Phospholipid compounds and uses thereof

Abstract

Disclosed are compounds and methods of using the compounds, alone or in combination with additional pharmaceutical agents, and pharmaceutical compositions of the compounds (Formula (I)) for treating viral infections.

Description

[0001] Cross-reference

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

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

[0004] In one aspect, the present invention provides compounds of formula I:

[0005]

[0006] Or its pharmaceutically acceptable salt, wherein:

[0007] Z 1 It is -CH2- or –CH2-CH2-;

[0008] Z 2 It is -CH2- or –CH2-CH2-;

[0009] X represents a chemical bond, -O-, or -(CR). 12A R 12B ) q -、-O(CR 12A R 12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-;in

[0010] Each R 12A Independently, it is H, C1-C6 alkyl, or phenyl;

[0011] Each R 12B Independently H or C1-C6 alkyl; or

[0012] R on the same carbon 12A and R 12B are joined together to form a C3-C6 cycloalkylene group;

[0013] R 13 is H, C1-C6 alkyl, or phenyl;

[0014] R 14 is H, C1-C6 alkyl, or phenyl;

[0015] q is 1 or 2;

[0016] R 1 is H, C1-C 20 alkyl, C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl containing one, two, or three heteroatoms selected from N, O, and S, C6-C 10 aryl, or 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from N, S, and O; wherein when R 1 is not H, R 1 is optionally substituted with one or two R 1A groups;

[0017] wherein each R 1A is independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; or wherein two R 1A on the same or adjacent carbon are joined together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring containing one, two, or three heteroatoms selected from N, S, and O;

[0018] R 2 is H or C1-C3 alkyl;

[0019] Y is absent, phenylene, or C3-C6 cycloalkylene;

[0020] R 3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0021] each R 4 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R 4 groups are taken together with an R 4 group on an adjacent carbon atom to form a double bond;

[0022] each R 5 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0023] R 6 It is H or -C(O)C1-C6 alkyl;

[0024] R 7 It is H or -C(O)C1-C6 alkyl; and

[0025] m is an integer from 10 to 21.

[0026] In another aspect, this disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0027] On the other hand, this disclosure provides a method for treating or preventing viral infection in a person in need, wherein the method comprises administering to the person a compound of formula I or a pharmaceutically acceptable salt thereof.

[0028] In another aspect, this disclosure provides a method for preparing a medicament for treating or preventing viral infections in people in need, characterized by using a compound of formula I or a pharmaceutically acceptable salt thereof.

[0029] On the other hand, this disclosure provides the use of compounds of formula I or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of viral infections in persons in need. Detailed Implementation

[0030] I. SUMMARY

[0031] The present invention relates to methods and compounds for treating or preventing viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxoviridae, and Coronaviridae families.

[0032] II. DEFINITIONS

[0033] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings:

[0034] As used herein, “compound of this disclosure” or “compound of formula I” means a compound of formula I or a pharmaceutically acceptable salt thereof. Similarly, the phrase “compound of formula (number)” means a compound of that formula or a pharmaceutically acceptable salt thereof.

