8 is H, C1-C3 alkyl, halo, or C1-C3 haloalkyl, and R 9 is H, C1-C3 alkyl, halo, or C1-C3 haloalkyl. In some embodiments, u is 1 and R 8 is H, C1-C3 alkyl or halo, and R 9 is H, C1-C3 alkyl or halo. In some embodiments, u is 1 and R 8 is H or C1-C3 alkyl, and R 9 is H or C1-C3 alkyl. In some embodiments, u is 1 and R 8is H or methyl, and R 9 is H or methyl. In some embodiments, u is 1 and R 8 H is R 9 H is H.

[0029] In some embodiments, the compound of formula I or II is formula III: [ka] The formula has the following characteristics (where n is an integer between 8 and 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 bonded, -O-, -(CR 12A R 12B )-,-O(CR 12A R 12B )-, or -OCR 12A R 12B -(CR 13 =CR 14 )-. In some embodiments, X is bonded, -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, or -OCR 12A R 12B -(CR 13 =CR 14 )-. In some embodiments, X is -O-, -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 -O-, -O(CR 12A R 12B )-, or -OCR 12A R 12B -(CR 13 =CR 14 )-. In some embodiments, X is -O-, -O(CR 12A R 12B )2-, or -OCR 12A R 12B -(CR 13 =CR 14 )-. In some embodiments, X is bonded, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - and in the formula, q is 1 or 2. In some embodiments, X is a bond, -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-. In some embodiments, X is bonded, -O-, -(CR 12A R 12B ) -, -O(CR 12A R 12B )-. In some embodiments, X is O. In some embodiments, X is -(CR 12A R 12B ) q - and in the formula, q is 1 or 2. In some embodiments, X is -(CR 12A R 12B )-. In some embodiments, X is -(CR 12A R 12B )2-. In some embodiments, X is -O(CR 12A R 12B ) q - and in the formula, q is 1 or 2. In some embodiments, X is -O(CR 12A R 12B )-. In some embodiments, X is -O(CR 12A R 12B )2-.

[0031] In some embodiments of the compounds of formulas I, II, and III, each R 12A Each R is independently H, C1-C6 alkyl, or phenyl, and each R 12B R is independently H or C1-C6 alkyl, 13 R is a C1-C6 alkyl or phenyl compound. 14 is H, C1-C6 alkyl or phenyl. In some embodiments, each R 12A Each R is independently H or C1-C6 alkyl, and each R 12B R is independently H or C1-C6 alkyl, 13 is H or C1-C6 alkyl, R 14 is H or C1-C6 alkyl. In some embodiments, each R 12A Each R is independently H or C1-C3 alkyl, and each R 12B R is independently H or C1-C3 alkyl, 13 is H or C1-C3 alkyl, and R 14 is H or C1-C3 alkyl. In some embodiments, each R 12A H is H, and each R 12B H is R 13 H is R 14 H is H.

[0032] In some embodiments of the compounds of formulas I, II, and III, X is a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - and in the formula, q is 1 or 2, and each R 12A Each R is independently H, C1-C6 alkyl, or phenyl, and each R 12B X is independently H or C1-C6 alkyl. In some embodiments of the compounds of formula I, X is a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B )q - and in the formula, q is 1 or 2, and each R 12A Each R is independently H or C1-C6 alkyl, and each R 12B X is independently H or C1-C6 alkyl. In some embodiments of the compounds of formula I, X is a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - and in the formula, q is 1 or 2, and each R 12A Each R is independently H or C1-C3 alkyl, and each R 12B X is independently H or C1-C3 alkyl. In some embodiments of the compound of formula I, X is a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - and in the formula, q is 1 or 2, and each R 12A H is H, and each R 12B is H. In some embodiments of the compounds of formula I, X is a bond, -O-, -CH2-, -CH2CH2-, -OCH2-, or -O(CH2)2-. In some embodiments of the compounds of formula I, X is a 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 - and in the formula, q is 1 or 2, and each R 12A Each R is independently H, C1-C6 alkyl, or phenyl, and each R 12B X is independently H or C1-C6 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B )q - and in the formula, q is 1 or 2, and each R 12A Each R is independently H or C1-C6 alkyl, and each R 12B X is independently H or C1-C6 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - and in the formula, q is 1 or 2, and each R 12A Each R is independently H or C1-C3 alkyl, and each R 12B X is independently H or C1-C3 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - and in the formula, q is 1 or 2, and each R 12A H is H, and each R 12B H is 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 )- and in the formula, R 12A R is H, C1-C6 alkyl or phenyl, 12B is H or C1-C6 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B )-,-O(CR 12A R 12B )- and in the formula, R 12A is H or C1-C6 alkyl, and R 12B is H or C1-C6 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B )-,-O(CR 12A R 12B )- and in the formula, R 12Ais H or C1-C3 alkyl, and R 12B is H or C1-C3 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B )-,-O(CR 12A R 12B )- and in the formula, R 12A H is R 12B H is 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-, and in the formula, each R 12A Each R is independently H, C1-C6 alkyl, or phenyl, and each R 12B X is independently H or C1-C6 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, and in the formula, each R 12A Each R is independently H or C1-C6 alkyl, and each R 12B X is independently H or C1-C6 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, and in the formula, each R 12A Each R is independently H or C1-C3 alkyl, and each R 12B X is independently H or C1-C3 alkyl. In some embodiments of the compound of formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, and in the formula, each R 12A H is H, and each R 12B H is H.

[0036] In some embodiments of the 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-, -OCH2-, -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 the compounds of formulas I, II, and III, X is -O-, -OCH2-, -OCH2-CH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -O-, -OCH2-, 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 the compounds of formulas I, II, and III, X is a bond. In some embodiments of the compounds of formulas I, II, or III, Y is phenylene or C3-C6 cycloalkylene. In some embodiments, Y is [ka] In some embodiments, Y is phenylene. In some embodiments, Y is [ka] In some embodiments, Y is a C3-C6 cycloalkylene. In some embodiments, Y is a cyclohexylene. In some embodiments, Y is [ka] 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.

[0039] In some embodiments, the compound of formula I, II, or III is formula IV: [ka] The formula has the following characteristics (where n is between 8 and 19):

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

[0041] In some embodiments of the compound 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 formulas I, II, III, or IV, each R 5R is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, each R 5 R is independently H, C1-C3 alkyl, halo, or C1-C3 haloalkyl. In some embodiments, each R 5 R is independently H, C1-C3 alkyl, or halo. In some embodiments, each R 5 R is independently H or C1-C3 alkyl. In some embodiments, each R 5 R is independently H, methyl, or ethyl. In some embodiments, each R 5 R is independently H or methyl. In some embodiments, each R 5 R is independently H or ethyl. In some embodiments, each R 5 is H. In some embodiments, each R 5 teeth , is methyl. In some embodiments, each R 5 It is ethyl.

[0043] In some embodiments of the compounds of formulas I, II, III, and IV, each R 4 R is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, each R 4 R is independently H, C1-C3 alkyl, halo, or C1-C3 haloalkyl. In some embodiments, each R 4 R is independently H, C1-C3 alkyl, or halo. In some embodiments, each R 4 R is independently H or C1-C3 alkyl. In some embodiments, each R 4 R is independently H, methyl, or ethyl. In some embodiments, each R 4 is H. In some embodiments, each R 4 is methyl. In some embodiments, each R 4 It is ethyl.

[0044] In some embodiments, compounds of formula I, II, III, or IV are of formula V: [ka] It has.

[0045] In some embodiments, the compound of formula I, II, III, IV, or V is formula Va: [ka] It has the formula V which has the formula.

[0046] In some embodiments, the compound of formula I, II, III, IV, or V is formula Vb: [ka] It has.

[0047] In some embodiments of compounds of formulas I, II, III, IV, V, Va, or Vb, R 3 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is H, C1-C3 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, or cyclopropyl. In some embodiments, R 3 These are H, methyl, ethyl, isopropyl, and cyclopropyl. In some embodiments, R 3 H is H. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 It is cyclopropyl.

[0048] In some embodiments of compounds of formula V, Va, or Vb, R 4R is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R 4 is H, C1-C3 alkyl, halo, or C1-C3 haloalkyl. In some embodiments, R 4 is H, C1-C3 alkyl, or halo. In some embodiments, R 4 is H or C1-C3 alkyl. In some embodiments, R 4 is H, methyl, or ethyl. In some embodiments, R 4 H is H. In some embodiments, R 4 is methyl. In some embodiments, R 4 It is ethyl.

[0049] In some embodiments of compounds of formula V, Va, or Vb, R 5 R is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R 5 is H, C1-C3 alkyl, halo, or C1-C3 haloalkyl. In some embodiments, R 5 is H, C1-C3 alkyl, or halo. In some embodiments, R 5 is H or C1-C3 alkyl. In some embodiments, R 5 is H, methyl, or ethyl. In some embodiments, R 5 is independently H or methyl. In some embodiments, R 5 is independently H or ethyl. In some embodiments, R 5 H is H. In some embodiments, R 5 is methyl. In some embodiments, R 5 It is ethyl.

[0050] In some embodiments, compounds of formulas I, II, III, IV, V, Va, or Vb are of formula VI: [ka] It is a compound of [the compound].

[0051] In some embodiments, compounds of formulas I, II, III, IV, V, Va, or VI are defined as formula VIA: [ka] It is a compound of [the compound].

[0052] In some embodiments, compounds of formula I, II, III, IV, V, Vb, or VI are defined as formula VIb: [ka] It is a compound of [the compound].

[0053] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 C1~C 20 Alkyl, C3~C 10 A 4-6 membered heterocycline containing one, two, or three heteroatoms selected from cycloalkyl, N, O, and S, C6-C 10 A 5-10 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, S, and O, R 1 The base can optionally consist of one or two R 1A It is substituted with a group. In some embodiments, R 1 H, C1-C6 alkyl, C3-C 10 A 4-6 membered heterocycline containing one, two, or three heteroatoms selected from cycloalkyl, N, O, and S, C6-C 10 A 5-10 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, S, and O, R 1 If it is not H, then R 1 The base is optionally one or two R 1A It is substituted with a group. In some embodiments, R 1 C1~C 20 Alkyl, C3~C 10A cycloalkyl or a 5-6 membered heterocycline containing one, two, or three heteroatoms selected from N, S, and O, R 1 The base can optionally consist of one or two R 1A It is substituted with a group. In some embodiments, R 1 C1-C6 alkyl, C3-C 10 A cycloalkyl or a 5-6 membered heterocycline containing one, two, or three heteroatoms selected from N, S, and O, R 1 The base can optionally consist of one or two R 1A It is substituted with a group. In some embodiments, R 1 C1~C 20 Alkyl, C3~C 10 Cycloalkyl, C6~C 10 A 5-10 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, S, and O, R 1 The base can optionally consist of one or two R 1A It is substituted with a group. In some embodiments, R 1 C1-C6 alkyl, C3-C 10 Cycloalkyl, C6~C 10 A 5-10 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, S, and O, R 1 The base can optionally consist of one or two R 1A It is replaced by several. In this embodiment, R 1 C1~C 20 Alkyl, C3~C 10 Cycloalkyl, or C6-C 10 It is aryl, R 1 The base can optionally consist of one or two R 1A It is substituted with a group. In some embodiments, R 1 C1-C6 alkyl, C3-C 10 Cycloalkyl, or C6-C 10 It is aryl, R 1 The base can optionally consist of one or two R 1AIt is substituted with a group. In some embodiments, R 1 C1~C 20 Alkyl, or C6-C 10 It is aryl, R 1 The base can optionally consist of one or two R 1A It is substituted with a group. In some embodiments, R 1 This refers to C1-C6 alkyl, or C6-C 10 It is aryl, R 1 The base can optionally consist of one or two R 1A It is substituted with a group. In some embodiments, R 1 The choice is to select one or two R 1A Substituted by the group, C1~C 20 It is alkyl. In some embodiments, R 1 The choice is to select one or two R 1A These are C1-C6 alkyl groups that are substituted with a specific group.

[0054] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 The choice is to select one or two R 1A C6~C substituted by a group 10 It is an arrow. In some embodiments, R 1 These are phenyl, naphthyl, thiophenyl, cyclohexyl, methyl, ethyl, or propyl.

[0055] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 It is not substituted. In some embodiments, R 1 This is one R 1A It is substituted with a group. In some embodiments, R 1 This is two R 1A It is substituted with a group. In some embodiments, each R 1A R is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, R1A These are independently methyl, phenyl, chloro, fluoro, methoxy, cyano, or CF3. In some embodiments, two R on the same or adjacent carbons 1A These are bonded together to form a 3-6 membered cycloalkyl or 4-6 membered heterocyclyl ring containing one, two, or three heteroatoms selected from N, S, and O. In some embodiments, two R atoms on the same or adjacent carbon atoms 1A These bond integrally to form a 3-6 membered cycloalkyl group. In some embodiments, two R groups on the same or adjacent carbon atoms 1A These bond integrally to form a 5-membered cycloalkyl group. In some embodiments, two R groups on the same or adjacent carbon atoms 1A These atoms bond together to form a 4-6 membered heterocyclyl ring containing one, two, or three heteroatoms selected from N, S, and O.

[0056] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 This is one R 1A It is substituted with a group. In some embodiments, R 1 This is two R's 1A It is substituted with a group. In some embodiments, each R 1A R is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, each R 1A R is independently methyl, phenyl, chloro, fluoro, methoxy, cyano, CHF2, or CF3. In some embodiments, each R 1A R is independently methyl, phenyl, chloro, fluoro, methoxy, cyano, or CF3. In some embodiments, each R 1A R is independently methyl, phenyl, chloro, fluoro, methoxy, ethoxy, cyano, CHF2, or CF3. In some embodiments, each R 1A R is independently methyl, phenyl, chloro, fluoro, methoxy, ethoxy, cyano, or CF3. In some embodiments, each R1A These are independently chloro, fluoro, or cyano. In some embodiments, at least one R 1A is cyano. In some embodiments, at least one R 1A It is cyano, and other R 1A If present, it is either cyano or halo.

[0057] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 C3~C 10 A 4-6 membered heterocycline containing one, two, or three heteroatoms selected from cycloalkyl, N, O, and S, C6-C 10 A 5-10 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, S, and O, R 1 The base consists of one or two R 1A It is substituted by a group. In some embodiments, at least one R 1A is cyano. In some embodiments, at least one R 1A It is cyano, and other R 1A If present, R is selected from the group consisting of C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, at least one R 1A It is cyano, and other R 1A If present, it is either cyano or halo.

[0058] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 C6~C 10 A 5-10 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, S, and O, R 1 The base consists of one or two R 1A It is substituted by a group. In some embodiments, at least one R 1Ais cyano. In some embodiments, at least one R 1A It is cyano, and other R 1A If present, R is selected from the group consisting of C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, at least one R 1A It is cyano, and other R 1A If present, it is either cyano or halo.

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

[0060] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 teeth, [ka] And each R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 R is independently H, C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl, and 1A2 , R 1A3 , and R 1A4 At least one of them is CN, R1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 At least three of them are H. In some embodiments, each R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 R is independently H, halo, or cyano, where R 1A2 , R 1A3 , and R 1A4 At least one of them is CN, R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 At least three of them are H.

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

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

[0063] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 teeth, [ka] [ka] Selected from the group consisting of -CH3, -C(CH3)3, and -C(CH3)2CH2CH3.

[0064] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 teeth, [ka] It is selected from the group consisting of the following.

[0065] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 teeth, [ka] [ka] It is selected from the group consisting of the following.

[0066] In some embodiments of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 teeth, [ka] It is selected from the group consisting of the following.

[0067] In some embodiments, compounds of formulas I, II, III, IV, V, Va, or Vb are of formula VII: [ka] (In the formula, each R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 R is independently H, C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl, and 1A2 , R 1A3 , and R 1A4 At least one of them is CN, R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 It is a compound of which at least three are H.

[0068] In some embodiments, compounds of formulas I, II, III, IV, V, Va, or VII Equation VIIa: [ka] (In the formula, each R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 R is independently H, C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl, and 1A2 , R 1A3 , and R 1A4 At least one of them is CN, R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 It is a compound of which at least three are H.

[0069] In some embodiments, compounds of formulas I, II, III, IV, V, Vb, or VII are defined as formula VIIb: [ka] (In the formula, each R 1A1 , R1A2 , R 1A3 , R 1A4 , and R 1A5 R is independently H, C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl, and 1A2 , R 1A3 , and R 1A4 At least one of them is CN, R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 It is a compound of which at least three are H.

[0070] Compounds of formula VII, VIIa, or VIIb, in some embodiments, each R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 These are independently H, halo, or cyano, and R 1A2 , R 1A3 , and R 1A4 At least one of them is CN, R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 At least three of them are H.

[0071] Compounds of formula VII, VIIa, or VIIb, in some embodiments, R 3 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is H, C1-C3 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, or cyclopropyl. In some embodiments, R 3 These are H, methyl, ethyl, isopropyl, and cyclopropyl. In some embodiments, R 3 H is several In this embodiment, R 3 is methyl. In some embodiments, R 3is ethyl. In some embodiments, R 3 It is cyclopropyl.

[0072] In some embodiments of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, VIb, VII, VIIa, or VIIb, R 6 and R 7 Both are H. In some embodiments, each R 6 and R 7 These are independently -C(O)C1~C6 alkyl groups. In some embodiments, each R 6 and R 7 R is independently H or -C(O)C1~C3 alkyl. In some embodiments, each R 6 and R 7 Independently, is H or -C(O)CH(CH)2. In some embodiments, R 6 H is R 7 is a -(CO)OC1~C6 alkyl group. In some embodiments, R 6 H is R 7 is a -C(O)C1~C3 alkyl group. In some embodiments, R 6 H is R 7 is -C(O)CH(CH)2. In some embodiments, R 7 H is R 6 is a -C(O)C1~C6 alkyl group. In some embodiments, R 7 H is R 6 is a -C(O)C1~C3 alkyl group. In some embodiments, R 7 H is R 6 It is -C(O)CH(CH)2.