[0035] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. For example, alkyl groups can have 1 to 20 carbon atoms (i.e., C1-C2). 20"Alkyl" means an alkyl group having from one to eight carbon atoms (i.e., C1-C8 alkyl), one to six carbon atoms (i.e., C1-C6 alkyl), or one to three carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1 -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0036] "Alkoxy" means an alkyl group of from one to twenty carbon atoms (i.e., C1-C20 alkoxy), one to twelve carbon atoms (i.e., C1-C12 alkoxy), one to eight carbon atoms (i.e., C1-C8 alkoxy), one to six carbon atoms (i.e., C1-C6 alkoxy), or one to three carbon atoms (i.e., C1-C3 alkoxy) having the formula -O-alkyl, wherein alkyl is as defined above. Examples of suitable alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), n-propyloxy (-OCH2CH2CH3), i-propyloxy (-OCH(CH3)2), n-butyloxy (-OCH2CH2CH2CH3), i-butyloxy (-OCH2CH(CH3)2), s-butyloxy (-OCH(CH3)CH2CH3), t-butyloxy (-OC(CH3)3), n-pentyloxy (-OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-ethylbutyloxy (-OCH2CH(CH2CH3)2), 3-methylbutyloxy (-OCH(CH3)CH2CH3), 4-methyl-2-pentyloxy (-OCH(CH3)CH2CH(CH3)2), 4-methyl-3-pentyloxy (-OCH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-pentyloxy (-OC(CH3)2CH(CH3)2), 3,3-dimethyl-2-pentyloxy (-OCH(CH3)C(CH3)3), 2-hexyloxy (-OCH2CH(CH3)CH2CH2CH3), 3-hexyloxy (-OCH(CH2CH3)(CH2CH2CH3)), 5-hexyloxy (-OCH2CH2CH2CH2CH2CH3), and the like. 20 "Alkoxy" means an alkyl group of from one to twenty carbon atoms (i.e., C1-C20 alkoxy), one to twelve carbon atoms (i.e., C1-C12 alkoxy), one to eight carbon atoms (i.e., C1-C8 alkoxy), one to six carbon atoms (i.e., C1-C6 alkoxy), or one to three carbon atoms (i.e., C1-C3 alkoxy) having the formula -O-alkyl, wherein alkyl is as defined above. Examples of suitable alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), n-propyloxy (-OCH2CH2CH3), i-propyloxy (-OCH(CH3)2), n-butyloxy (-OCH2CH2CH2CH3), i-butyloxy (-OCH2CH(CH3)2), s-butyloxy (-OCH(CH3)CH2CH3), t-butyloxy (-OC(CH3)3), n-pentyloxy (-OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-ethylbutyloxy (-OCH2CH(CH2CH3)2), 3-methylbutyloxy (-OCH(CH3)CH2CH3), 4-methyl-2-pentyloxy (-OCH(CH3)CH2CH(CH3)2), 4-methyl-3-pentyloxy (-OCH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-pentyloxy (-OC(CH3)2CH(CH3)2), 3,3-dimethyl-2-pentyloxy (-OCH(CH3)C(CH3)3), 2-hexyloxy (-OCH2CH(CH3)CH2CH2CH3), 3-hexyloxy (-OCH(CH2CH3)(CH2CH2CH3)), 5-hexyloxy (-OCH2CH2CH2CH2CH2CH3), and the like. 12Alkoxy groups are alkoxy groups with 1 to 8 carbon atoms (i.e., C1-C8 alkoxy groups), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy groups), or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy groups). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), tert-butoxy (-OC(CH3)3 or -OtBu), etc.

[0037] "Haloalkyl" is an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl moiety of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20 Halogenated alkyl groups), 1 to 12 carbon atoms (i.e., C1-C1), 12 Halogenated alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl groups), 1 to 6 carbon atoms (i.e., C1-C6 alkyl groups), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl groups). Examples of suitable alkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, etc.

[0038] "Aryl" refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracene, biphenyls, etc.

[0039] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic systems. As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0040] As used herein, the term "halogenated group" refers to -F, -Cl, -Br, or -I. In one embodiment, the halogenated group is -F or -Cl. In another embodiment, the halogenated group is -F.

[0041] "Heterocyclo" or "heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Heterocyclyl groups can be a single ring or multiple rings, where the multiple rings can be fused, bridged, or spiro. As used herein, heterocyclyl groups have 3 to 20 ring atoms (i.e., 3- to 20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., 4- to 12-membered heterocyclyl), 4 to 8 ring atoms (i.e., 4- to 8-membered heterocyclyl), or 4 to 6 ring atoms (i.e., 4- to 6-membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. The term heterocyclo or heterocyclyl does not encompass heteroaryl or overlap with it as defined below.

[0042] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple condensed rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring atoms (i.e., C 3-12 heteroaryl), or 3 to 8 ring atoms (i.e., C 3-8 heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass aryl or overlap with it as defined above.

[0043] The term "optionally substituted" with respect to a particular moiety (e.g., an optionally substituted aryl group) of a compound of Formula I means a moiety in which all substituents are hydrogen or in which one or more hydrogens of the moiety can be replaced by a listed substituent.

[0044] Unless otherwise indicated, carbon atoms of a compound of Formula I are intended to have a valence of four. If, in some chemical structures herein, a carbon atom does not have sufficient number of variables attached to generate a valence of four, it shall be presumed that the remaining carbon substituents necessary to provide a valence of four are hydrogens.

[0045] Unless otherwise indicated, the term "treatment" as used herein means reversing, alleviating, or inhibiting the progress of the disease or disorder to which such term applies, or one or more symptoms of such disease or disorder, or preventing the disease or disorder or one or more symptoms of such disease or disorder. The term "treatment" as used herein refers to the act of treating, as "treatment" is defined above.

[0046] As used herein, the term "therapeutically effective amount" is the amount of a compound of Formula I present in a composition described herein that is required to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, that is required to produce the intended physiological response or desired biological effect in the bloodstream of a subject to be treated when such a composition is administered by the selected route of administration. The precise amount will depend on a number of factors, for example, the specific compound of Formula I, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition and its intended use, and patient considerations such as the severity of the disease, patient cooperation, and the like, and can be readily determined by one of skill in the art based on the information provided herein.

[0047] The term "adjacent carbons" as used herein means consecutive carbon atoms that are directly connected to each other. For example, in , C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, and C4 and C5 are adjacent carbons. Similarly, in , C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, and C4 and C5 are adjacent carbons, C5 and C6 are adjacent carbons, and C6 and C1 are adjacent carbons.

[0048] Certain commonly used alternative chemical names can or can not be used. For example, divalent groups such as divalent "alkyl", divalent "aryl", divalent "cycloalkyl", and the like, can also be referred to as "alkylene" (or "alkylenyl" or "alkylyl") groups; "arylene" (or "arylenyl" or "arylyl") groups; "cycloalkylene" (or "cycloalkylenyl" or "cycloalkylyl") groups, respectively.

[0049] III. COMPOUNDS

[0050] Provided herein are compounds of Formula I:

[0051]

[0052] or a pharmaceutically acceptable salt thereof, wherein:

[0053] Z 1 is -CH2- or -CH2-CH2-;

[0054] Z 2 is -CH2- or -CH2-CH2-;

[0055] X is a bond, -O-, -(CR 12A R 12B ) q -CH2-, 12A R 12B ) q - or -OCR 12A R 12B -

[0056] (CR 13 =CR 14 )-; wherein

[0057] each R 12A is independently H, C1-C6 alkyl or phenyl;

[0058] each R 12B is independently H or C1-C6 alkyl; or

[0059] R 12A and R 12B on the same carbon are joined to form a C3-C6 cycloalkylene group;

[0060] R 13 is H, C1-C6 alkyl or phenyl;

[0061] R 14 is H, C1-C6 alkyl or phenyl;

[0062] q is 1 or 2;

[0063] R 1 is H, C1-C 20 alkyl, C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl containing one, two or three heteroatoms selected from N, O and S, C6-C 10 aryl or 5- to 10-membered heteroaryl containing one, two or three heteroatoms selected from N, S and O; wherein when R 1 is other than H, the R 1 group is optionally substituted by one or two R 1A groups;

[0064] wherein each R 1A is independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano or C1-C3 haloalkyl; or wherein two R 1A on the same or adjacent carbon are joined to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S and O;

[0065] R 2 is H or C1-C3 alkyl;

[0066] Y is absent, phenylene, or C3-C6cycloalkylene;

[0067] R 3 is H, C1-C3alkyl, halo, C1-C3haloalkyl, or C3-C6cycloalkyl;

[0068] each R 4 is independently H, C1-C3alkyl, halo, C1-C3haloalkyl, or C3-C6cycloalkyl; or R 4 groups together form a double bond with one adjacent carbon atom’s R 4 group;

[0069] each R 5 is independently H, C1-C3alkyl, halo, C1-C3haloalkyl, or C3-C6cycloalkyl;

[0070] R 6 is H or -C(O)C1-C6alkyl;

[0071] R 7 is H or -C(O)C1-C6alkyl; and

[0072] m is an integer from 10 to 21.