[0073] In some embodiments, compounds of formulas I, II, III, IV, V, Va, Vb, VIa, or VIb are [ka] [ka] [ka] Selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0074] In some embodiments, compounds of formulas I, II, III, IV, V, Va, Vb, VIa, or VIb are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, it is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0075] In some embodiments, compounds of formulas I, II, III, IV, V, Va, Vb, VIa, or VIb are [ka] Alternatively, it is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0076] In some embodiments, compounds of formulas I, II, III, IV, V, Va, Vb, VI, Via, VIb, VII, VIIa, or VIIb are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, it is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0077] In some embodiments, the compound of formula I, II, III, IV, V, Va, Vb, VIa, VIb, VII, VIIa, or VIIb is selected from the group consisting of the compounds described below in Examples 9, 16, 23, 26, 30, 31, 34-36, 39, 50, 51, 53, 54, 65-86, 93-96, 98-109, 111-119, and 124-130.

[0078] In some embodiments, the compounds of formulas I, II, III, IV, V, Va, Vb, VIa, VIb, VII, VIIa, or VIIb are selected from the group consisting of the compounds described below in Examples 9, 16, 23, 26, 30, 31, 34-36, 39, 50, 51, 53, 65-71, 73, 75-82, 84, 86, 93-96, 98-103, 107-109, 111-113, 116-119, and 124-130, or pharmaceutically acceptable salts thereof.

[0079] Any reference to the compounds of the present invention described herein also includes references to their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of the compounds of the present invention include alkali metals or alkaline earth elements (e.g., Na + Li + , K + Ca +2 , and Mg +2 ), ammonium and NR4 + Examples of salts derived from suitable bases such as (wherein R is defined herein). Examples of pharmaceutically acceptable salts of nitrogen atoms or amino groups include (a) inorganic acids (b) For example, acid addition salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc. (b) For example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene Examples include salts formed from organic acids such as disulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, and leucine; (c) salts formed from elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of compounds with a hydroxyl group include Na + and NR4 +Examples include anions of the above compounds combined with suitable cations such as the following.

[0080] 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, crystalline polymorphism means the ability of a crystalline compound to exist in different crystalline structures. Crystalline polymorphism may arise from differences in crystalline packing (packing polymorphism) or from differences in packing between different conformational isomers (conformational polymorphisms) of the same molecule. As used herein, crystalline pseudopolymorphism means the ability of a compound's hydrate or solvate to exist in different crystalline structures. Pseudopolymorphisms of the present invention may exist due to differences in crystalline packing (packing pseudopolymorphism) or from differences in packing between different conformational isomers (conformational pseudopolymorphisms) of the same molecule. The present invention comprises all polymorphs and pseudopolymorphs of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, or IIIc and their pharmaceutically acceptable salts.

[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 also exist as amorphous solids. As used herein, an amorphous solid is a solid that lacks long-range order in the positions of atoms within the solid. This definition also applies when the crystal size is 2 nanometers or less. Amorphous forms of the present invention can be prepared using additives containing solvents. The present invention comprises all amorphous forms of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, and their pharmaceutically acceptable salts.

[0082] For therapeutic purposes, salts of the active ingredients of the compounds of the present invention are pharmaceutically acceptable; that is, they are salts derived from pharmaceutically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also find uses, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether derived from pharmaceutically acceptable acids or bases or not, are within the scope of the present invention.

[0083] Furthermore, it should be understood that the compositions described herein include their non-ionized forms, as well as combinations of the compounds of the present invention in zwitterionic forms and hydrates with stoichiometric amounts of water.

[0084] It should be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs, and pharmaceutically acceptable salts thereof of compounds within the range of formulas I, II, III, IV, V, Va, Vb, VI, VIa, or VIb are encompassed by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

[0085] Examples are given by formulas I, II, III, IV, V, Va, Vb, VI, VIa, or VIb. The compounds of the present invention may have a chiral center, for example, a chiral carbon or phosphorus atom. Therefore, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the present invention include optical isomers concentrated or decomposed to any or all asymmetric chiral atoms. In other words, chiral centers evident from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and diastereomer mixtures, as well as individual isolated or synthesized optical isomers substantially free of their enantiomer or diastereomer partners, are all within the scope of the present invention. Racemic mixtures can be separated into their individual substantially optically pure isomers by appropriate techniques, such as separation of diastereomer salts formed with an optical activity enhancer, e.g., an acid or base, followed by the reverse conversion to an optically active substance. In most cases, the desired optical isomer is synthesized by stereospecific reactions starting from a suitable stereoisomer of the desired starting material.

[0086] The stereochemical definitions and rules used herein generally follow those of SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the rotation of plane-polarized light by the compound, and S, (-), or 1 means that the compound is levorotatory, while compounds with the prefixes R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical to each other except that they are mirror images of each other. Certain stereoisomers may be called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to equimolar mixtures of two enantiomer species that lack optical activity.

[0087] The compounds of the present invention may also exist as tautomers in certain cases. Although only one delocalized resonance structure may be described, all such forms are intended within the scope of the present invention. For example, en-amine tautomers may exist for purines, pyrimidines, imidazoles, guanidines, amidines, and tetrazoles, and all of their possible tautomers are within the scope of the present invention.

[0088] 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 both the unlabeled and isotopically labeled forms of the compounds. The isotopically labeled compounds have the structure represented by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include: 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I, are included, but are not limited to these. Various isotope-labeled compounds of this disclosure include, for example, 3 H, 13 C and 14 These are compounds that incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds are 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 drug or substrate tissue distribution assays, or in patients. It may be useful in radiation therapy.

[0089] This disclosure also includes compounds of formula I, in which 1 to x hydrogens bonded to a carbon atom are exchanged by deuterium, where x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful in extending 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. 5(12):524-527 (1984). In consideration of this disclosure, such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens are exchanged by deuterium.

[0090] The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure are improved DMPKs (drugs) in terms of distribution, metabolism, and excretion (ADME). It may possess metabolic and pharmacokinetic properties. Substitution with heavier isotopes, such as deuterium, may result in certain therapeutic benefits due to greater metabolic stability, e.g., increased half-life in vivo, reduced dosage requirements, and / or improved therapeutic index. 18 1F-labeled compounds may be useful in PET or SPECT testing. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting readily available isotope-labeling reagents with non-isotope-labeling reagents, by performing the procedures disclosed in the scheme or the examples and preparations described below. In this context, deuterium is understood to be a substituent in the compounds of formula I.

[0091] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in the isotopic composition of the natural abundance of hydrogen. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0092] Whenever a compound described herein is substituted with, for example, one or more of the same groups denoting "R" or "R", it will be understood that the groups may be the same or different, that is, each group is selected independently.

[0093] Wavy Line [ka] This indicates the site of covalent bonding to an adjacent substructure, group, part, or atom.

[0094] 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 contain excipients, lubricants, fillers, binders, etc. Aqueous formulations are generally isotonic when prepared in a sterile form and intended for delivery by means other than oral administration. All formulations may optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Examples of excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, and carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. The pH of the formulations is typically in the range of about 3 to about 11. The pH is approximately 7 to 10. In some embodiments, the pH of the formulation is in the range of approximately 2 to approximately 5, but is typically approximately 3 to 4.

[0095] While the compounds of this disclosure ("active ingredients") can be administered alone, it may be preferable to present them as pharmaceutical formulations. Formulations for both animal and human use of the present invention comprise at least one active ingredient, as defined above, along with one or more acceptable carriers and optionally other additional therapeutic ingredients, in particular additional therapeutic active ingredients discussed herein. The carriers must be "acceptable" in the sense that they are compatible with the other components of the formulation and are physiologically harmless to their recipient.

[0096] The formulations include those suitable for the aforementioned routes of administration. The formulations may conveniently be presented in unit dosage forms and may be prepared by any suitable method known in the field of pharmacy. Techniques and formulations are generally 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 minor components. Generally, formulations are prepared by homogeneously and closely associating the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0097] 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 presented as separate units such as capsules, cachetes, or tablets, each containing a predetermined amount of the active ingredient, and may be presented as powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, lick, or paste.

[0098] In some embodiments, tablets are prepared by compressing or molding with one or more auxiliary components as optional. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant using a suitable machine. Molded tablets may be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent using a suitable machine. Tablets may be optionally coated or scored and optionally formulated to provide sustained or controlled release of the active ingredient from there.

[0099] For infections of the eyes or other external tissues, such as the mouth and skin, the formulation is applied as a topical ointment or cream containing, for example, 0.075 to 20% by weight (containing active ingredient in the range of 0.1% to 20% in increments such as 0.1% by weight, 0.6% by weight, 0.7% by weight, etc.), preferably 0.2 to 15% by weight, and most preferably 0.5 to 10% by weight of the active ingredient. When formulated as an ointment, the active ingredient may be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream having an oil-in-water cream base.

[0100] If necessary, the aqueous phase of the cream base may contain, for example, at least 30% w / w of polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400), as well as mixtures thereof. The topical formulation may preferably contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0101] The oily phase of the emulsion of the present invention may consist of known components in known forms. The phase may simply contain an emulsifier (alternatively known as an emulsion), but preferably contains at least one emulsifier and a mixture of fat or oil, or a mixture of both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferable to include both oil and fat. Together, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, and the wax, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersion phase of a cream formulation.

[0102] Suitable emulsions and emulsion stabilizers for use in the formulations of the present invention include TWEEN® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Further suitable emulsions and emulsion stabilizers for use in the formulations of the present invention include TWEEN® 80.

[0103] The selection of suitable oils or fats for the formulation is based on achieving the desired aesthetic properties. The cream should preferably be a non-greasy, stain-free, washable product with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters, such as diisoadipates, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or blends of branched esters known as Crodamol CAP may be used, with the latter three being preferred esters. These may be used alone or in combination, depending on the required properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0104] A pharmaceutical formulation according to the present invention comprises the compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic agents. The pharmaceutical formulation containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, in order to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or with wax.

[0105] Formulations for oral use may also be presented as rigid 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 water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0106] The aqueous suspension of the present invention contains an active material mixed with excipients suitable for the production of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, as well as dispersants or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxides and partial esters derived from fatty acids, and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins. In some embodiments, the suspension agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), for example, Captisol®.

[0107] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings as described above can be added to provide an oral preparation with a pleasant mouthfeel. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0108] The dispersible powders and granules of the present invention, suitable for preparing aqueous suspensions by the addition of water, provide active ingredients when 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 colorants, may also be present.

[0109] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. 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 acacia gum and tragacanth gum, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, as well as condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavorings. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, or colorings.

[0110] The pharmaceutical compositions of the present invention may be in the form of sterile injection preparations, such as sterile aqueous or oily suspensions for sterile injection. These suspensions may be formulated according to known techniques using the preferred dispersants or wetting agents and suspending agents described above. The sterile injection preparations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butane-diol, or they may be prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils may conventionally be used as solvents or suspension media. For this purpose, any solvent-free fixative oil containing synthetic monoglycerides or diglycerides may be used. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injections. Acceptable vehicles and solvents that may be used include water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0111] The amount of active ingredient that may be combined with a carrier to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active ingredient combined with a suitable and convenient amount of carrier, which can vary from approximately 5 to approximately 95% (by weight) of the total composition. Pharmaceutical compositions can be prepared to provide an amount that is easily measurable for administration. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 to 500 μg of active ingredient per milliliter of solution to allow for the injection of a suitable volume at a rate of approximately 30 mL / hour.

[0112] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent of the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5 to 20%, more favorably 0.5 to 10%, and particularly about 1.5% w / w.

[0113] Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in flavored base ingredients, usually sucrose and acacia or tragacanth; pastels containing the active ingredient in gelatin and glycerin, or inert base ingredients such as sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0114] Formulations for rectal administration may be presented as suppositories having a suitable base, for example, containing cocoa butter or salicylate.

[0115] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or nasal administration have particle sizes, for example, in the range of 0.1 to 500 micrometers, such as 0.5, 1, 30, 35, and are administered by rapid inhalation through the nasal route or by inhalation through the mouth to reach the alveoli. 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 powder. In some embodiments, the compounds used herein are formulated and administered as a spray formulation. In some embodiments, the compounds used herein are formulated for delivery by face mask. In some embodiments, the compounds used herein are formulated for delivery by face tent.

[0116] Formulations suitable for intravaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations, each containing an active ingredient and a carrier known to be suitable in the art.

[0117] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile infusion solutions that may contain antioxidants, buffers, bacteriostads, and solutes to make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0118] The formulations are presented in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as sterile water for injection, immediately before use. Immediate injection solutions and suspensions are prepared from the sterile powders, granules, and tablets of the types described above. Preferred unit dose formulations contain the daily dose or unit daily subdose of the active ingredient as listed above herein, or appropriate fractions thereof.

[0119] In addition to the components specifically mentioned above, the formulations of the present invention may include other conventional drugs in the art with respect to the type of formulation in question. For example, those suitable for oral administration may include flavoring agents. Please understand what you gain.

[0120] The present invention further provides a veterinary composition comprising at least one of the above-mentioned active ingredients, as defined together with a veterinary carrier therefor.

[0121] Veterinary carriers are substances useful for administering compositions, and may be solid, liquid, or gaseous substances that are inert or acceptable in veterinary technology and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0122] 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, in which the release of the active ingredient is controlled and regulated to enable less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0123] V. Kit Kits comprising compounds disclosed herein (e.g., compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, or VIb), pharmaceutically acceptable salts thereof, stereoisomers thereof, mixtures of stereoisomers thereof, or tautomers thereof are also provided. In some embodiments, the kits described herein may include labels and / or instructions for use for the use of the compounds in the treatment of a disease or condition in a subject (e.g., a human) that requires them. In some embodiments, the disease or condition is a viral infection.

[0124] In some embodiments, the kit may also include instructions for use of one or more additional therapeutic agents and / or for using the additional therapeutic agents in combination with the compounds of Formula I in the treatment of a disease or condition in a subject (e.g., a human) that requires them.

[0125] In some embodiments, the kits provided herein contain individual unit doses of the compound described herein, or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates. Examples of individual dose units include pills, tablets, capsules, pre-filled syringes, or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective dose of the compound in question, or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates. In some embodiments, the kits may consist of a single dose unit and several other dose units, such as the number of dose units required for a particular regimen or period.

[0126] Products 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 are also provided. In some embodiments, the container for the product may be a vial, a bottle, an ampoule, a pre-filled syringe, a blister package, a tin can, a bottle, a box, an intravenous bag, an inhaler, or a sprayer.

[0127] VI. Administration One or more compounds of the present invention are administered by any route appropriate to the condition to be treated. Preferred routes include oral, rectal, inhalation, pulmonary, topical (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 intravenously. It will be understood that the preferred route may vary, for example, depending on the recipient's condition.

[0128] In the present invention's method for treating a viral infection, the compounds of the present invention may be administered at any time to a person who may have been in contact with the virus or who is already suffering from the viral infection. In some embodiments, the compounds of the present invention may be administered prophylactically to a person who has been in contact with a person suffering from a viral infection or who is at risk of being in contact with a person suffering from a viral infection, such as a healthcare provider. In some embodiments, the administration of the compounds of the present invention may be to a person who has tested positive for a viral infection but is not yet showing symptoms of the viral infection. In some embodiments, the administration of the compounds of the present invention may be to a person at the onset of symptoms of a viral infection.

[0129] In some embodiments, the methods disclosed herein involve event-driven administration of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject.

[0130] As used herein, the terms “event-driven” or “event-driven administration” refer to the administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, (1) before an event that exposes an individual to the virus (or otherwise increases the risk of an individual becoming infected with the virus) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event), and / or (2) during an event (or two or more recurring events) that exposes an individual to the virus (or otherwise increases the risk of an individual becoming infected with the virus), and / or (3) after an event (or after the last event in a series of recurring events) that exposes an individual to the virus (or otherwise increases the risk of an individual becoming infected with the virus). In some embodiments, event-driven administration is performed before exposure to the virus of interest. In some embodiments, event-driven administration is performed after exposure to the virus of interest. In some embodiments, event-driven administration is performed both before and after exposure to the virus of interest.

[0131] In certain embodiments, the methods disclosed herein include, for example, pre-exposure prophylaxis (PrEP) and pre-exposure prophylaxis (PrEP) before and / or after an event that exposes an individual to the virus, or an event that otherwise increases the risk of an individual becoming infected with the virus. This includes administering the drug as / or post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0132] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered prior to exposure to the virus in question.

[0133] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered before and after exposure to the virus of interest.

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

[0135] An example of an event-driven dosing regimen includes administering compound I or a pharmaceutically acceptable salt thereof within 24 hours to 2 hours prior to exposure to the virus, followed by administration of compound I or a pharmaceutically acceptable salt thereof every 24 hours during the exposure period, followed by further administration of compound I or a pharmaceutically acceptable salt thereof after the last exposure, and finally one more administration of compound I or a pharmaceutically acceptable salt thereof 24 hours later.

[0136] Further examples of event-driven dosing regimens include administering the virus within 24 hours prior to exposure. This involves administering a compound of formula I, or a pharmaceutically acceptable salt thereof, daily during the exposure period, followed by a final dose (which may be an increased dose, such as double the dose) approximately 24 hours after the last exposure.

[0137] The effective dose of the active ingredient is determined by the clinician using conventional dose-escalation studies, depending at least on the nature of the condition being treated, toxicity, whether the compound is used prophylactically or for active viral infections, the method of delivery, and the pharmaceutical formulation. This can be expected to be approximately 0.0001 to 100 mg / kg body weight per day, typically about 0.01 to 10 mg / kg body weight per day, more typically about 0.01 to 5 mg / kg body weight per day, and most typically about 0.05 to 0.5 mg / kg body weight per day. For example, a candidate daily dose for an adult weighing approximately 70 kg is in the range of 1 mg to 1000 mg, preferably 5 mg to 500 mg, and may take the form of a single or multiple dose.

[0138] Any suitable duration of administration of the compound of the present invention is intended. For example, administration may range from 1 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. Administration may also range from 1 to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer administration periods are also intended.

[0139] In some embodiments, the compounds disclosed herein are administered once daily. In some embodiments, the compounds disclosed herein are administered once every other day. In some embodiments, the compounds disclosed herein are administered once a week. In some embodiments, the compounds disclosed herein are administered twice a week.

[0140] In some embodiments, one or more compounds disclosed herein are administered once daily. The once-daily dose may be administered for, for example, up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, or up to 1 month or more, as needed. In some embodiments, the once-daily dose may be 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.

[0141] In some embodiments, one or more compounds disclosed herein are administered once daily for about 6 to 12 days, for example, about 8 to 10 days. In some embodiments, one or more compounds are administered once daily for about 9 days. In some embodiments, one or more compounds are administered once daily for about 10 days. In some embodiments, about 50 to 150 mg of one or more 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 compounds disclosed herein is administered once daily for about 5 to 12 days, for example, about 10 days.