[0073] In some embodiments of the compound of formula I, Z 1 is -CH2- and Z 2 is -CH2-. In some embodiments, Z 1 and at least one of Z 2 is -CH2-CH2-. In some embodiments, Z 1 and Z 2 are both -CH2-CH2-. In some embodiments, Z 1 is -CH2-CH2- and Z 2 is -CH2-. In some embodiments, Z 1 is -CH2- and Z 2 is -CH2-CH2-.

[0074] In some embodiments, the compound of formula I has formula II:

[0075]

[0076] wherein

[0077] R 8 is H, C1-C3alkyl, halo, C1-C3haloalkyl, or C3-C6cycloalkyl;

[0078] R 9H, C1-C3alkyl, halo, C1-C3haloalkyl, or C3-C6cycloalkyl;

[0079] w and v are independently integers from 10 to 21;

[0080] u is 0 or 1; and

[0081] w + u + v is an integer from 10 to 21.

[0082] In some embodiments of the compound of Formula II, u is 0. In some embodiments, u is 1. In some embodiments, u is 1, R 8 H, C1-C3alkyl, halo, C1-C3haloalkyl, or C3-C6cycloalkyl, and R 9 H, C1-C3alkyl, halo, C1-C3haloalkyl, or C3-C6cycloalkyl. In some embodiments, u is 1, R 8 H, C1-C3alkyl, halo, or C1-C3haloalkyl, and R 9 H, C1-C3alkyl, halo, or C1-C3haloalkyl. In some embodiments, u is 1, R 8 H, C1-C3alkyl, or halo, and R 9 H, C1-C3alkyl, or halo. In some embodiments, u is 1, R 8 H, or C1-C3alkyl, and R 9 H, or C1-C3alkyl. In some embodiments, u is 1, R 8 H, or methyl, and R 9 H, or methyl. In some embodiments, u is 1, R 8 H, and R 9 H.

[0083] In some embodiments, the compound of Formula I or II has Formula III:

[0084]

[0085] wherein n is an integer from 8 to 19.

[0086] In some embodiments of the compound of Formula 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)-, -O(CR 12A R 12B )-, -O(CR 12A R 12B )-, or -OCR 12A R 12B -(CR 13 =CR 14 )-. In some embodiments, X is a bond, -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 )-. 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 a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, wherein 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 a bond, -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 - wherein 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 - wherein 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-.

[0087] In some embodiments of the compounds of Formula I, II, and III, each R 12A is independently H, C1-C6 alkyl, or phenyl; each R 12B is independently H or C1-C6 alkyl; R 13 is H, C1-C6 alkyl, or phenyl; and R 14 is H, C1-C6 alkyl, or phenyl. In some embodiments, each R 12A is independently H or C1-C6 alkyl; each R 12B is independently H or C1-C6 alkyl; R 13 is H or C1-C6 alkyl; and R 14 is H or C1-C6 alkyl. In some embodiments, each R 12A is independently H or C1-C3 alkyl, each R 12B is independently H or C1-C3 alkyl, R 13 is H or C1-C3 alkyl, and R 14 is H or C1-C3 alkyl. In some embodiments, each R 12A is H, each R 12B is H, R 13 is H, and R 14 is H.

[0088] In some embodiments of the compounds of Formula I, II, and III, X is a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -; wherein q is 1 or 2; each R12A Independently H, C1-C6 alkyl or phenyl; and each R 12B Independently, it is H or a C1-C6 alkyl group. In some embodiments of compounds of formula I, X is a chemical bond, -O-, -(CR) 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H or C1-C6 alkyl; and each R 12B Independently, it is H or a C1-C6 alkyl group. In some embodiments of compounds of formula I, X is a chemical bond, -O-, -(CR) 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H or C1-C3 alkyl; and each R 12B Independently, it is H or a C1-C3 alkyl group. In some embodiments of compounds of formula I, X is a chemical bond, -O-, -(CR) 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A For H; and for each R 12B H is used. In some embodiments of compounds of Formula I, X is a chemical bond, -O-, -CH2-, -CH2CH2-, -OCH2-, or -O(CH2)2-. In some embodiments of compounds of Formula I, X is a chemical bond, -O-, -OCH2, or -CH2CH2.

[0089] In some embodiments of the compounds of formulas I, II, and III, X is -O-, -(CR 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H, C1-C6 alkyl or phenyl; and each R 12B Independently, it is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B ) q-、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H or C1-C6 alkyl; and each R 12B Independently, it is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A Independently H or C1-C3 alkyl; and each R 12B Independently, it is an H or C1-C3 alkyl group. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B ) q -、-O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A For H; and for each R 12B For H.

[0090] In some embodiments of the compounds of formulas I, II, and III, X is -O-, -(CR 12A R 12B )-、-O(CR 12A R 12B )-; where R 12A It is H, C1-C6 alkyl or phenyl; and R 12B It is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B )-、-O(CR 12A R 12B )-, where R 12A It is H or C1-C6 alkyl, and R 12B It is H or C1-C6 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B )-、-O(CR 12A R 12B )-, where R 12A It is H or C1-C3 alkyl, and R 12B It is H or C1-C3 alkyl. In some embodiments of compounds of formula I, X is -O-, -(CR-, ... 12A R 12B)-, -O(CR 12A R 12B )-; wherein R 12A is H, and R 12B is H.

[0091] In some embodiments of the compounds of Formula I, II, and III, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-; wherein each R 12A is independently H or C1-C6 alkyl or phenyl; and each R 12B is independently H or C1-C6 alkyl. In some embodiments of the compounds of Formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, wherein each R 12A is independently H or C1-C6 alkyl, and each R 12B is independently H or C1-C6 alkyl. In some embodiments of the compounds of Formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, wherein each R 12A is independently H or C1-C3 alkyl, and each R 12B is independently H or C1-C3 alkyl. In some embodiments of the compounds of Formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-; wherein each R 12A is H, and each R 12B is H.

[0092] In some embodiments of the compounds of Formula 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-.

[0093] In some embodiments of the compounds of Formula I, II, and III, X is -0-, -OCH2-, -OCH2-CH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -0-, -OCH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -0-. In some embodiments, X is -OCH2-. In some embodiments, X is -OCH2-CH2-. In some embodiments, X is -OCH2-(CH=CH)-.

[0094] In some embodiments of the compounds of Formula I, II, or III, X is a bond. In some embodiments of the compounds of Formula I, II, or III, Y is phenylene or C3-C6 cycloalkylene. In some embodiments, Y is In some embodiments, Y is phenylene. In some embodiments, Y is In some embodiments, Y is C3-C6 cycloalkylene. In some embodiments, Y is cyclohexylene. In some embodiments, Y is In some embodiments, Y is absent. In some embodiments, Y is absent or phenylene. In some embodiments, Y is absent or C3-C6 cycloalkylene.

[0095] In some embodiments, the compounds of Formula I, II, or III have Formula IV:

[0096]

[0097] wherein n is an integer from 8 to 19.

[0098] In some embodiments of the compounds of Formula I, II, III, or IV, R 2 is H. In some embodiments, R 2 is C1-C3 alkyl. 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 is H or ethyl.

[0099] 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.