[0142] VII.How to use This disclosure also includes a method for treating or preventing a viral infection in a subject in need (e.g., a human), which involves administering the compounds disclosed herein to the subject.

[0143] In some embodiments, the present disclosure provides a method for treating a viral infection in a subject in need (e.g., a human), which comprises administering a compound described herein to the subject in need.

[0144] In some embodiments, the present disclosure relates to a method for treating or preventing a viral infection in a subject (e.g., a human) that requires such treatment, comprising the compounds disclosed herein. This includes administering the drug in conjunction with at least one additional active therapeutic or prophylactic agent.

[0145] In some embodiments, the present disclosure provides a method for treating or preventing a viral infection in a subject (e.g., a human) that requires such treatment, comprising administering a compound disclosed herein along with at least one additional active therapeutic agent to the subject.

[0146] In some embodiments, the present disclosure provides a method for inhibiting viral polymerase in cells, wherein virus-infected cells are brought into contact with a compound disclosed herein, thereby inhibiting viral polymerase.

[0147] In some embodiments, the present disclosure provides a method for inhibiting viral polymerase in cells, wherein virus-infected cells are brought into contact with the compounds disclosed herein and at least one additional active therapeutic agent, thereby inhibiting viral polymerase.

[0148] The use of the compounds disclosed herein for use in treating or preventing viral infections in subjects where such treatment is needed is also provided. For example, the use of the compounds disclosed herein for use in treating viral infections in subjects where such treatment is needed is provided.

[0149] In some embodiments, the viral infection is a paramyxoviridae virus infection. Accordingly, in some embodiments, the disclosure provides a method for treating a paramyxoviridae virus infection in a subject (e.g., a human) that requires such treatment, the method comprising administering a compound disclosed herein to the subject. Examples of paramyxoviridae viruses include, but are not limited to, nipah virus, hendra virus, measles, mumps, and parainfluenza virus. In some embodiments, the paramyxoviridae virus is sosuga virus.

[0150] In some embodiments, the viral infection is a Pneumoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method for treating a Pneumoviridae virus infection in a person in need thereof, the method comprising administering a compound provided herein to a person. Examples of Pneumoviridae viruses include, but are not limited to, respiratory syncytial viruses and human metapneumoviruses. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0151] In some embodiments, the present disclosure provides compounds disclosed herein for use in treating Pneumoviridae virus infections in humans in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0152] In some embodiments, the Disclosure provides a method for treating RSV infection in a person in need thereof, the method comprising administering a compound provided herein to the person. In some embodiments, the person has chronic respiratory syncytial virus infection. In some embodiments, the person has acute RSV infection.

[0153] In some embodiments, a method for inhibiting RSV replication comprises administering a compound disclosed herein to a person in need thereof, wherein the administration is by inhalation. A method is provided.

[0154] In some embodiments, the present disclosure provides a method for reducing the viral load associated with RSV infection, the method comprising administering a compound disclosed herein to a person infected with RSV.

[0155] In some embodiments, the viral infection is a picornaviridae virus infection. In some embodiments, the disclosure provides a method for treating a picornaviridae virus infection in a person in need thereof, the method comprising administering a compound of the disclosure to a person. Picornaviridae viruses are enteroviruses that cause a mixed group of infections, including herpangina, aseptic meningitis, flu-like syndrome (human rhinovirus infection), nonparalytic polio-like syndrome, epidemic pleuritic pain (an acute, febrile, infectious disease that typically occurs during epidemics), hand, foot, and mouth disease, pediatric and adult pancreatitis, 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 embodiments, picornaviridae virus infections are selected from the group consisting of coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

[0156] In some embodiments, the present disclosure provides compounds for use in treating picornaviridae virus infections in humans in need. In some embodiments, the picornaviridae virus infection is human rhinovirus infection.

[0157] In some embodiments, the viral infection is a flavivirid virus infection. Accordingly, in some embodiments, the disclosure provides a method for treating a flavivirid virus infection in a person in need thereof, the method comprising administering a compound described herein to a person. Representative flavivirid viruses include, but are not limited to, dengue fever, yellow fever, West Nile fever, Zika fever, Japanese encephalitis virus, and hepatitis C (HCV). In some embodiments, the flavivirid virus infection is dengue fever virus infection. In some embodiments, the flavivirid virus infection is yellow fever virus infection. In some embodiments, the flavivirid virus infection is West Nile fever virus infection. In some embodiments, the flavivirid virus infection is Zika virus infection. In some embodiments, the flavivirid virus infection is Japanese encephalitis virus infection. In some embodiments, the flavivirid virus infection is hepatitis C virus infection.

[0158] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure for the treatment of flavivirid virus infections in humans in need. In some embodiments, the flavivirid virus infection is dengue fever virus infection. In some embodiments, the flavivirid virus infection is yellow fever virus infection. In some embodiments, the flavivirid virus infection is West Nile fever virus infection. In some embodiments, the flavivirid virus infection is Zika virus infection. In some embodiments, the flavivirid virus infection is hepatitis C virus infection.

[0159] In some embodiments, the viral infection is a filoviral virus infection. Therefore, in some embodiments, this specification refers to a filoviral virus infection. The present invention provides a method for treating a person in need of such treatment, the method comprising administering a compound disclosed herein to a person. Representative filoviridae viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Tai forest, or Reston variant) and Marburg virus. No. In some embodiments, a filoviridae virus infection is Ebola virus infection. In some embodiments, a filoviridae virus infection is Marburg infection.

[0160] In some embodiments, the present disclosure provides compounds for use in treating filoviral infections in humans in need. In some embodiments, the filoviral infection is Ebola virus infection. In some embodiments, the filoviral infection is Marburg infection.

[0161] In some embodiments, the viral infection is a coronavirus infection. Therefore, in some embodiments, the Specified provides a method for treating a coronavirus infection in a person in need, the method comprising administering a compound provided herein to the person. 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 coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus (PEDV or HKUCoV isolates, e.g., 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. In some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0162] In some embodiments, the present disclosure provides compounds for use in treating coronavirus infections in humans in 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 coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus (PEDV or HKUCoV isolates, e.g., 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 (COVID-19).

[0163] In some embodiments, the viral infection is an arenaviridae virus infection. Accordingly, in some embodiments, the disclosure provides a method for treating an arenaviridae virus infection in a person in need thereof, the method comprising administering a compound disclosed herein to a person. In some embodiments, the arenaviridae virus infection is Lassa infection or Junin infection.

[0164] In some embodiments, the present disclosure provides compounds for use in treating arenaviridae virus infections in humans in need thereof. In some embodiments, the arenaviridae virus infection is Lassa infection or Junin infection.

[0165] In some embodiments, the viral infection is an orthomyxovirus infection, such as an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0166] In some embodiments, the viral infection is a nairovirus infection. Accordingly, in some embodiments, the Disclosure provides a method for treating a nairovirus infection in a person in need thereof, the method comprising administering a compound disclosed herein to a person. In some embodiments, the nairovirus infection is a Crimean-Congo hemorrhagic fever virus infection. In some embodiments, the viral infection is a hazardous virus infection.

[0167] As will be more fully described herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a viral infection, together with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected individual simultaneously with the compounds disclosed herein, or before or after administration of the compounds disclosed herein.

[0168] VIII. Combination Therapy The compounds described herein can also be used in combination with one or more additional therapeutic or prophylactic agents. Accordingly, methods for treating viral infections in subjects in need thereof are also provided herein, the methods comprising administering the compounds disclosed herein and one or more additional therapeutic or prophylactic agents to a subject in a therapeutically effective amount. In some embodiments, the methods involve administering the compounds disclosed herein and one or more additional therapeutic agents to a subject in a therapeutically effective amount.

[0169] In some embodiments, additional therapeutic agents include antiviral agents. Any suitable antiviral agent can be used in the method 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, mitotic inhibitors, and combinations thereof.

[0170] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0171] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is vidarabine, entecavir (ETV). ), terbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof The following group is selected. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, β-D-N4-hydroxycytidine, or a combination thereof.

[0172] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetate. In some embodiments, the additional therapeutic agent is foscarnet.

[0173] In some embodiments, additional therapeutic agents are nucleoside reverse transcriptase inhibitors. In some embodiments, antiviral agents include zidovudine, didanosine, zalcitabine, stabudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0174] In some embodiments, additional therapeutic agents are non-nucleoside reverse transcriptase inhibitors. In some embodiments, antiviral agents are selected from the group consisting of nevirapine, delaviridine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0175] In some embodiments, the additional therapeutic agent 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, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of boxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, pedroprevir, sobaprevir, deldeprevir, naraprevir, and combinations thereof.

[0176] In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir.

[0177] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ivalizumab, fostemsavir, leronlimab, ivalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immunoglobulin, intravenous [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella-zoster immunoglobulin [VZIG], and combinations thereof.

[0178] In some embodiments, the additional therapeutic agent is an acyclic guanosine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valacyclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0179] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof.

[0180] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide-type NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside-type NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0181] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, additional therapeutic agents are selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0182] In some embodiments, the additional therapeutic agent is interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alphacon 1, interferon alpha 1b, interferon alpha 2a, interferon alpha 2b, pegylated interferon alphacon 1, pegylated interferon alpha 1b, pegylated interferon alpha 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is interferon alphacon 1, interferon The following are selected from the group consisting of interferon alfa-1b, interferon alfa-2a, interferon alfa-2b, and pegylated interferon alfa-2a (PegIFNα-2a) and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon-1, pegylated interferon alfa-2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alfa-2a, pegylated interferon alfa-2b, or a combination thereof.

[0183] In some embodiments, the additional therapeutic agent is an immunostimulant. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is a mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of homivirsen, podophyllox, imiquimod, synecatechin, and combinations thereof.

[0184] In some embodiments, additional therapeutic agents are selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0185] In some embodiments, additional therapeutic agents are drugs for the treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir.

[0186] In some embodiments, the additional therapeutic agent is a drug for treating picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-butionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is lupintrivir.

[0187] In some embodiments, the additional therapeutic agent is a drug for the treatment of malaria. In some embodiments, the additional therapeutic agent is chloroquine.

[0188] In some embodiments, additional therapeutic agents are selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronarizine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronarizine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomemesylate, ganapraside, DSM-265, sipalgamin, artemison, and combinations thereof.

[0189] In some embodiments, the additional therapeutic agent is a drug for the treatment of coronavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, lampirase, nafamostat, LB-2, AM-1, anti-piroporin, and combinations thereof.

[0190] In some embodiments, additional therapeutic agents are drugs for the treatment of the Ebola virus. For example, in some embodiments, additional therapeutic agents are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dolonedarone, Verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidine-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7- The following are selected from the group consisting of [h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN Filo, brincidofovir, Vaxart adenovirus vector 5-based Ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, 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.

[0191] In some embodiments, the additional therapeutic agent is a drug for the treatment of HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, radarbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of GS-9256, vedroprevir, boxilaprevir, and combinations thereof.

[0192] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0193] In some embodiments, the additional therapeutic agent is an anti-HBV agent. For example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof. Examples of additional anti-HBV agents include α-hydroxytropolone, amdoxovir, antroquinonol, β-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, erbucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, virinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mibotylate, feron, GST-HG-131, levamisol, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, 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, picroside, DasKloster-0039, heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sofosbuvir, ledipasvir, UB-551, and ZH-2N, and U.S. Patent Application Publication No. 20150210 682 (Roche), 2016 / 0122344 (Roche), International Publication 2015173164, 2016023877, U.S. Patent Application Publication 2015252057(A) (Roche), International Publication 16128335(A1) (Roche), International Publication 16120186(A1) (Roche), U.S. Patent Application Publication 2016237090(A) (Roche), International Publication 16107833(A1 Examples of compounds disclosed in Roche Patent Publication No. 16107832(A1)(Roche), U.S. Patent Publication No. 2016176899(A)(Roche), International Publication No. 16102438(A1)(Roche), International Publication No. 16012470(A1)(Roche), U.S. Patent Publication No. 2016220586(A)(Roche), and U.S. Patent Publication No. 2015031687(A)(Roche) include, but are not limited to, those disclosed in U.S. Patent Publication No. 16107832(A1)(Roche), U.S. Patent Publication No. 2016220586(A)(Roche), and U.S. Patent Publication No. 2015031687(A)(Roche). In some embodiments, additional therapeutic agents are HBV polymerase inhibitors. Examples of DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, and Examples include, but are not limited to, entecavir (BARACLUDE®), entecavir maleate, terbivudine (TYZEKA®), filosilovir, pradefovir, crevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metakavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234. In some embodiments, additional therapeutic agents are HBV capsid inhibitors.

[0194] In some embodiments, the additional therapeutic agent is a drug for the treatment of HIV. In some embodiments, the additional 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.

[0195] In some embodiments, additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), and cell therapies (e.g., chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0196] In some embodiments, additional therapeutic agents are selected from the group consisting of HIV combination drugs, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latent infection reactivators, capsid inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, as well as combinations thereof.

[0197] In some embodiments, additional therapeutic agents are HIV concomitant drugs. Examples of HIV concomitant drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); and STRIBILD® (elvitegravir, cobicistapine). Tenofovir disoproxil fumarate and emtricitabine); TRUVADA(registered trademark)(Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY(registered trademark)(Tenofovir alafenamide and emtricitabine); ODEFSEY(registered trademark)(Tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA(registered trademark)(Tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); SYMTUZA(registered trademark)(Daruna Tenofovir, tenofovir alafenamide hemi fumarate, emtricitabine, and cobicistat); SYMFI (trademark) (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU (trademark) (lamivudine, and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemi fumarate and emtricitabine; tenofovir alafenamide hemi fumarate, emtricitabine, and rilpivirine; tenofovir alafenamide Dohemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine) n;ABC+AZT+3TC);atazanavir and cobicistat;atazanavir sulfate and cobicistat;atazanavir sulfate and ritonavir;darunavir and cobicistat;dolutegravir and rilpivirine;dolutegravir and rilpivirine hydrochloride;dolutegravir, abacavir sulfate, and lamivudine;lamivudine, nevirapine, and zidovudine;raltegravir and lamivudine;doravirine, lamivudine, and tenofovir disoproxil fumarate;doravirine, lamivudine, and tenofovir disoproxil;Examples include, but are not limited to, dapivine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirine + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine.

[0198] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and cobicistat. In some embodiments, additional therapeutic agents are selected from the group consisting of amprenavir, atazanavir, blekanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0199] In some embodiments, additional therapeutic agents are HIV integrase inhibitors. For example In some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is bictegravir, elvitegravir, curcumin, curcumin derivatives, chicolinic acid, derivatives of chicolinic acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tilphostine, derivatives of tilphostine, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, A The following are selected from the group consisting of VX-15567, BMS-986197, cabotegravir (long-acting injection), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbendesulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0200] In some embodiments, additional therapeutic agents are HIV entry inhibitors. For example, in some embodiments, additional therapeutic agents are selected from the group consisting of enfvirtide, maraviroc, and combinations thereof. Further examples of HIV entry inhibitors include, but are not limited to, cenicliviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, bicliviroc, maraviroc, cenicliviroc, leronrimab (PRO-140), adaptervir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include prelixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0201] In some embodiments, the additional therapeutic agent is an HIV nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an HIV non-nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor.

[0202] In some embodiments, additional therapeutic agents are nucleoside or nucleotide inhibitors of HIV reverse transcriptase. For example, additional therapeutic agents include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX Selected from the group consisting of EC(registered trademark) (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, sensabudine, didanosine, erbucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fodivudine tidoxil, islatravir, lamivudine, phosphazide, stabudine, zalcitabine, zidovudine, lovahovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0203] In some embodiments, additional therapeutic agents are non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase. For example, additional agents include dapivine, delaviridine, delaviridine mesylate, doravirine, efavirenz, etravirine, lentinan, and MK-8. The drug is selected from the group consisting of 583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, el-sulfavirine rilup (VM-1500), or combinations thereof.

[0204] In some embodiments, additional therapeutic agents include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FT) C); DESCOVY (registered trademark) (tenofovir alafenamide and emtricitabine); ODEFSEY (registered trademark) (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (registered trademark) (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; T RIUMEQ(registered trademark) (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA(registered trademark) (KALETRA(registered trademark); lopinavir and ritonavir); COMBIVIR(registered trademark) (zidovudine and lamivudine; AZT+3TC); EPZICOM(registered trademark) (LIVEXA(registered trademark); abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR(registered trademark) (abacavir sulfate) Salts, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastine; fosanprenavir; fosanprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine;Selected from: stabudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirudine; delavirudine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0205] In some embodiments, additional therapeutic agents are selected from the group consisting of colistin, barbicin, icatibant, bepotastine, epirubicin, epoprosetonol, bapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobubi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0206] In some embodiments, additional therapeutic agents are inhibitors of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI gene ID: 695). For example, in some embodiments, additional therapeutic agents are (S)-6-amino-9-(1-(buta-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib The group consists of bu (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebratinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calkens, dambatrichen, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is tilphostine A9 (A9).

[0207] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of MRTX-849 (G12C) and K-Ras (G12D) selective inhibitory peptides, including 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, KRpep-2 (Ac-RRRRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0208] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib.

[0209] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, RNA vaccine, attenuated live vaccine, therapeutic vaccine, prophylactic vaccine, protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is an attenuated live RSV vaccine MEDI-559, a human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immunoglobulin, intravenous [RSV-IGIV], and a combination thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pedialix, Engerix-B, and Recomvivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, e.g., Zostavix and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, e.g., cervical, Gardasil 9, and Gardasil. In some embodiments, the additional 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 vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Fluud, Flualix, Flublock, Flucellvax, Fluraval, Fluvirin, and Fluzon), and (iii) a quadrivalent vaccine for influenza A and B viruses (FluMist, Flualix, Fluzon, and Fluraval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., adenovirus type 4 and type 7 vaccines, live, oral). In some embodiments, the additional 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 additional therapeutic agent is a hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the additional therapeutic agent is a poliovirus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a smallpox virus vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCoV vaccine.

[0210] In some embodiments, the additional therapeutic agent is an antibody, such as a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCoV 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 additional therapeutic agent is the anti-SARS CoV antibody CR-3022. In some embodiments, the additional therapeutic agent is the aPD-1 antibody. In some embodiments, the additional therapeutic agent is REGN-COV2. In some embodiments, the additional therapeutic agent is LY-CoV555.

[0211] In some embodiments, the additional therapeutic agent is an injection of recombinant cytokine gene-derived protein.

[0212] In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimozivir, and combinations thereof.

[0213] In some embodiments, additional therapeutic agents are selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0214] In some embodiments, additional therapeutic agents include 6'-fluorinated aristemycin analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASC09F, GC376, GC813, phenylisoserine derivatives, neuroimidase inhibitor analogs, pyrithiobac derivatives, bananin and 5-hydroxychromone derivatives, SSYA10-001, griffiscin, HR2P-M1, HR2P-M2, P21S10, dihydrotancinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, arisporivir, imatinib mesylate, dasatinib, selmeth The group is selected from nib, trametinib, rapamycin, salakatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophylline inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivatives N30, mycophenolic acid, silvestrol, and combinations thereof.

[0215] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for example, an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is a viral antibody against 2019-nCoV.

[0216] In some embodiments, the additional therapeutic agent is a steroid, such as a corticosteroid. In some embodiments, the additional therapeutic agent is dexamethasone.

[0217] The compositions of the present invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infection, preferably other active therapeutic agents are active against coronavirus infections, e.g., 2019-nCoV virus infection. The compounds and compositions of the present invention are also parenteral fluids (including dextrose saline and Ringer's lactate solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactic agents, fever and analgesics, 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, immunomodulators (e.g., interferon), other small molecules or biological antivirals that target 2019-nCoV. It is intended for use in conjunction with general care provided to patients with 2019-nCoV virus infection, including drugs (not limited to lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, analgesics, and antimalarial agents (including artemether and artemether-lumefantrine combination therapy), typhoid fever (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or drugs for other common diseases in the patient population such as bacterial dysentery. In some embodiments, an additional therapeutic agent is dihydroartemisinin / piperaquine.

[0218] In some embodiments, the additional therapeutic agent is an immunomodulator. Examples of immunotherapy agents 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 cell death ligand 1 (Pd-L1) modulators; IL-15 modulators, DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon α; interferon α-2b; interferon α-n3; PEGylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine 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, normuferon, peginterferon α-2a, peginterferon α-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulator, RIG-I modulator, NOD2 modulator, SB-9200, and IR-103 Examples include: In some embodiments, the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0219] In some embodiments, additional therapeutic agents are IL-6 inhibitors, such as tocilizumab, sarilumab, or a combination thereof.

[0220] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For example, the additional therapeutic agent may be adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0221] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, baricitinib, filgotinib, olumiant, or a combination thereof.

[0222] In some embodiments, additional therapeutic agents include anti-inflammatory drugs, such as pirfenidone.

[0223] In some embodiments, additional therapeutic agents are antibiotics for secondary bacterial pneumonia. For example, additional therapeutic agents may be macrolide antibiotics (e.g., aziromycin, clarithromycin, and mycoplasma pneumoniae), fluoroquinolones (e.g., ciprofloxacin and levofloxacin), tetracyclines (e.g., doxycycline and tetracycline), or combinations thereof.

[0224] In some embodiments, the compounds disclosed herein are used in combination with standard treatments for pneumonia (e.g., Pediatric Community Pneumonia). See Guidelines, CID 2011:53(1 October). Treatment of pneumonia generally involves curing the infection and preventing complications. Specific treatments depend on several factors, including the type and severity of the pneumonia, age, and the individual's overall health. These options include (i) antibiotics, (ii) antitussives, and (iii) antipyretics / analgesics (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, an additional therapeutic agent is the bromhexine antitussive.

[0225] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin derived from recovered COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusions. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0226] In some embodiments, additional therapeutic agents are TLR agonists. Examples of TLR agonists include, but are not limited to, besatrimod (GS-9620), GS-986, IR-103, refitrimod, chilsotrimod, lintatrimod, DSP-0509, AL-034, G-100, covitrimod, AST-008, motrimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellatrimod, and RO-7020531.

[0227] In some embodiments, additional therapeutic agents are selected from the group consisting of bortezomid, flurazepam, ponatinib, sorafenib, paramethasone, crocoltrone, flucloxacillin, certindol, clibidipine, atorvastatin, cinorazepam, clofazimine, fosaprepitant, and combinations thereof.

[0228] In some embodiments, additional therapeutic agents are kalimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplasmab, GD31 (Rhizobium), NLRP inflammasome inhibitors, or α-ketoamines. In some embodiments, additional therapeutic agents are recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, additional therapeutic agents are This is a viral macrophage inflammatory protein (vMIP).

[0229] In some embodiments, the additional therapeutic agent is an anti-biloporin therapeutic agent. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents are described in International Publication Nos. 2004 / 112687, 2006 / 135978, 2018 / 145148, and 2009 / 018609.

[0230] Furthermore, any of the compounds of this disclosure may be combined with one or more additional active therapeutic agents in single dosage forms for simultaneous or sequential administration to patients. Combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0231] Co-administration of the compounds disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of the compounds disclosed herein with one or more other active therapeutic agents such that both therapeutically effective amounts of the compounds disclosed herein and one or more other active therapeutic agents are present in the patient's body.

[0232] Co-administration includes administering a unit dose of the compound of the present invention before or after the administration of a unit dose of one or more other active therapeutic agents, for example, within a few seconds, minutes, or hours of the administration of 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 a few 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 a few seconds or minutes. In some cases, it may be preferable 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 later (e.g., 1 to 12 hours). In other embodiments, it may be preferable 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 later (e.g., 1 to 12 hours).

[0233] Combination therapy can provide a "synergistic" effect, meaning that the combined active ingredients used together produce a greater effect than the combined effect of the compounds used individually. A synergistic effect can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) in several other regimens. In the case of alternating therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, by different injections in separate tablets, pills, capsules, or syringes. Generally, during alternating therapy, the effective dose of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, the effective doses of two or more active ingredients are administered together. A synergistic antiviral effect exhibits a greater antiviral effect than the predicted pure additive effect of the individual compounds in the combination.

[0234] 1. Combination therapy for the treatment of Pneumoviridae The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Pneumoviridae virus infections, other active therapeutic agents are preferably active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. Non-limiting examples of these other active therapeutic agents against RSV include ribavirin, palivizumab, motavizumab, 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 active therapeutic agents effective 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 presatovir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAbs; and viral replication inhibitors such as nitazoxanide.

[0235] In some embodiments, other active therapeutic agents may include, but are not limited to, MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI δM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccines, as vaccines for the treatment or prevention of RSV.

[0236] Other active therapeutic agents effective 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.

[0237] In some embodiments, other active therapeutic agents may be vaccines for the treatment or prevention of metapneumovirus infections, including but not limited to mRNA-1653 and rHMPV-Pa vaccines.

[0238] 2. Combination therapy for the treatment of picornaviridae The compounds provided herein are also used in combination with other active therapeutic agents. In the case of treating picornaviridae virus infections, preferably the other active therapeutic agents are active against picornaviridae virus infections, particularly enterovirus infections. Non-limiting examples of these other active therapeutic agents include capsid binding inhibitors, e.g., preconalil, BTA-798 (bapendavir), and other compounds disclosed by Wu et al. (U.S. Patent No. 7,078,403) and Watson (U.S. Patent No. 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.

[0239] In some embodiments, other active therapeutic agents may include, but are not limited to, EV71 vaccine, TAK-021, and EV-D68 adenovector-based vaccines, as vaccines for the treatment or prevention of picornaviridae virus infections.

[0240] 3. Combination therapy for respiratory infections Many infections caused by Pneumoviridae and Picornaviridae viruses are respiratory infections. Therefore, additional active therapeutic agents used to treat respiratory symptoms and sequelae of infection may be used in combination with the compounds provided herein. These additional agents are preferably administered orally or by direct inhalation. For example, Other preferred additional therapeutic agents to be combined with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.

[0241] Glucocorticoids Glucocorticoids, first introduced in 1950 as an asthma treatment (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent, consistent, and effective treatment for this disease, although their mechanisms of action are not yet fully understood (Morris, J. Allergy Clin. Immunol., 75(1 Pt)1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with significant undesirable side effects such as trunk obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit its use as a long-term treatment (Goodman and Gilman, 10th edition, 2001). The solution to systemic side effects is to deliver steroids directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to mitigate the severe adverse effects of oral steroids. Non-limiting examples of corticosteroids that may be used in combination with the compounds provided in the substantive include dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etavonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone fluonate, fluticasone, AZD-7594, ciclesonide; or pharmaceutically acceptable salts thereof.

[0242] Anti-inflammatory drugs Other anti-inflammatory agents acting through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. Applying “anti-inflammatory signaling modulators” (referred to as AISTMs in this document), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB by IKK inhibition), or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K, EGFR, or Syk), is a logical approach to stopping inflammation because these small molecules target a limited number of common intracellular pathways, i.e., signaling pathways that are critical points for anti-inflammatory therapeutic interventions (see review by PJBarnes, 2006). These non-limiting additional therapeutic agents include 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylaminoethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloropyridine-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloropyridine-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indole-3-yl]-2-oxoacetamide (PDE-4 inhibitor AWD) 12-281); 8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridine-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfini [4-(4-fluorophenyl)-1H-imidazole-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-pyridine-4-yl-1H-imidazole-2-yl]-buta-3-in-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanecarboxylic acid 2-diethylaminoethyl ester (Shiromilast) Examples include the PDE-4 inhibitor 2-diethyl-ethyl ester prodrug; (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholine-4-yl-propoxy)-quinazoline-4-yl]amine (gefinib, an EGFR inhibitor); and 4-(4-methyl-piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-ylpyrimidine-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor).

[0243] β2-adrenergic receptor agonist bronchodilator Combinations of inhaled β2-adrenergic receptor agonist bronchodilators, such as formoterol, albuterol, or salmeterol, with the compounds provided herein are also preferred, but not limited, combinations useful for the treatment of respiratory viral infections.

[0244] Combinations of inhaled β2-adrenergic receptor agonist bronchodilators such as formoterol or salmeterol, which contain an ICS, are also used to treat both bronchial stenosis and inflammation (Symbicort® and Advair®, respectively). Combinations of these ICS and β2-adrenergic receptor agonists together with the compounds provided herein are also preferred, but not limited to, combinations useful for treating respiratory viral infections.

[0245] Other examples of β2 adrenergic receptor agonists include vedradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, avesiderol, salbutamol, alformoterol, revalbuterol, fenoterol, and TD-5471.

[0246] Anticholinergic drugs Anticholinergics may be useful for the treatment or prevention of pulmonary bronchoconstriction and are therefore useful as additional therapeutic agents to be combined with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergic drugs have shown therapeutic efficacy in humans for controlling cholinergic tones in COPD (Witek, 1999): muscarinic receptor antagonists (especially of the M3 subtype); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)-propionyl]-pyrrolidine-2-carbonyl}pyrrolidine-2-carboxylic acid (1-methyl-piperidine-4-ylmethyl)amide; 3-[3-(2-diethylaminoacetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycinate); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2- 1-Azabicyclo[2.2.2]octa-3-yl carboxylic acid (solifenacin); 1-Azabicyclo[2.2.2]octa-3-yl 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyrate (levatropate); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidine-3-yl}-2,2-diphenyl-acetamide (dalifenacin); 4-Azepan-1-yl-2,2-diphenyl-butylamide (buzepide); 7-[3-(2-diethylaminoacetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (oxytropium-N,N-diethylglycinate) );7-[2-(2-diethylaminoacetoxy)-2,2-dithiophen-2-ylacetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(thiotropium-N,N-diethylglycinate);dimethylaminoacetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methylphenyl ester(tolterodine-N,N-dimethylglycinate);3-[4,4-bis-(4-fluorophenyl)-2-oxoimidazolidined-1-yl]-1-methyl-1-(2-oxo-2-pyridine-2-ylethyl)-pyrrolidinium;1-[1-(3-fluorobenzyl)-piperidine-4-yl]-4,4-bis-(4-fluorophenyl)-imidazolidined- 2-one; 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]octa-3-yl)-1-phenyl-propa-2-in-1-ol; 3-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane(acridinium-N,N-diethylglycinate); or (2-diethylamino-acetoxy)-di-thiophen-2-yl-acetate 1-methyl-1-(2-phenoxy-ethyl)-piperidine-4-yl ester; lebefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, bencycloxidium bromide, etc., but not limited to these.

[0247] Mucus dissolving agent The compounds provided herein may also be combined with mucolytics to treat both the infection and symptoms of respiratory infections. A non-limiting example of a mucolytic is ambroxol. Similarly, the compounds may be combined with expectorants to treat both the infection and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0248] Hypertonic saline sprays are used to improve immediate and long-term clearance of the small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds provided herein can also be combined with hypertonic saline sprays, particularly when viral infections are accompanied by bronchiolitis. The combination of the compounds provided herein with hypertonic saline may also include any of the additional agents discussed above. In some embodiments, approximately 3% hypertonic saline is used.

[0249] 4. Combination therapy for the treatment of flaviviral virus infections The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In the case of treating flavivirid virus infections, preferably, the other active therapeutic agents are active against flavivirid virus infections.

[0250] Other active therapeutic agents for the treatment of dengue virus infection include, but are not limited to, host cell factor modulators such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors such as cergocivir; platelet activating factor receptor (PAFR) antagonists such as modipafant; 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.

[0251] In some embodiments, other active therapeutic agents may include, but are not limited to, TetraVax-DV, Dengvaxia®, DPIV-001, TAK-003, live attenuated dengue vaccine, quadrivalent dengue vaccine, quadrivalent DNA vaccine, rDEN2δ30-7169; and DENV-1 PIV, as vaccines for the treatment or prevention of dengue fever.

[0252] 5. Combination therapy for the treatment of filoviral virus infections The compounds provided herein are also used in combination with other active therapeutic agents. In the case of treating filoviral infections, preferably the other active therapeutic agents are active against filoviral infections, particularly Marburg virus infection, Ebola virus infection, and Queva virus infection. Non-limiting examples of these other active therapeutic agents include ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, doronedarone, verapamil, and Ebola convalescent plasma. Plasma, ECP), TKM-100201, BCX4430((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidine-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] RNA polymerase inhibitors such as quinolone-1,7-diamines, rNAPc2, OS-2966, brincidofovir, remdesivir; galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cell factor modulators such as GMV-006; cadherin-5 / factor Ia modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0253] Other non-limited therapeutic agents active against Ebola include α-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3-binding nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonist HLA class II antigen modulators, host cell factor modulators, interferon α-ligands, neutral α-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).

[0254] In some embodiments, other active therapeutic agents may be vaccines for the treatment or prevention of 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, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5 Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0255] The compounds provided herein may also be used in combination with phosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with the translation process by forming base-paired double helices with specific RNA sequences. An example of a PMO is AVI-7. Examples include, but are not limited to, AVI-287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0256] The compounds provided herein also include parenteral fluids (including dextrose saline and Ringer's lactate solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal, antipyretic, and These medications are intended for use in conjunction with general care provided to patients with filoviral virus infections, including analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory drugs (such as ibuprofen), analgesics, and antimalarial drugs (including artemether and artesunate-mefantrine combination therapy), typhoid fever (including quinolone antibiotics such as ciprofloxacin, macrolid antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or medications for other common illnesses in patient populations such as bacterial dysentery.

[0257] IX. Preparation of Compounds In some embodiments, the disclosure provides processes and intermediates useful for preparing the compounds provided herein or pharmaceutically acceptable salts thereof.

[0258] The compounds described herein can be purified by any chromatographic technique known in the art, such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase, such as normal-phase, reverse-phase, and ionic resins, can be used. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0259] During any of the processes for preparing the compounds provided herein, it may be necessary and / or desirable to protect the sensitive or reactive groups in any of the molecules involved. This is as described in TWGreene and PGMWuts, "Protective Groups in Organic Synthesis," 4 th This can be achieved by conventional protecting groups, as described in standard studies such as Wiley, New York 2006. The protecting groups can be removed in a convenient subsequent step using methods known from the art.

[0260] Here, exemplary chemicals useful in the methods of the embodiments are described by reference to the exemplary synthesis schemes for their general preparations herein and the specific examples below. Those skilled in the art will recognize that to obtain the various compounds herein, the desired products can be obtained by suitably selecting the starting materials such that the ultimately desired substituent is supported through the reaction scheme, with or without protection as necessary. Alternatively, it may be necessary or desirable to use a suitable group that is supported through the reaction scheme and can be appropriately replaced with the desired substituent instead of the ultimately desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be carried out in any order that is suitable for the functionality of the particular pendant group.