[0100] In some embodiments of the compound of Formula I, II, III, or IV, each R 5 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, each R 5 is independently H, C1-C3 alkyl, halo, or C1-C3 haloalkyl. In some embodiments, each R 5 is independently H, C1-C3 alkyl, or halo. In some embodiments, each R 5 is independently H or C1-C3 alkyl. In some embodiments, each R 5 is independently H, methyl, or ethyl. In some embodiments, each R 5 is H. In some embodiments, each R 5 is methyl. In some embodiments, each R 5 is ethyl. 5 is H. In some embodiments, each R 5 is methyl. In some embodiments, each R 4 is ethyl.

[0101] In some embodiments of the compound of Formula I, II, III, and IV, each R 4 is independently H, C1-C3 alkyl, halo, or C1-C3 haloalkyl. In some embodiments, each R 4 is independently H, C1-C3 alkyl, or halo. In some embodiments, each R 4 is independently H or C1-C3 alkyl. In some embodiments, each R 4 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 is ethyl.

[0102] In some embodiments, the compound of Formula I, II, III, or IV has Formula V:

[0103]

[0104] In some embodiments, the compound of Formula I, II, III, IV, or V has Formula Va:

[0105]

[0106] In some embodiments, the compound of Formula I, II, III, IV, or V has Formula Vb:

[0107]

[0108] In some embodiments of the compound of Formula 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 H, methyl, ethyl, propyl, or cyclopropyl. In some embodiments, R 3 is H, methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is cyclopropyl.

[0109] In some embodiments of the compound of Formula V, Va, or Vb, R 4 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 is H. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl.

[0110] In some embodiments of the compound of Formula V, Va, or Vb, R 5independently 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 is H. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl.

[0111] In some embodiments, the compound of Formula I, II, III, IV, V, Va, or Vb is a compound of Formula VI:

[0112]

[0113] In some embodiments, the compound of Formula I, II, III, IV, V, Va, or VI is a compound of Formula VIa:

[0114]

[0115] In some embodiments, the compound of Formula I, II, III, IV, V, Vb, or VI is a compound of Formula VIb:

[0116]

[0117] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, R 1 is C1-C 20 alkyl, C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl containing one, two, or three heteroatoms each independently selected from N, O, and S, C6-C 10 aryl, or 5- to 10-membered heteroaryl containing one, two, or three heteroatoms each independently selected from N, S, and O; wherein R 1 is optionally substituted with one or two R 1A groups. In some embodiments, R 1 is H, C1-C6 alkyl, C3-C 10Cycloalkyl groups, containing one, two, or three heteroatoms selected from N, O, and S, consisting of 4 to 6-membered heterocyclic groups, C6-C. 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein when R 1 When R is not H, 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 For C1-C 20 Alkyl, C3-C 10 Cycloalkyl or a 5- to 6-membered heterocyclic group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 It is a C1-C6 alkyl group, C3-C 10 Cycloalkyl or a 5- to 6-membered heterocyclic group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 For C1-C 20 Alkyl, C3-C 10 cycloalkyl, C6-C 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 It is a C1-C6 alkyl group, C3-C 10 cycloalkyl, C6-C 10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 For C1-C 20 Alkyl, C3-C 10 cycloalkyl or C6-C 10 Aryl; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R 1 C1-C6 alkyl, C3-C 10 cycloalkyl or C6-C 10 Aryl; wherein R 1 The group is optionally surrounded by one or two R groups. 1A Group substitution. In some embodiments, R1 C1-C6alkyl or C6-C10aryl; wherein R 20 C1-C6alkyl or C6-C10aryl; wherein R 10 C1-C6alkyl or C6-C10aryl; wherein R 1 C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 1 C1-C6alkyl or C6-C10aryl; wherein R 10 C1-C6alkyl or C6-C10aryl; wherein R 1 C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 1 C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 20 C1-C6alkyl or C6-C10aryl; wherein R 1 C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R

[0118] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 10 C1-C6alkyl or C6-C10aryl; wherein R 1 C1-C6alkyl or C6-C10aryl; wherein R

[0119] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is unsubstituted. In some embodiments, R 1 is substituted with one R 1A C1-C6alkyl or C6-C10aryl; wherein R 1 C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R 1A C1-C6alkyl or C6-C10aryl; wherein R1A connected together to form a 4- to 6-membered heterocyclyl ring containing one, two, or three heteroatoms selected from N, S, and O.