[0261] The methods of this disclosure generally provide specific enantiomers or diastereomers as desired products, but the stereochemistry of the enantiomers or diastereomers is not determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is drawn without exhibiting stereochemistry at that particular stereocenter, even if the compound may be substantially enantiomerically or diastereomerically pure. [Examples]

[0262] Typical synthesis methods of the compounds of this disclosure are described in the following scheme and in the following specific examples. X. Example Intermediate 1-2: (R)-2-(benzyloxy)-3-(octadecyloxy)propylbis(4-nitrophenyl)phosphate [ka]

[0263] 4-nitrophenyl phosphorodichloride (1.41 g, 5.52 mmol) was dissolved in DCM (36 mL). The resulting solution was cooled in an ice bath, and another solution of 1-O-octadecyl-2-O-benzyl-sn-glycerol (intermediate 1-1, 2 g, 4.6 mmol) in DCM (10 mL) was added. Then, triethylamine (1.12 g, 11 mmol) was added dropwise. The ice bath was then removed. After 1 hour and 45 minutes, an additional triethylamine (0.239 g, 2.35 mmol) was added, followed by the addition of 4-nitrophenol. The progress of the reaction was monitored by LC / MS and TLC. The reaction product was diluted with Et2O, and the resulting solid was removed by filtration. The filtrate was concentrated, and intermediates 1-2 were isolated by silica gel column chromatography (25 g loaded cartridge, 120 g Combiflash® HP Gold Column, eluent gradient of 100% hexane to 30% siRNA / hexane). 1 H NMR (400MHz, chloroform-d) δ8.21-8.08(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 1P NMR (162 MHz, 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-(benzyloxy)-3-(octadecyloxy)propyl)(4-nitrophenyl)phosphate [ka]

[0264] Intermediate 1-2 (0.503 g, 0.664 mmol) and intermediate 1-3 (J.Med.Chem, 2017, 60(5), p.1648; 0.2 g, 0.604 mmol) were dissolved in THF. MgCl2 (0.287 g, 3.02 mmol) was added all at once at room temperature. The reaction mixture was placed in a 50°C bath and stirred for 10 minutes. DIPEA was added dropwise to the resulting mixture. The progress of the reaction was monitored by LC / MS. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was transferred to DCM using sonication, and intermediate 1-4 was placed on silica gel. Isolation was performed by column chromatography (12g loaded cartridge, 40g Combiflash® HP Gold Column, eluent gradient of 100% hexane to 100% SiO). 1H NMR (400MHz, chloroform-d) δ7.93-7.86(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), 3.3 6(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 1P NMR (162 MHz, chloroform-d) δ -7.275 (s), -7.608 (s). MS m / z = 949.10[M+1] Intermediate 1-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2,2-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-(benzyloxy)-3-(octadecyloxy)propyl)hydrogen phosphate [ka]

[0265] Intermediate 1-4 (0.169 g, 0.178 mmol) was dissolved in THF (4 mL). To this solution, 1 N NaOH aqueous solution (0.0249 g, 0.623 mmol) was added dropwise. After the addition of the NaOH solution was complete, the reaction mixture was placed in a 50°C bath. The progress of the reaction was monitored by LC / MS. Once intermediate 1-4 was consumed, the reaction mixture was cooled in an ice bath. 2 N 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 incorporated into DCM by sonication. Intermediate 1-5 was isolated by silica gel column chromatography (12 g loaded cartridge, 24 g Combiflash® HP Gold Column, eluent gradient of 100% DCM to 20% MeOH / DCM). 1 H NMR (400MHz, MeOH-d3) δ7.86(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) δ2.852--0.151(brs). MS m / z=828.69[M+1], 1656.24[2M+1] Intermediate 1-6: Triethylammonium(R)-2-(benzyloxy)-3-(octadecyloxy)propyl(2-chlorophenyl)phosphate [ka]

[0266] 1,2,4-triazole (1.33 g, 19.3 mmol) and triethylamine (2.69 mL, 19.3 mmol) were sequentially added at 0°C to a stirred solution of 2-chlorophenyl phosphorodichloride (1.45 mL, 8.97 mmol) in acetonitrile (30 mL), and the resulting mixture was warmed 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 cannula. After 5 hours, triethylamine (5.0 mL) and water (1.5 mL) were sequentially added. After 25 minutes, saturated sodium bicarbonate aqueous solution was added. After 10 minutes, saturated sodium bicarbonate aqueous solution 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 obtain intermediates 1-6. 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R-2-(benzyloxy)-3-(octadecyloxy)propyl)(2-chlorophenyl)phosphate [ka]

[0267] 1-(mesitylsulfonyl)-3-nitro-1H-1,2,4-triazole (4.02 g, 13.6 mmol), intermediates 1-3 (3.00 g, 9.05 mmol), and 1-methylimidazole (1.08 mL, 13.6 mmol) were sequentially added at room temperature to a stirred solution of intermediates 1-6 (5.92 g, 8.15 mmol) in pyridine. After 4 hours, the resulting mixture was cooled to 0°C, and saturated sodium bicarbonate aqueous solution and brine were sequentially added. 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 flash column chromatography on silica gel (in hexane, 0% to 100% ethyl acetate) to obtain intermediates 1-7. LCMS: 938.5. Alternative synthesis method for intermediates 1-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2,2-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-(benzyloxy)-3-(octadecyloxy)propyl)hydrogen phosphate [ka]

[0268] A solution of tetrabutylammonium fluoride (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) at room temperature. 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 resulting mixture was concentrated under reduced pressure. Dichloromethane and water were added sequentially, and hydrogen chloride aqueous solution (2.0 M) was added 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 flash column chromatography using silica gel (0-20% methanol in dichloromethane) to obtain 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). [ka]

[0269] 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 aqueous HCl (1.25 mL, 14.9 mmol) was added dropwise. The cold bath was removed and the reactants were vigorously stirred. The progress of the reaction was monitored by LC / MS. After consumption of intermediates 1-5, the reactants were concentrated. The residue was taken to a mixture of MeOH and DCM and concentrated. The resulting residue was taken to DCM and compound 1 was isolated by silica gel column chromatography (12 g loaded cartridge, 24 g Combiflash® HP Gold Column, eluent gradient of 100% DCM to 20% MeOH / DCM). 1H NMR (400MHz, ACN-d3) δ7.85(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, 2 H), 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 [ka]

[0270] A tetrahydrofuran (2.0 mL) solution of R-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (159 mg, 347 μmol) (described in Bartolmas, T.; Heyn, T.; Mickeleit, M.; Fischer, A.; Reutter, W.; Kolb, MJ Med. Chem. 2005, 48, 6750) was added via cannula to a vigorously stirred mixture of a tetrahydrofuran (3.0 mL) solution of sodium hydride (60 wt% dispersion in mineral oil, 46.6 mg, 1.22 mmol) at 0°C. After 30 minutes, 4-(bromomethyl)-1,1'-biphenyl (300 mg, 1.22 mmol) was added, and the resulting mixture was warmed to room temperature. After 21 hours, saturated ammonium chloride aqueous solution (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 flash column chromatography on silica gel (in hexane with 0%-5% ethyl acetate) to obtain intermediate 2-1. 1 ¹H NMR (400 MHz, 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-(octadecyloxy)propane-1-ol [ka]

[0271] A solution of tetrabutylammonium fluoride (1.0 M, 756 μL, 760 μmol in tetrahydrofuran) was added via syringe to a stirred solution of intermediate 2-1 (200 mg, 320 μmol) in tetrahydrofuran (3.0 mL) at room temperature. After 85 minutes, saturated aqueous ammonium chloride (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 flash column chromatography on silica gel (in hexane with 0% to 30% ethyl acetate) to obtain intermediate 2-2. LCMS: 533.4[M+Na] + . Intermediate 2-3: (R)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propylbis(4-nitrophenyl)phosphate [ka]

[0272] Triethylamine (10.8 μL, 77.8 μmol) was added via syringe at 0°C to a stirred mixture of intermediate 2-2 (33.1 mg, 64.8 μmol), 4-nitrophenyl phosphorodichloride (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 phosphorodichloride (20.0 mg, 78.1 μmol) and triethylamine (20.0 μL, 143 μmol) were added sequentially. After 60 minutes, 4-nitrophenyl phosphorodichloride (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% by weight, 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 flash column chromatography on silica gel (in hexane, 0-30% ethyl acetate) to obtain intermediates 2-3. 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl)(4-nitrophenyl)phosphate [ka]

[0273] 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), aqueous sodium hydroxide solution (2.0 M, 4 mL), and water (10 mL) was added. Ethyl acetate (60 mL) was added, 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 flash column chromatography on silica gel (in dichloromethane, 0-4.5% methanol) to obtain intermediates 2-4. 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)hydrogen phosphate [ka]

[0274] A sodium hydroxide aqueous solution (2.0 M, 276 μL, 552 μmol) was added via syringe at room temperature 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, a sodium hydroxide aqueous solution (2.0 M, 150 μL, 300 μmol) was added via syringe. After 150 minutes, the resulting mixture was cooled to room temperature. A hydrogen chloride aqueous solution (2.0 M, 400 μL) and a mixture of citric acid (706 mg), sodium hydroxide aqueous solution (2.0 M, 3.67 mL), hydrogen chloride aqueous solution (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 vigorously stirred at room temperature. Concentrated hydrogen chloride (625 μL, 7.5 mmol) was added by 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 sequentially extracted 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 reverse-phase preparative HPLC (2-propanol / water) to obtain compound 2. 1 H NMR (400MHz, DMSO-d6-methanol-d4) δ7.92(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)propan-1-ol [ka]

[0275] A mixture of vigorously stirred (S)-3-(octadecyloxy)propane-1,2-diol (250 mg, 726 μmol), cyclohexanecarbaldehyde (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 Celite, and the filter cake was extracted with dichloromethane (8 mL). The combined filtrate was stirred and cooled to -40°C. A solution of diisobutylaluminum hydride (1.0 M, 5.80 mL, 5.8 mmol in toluene) 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. After 22 hours, 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 flash column chromatography using silica gel (in hexane, 0-10% ethyl acetate) to obtain intermediate 3-1. 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)hydrogen phosphate [ka]

[0276] Compound 3 is (S)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-( Compound 2 was synthesized using (S)-2-(cyclohexylmethoxy)-3-(octadecyloxy)propan-1-ol instead of octadecyloxy)propan-1-ol, in the same manner as compound 2. 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)propan-1-ol [ka]

[0277] Intermediate 4-1 was synthesized in the same manner as intermediate 2-4, using 2-(bromomethyl)naphthalene instead of 4-(bromomethyl)-1,1'-biphenyl. 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-(naphthalene-2-ylmethoxy)-3-(octadecyloxy)propyl)hydrogen phosphate(4). [ka]

[0278] A sodium hydroxide aqueous solution (2.0 M, 800 μL, 1.6 mmol) was added via syringe at room temperature 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. A hydrogen chloride aqueous solution (2.0 M, 800 μL) and a mixture of citric acid (706 mg), sodium hydroxide aqueous solution (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 vigorously stirred 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 reverse-phase preparative HPLC (2-propanol / water) to obtain compound 4. It was obtained as an ethylammonium salt. 1 ¹H 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 [ka]

[0279] (R)-Oxirane-2-ylmethyl-4-methylbenzenesulfonate (507 mg, 2.22 mmol) and 1-hexadecanol (547 mg, 2.26 mmol) were dissolved in DCM (10 mL) and treated with a few drops of trifluoroborane etherate. The resulting solution was stirred for 18 hours, at which point the solvent was removed under reduced pressure, and the resulting residue was precipitated from hexane to obtain intermediate 5-1. 1 H 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 [ka]

[0280] Intermediate 5-1 (216 mg, 0.459 mmol) was dissolved in dioxane (4 mL), treated with benzyl 2,2,2-trichloroethaneimidate (0.175 mL, 0.942 mmol), and then treated with a few drops of trifluoromethanesulfonic acid. The reaction mixture was stirred for 90 minutes, at which point additional benzyl 2,2,2-trichloroethaneimidate (0.1 mL, 0.538 mol) and a few drops of trifluoromethanesulfonic acid were added. The reaction mixture was stirred for 18 hours, at which point additional benzyl 2,2,2-trichloroethaneimidate (0.2 mL, 1.08 mmol) and a few drops of trifluoromethanesulfonic acid were added. The reaction mixture was stirred for 90 minutes, at which point the reaction mixture was diluted with dichloromethane, washed sequentially with saturated sodium bicarbonate aqueous solution and water, dried with sodium sulfate, filtered, and evaporated under reduced pressure. Intermediate 5-2 was isolated from the resulting residue by silica gel column chromatography (0-20% SiO:hexane eluate gradient). 1 H 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, 1 H), 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)propane-1-ol [ka]

[0281] Intermediate 5-2 (257 mg, 0.458 mmol) was dissolved in DMSO (10 mL), treated with sodium nitrite (976 mg, 14.1 mmol), and then heated at 40°C for 18 hours. At this point, the reaction mixture was diluted with water, extracted with dichloromethane, dried over sodium sulfate, filtered, and evaporated under reduced pressure. Intermediate 5-3 was isolated from the resulting residue by silica gel column chromatography (0-25% siRNA:hexane eluate gradient). 1 1H NMR (400 MHz, 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)propylbis(4-nitrophenyl)phosphate [ka]

[0282] 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 minutes, 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 hour. Then, triethylamine (0.100 mL, 0.717 mmol) and 4-nitrophenol (160 mg, 1.15 mmol) were added, and stirring was continued for 20 minutes. At this point, the reaction mixture was diluted with diethyl ether, filtered to remove the solid, and the filtrate was evaporated under reduced pressure. Intermediate 5-4 was isolated from the resulting residue by silica gel column chromatography (0-20% ethylacetate:hexane eluate gradient). 1 1H NMR (400 MHz, 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=6.7H z, 2H), 1.56 (t, J=7.0Hz, 2H), 1.27 (d, J=2.9Hz, 28H), 0.90 (t, J=6.8Hz, 3H). 31 1P NMR (162 MHz, chloroform-d) δ. 13.36 (t, J=7.9 Hz). Intermediate 5-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2,2-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-(benzyloxy)-3-(hexadecyloxy)propyl)(4-nitrophenyl)phosphate [ka]

[0283] 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 minutes, at which point N,N-diisopropylethylamine (0.0500 mL, 0.287 mmol) was added, and stirring was continued at 50°C for a further 2 hours. The solvent was removed under reduced pressure, and intermediate 5-5 was isolated from the resulting residue by silica gel column chromatography (0-5% MeOH:DCM eluate gradient). 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, 2 H), 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 1P NMR (162 MHz, chloroform-d) δ. 7.24 (q, J=7.2 Hz), -7.60 (q, J=7.4 Hz). 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) [ka]

[0284] Intermediate 5-5 (13.0 mg, 0.0141 mmol) was dissolved in THF (1 mL, THF), treated with a 2 M aqueous solution of NaOH (0.075 mL, 0.15 mmol), and heated to 50°C. The reaction solution was stirred for 2 hours, at which point the reaction flask was placed in an ice bath and acidified with concentrated aqueous HCl. The reaction solution was warmed to room temperature and stirred for 18 hours, at which point triethylamine was titrated until the yellow color persisted, and the solvent was removed under reduced pressure. The resulting residue was taken to a 4:1 MeOH:dioxane mixture, and compound 5 was isolated as triethylammonium salt by preparative HPLC (60-100% water:i-PrOH eluate gradient). 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-(heptadecyloxy)propyl)hydrogen phosphate [ka]

[0285] Compound 6 was synthesized as a triethylammonium salt using 1-heptadecanol instead of 1-hexadecanol, in the same manner as compound 5. 1 H NMR (400MHz, DMSO-d6) δ7.91(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=7.5 Hz, 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-(nonadecyloxy)propyl)hydrogen phosphate(7). [ka]

[0286] Compound 7 was synthesized as a triethylammonium salt using 1-nonadecanol instead of 1-hexadecanol, in a similar manner to compound 5. 1H 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-(icosyloxy)propyl)hydrogen phosphate [ka]

[0287] Compound 8 was synthesized as a triethylammonium salt using 1-icosanol instead of 1-hexadecanol, in a similar manner to compound 5. 1 1H NMR (400 MHz, 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), 3.8 5(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] [ka]

[0288] A mixture of (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (6.68 g, 50.6 mmol), potassium hydroxide powder (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 water formed by azeotropic distillation. The reaction mixture was then cooled to room temperature, filtered, and the volume of the 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 dried over Na₂SO₄, filtered, and the solvent was removed under reduced pressure to obtain the intermediate. 1 H NMR (400MHz, chloroform-d) δ4.29(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).

[0289] To a solution of the crude intermediate (5 g, 13 mmol) in methanol (80 mL), a 2 M HCl solution (13 mL, 26 mmol) was added, and the solution was heated under reflux for 4 hours. After cooling to room temperature, the mixture was poured into water, the organic layer was extracted with ether, dried over Na2SO4, and the solvent was removed under vacuum to obtain a small volume. The product was precipitated from hexane to obtain intermediate 9-1. 1 ¹H NMR (400 MHz, 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=6.9 Hz, 2H), 1.28 (s, 30H), 0.96-0.84 (m, 3H). Intermediate 9-2: 1-O-octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol [ka]

[0290] To a solution of (S)-3-(octadecyloxy)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), tert-butylchlorodimethylsilane (1.44 g, 9.58 mmol) was added at 0°C. After stirring at room temperature for 5 hours, the reaction mixture was diluted with water (10 mL), then extracted with CH2Cl2, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by flash chromatography (0-30% siRNA in hexane) to obtain the product. 1 H NMR (400MHz, chloroform-d) δ3.93-3.77(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)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0291] NaH (60% oil 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 at 0°C, a solution of 4-(bromomethyl)benzonitrile (493 mg, 2.52 mmol) in THF (3 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction product was quenched with water (15 mL). The mixture was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-30% ethyl acetate in hexane) to obtain the product. 1 ¹H NMR (400 MHz, 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-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0292] To a solution of silyl-protecting compound 9-3 (480 mg, 0.836 mmol) in 0°C THF (3.6 mL), 1 M TBAF (1 mL, 1 mmol) in THF was added and the mixture was stirred for 1 hour. This was diluted with water (3 mL) and extracted with RINKAN (2 × 10 mL). The combined organic layer was washed with water (2 × 5 mL), the brine was dried (Na₂SO₄), and evaporated. The residue was purified by column chromatography (silica gel, 0% to 60% ethyl acetate / hexane) to obtain the product. 1H NMR (400MHz, DMSO-d6) δ7.81(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: tert-butyl(7-((3aR,4R,6R,6aR)-6-((((2-chlorophenoxy)((R)-2-((4-cyanobenzyl)oxy)-3-(octadecyloxy)propoxy)phosphoryl)oxy)methyl)-4-cyano-2,2-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-yl)carbamate [ka]

[0293] A solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 μL, 0.62 mmol) in anhydrous THF (0.4 mL) was mixed with a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). 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-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile (107 mg, 0.232 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by flash chromatography using silica gel (0-15% MeOH in CH2Cl2) to obtain the compound (136 mg, 55%). 1H NMR (400MHz, chloroform-d) δ8.35-8.10(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 1P NMR (162 MHz, 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) [ka]

[0294] The above intermediate (130 mg, 0.122 mmol) was dissolved in THF (2.5 mL), and 0.5 N NaOH (0.9 mL, 3.6 equivalents) was added. The mixture was stirred at 50°C for 4 hours. The progress of the reaction 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 pH 3 buffer solution and brine, and extracted twice with a mixture of DCM and MeOH. The combined organic phases were combined and dried on anhydrous Na2SO4. The mixture was then filtered, evaporated, and the residue was obtained.