[0120] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is substituted with one R 1A group. In some embodiments, R 1 is substituted with two R 1A groups. In some embodiments, each R 1A is independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl. In some embodiments, each R 1A is independently methyl, phenyl, chloro, fluoro, methoxy, cyano, CHF2, or CF3. In some embodiments, each R 1A is independently methyl, phenyl, chloro, fluoro, methoxy, cyano, or CF3. In some embodiments, each R 1A is independently methyl, phenyl, chloro, fluoro, methoxy, ethoxy, cyano, CHF2, or CF3. In some embodiments, each R 1A is independently methyl, phenyl, chloro, fluoro, methoxy, ethoxy, cyano, or CF3. In some embodiments, each R 1A is independently chloro, fluoro, or cyano. In some embodiments, at least one R 1A is cyano. In some embodiments, at least one R 1A is cyano, and the other R 1A , if present, is cyano or halo.

[0121] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl containing one, two, or three heteroatoms selected from N, O, and S, C6-C 10 aromatic, or 5- to 10-membered heteroaromatic containing one, two, or three heteroatoms selected from N, S, and O; wherein the R 1 group is substituted with one or two R 1A groups. In some embodiments, at least one R 1A is cyano. In some embodiments, at least one R 1A is cyano, and the other R 1A , if present, 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 R1A is cyano, and the other R 1A is cyano or halo, if present.

[0122] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is C6-C 10 aryl or 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from N, S, and O; wherein R 1 is substituted with one or two R 1A groups. In some embodiments, at least one R 1A is cyano. In some embodiments, at least one R 1A is cyano, and the other R 1A is, if present, 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 is cyano, and the other R 1A is cyano or halo, if present.

[0123] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is phenyl; wherein R 1 is substituted with one or two R 1A groups. In some embodiments, at least one R 1A is cyano. In some embodiments, at least one R 1A is cyano, and the other R 1A is, if present, 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 is cyano, and the other R 1A is cyano or halo, if present.

[0124] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is each R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 is, independently, H, C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein R 1A2at least one of R 1A3 and R 1A4 is CN, and at least three of R 1A1 , R 1A2 R 1A3 R 1A4 , and R 1A5 are H. In some embodiments, each R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 is independently H, halo, or cyano; wherein at least one of R 1A2 , R 1A3 , and R 1A4 is CN; and at least three of R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 is H.

[0125] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is selected from the group consisting of H, -CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -C(CH3)2CH2CH3, and -C 16 H 33 .

[0126] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is selected from the group consisting of H, -CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -C(CH3)2CH2CH3, and -C 16 H 33 .

[0127] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is selected from the group consisting of: -CH3, -C(CH3)3, and -C(CH3)2CH2CH3.

[0128] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is selected from the group consisting of:

[0129]

[0130] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is selected from the group consisting of:

[0131]

[0132]

[0133] In some embodiments of the compounds of Formula I, II, III, IV, V, Va, Vb, VI, Via, and VIb, R 1 is selected from the group consisting of:

[0134]

[0135] In some embodiments, the compound of Formula I, II, III, IV, V, Va, or Vb is a compound of Formula VII:

[0136]

[0137] wherein each R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 is independently H, C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein at least one of R 1A2 , R 1A3 , and R 1A4 is CN, and at least three of R 1A1 , R 1A2 , R 1A3 , R 1A4 , and R 1A5 is H.

[0138] In some embodiments, the compound of Formula I, II, III, IV, V, Va, or VII is a compound of Formula VIIa:

[0139]

[0140] wherein each R 1A1 , R 1A2 , R 1A3 , R 1A4 and R 1A5 is independently H, C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein at least one of R 1A2 , R 1A3 and R 1A4 is CN, and at least three of R 1A1 , R 1A2 , R 1A3 , R 1A4 and R 1A5 is H.