[0295] The residue was dissolved in THF (0.6 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HCl (0.12 mL) was added. The cold bath was removed, and the reaction mixture was vigorously stirred 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 obtain compound 9. 1 H NMR (400MHz, methanol-d4) δ8.07-8.21(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 (162 MHz, 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)propyl)hydrogen phosphate(10) [ka]

[0296] Compound 10 was synthesized in the same manner as compound 9, using 4-methoxybenzyl bromide instead of 4-cyanobenzyl bromide. 1 ¹H NMR (400 MHz, 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) [ka]

[0297] Compound 11 was synthesized in the same manner as compound 9, using 4-trifluoromethylbenzyl bromide instead of 4-cyanobenzyl bromide. 1 H NMR (400MHz, DMSO-d6) δ7.92(m, 3H, 2 protons 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, D2 O 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)phosphate triethylammonium [ka]

[0298] 2-chlorophenyl phosphorodichloride (2.2 g, 8.97 mmol) was dissolved in acetonitrile (30 mL) and cooled to 0°C. To this solution, 1,2,4-triazole (1.33 g, 19.3 mmol), followed by TEA (2.69 mL, 19.3 mmol) was slowly added. The cooling bath was removed and the mixture was stirred at room temperature for 45 minutes. To the stirred mixture, a solution of (S)-2-(benzyloxy)-3-(octadecyloxy)propan-1-ol (3.9 g, 8.97 mmol) in pyridine (40 mL) was slowly added and the mixture was stirred at room temperature for 4 hours. TEA (2.69 mL), followed by water (1.5 mL), was added to the mixture and stirred for 25 minutes, then saturated NaHCO3 (20 mL) was added and stirred for a further 10 minutes. The reaction mixture was diluted with saturated NaHCO3 and then extracted with DCM (2 × 100 mL). The combined organic layers were washed with a 1:1:1 mixture (180 mL) of water, brine, and saturated NaHCO3. The combined organic layers were dried over Na2SO4, concentrated, co-evaporated with toluene (50 mL x 2), and dried under high vacuum. The crude product was dissolved in 5% MeOH / DCM, packed into a 220 g gold column, and eluted with 0-40% MeOH. The product was eluted with 20% MeOH / DCM as two broad peaks (peak streak length), and the pure fractions (confirmed by TLC / LCMS) were combined and concentrated to obtain intermediate 12-1. Ta. MS m / z = 625.4 [M+1] 1 H NMR (400MHz, DMSO-d6) δ9.90(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). 31P 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-(benzyloxy)-3-(octadecyloxy)propyl)(2-chlorophenyl)phosphate. [ka]

[0299] Intermediate 12-1 (3.0 g, 9.05 mmol) was dissolved in pyridine (80 mL). To this solution, 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (4.02 g, 13.6 mmol), 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 slowly adding saturated NaHCO3 aqueous solution. The aqueous layer was diluted with a 1:1:1 mixture of water, saturated NaHCO3 aqueous solution, and brine. The aqueous layer was extracted with DCM (2 × 400 mL), the combined organic matter was dried over Na2SO4, and removed by filtration. The filtrate was concentrated, and intermediate 12-2 was isolated by silica gel column chromatography (220 g Combiflash® HP Gold Column, eluent gradient of 0-100% siRNA / hexane). 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-chlorophenyl)phosphate. [ka]

[0300] 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 4 hours. After completion, the reaction mixture was concentrated, and the residue was co-evaporated in THF (2 × 30 mL) and DCM (2 × 30 mL). The resulting residue was taken into DCM, and intermediate 12-3 was isolated by silica gel column chromatography (40 g Combiflash® HP Gold Column, eluent gradient of 0-40% MeOH / DCM). 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. 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-diylbis(2-methylpropanoate). [ka]

[0301] To a mixture of intermediate 12-3 (0.5 g, 0.557 mmol), 2-methylpropanoic acid (98.1 mg, 1.11 mmol), and EDCI (0.427 mg, 2.23 mmol) in DCM (10 mL), DMAP (0.272 mg, 2.23 mmol) was added all at once. The resulting mixture was stirred at room temperature for 1.2 hours. The reaction product was diluted with DCM, washed with water, then with 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, which were made identical by LC-MS and used in the next step. 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-ylisobutyrate(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-diylbis(2-methylpropanoate)(13). [ka]

[0302] 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) followed by water (1.25 mL) was added. To the resulting clear homogeneous solution, a 1 M solution of TBAF in THF (1.8 mL, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Once the reaction was complete, it was homogenized by LC-MS, the reaction mixture was cooled in an ice bath, and quenched with saturated NaHCO3 aqueous solution (5 mL). The reaction mixture was concentrated to remove most of the volatile substances 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 with saturated NaHCO3 aqueous solution to a pH of 8), dried over Na2SO4, and removed by filtration. The filtrate was concentrated, the crude product was dissolved in a mixture of MeOH / dioxane / water (approximately 6:1:0.1 mL), sonication was performed to complete dissolution, the mixture was filtered, and the product was purified by preparative HPLC (Gemini, 10 μM, NX-C18, 110 Å 250 × 30 mm column, gradient of 60–100% acetonitrile / water for 16 minutes, and 100% acetonitrile for 16 minutes) to obtain compounds 12 and 13. compound 12 MS m / z = 858.5 [M+1] 1 ¹H NMR (400MHz, chloroform-d) δ 8.05 (s, 1H), 7.28 (s, 5H), 6.94 (d, J=4.6Hz, 1H), 6.64 (d, J=4.7Hz, 1H), 6.27 (d, J=5.9Hz, 1H), 5.61 (s, 2H), 5.53 (dd, J=5.9, 4.2Hz, 1H), 4.65 (q, J=4.1Hz, 1H), 4.41 (q d, J=12.3, 4.1Hz, 2H), 4.28-4.03(m, 1H), 4.02-3.84(m, 1H), 3.87-3.59(m, 2H), 3.58-3.22(m, 1 H), 2.80-2.48(m, 3H), 1.48(d, J=32.7Hz, 2H), 1.39-1.04(m, 38H), 0.93(dt, J=23.4, 7.1Hz, 3H). compound 13 MS m / z = 928.5 [M+1] 1 H NMR (400MHz, chloroform-d) δ7.87(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=6.0H) z, 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-octadecoxy-propane-2-ol [ka]

[0303] A solution of t-butyldimethylsilyl chloride (350 mg, 2.32 mmol) in dichloromethane (2 mL) is mixed with (2S)-3-octadecoxypropane-1,2-diol (500 mg, 1.45 mmol) in dichloromethane (5 mL). The mixture was added to a solution of imidazole (198 mg, 2.90 mmol) over 1 minute at 0°C. After 2 hours, the ice bath was removed. After 3 hours, the reaction mixture was washed with water (5 mL). The aqueous layer 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 flash chromatography (0-30% ethyl acetate / hexane). The fractions containing the product were combined, and the solvent was removed under reduced pressure to obtain intermediate 14-0. 1 H NMR (400MHz, chloroform-d) δ3.83(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-octadecoxy-propoxy]-dimethyl-silane [ka]

[0304] A 60% sodium hydride dispersion 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 in tetrahydrofuran (2 mL) (320 mg, 0.697 mmol) 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 reaction products were quenched with water (10 mL) at 0°C. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-20% ethyl acetate / hexane, using ELSD detection). The fractions containing the product were combined, and the solvent was removed under reduced pressure to obtain intermediate 14-1. 1H NMR (400MHz, chloroform-d) δ7.25(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 (376 MHz, chloroform-d): δ -138.62–-138.83 (m), -140.54–-140.77 (m). Intermediate 14-2: (2S)-2-[(3,4-difluorophenyl)methoxy]-3-octadecoxy-propane-1-ol [ka]

[0305] A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.995 mL, 0.995 mmol) was added to a solution of intermediate 14-1 in tetrahydrofuran (5 mL) (194 mg, 0.332 mmol). After 45 minutes, the reaction mixture was diluted with ethyl acetate (20 mL). The organic layer 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 flash chromatography (using 0-20% ethyl acetate / hexane, ELSD). The fractions containing the product were combined, and the solvent was removed under reduced pressure to obtain intermediate 14-2. Intermediate 14-3: [(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecoxypropyl]bis(4-nitrophenyl)phosphate [ka]

[0306] A solution of intermediate 14-2 (143 mg, 0.304 mmol) in dichloromethane (2 mL) was added at 0°C to a solution of 4-nitrophenyl phosphorodichloride (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 product was diluted with ethyl acetate (20 mL) and washed with water (2 × 5 mL) and brine (5 mL). The residue was subjected to flash chromatography (0-50% ethyl acetate / hexane). The fractions containing the product were combined, and the solvent was removed under reduced pressure to obtain intermediate 14-3. 1 H NMR (400MHz, chloroform-d) δ8.30-8.19(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). 19 F NMR (376 MHz, chloroform-d) δ -137.88 (ddd, J=21.0, 11.1, 8.0 Hz), -139.15 to -139.37 (m). 31 1P NMR (162 MHz, chloroform-d)δ-13.10 (t, J=8.0 Hz). 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-fluoro[3,4-d][1,3]dioxol-6-yl]methyl[(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecoxypropyl](4-nitrophenyl)phosphate [ka]

[0307] Magnesium chloride is added to a solution of intermediate 14-3 (52.2 mg, 0.0658 mmol) and intermediate 1-3 (20.7 mg, 0.0625 mmol) in tetrahydrofuran (5 mL). Nesium (31.3 mg, 0.329 mmol) was added. The mixture was stirred at 50°C for 15 minutes. The mixture was cooled briefly, and N,N-diisopropylethylamine (0.057 mL, 0.329 mmol) was added. After 2 minutes, the reaction product was quenched with water (5 mL) and brine (5 mL). The mixture was extracted with 2-methyltetrahydrofuran (3 × 10 mL). The combined organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-10% methanol / dichloromethane). The fractions containing the product were combined, and the solvent was removed under reduced pressure to obtain intermediate 14-4. 1 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) H), 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 (377 MHz, chloroform-d) δ -137.94–-138.19 (m), -139.46–-139.82 (m). 311P 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)propyl)hydrogen phosphate(14) [ka]

[0308] A solution of sodium hydroxide (1N, 0.14 mL, 0.14 mmol) was added to a solution of intermediate 14-4 (34.4 mg, 0.0349 mmol) in tetrahydrofuran (5 mL), and the mixture was heated at 50°C. After 2 hours, the starting material remained. 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 phase was washed with brine (10 mL) and dried on sodium sulfate. The residue was subjected to flash 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-fluoro[3,4-d][1,3]dioxol-6-yl]methyl[(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecexoxypropyl]hydrogen phosphate. MS m / z[M+1]=864.28

[0309] Concentrated hydrochloric acid (12N, 0.30 mL, 3.69 mmol) was added to a solution of hydrogen phosphate (24.5 mg, 0.0295 mmol) of [(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-fluoro[3,4-d][1,3]dioxol-6-yl]methyl[(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecoxypropyl]phosphate hydrogen (24.5 mg, 0.0295 mmol). After 2 hours, triethylamine (0.51 mL, 3.69 mmol) was added. The minimum amount of methanol was added to the mixture to dissolve all solids. The solution 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 placed in 1,4-dioxane (5 mL) and subjected to lyophilization. Further purification was necessary. 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 dissolved in 1,4-dioxane (5 mL) and subjected to lyophilization to obtain compound 14. 1 H NMR (400MHz, DMSO-d6) δ12.13-12.04(m, 0.15H), 8.12-7.67(m, 3H), 7.42-7.24(m, 2H), 7.18-7.1 0(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. 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) δ0.26~-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-3,4-dihydroxytetrahydrofuran-2-yl]methyl[(2R)-2-[(3,5-difluorophenyl)methoxy]-3-octadecoxypropyl]hydrogen phosphate (15) [ka]

[0310] Compound 15 was synthesized in the same manner as compound 14, using 5-(bromomethyl)-1,3-difluorobenzene instead of 4-(bromomethyl)-1,2-difluorobenzene. 1 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 (377 MHz, methanol-d4) δ-112.53 (t, J=8.3 Hz). 31 NMR (162 MHz, 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-3,4-dihydroxytetrahydrofuran-2-yl]methyl[(2R)-2-[(3-cyano-5-fluorophenyl)methoxy]-3-octadecoxypropyl]hydrogen phosphate (16) [ka]

[0311] Compound 16 was synthesized in the same manner as compound 14, using 5-(bromomethyl)-1-cyano-3-fluorobenzene instead of 4-(bromomethyl)-1,2-difluorobenzene. 1 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), 4.00-3.83(m, 2H), 3.79-3.63(m, 1.7 H), 3.62-3.44(m, 2H), 3.44-3.35(m, 2H), 1.61-1.48(m, 2H), 1.40-1.20(m, 30H), 0.91(t, J=6.6Hz, 3H). 19 F NMR (377 MHz, methanol-d4) δ-112.78 (t, J=8.8 Hz). 31 NMR (162 MHz, 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-3,4-dihydroxytetrahydrofuran-2-yl]methyl[(2R)-2-[(3-cyano-5-fluorophenyl)methoxy]-3-octadecoxypropyl]hydrogen phosphate (17). [ka]

[0312] Compound 17 was synthesized in the same manner as compound 14, using 4-(bromomethyl)-2-chloro-1-fluorobenzene instead of 4-(bromomethyl)-1,2-difluorobenzene. 1 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, 1 H), 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), 3.5 9-3.42(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 (377 MHz, methanol-d4) δ-120.49 (td, J=8.4, 4.9 Hz). 31 NMR (162 MHz, methanol-d4) δ-0.26. MS m / z[M+1]=840.18 Intermediate 18-1: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol [ka]

[0313] A solution of octadecane-1-ol (10.1 g, 37.4 mmol) in tetrahydrofuran (30 mL) was added by cannula at 0°C to a vigorously stirred mixture of sodium hydride (1.50 g, 39.1 mmol). A reflux condenser was attached to the reaction mixture and heated to 80°C. After 2 hours, tert-butyl-dimethyl-[[(2S-oxiran-2-yl]methoxy]silane (4.70 g, 25.0 mmol) was added by syringe. After 17 hours, the reaction mixture was cooled to room temperature. Saturated ammonium chloride aqueous solution (50 mL), water (100 mL), and diethyl ether (200 mL) were added sequentially. The organic layer was extracted, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% ethyl acetate in hexane) to obtain intermediate 18-1. Intermediate 18-2: [(2S-2-benzyloxy-3-octadecoxy-propoxy]-tert-butyl-dimethyl-silane [ka]

[0314] A solution of intermediate 18-1 (300 mg, 650 μmol) in tetrahydrofuran (3.0 mL) was added by syringe at 0°C 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 by syringe. The reaction mixture was warmed 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 rinsed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-20% ethyl acetate in hexane) to obtain intermediate 18-2. Intermediate 18-3: (2R)-2-benzyloxy-3-octadecoxy-propane-1-ol [ka]

[0315] A solution of tetrabutylammonium fluoride (1.0 M, 623 μL, 623 μmol in tetrahydrofuran) was added by 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 flash chromatography on silica gel (in hexane with 0-20% ethyl acetate) to obtain intermediate 18-3. Intermediate 18-4: [(2S)-2-benzyloxy-3-octadecoxypropyl]bis(4-nitrophenyl)phosphate [ka]

[0316] Intermediate 18-4 was prepared using intermediate 18-3 instead of intermediate 2-2, in the same manner as intermediate 2-3. 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-fluoro[3,4-d][1,3]dioxol-6-yl]methyl[(2S)-2-benzyloxy-3-octadecoxypropyl](4-nitrophenyl)phosphate. [ka]

[0317] Intermediate 18-5 was prepared using intermediate 18-4 instead of intermediate 2-3, in the same manner as intermediate 2-4. 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) [ka]

[0318] A sodium hydroxide aqueous solution (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) at 50°C. After 90 minutes, the resulting mixture was cooled to room temperature. A few drops of concentrated hydrochloric acid were added until the pH of the resulting mixture was less than 1. After 16 hours, triethylamine was added until the pH of the mixture was greater than 7, as indicated by the persistence of a yellow color. The mixture was purified by reverse-phase preparative HPLC (2-propanol / water) to obtain compound 18 as a complex with trimethylamine. 1H NMR (400MHz, methanol-d4) δ7.87(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, 2 H), 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), 3.4 7-3.42(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-(propa-1-en-2-yl)-2-sulfidehexahydrobenzo[d][1,3,2]oxatiaphosphol-2-yl)oxy)methyl)tetrahydrofluoro[3,4-d][1,3]dioxol-4-carbonitrile [ka]

[0319] 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 intermediate 1-3 (1.00 g, 3.02 mmol), (2R,3aR,6S,7aR)-3a-methyl-2-((perfluorophenyl)thio)-6-(propa-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxatiaphosphol 2-sulfide (1.75 g, 3.92 mmol), and acetonitrile (24.0 mL) at room temperature. After 10 minutes, saturated aqueous ammonium chloride (1.0 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 flash column chromatography using silica gel (in dichloromethane with 0-10% methanol) to obtain intermediate 19-0. LCMS: 578.2. Intermediate 19-1: (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-2-oxide-6-(propa-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxatiaphosphol-2-yl)oxy)methyl)tetrahydrofluoro[3,4-d][1,3]dioxol-4-carbonitrile [ka]

[0320] Selenium dioxide (316 mg, 2.84 mmol) was added at room temperature to a solution of intermediate 19-0 (1.57 g, 2.71 mmol) in acetonitrile (23.5 mL) and water (8.9 mL), which had been vigorously stirred. After 60 minutes, ethyl acetate (250 mL) was added, and the resulting suspension was filtered through Celite. 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 flash column chromatography on silica gel (in dichloromethane, 0-10% methanol) to obtain intermediate 19-1. LCMS: 562.2. Intermediate 19-2: (S)-2-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)-3-(octadecyloxy)propan-1-ol [ka]

[0321] Using a syringe, potassium bis(trimethylsilyl)amide solution (1.0 M, 382 μL, 380 μmol in tetrahydrofuran) was added over 1 minute at 0°C to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (159 mg, 347 μmol) in tetrahydrofuran (1.0 mL). After 10 minutes, 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (223 mg, 869 μmol) was added, and the resulting mixture was warmed 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 two-phase mixture was vigorously stirred. 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 flash column chromatography on silica gel (0% to 30% ethyl acetate in hexane) to obtain 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-(octadecyloxy)propyl)hydrogen phosphate(19) [ka]

[0322] 1,8-Diazabicyclo[5.4.0]undeca-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) at room temperature. 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 reverse-phase preparative HPLC (methanol / water, 0.1% trifluoroacetic acid) to obtain compound 19. 1 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 3P NMR (162 MHz, methanol-d4): δ 0.19. LC-MS: 872.4 [MHz] - . 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-(thiophen-3-ylmethoxy)propyl)hydrogen phosphate(20) [ka]

[0323] Compound 20 was synthesized in the same manner as compound 4, using 3-(bromomethyl)thiophene instead of 2-(bromomethyl)naphthalene. 1 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-methyloxiran-2-yl)methoxy)silane [ka]

[0324] Chlorotriisopropylsilane (5.38 mL, 25.2 mmol) was added via syringe over 2 minutes at 0°C to a stirred mixture of (S)-(2-methyloxiran-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 warmed to room temperature. After 20 hours, the resulting mixture was poured into a two-phase mixture of diethyl ether (100 mL) at 0°C, aqueous citric acid (10% wt / v, 10 mL), and water (80 mL). The resulting two-phase mixture was stirred, and the layers were separated. The organic layer was washed with a mixture of water and saturated aqueous sodium bicarbonate (10:1 v:v, 90 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in silica gel (0-4% ethyl acetate in hexane) to obtain intermediate 21-1. LCMS: 245.2. Intermediate 21-2: (R)-2-methyl-1-(octadecyloxy)-3-((triisopropylsilyl)oxy)propan-2-ol [ka]

[0325] 1-Octadecanol (2.13 g, 7.88 mmol) was added at room temperature to a vigorously stirred mixture of sodium hydride (60% by weight 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 cannula, 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 flash column chromatography in silica gel (0-100% dichloromethane in hexane, followed by 0-2% ethyl acetate in dichloromethane) to obtain 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)hydrogen phosphate(21) [ka]

[0326] Compound 21 was synthesized in the same manner as compound 4, using benzyl bromide instead of 2-(bromomethyl)naphthalene and intermediate 21-2 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol. 1H NMR (400MHz, methanol-d4) δ7.93(s, 1H), 7.32(d, J=7.2Hz, 2H), 7.29-7.23(m, 2H), 7.23-7.16(m, 1H), 7.07(d, J=4. 7Hz, 1H), 7.03(d, J=4.7Hz, 1H), 4.80(d, J=5.3Hz, 1H), 4.56(s, 2H), 4.34(d, J=4.8Hz, 1H), 4.26(t, J=5.4Hz, 1H) , 4.16(dt, J=11.6, 4.2Hz, 1H), 4.07(dt, J=10.3, 4.1Hz, 1H), 3.93(dd, J=10.3, 3.9Hz, 1H), 3.85(dd, J=10.3, 4.1 Hz, 1H), 3.56-3.37(m, 3H), 3.23(q, J=7.3Hz, 6H), 1.62-1.49(m, 2H), 1.45-1.08(m, 42H), 0.92(t, J=6.7Hz, 3H). LCMS:800.3[MH] - . Intermediate 22-1: (R)-(4-(benzyloxy)-3-((octadecyloxy)methyl)butyl)benzene [ka]

[0327] Sodium hydride (60% by weight dispersion in mineral oil, 186 mg, 4.64 mmol) was added at room temperature to a vigorously stirred solution of (R)-2-((benzyloxy)methyl)-4-phenylbutan-1-ol (419 mg, 1.55 mmol) (Muehlman, A.; Lindberg, J.; Classon, B.; Unge, T.; Hallberg, A.; Samulsson, B. J. Med. Chem. 2001, 44, 3407) in N,N-dimethylformamide (2.5 mL). 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 flash column chromatography on silica gel (0-20% ethyl acetate in hexane) to obtain intermediate 22-1. LCMS: 545.4[M+Na] + . Intermediate 22-2: (S)-2-((octadecyloxy)methyl)-4-phenylbutan-1-ol [ka]

[0328] A vigorously stirred mixture of intermediate 22-1 (535 mg, 1.02 mmol), palladium (10% by weight on carbon, 109 mg, 102 μmol), tetrahydrofuran (3.0 mL), and ethanol (3.0 mL) was placed at room temperature under a hydrogen gas atmosphere (balloon). After 13 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 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)phosphate hydrogen (22) [ka]

[0329] Compound 22 was synthesized in the same manner as compound 2, using intermediate 22-2 instead of intermediate 2-2. 1 ¹H NMR (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), 1.6 6(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[MH] - . Intermediate 23-1: (S)-2-chloro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0330] Intermediate 23-1 was synthesized in the same manner as intermediate 2-2, using 4-(bromomethyl)-2-chlorobenzonitrile 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3-chloro-4-cyanobenzyl)oxy)-3-(octadecyloxy)propyl)(2-chlorophenyl)phosphate [ka]

[0331] 2-chlorophenyl phosphorodichloride (33.3 μL, 206 μmol) was added at room temperature using a 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 cannula. 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 flash column chromatography on silica gel (in dichloromethane with 0-5% methanol) to obtain 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) [ka]

[0332] A solution of tetrabutylammonium fluoride (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) at room temperature. After 4 hours, chlorotrimethylsilane (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 reverse-phase preparative HPLC (2-propanol / water, 0.1% trifluoroacetic acid) to obtain compound 23. 1 ¹H 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=5.2 Hz, 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[MH] - . Intermediate 24-1: (S)-2-(benzyloxy)-3-((15-methylhexadecyl)oxy)propan-1-ol [ka]

[0333] Intermediate 24-1 was synthesized in the same manner as intermediate 9-4, using benzyl bromide instead of 4-(bromomethyl)benzonitrile 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) [ka]

[0334] Compound 24 was synthesized in the same manner as compound 19, using intermediate 24-1 instead of intermediate 19-2. 1 H NMR (400MHz, methanol-d4) δ8.01(s, 1H), 7.36-7.32(m, 2H), 7.32-7.26(m, 2H), 7.26-7.19(m, 2H), 7.1 7(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[MH] - . 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)phosphate hydrogen(25) [ka]

[0335] Compound 25 was synthesized in the same manner as compound 55, using 1,4-butanediol instead of 1,3-propanediol and 1-bromohexadecane instead of 1-bromoheptadecane. 1 H NMR (400MHz, methanol-d4) δ7.89(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), 4.2 8(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)propan-2-yl)oxy)methyl)isophthalonitrile [ka]

[0336] Using a syringe, potassium bis(trimethylsilyl)amide solution (1.0 M, 490 μL, 490 μmol in tetrahydrofuran) was added at 0°C to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-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 warmed 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 flash column chromatography using silica gel (0-10% ethyl acetate in hexane) to obtain intermediate 26-1. LCMS: 621.5[M+Na] + . Intermediate 26-2: (S)-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)isophthalonitrile [ka]

[0337] Intermediate 26-2 was synthesized using the same method as intermediate 2-2, but with intermediate 26-1 used instead of intermediate 2-1. 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3,5-dicyanobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate [ka]

[0338] Intermediate 26-3 was synthesized using intermediate 26-2 instead of intermediate 23-1, in the same manner as intermediate 23-2. 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)propyl)hydrogen phosphate(26) [ka]

[0339] A solution of tetrabutylammonium fluoride (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) at room temperature. After 82 minutes, chlorotrimethylsilane (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 reverse-phase preparative HPLC (methanol / water, 0.1% trifluoroacetic acid) to obtain compound 26. 1 H NMR (400MHz, methanol-d4) δ8.07(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), 3.6 3-3.41(m, 4H), 1.65-1.51(m, 2H), 1.38-1.22(m, 30H), 0.95-0.86(m, 3H). LCMS: 836.4[MH] - . Intermediate 27-1: tert-butyldimethyl((2R)-3-(octadecyloxy)-2-(1-phenylethoxy)propoxy)silane [ka]

[0340] Intermediate 27-1 was synthesized as a 1:1 mixture of diastereomers in the same manner as intermediate 5-2, using (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol instead of intermediate 5-1, and (R)-1-phenylethyl 2,2,2-trichloroacetimidate (WO2011059021) instead of benzyl 2,2,2-trichloroacetimidate. LCMS: 585.6[M+Na] + . Intermediate 27-2: (2S)-3-(octadecyloxy)-2-(1-phenylethoxy)propan-1-ol (a diastereomer that rapidly elutes on silica gel) Intermediate 28-1: (2S)-3-(octadecyloxy)-2-(1-phenylethoxy)propan-1-ol (a diastereomer that elutes slowly on silica gel) [ka]

[0341] Intermediates 27-2 and 28-1 were synthesized in the same manner as intermediate 2-2, using intermediate 27-1 instead of intermediate 2-1. The diastereomers were separated by flash column chromatography on silica gel (0-9% ethyl acetate in hexane) to obtain intermediate 27-2 (fast-eluting diastereomer) and intermediate 28-1 (slow-eluting diastereomer). Intermediate 27-2: LCMS: 471.4[M+Na] + Intermediate 28-1: LCMS: 471.4[M+Na] + . 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)hydrogen phosphate(27) [ka]

[0342] Compound 27 was synthesized in the same manner as compound 26, using intermediate 27-2 instead of intermediate 26-2. 1H NMR (400MHz, methanol-d4) δ8.06(s, 1H), 7.40-7.19(m, 6H), 7.17(d, J=4.8Hz, 1H), 4.83-4.69(m, 2H), 4.36-4.28(m, 1H), 4.22(t, J=5.4Hz, 1H), 4.16-4.0 5(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=6.4Hz, 3H), 1.37-1.21(m, 30H), 0.92(t, J=6.7Hz, 3H). LCMS: 800.3 [MH] - . 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)hydrogen phosphate(28) [ka]

[0343] Compound 28 was synthesized in the same manner as compound 26, using intermediate 28-1 instead of intermediate 26-2. 1 H NMR (400MHz, methanol-d4) δ8.07(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), 4.30-4.1 6(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[MH] - . Intermediate 29-1: 2,2-dimethyl-5-(phenoxymethyl)-1,3-dioxane [ka]

[0344] Methanesulfonyl chloride (1.53 mL, 19.8 mmol) was added via syringe over 3 minutes at 0°C to a stirred mixture of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (2.41 g, 16.5 mmol), triethylamine (3.21 mL, 23.1 mmol), and dichloromethane (35 mL). The resulting mixture was warmed to room temperature. After 4 hours, diethyl ether (200 mL) was added. The organic layer was sequentially washed with a mixture of aqueous phosphoric acid solution (85% wt / wt, 1.13 mL) in water (100 mL) and a mixture of water and saturated sodium bicarbonate solution (5:1 v:v, 60 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was then treated with N,N-dimethylformamide ( Dissolve in 25 mL at room temperature, and the resulting solution was vigorously stirred. 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 resulting 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 flash column chromatography on silica gel (0-100% ethyl acetate in hexane) to obtain intermediate 29-1. LCMS: 245.1[M+Na] + . Intermediate 29-2: 2-(phenoxymethyl)propane-1,3-diol [ka]

[0345] 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) at room temperature. After 4.5 hours, sodium bicarbonate (1.02 g, 12.1 mmol) was added, and the resulting mixture was vigorously stirred. After 10 minutes, ethyl acetate (100 mL) and anhydrous magnesium sulfate were added, and the resulting suspension was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (0-100% ethyl acetate in hexane) to obtain intermediate 29-2. LCMS: 183.0. Intermediate 29-3: 3-(octadecyloxy)-2-(phenoxymethyl)propan-1-ol [ka]

[0346] Potassium bis(trimethylsilyl)amide solution (1.0 M, 2.63 mL, 2.6 mmol in tetrahydrofuran) 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) at 0°C, and the resulting mixture was warmed 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 flash column chromatography on silica gel (0-25% ethyl acetate in hexane) to obtain 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-dihydroxytetrahydr Lofran-2-yl)methyl(3-(octadecyloxy)-2-(phenoxymethyl)propyl)hydrogen phosphate (29) [ka]

[0347] Compound 29 was synthesized as a 1:1 mixture of diastereomers in the same manner as compound 26, using intermediate 29-3 instead of intermediate 26-2. 1 H NMR (400MHz, methanol-d4) δ8.00(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[MH] - . Intermediate 30-1: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-yl 4-methylbenzenesulfonate [ka]

[0348] 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) were stirred together, to which 4-toluenesulfonyl chloride (929 mg, 4.87 mmol) was added at 0°C. After 2 minutes, the resulting mixture was heated to room temperature. After 170 minutes, 4-(dimethylamino)pyridine (67.0 mg, 548 μmol) was added. After 30 minutes, the resulting mixture was heated to 65°C. After 17 hours, the resulting 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 sequentially washed with water (100 mL) and a mixture of water and saturated sodium bicarbonate aqueous solution (5:1 v:v, 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 50% dichloromethane in hexane) to obtain intermediate 30-1. LCMS: 635.4[M+Na] + . Intermediate 30-2: (S)-3-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)benzonitrile [ka]

[0349] Potassium tert-pentoxide solution (1.7 M in toluene, 461 μL, 783 μmol) was added over 1 minute via syringe to a vigorously stirred mixture of intermediate 30-1 (160 mg, 261 μmol), 3-hydroxybenzonitrile (103 mg, 861 μmol), and N-,N-dimethylformamide (0.6 mL) at 0°C. 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. A solution of tetrabutylammonium fluoride (1.0 M, 1.07 mL, 1.1 mmol in tetrahydrofuran) was added using a syringe. After 60 minutes, saturated aqueous ammonium chloride (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 flash column chromatography on silica gel (0-30% ethyl acetate in hexane) to obtain a mixture of intermediate 30-2. The mixture was purified by flash column chromatography on basic alumina (0-15% ethyl acetate in hexane) to obtain 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-(octadecyloxy)propyl)hydrogen phosphate(30) [ka]

[0350] Compound 30 was synthesized in the same manner as compound 19, using intermediate 30-2 instead of intermediate 19-2. 1 H NMR (400MHz, methanol-d4) δ8.06(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(d d, 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[MH] - . Example 31: ((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-fluorophenoxy)-3-(octadecyloxy)propyl)hydrogen phosphate(31) [ka]

[0351] Compound 31 was synthesized in the same manner as compound 30, using 3-fluoro-5-hydroxybenzonitrile instead of 3-hydroxybenzonitrile. 1H NMR (400MHz, methanol-d4) δ8.09(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[MH] - . 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) [ka]

[0352] Compound 32 was synthesized in the same manner as compound 19, using 1-(bromomethyl)-3-(difluoromethyl)benzene instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene. 1 H NMR (400MHz, DMSO-d6) δ7.94(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) [ka]

[0353] Compound 33 was synthesized in the same manner as compound 19, using 1-(bromomethyl)-4-(difluoromethyl)benzene instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene. 1 H NMR (400MHz, DMSO-d6) δ7.95(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-(heptadecyloxy)propan-2-ol [ka]

[0354] Intermediate 34-1 was synthesized in the same manner as intermediate 9-2, using (S)-3-(heptadecyloxy)propane-1,2-diol instead of (S)-3-(octadecyloxy)propane-1,2-diol. 1¹H 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-(heptadecyloxy)propyl)hydrogen phosphate(34) [ka]

[0355] Compound 34 was synthesized in the same manner as compound 19, using 3-(bromomethyl)benzonitrile instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene and intermediate 34-1 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol. 1 H NMR (400MHz, DMSO-d6, drop CD3OD) δ7.96(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, 2 H), 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) [ka]

[0356] Compound 35 was synthesized in the same manner as compound 19, using 3-(bromomethyl)-5-fluorobenzonitrile instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene and intermediate 34-1 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol. 1 H NMR (400MHz, DMSO-d6, drop CD3OD)δ7.92(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), 3.1 3(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-(heptadecyloxy)propyl)hydrogen phosphate(36) [ka]

[0357] Compound 36 was synthesized in the same manner as compound 19, using 4-(bromomethyl)benzonitrile instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene and intermediate 34-1 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-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)propyl)hydrogen phosphate(37) [ka]

[0358] Compound 37 is 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl) Compound 19 was synthesized in the same manner as compound 19, using 1-(bromomethyl)-4-methoxybenzene instead of benzone and intermediate 34-1 instead of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol. 1H NMR (400MHz, DMSO-d6, drop CD3OD) δ7.93(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-(octadecyloxy)-2-phenoxypropane-1-ol [ka]

[0359] Triphenylphosphan (80.0 mg, 0.305 mmol) was added to a solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (109 mg, 0.237 mmol), phenol (41.0 mg, 0.436 mmol), and diisopropyl azodicarboxylate (0.0750 mL, 0.359 mmol) in tetrahydrofuran THF (2 mL), cooled to 0°C. The reaction mixture was gradually warmed to room temperature and stirred for 24 hours. At this point, the solvent was removed under reduced pressure, and the crude product was absorbed onto silica gel. This was purified by flash column chromatography on silica gel (in hexane with 0-10% ethyl acetate) to obtain (S)-tert-butyldimethyl(3-(octadecyloxy)-2-phenoxypropoxy)silane. 1 H NMR (400MHz, chloroform-d) δ7.33-7.22(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=1 0.4, 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).

[0360] A 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.500 mL, 0.500 mmol) was added to a solution of (S)-tert-butyldimethyl(3-(octadecyloxy)-2-phenoxypropoxy)silane (84.0 mg, 0.157 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred for 1 hour, at which point the reaction mixture was diluted with ethyl acetate and washed sequentially three times with water, followed by once with saturated sodium chloride aqueous solution. The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (in hexane with 0%-20% ethyl acetate) to obtain intermediate 38-1. 1 H NMR (400MHz, chloroform-d) δ7.38-7.29(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-(octadecyloxy)-2-(phenoxypropyl)hydrogen phosphate(38) [ka]

[0361] Compound 38 was synthesized in the same manner as compound 2, using intermediate 38-1 instead of intermediate 2-2. 1H NMR (400MHz, methanol-d4) δ7.93(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) [ka]

[0362] Compound 39 was synthesized as a 1:1 mixture of diastereomers by substituting 3-(bromomethyl)-5-fluorobenzonitrile with 3-(bromomethyl)benzonitrile, in the same manner as for compound 16. 1 H NMR (400MHz, methanol-d4) δ7.89(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), 3.44-3.3 7(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). 31P NMR (162 MHz, 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) [ka]

[0363] Compound 40 was synthesized as a 1:1 mixture of diastereomers by substituting 3-(bromomethyl)-5-fluorobenzonitrile with 1-(bromomethyl)-4-methylbenzene, in the same manner as compound 16. 1 H NMR (400MHz, methanol-d4) δ7.87(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, 2 H), 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 NMR (162 MHz, 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)hydrogen phosphate(41) [ka]

[0364] Compound 41 was synthesized as a 1:1 mixture of diastereomers by substituting 3-(bromomethyl)-5-fluorobenzonitrile with 1-(bromomethyl)-4-chlorobenzene, in the same manner as compound 16. 1 H NMR (400MHz, methanol-d4) δ7.87(s, 1H), 7.30(d, J=8.3Hz, 2H), 7.25(d, J=8.3Hz, 2H), 6.98(d, J=4.6H) z, 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 1P NMR (162 MHz, 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)hydrogen phosphate(42) [ka]

[0365] Compound 42 was synthesized as a 1:1 mixture of diastereomers by substituting 3-(bromomethyl)-5-fluorobenzonitrile with 1-(bromomethyl)-2-fluorobenzene, in the same manner as compound 16. 1 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, 1 H), 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 (162 MHz, methanol-d4) δ-0.01. 19 F NMR (376 MHz, methanol-d4) δ-121.40 (dt, J=12.1, 6.1 Hz). 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)propyl)hydrogen phosphate (43) [ka]

[0366] Compound 43 was synthesized as a 1:1 mixture of diastereomers by substituting 3-(bromomethyl)-5-fluorobenzonitrile with 2-(bromomethyl)-1,3-difluorobenzene, in the same manner as compound 16. 1 ¹H NMR (400 MHz, 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 NMR (162 MHz, methanol-d4) δ-0.93. 19 F NMR (376 MHz, methanol-d4) δ-117.21 (t, J=6.9 Hz). 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-(octadecyloxy)propyl)hydrogen phosphate (44). [ka]

[0367] Compound 44 was synthesized as a 1:1 mixture of diastereomers by substituting 3-(bromomethyl)-5-fluorobenzonitrile with iodomethane, in the same manner as compound 16. 1H NMR (400MHz, methanol-d4) δ7.90(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 NMR (162 MHz, 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)hydrogen phosphate(45) [ka]

[0368] Compound 45 was synthesized as a 1:1 mixture of diastereomers by substituting 3-(bromomethyl)-5-fluorobenzonitrile with 1-(bromomethyl)-3-fluorobenzene, in the same manner as for compound 16. 1H NMR (400MHz, methanol-d4) δ7.87(s, 1H), 7.28(td, J=8.0, 5.7Hz, 1H), 7.15-7.05(m, 2H), 6.99(d, J=4.6Hz, 1 H), 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 NMR (162 MHz, methanol-d4) δ 0.17. 19 F NMR (377 MHz, methanol-d4) δ-116.09 (td, J=9.3, 5.7 Hz). LCMS:806.20[M+H] + Intermediate 46-1: (R)-tert-butyldimethyl(2-((2-methylallyl)oxy)-3-(octadecyloxy)propoxy)silane [ka]

[0369] Intermediate 46-1 is replaced with 3-bromomethyl-1,1'-biphenyl instead of 4-(bromomethyl)-1,1'-biphenyl. It was prepared using mo-2-methylpropene in the same manner as intermediate 2-1. 1 H NMR (400MHz, chloroform-d) δ5.02-4.98(m, 1H), 4.89(m, 1H), 4.06(s, 2H), 3.69(dd, J=5.1, 1.6Hz, 1H), 3.5 8-3.51(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-(octadecyloxy)propan-1-ol [ka]

[0370] A solution of tetrabutylammonium fluoride (1.0 M, 1.05 mL, 1.05 mmol in tetrahydrofuran) was added at room temperature using a syringe to a stirred solution of intermediate 46-1 (179 mg, 359 μmol) in tetrahydrofuran (10 mL). After 150 minutes, aqueous 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 flash chromatography on silica gel (in hexane with 0-25% ethyl acetate) to obtain 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-(octadecyloxy)propane-1-ol [ka]

[0371] A vigorously stirred mixture of intermediate 46-2 (140 mg, 351 μmol), platinum (10% by weight on carbon, 193 mg, 98.0 μmol), tetrahydrofuran (1.5 mL), and ethanol (4.5 mL) was placed at room temperature under a hydrogen gas atmosphere (balloon). After 16 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain intermediate 46-3. 1 ¹H NMR (400 MHz, 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-(octadecyloxy)propylbis(4-nitrophenyl)phosphate [ka]

[0372] Intermediate 46-4 was prepared using intermediate 46-3 instead of intermediate 2-2, in the same manner as intermediate 2-3. 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-isobutoxy-3-(octadecyloxy)propyl)(4-nitrophenyl)phosphate [ka]

[0373] Intermediate 46-5 was prepared using intermediate 46-4 instead of intermediate 2-3, in the same manner as intermediate 2-4. 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-(octadecyloxy)propyl)hydrogen phosphate (46). [ka]

[0374] Compound 46 was prepared in the same manner as compound 18, using intermediate 46-5 instead of intermediate 18-5. 1 ¹H NMR (400 MHz, 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 [ka]

[0375] Acetone (458 μL, 6.18 mmol) was added by 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) at room temperature. 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 flash chromatography on silica gel (in hexane with 0-30% ethyl acetate) to obtain intermediate 47-1. 1 ¹H 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-(octadecyloxy)propan-1-ol [ka]

[0376] Dichloroborane methyl sulfide complex (52 μL, 380 μmol) was added by syringe at -60°C 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, aqueous ammonium chloride (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 flash chromatography on silica gel (in hexane with 0-30% ethyl acetate) to obtain intermediate 47-2. 1 ¹H 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, 2 H), 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-(octadecyloxy)propylbis(4-nitrophenyl)phosphate [ka]

[0377] Intermediate 47-3 was prepared using intermediate 47-2 instead of intermediate 46-3, in the same manner as intermediate 46-4. 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-isopropoxy-3-(octadecyloxy)propyl)(4-nitrophenyl)phosphate [ka]

[0378] Intermediate 47-4 was prepared using intermediate 47-3 instead of intermediate 46-4, in the same manner as intermediate 46-5. 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-(octadecyloxy)propyl)hydrogen phosphate (47). [ka]

[0379] Potassium trimethylsilanolate (9.8 mg, 77 μmol) was added at room temperature 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 pH of the mixture exceeded 7, as indicated by the persistence of yellow coloration. The mixture was purified by reverse-phase preparative HPLC (2-propanol / water) to obtain compound 47 as a salt with triethylamine. 1¹H NMR (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)dimethylsilane [ka]

[0380] Sodium hydride (60% by weight dispersion in mineral oil, 74 mg, 1.94 mmol) was added at 0°C to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-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 warmed 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 fraction was then washed with brine (25 mL) and dried on magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0% to 20% ethyl acetate in hexane) to obtain intermediate 48-1. 1H NMR (400MHz, chloroform-d) δ7.51(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)propane-1-ol [ka]

[0381] Tetrabutylammonium fluoride (1.0 M, 0.63 mL, 0.63 mmol in tetrahydrofuran) was added at 0°C 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 fraction was then washed with brine (25 mL) and dried on magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0% to 50% ethyl acetate in hexane) to obtain intermediate 48-2. 1 H NMR (400MHz, chloroform-d) δ7.49(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate [ka]

[0382] 2-chlorophenyl phosphorodichloride (64.6 μL, 392 μmol) was added using a syringe at room temperature 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, intermediates 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, tetrahydrofuran (0.7 mL) was added. A solution of intermediate 48-2 (148 mg, 294 μmol) in ) was added via a cannula. 1-methylimidazole (20 μL, 392 μmol) was 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 flash column chromatography on silica gel (in dichloromethane with 0-10% methanol) to obtain intermediate 48-3. 1H NMR (400MHz, chloroform-d) δ8.01 (d, J=1.6Hz, 1H), 7.45-7.34 (m, 4H), 7.21-7.06 (m, 3H), 7.0 1(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propyl)hydrogen phosphate [ka]

[0383] Sodium hydroxide (0.5N, 715 μL, 357 μmol) was added to a solution of 48-3 (100 mg, 99.3 μmol) in tetrahydrofuran (4 mL), 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 flash column chromatography on silica gel (in dichloromethane with 0-30% methanol) to obtain intermediate 48-4. 1H NMR (400MHz, methanol-d4) δ7.88(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)propyl)hydrogen phosphate(48) [ka]

[0384] Concentrated hydrochloric acid (52.4 μL, 629 μmol) was added to a solution of intermediate 48-4 (47 mg, 52.4 μmol) in 0.5 mL of tetrahydrofuran. 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. Following filtration and concentration, the residue was purified by flash column chromatography on silica gel (0-50% methanol in dichloromethane) to obtain compound 48. 1¹H 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 [ka]

[0385] Intermediate 49-1 was prepared in the same manner as 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)propan-1-ol [ka]

[0386] Intermediate 49-2 was prepared using 49-1 instead of intermediate 18-2, in the same manner as intermediate 18-3. 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3-chloro-4-methoxybenzyl)oxy)-3-(octadecyloxy)propyl)(2-chlorophenyl)phosphate [ka]

[0387] Intermediate 49-3 was prepared using intermediate 49-2 instead of intermediate 23-1, in the same manner as intermediate 23-2. 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)hydrogen phosphate(49) [ka]

[0388] Tetrabutylammonium fluoride (1.0 M, 25 μL, 25 μmol in tetrahydrofuran) 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, chlorotrimethylsilane (6 μL, 50 μmol) and concentrated hydrochloric acid (200 μL, 2.40 mmol) were added sequentially. The resulting mixture was purified by reverse-phase preparative HPLC (methanol / water, 0.1% trifluoroacetic acid) to obtain compound 49. 1¹H 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, 3 H), 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)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0389] Intermediate 50-1 was prepared in the same manner as intermediate 2-1, using 2-(bromomethyl)benzonitrile instead of 4-(bromomethyl)-1,1'-biphenyl. 1 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, 2 H), 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-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0390] Intermediate 50-2 was prepared using 50-1 instead of intermediate 18-2, in the same manner as intermediate 18-3. 1 H NMR (400MHz, chloroform-d) δ7.72-7.66(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((2-cyanobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate [ka]

[0391] Intermediate 50-3 was synthesized in the same way as intermediate 23-2, using intermediate 50-2 instead of intermediate 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-( Octadecyloxypropyl Hydrogen Phosphate (50) [ka]

[0392] Compound 50 was synthesized in the same manner as intermediate 49, using intermediate 50-3 instead of intermediate 49-3. 1 H NMR (400MHz, methanol-d4) δ8.06(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)propan-2-yl)oxy)methyl)-4-fluorobenzonitrile [ka]

[0393] Intermediate 51-1 was prepared in the same manner as intermediate 2-1, using 2-(bromomethyl)-4-fluorobenzonitrile instead of 4-(bromomethyl)-1,1'-biphenyl. 1H NMR (400MHz, chloroform-d) δ7.64(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-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0394] Intermediate 51-2 was prepared using 51-1 instead of intermediate 18-2, in the same manner as intermediate 18-3. 1 H NMR (400MHz, chloroform-d) δ7.69(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, 2 H), 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). [ka]

[0395] Example 51 was prepared in the same manner as compound 19, using intermediate 51-2 instead of compound 19-2. 1 H NMR (400MHz, methanol-d4) δ7.87(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, 2 H), 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-(octadecyloxy)propyl)hydrogen phosphate(52). [ka]

[0396] Compound 52 was prepared in the same manner as compound 19, using 5-(bromomethyl)-2,3-dihydro-1H-indene instead of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene. 1H NMR (400MHz, methanol-d4) δ7.87(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=5.3 Hz, 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)propan-2-yl)oxy)methyl)-3-fluorobenzonitrile: [ka]

[0397] NaH (60% oil 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 product was quenched with water (15 mL). The mixture was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-30% siRNA in hexane) to obtain the product. Intermediate 53-2: (S)-3-fluoro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile: [ka]

[0398] To a solution of a silyl-protecting compound (342 mg, 0.578 mmol) in THF (3.3 mL) at 0°C, 1 M TBAF (1 mL, 1 mmol) in THF was added and the mixture was stirred for 1 hour. This was diluted with water (3 mL) and extracted with RINKAN (2 × 10 mL). The combined organic layers were washed with water (2 × 5 mL), the brine was dried (Na₂SO₄), evaporated, and the residue was purified by X-column chromatography using silica gel (in hexane, 0-60% ethyl acetate) to obtain 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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate: [ka]

[0399] A solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 μL, 0.62 mmol) in anhydrous THF (0.4 mL) was mixed with a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). The mixture was stirred for 30 minutes and then filtered. To the filtrate, an additional THF (1.2 mL), nucleoside (77 mg, 0.232 mmol), and 1-methylimidazo were added. (26 mg, 0.31 mmol) was added sequentially. After 1 hour, (S)-3-fluoro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile (107 mg, 0.232 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed, and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to obtain the compound. 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) [ka]

[0400] 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 progress of the reaction was monitored by TLC. After the intermediate was almost 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.

[0401] The residue was dissolved in THF (1.5 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HCl (0.3 mL) was added. The cold bath was removed, and the reaction mixture was vigorously stirred 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. 1H NMR (400MHz, methanol-d4) δ7.91(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 NMR (162 MHz, methanol-d4): δ 0.28. MS: 831.22 (M+1). Intermediate 54-1: (R)-4-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile: [ka]

[0402] Intermediate 54-1 was synthesized using the same method as intermediate 53-1. Intermediate 54-2: (S)-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile [ka]

[0403] Intermediate 54-2 was synthesized using the same method as intermediate 53-2. 1 H NMR (400MHz, chloroform-d) δ7.50(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate: [ka]

[0404] A solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 μL, 0.62 mmol) in anhydrous THF (0.4 mL) was mixed with a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). 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-(octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile (115 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed, and the residue was purified by flash chromatography using silica gel (0-15% MeOH in CH2Cl2) to obtain the compound. 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)hydrogen phosphate(54) [ka]

[0405] The above 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 progress of the reaction was monitored by TLC. After the intermediate was almost 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.

[0406] The residue was dissolved in THF (1.5 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HCl (0.3 mL) was added. The cold bath was removed, and the reaction mixture was vigorously stirred 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) δ7.94(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-(heptadecyloxy)propan-1-ol: [ka]

[0407] To a solution of 1,3-propanediol (1.03 g, 13.5 mmol) in dry DMF (6 mL), NaH (60% oil dispersion; 0.172 g, 4.5 mmol) was added in fractions at 0°C, and the mixture was stirred at room temperature for 10 minutes. 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 hours. 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 flash column chromatography (silica gel; AcOEt / hexane, 1:2) to obtain the product as a solid. 1 H NMR (400MHz, chloroform-d) δ3.87-3.77(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate: [ka]

[0408] A solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 μL, 0.62 mmol) in 0.4 mL of anhydrous THF was mixed with a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). 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-(heptadecyloxy)propan-1-ol (74 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed, and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to obtain the compound. 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) [ka]

[0409] The above intermediate 55-2 (100 mg, 0.122 mmol) was dissolved in THF (1.2 mL), and 1N 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. TMSC was added to the mixture. 1 (0.19 mL, 1.47 mmol) was added, 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 in water containing 0.1% TFA) to obtain the product. 1H NMR (400MHz, methanol-d4) δ8.10(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). 31 1P NMR (162 MHz, methanol-d4) δ-0.01. MS: 668.24 (M+1). Intermediate 56-1: 3-deceoxypropane-1-ol: [ka]

[0410] Intermediate 56-1 was synthesized using 1-bromodecane as the alkylating agent, in the same manner as intermediate 55-1. 1 H NMR (400MHz, DMSO-d6) δ4.36(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(3-(decyloxy)propyl)phosphate: [ka]

[0411] Intermediate 56-2 was synthesized using intermediate 3-deceoxypropan-1-ol in the same manner as intermediate 55-2. 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-(decyloxy)propyl)hydrogen phosphate (56) [ka]

[0412] 1,1,3,3-tetramethylguanidine (61 mg, 0.5 mg) in THF (1 mL) 3 mmol) and syn-2-pyridinealdoxime (0.11 g, 0.88 mmol) were added to a solution of 56-2 (63 mg, 0.088 mmol) in THF (1.8 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography using 0-50% MeOH in DCM to obtain the product. MS: 610.20 (M+1). The above product was dissolved in THF (0.5 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HCl (0.1 mL) was added. The cold bath was removed, and the reaction mixture was vigorously stirred for 3 hours. The mixture was neutralized with Na2CO3, diluted with MeOH, and filtered. The solution was purified by preparative HPLC using Gilson preparative HPLC (Gemini column, 40-100% CH3CN in 0.1% TFA-containing H2O) to obtain the product. 1 H NMR (400MHz, methanol-d4) δ8.07(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 (162 MHz, methanol-d4): δ 0.18. MS: 570.16 (M+1). Preparation of intermediate 57-1: 3-dodecoxypropan-1-ol: [ka]

[0413] Intermediate 57-1 was synthesized using 1-bromodecane as the alkylating agent, in the same manner as intermediate 55-1. 1 H NMR (400MHz, DMSO-d6) δ4.36(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(3-(dodecyloxy)propyl)phosphate [ka]

[0414] Intermediate 57-2 was synthesized using intermediate 3-dodecocypropan-1-ol in the same manner as intermediate 55-2. 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) [ka]

[0415] Compound 57 was synthesized using the same method as 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 NMR (162 MHz, methanol-d4): δ 0.22. MS: 596.18 (M+1). Preparation of intermediate 58-1:3-(tetradecyloxy)propan-1-ol: [ka]

[0416] Intermediate 58-1 was synthesized using 1-bromotetradecane as the alkylating agent, in the same manner as intermediate 55-1. 1 H NMR (400MHz, DMSO-d6) δ4.36(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(3-(tetradecyloxy)propyl)phosphate: [ka]

[0417] Intermediate 58-2 was synthesized using intermediate 3-(tetradecyloxy)propan-1-ol in the same manner as intermediate 55-2. 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-(tetradecyloxy)propyl)hydrogen phosphate (58) [ka]

[0418] Compound 58 was synthesized in the same manner as compound 56. 1 H 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 NMR (162 MHz, methanol-d4): δ 0.09. MS: 626.19 (M+1). Preparation of intermediate 59-1:3-octadecoxypropan-1-ol: [ka]

[0419] Intermediate 59-1 was synthesized using 1-bromooctadecane as the alkylating agent, in the same manner as intermediate 55-1. 1 H NMR (400MHz, DMSO-d6) δ4.36(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-dimethyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(3-(octadecyloxy)propyl)phosphate [ka]

[0420] Intermediate 59-2 was synthesized using interme...

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