[0141] In some embodiments, the compound of Formula I, II, III, IV, V, Vb, or VII is a compound of Formula VIIb:

[0142]

[0143] wherein each R 1A1 , R 1A2 , R 1A3 , R 1A4 and R 1A5 is independently H, C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein at least one of R 1A2 , R 1A3 and R 1A4 is CN, and at least three of R 1A1 , R 1A2 , R 1A3 , R 1A4 and R 1A5 is H.

[0144] In some embodiments of the compound of Formula VII, VIIa, or VIIb, each R 1A1 , R 1A2 , R 1A3 , R 1A4 and R 1A5 is independently H, halo, or cyano; wherein at least one of R 1A2 , R 1A3 and R 1A4 is CN, and at least three of R 1A1 , R 1A2 , R 1A3 , R 1A4 and R 1A5 is H.

[0145] In some embodiments of the compound of Formula VII, Vila, or VIIb, 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 H, methyl, ethyl, propyl, or cyclopropyl. In some embodiments, R 3 is H, methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is cyclopropyl.

[0146] In some embodiments of the compound of Formula I, II, III, IV, V, Va, Vb, VI, Via, VIb, VII, Vila, or VIIb, R 6 and R 7 are each H. In some embodiments, each R 6 and R 7 is independently -C(O)C1-C6 alkyl. In some embodiments, each R 6 and R 7 is independently H or -C(O)C1-C3 alkyl. In some embodiments, each R 6 and R 7 is independently H or -C(O)CH(CH)2. In some embodiments, R 6 is H and R 7 is -C(O)C1-C6 alkyl. In some embodiments, R 6 is H and R 7 is -C(O)C1-C3 alkyl. In some embodiments, R 6 is H and R 7 is -C(O)CH(CH)2. In some embodiments, R 7 is H and R 6 is -C(O)C1-C6 alkyl. In some embodiments, R 7 is H and R 6 is -C(O)C1-C3 alkyl. In some embodiments, R 7 is H and R 6 is -C(O)CH(CH)2.

[0147] In some embodiments, the compound of Formula I, II, III, IV, V, Va, Vb, VIa, or VIb is selected from the group consisting of:

[0148]

[0149] and pharmaceutically acceptable salts thereof.

[0150] In some embodiments, the compound of Formula I, II, III, IV, V, Va, Vb, VIa, or VIb is selected from the group consisting of:

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the compound of Formula I, II, III, IV, V, Va, Vb, VIa, or VIb is selected from the group consisting of:

[0161] or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the compound of Formula I, II, III, IV, V, Va, Vb, VI, VIa, VIb, VII, VIIa, or VIIb is selected from the group consisting of:

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] or pharmaceutically acceptable salts thereof.

[0171] In some embodiments, the compound of Formula I, II, III, IV, V, Va, Vb, VIa, VIb, VII, VIIa, or VIb is selected from the group consisting of the compounds described in the following 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.

[0172] In some embodiments, the compound of Formula I, II, III, IV, V, Va, Vb, VIa, VIb, VII, VIIa, or VIb is selected from the group consisting of the compounds described in the following 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.

[0173] Any reference to a compound of the application described herein also includes reference to a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of a compound of the application include those derived from appropriate bases such as alkali or alkaline earth (e.g., Na + , Li + , K + , Ca +2 , and Mg +2 ), ammonium and NR4 +salts of amines include: (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, o-benzoic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of hydroxyl compounds include the anion of the compound with a suitable cation such as Na + and combinations of NR4 +

[0174] The compounds disclosed herein (e.g., compounds of Formulae I, II, III, IV, V, Va, Vb, VI, Via, and VIb) and pharmaceutically acceptable salts thereof can exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can arise from differences in crystal packing (packing polymorphism) or from packing differences between different conformational isomers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures. Pseudopolymorphs of the present application can exist due to differences in crystal packing (packing pseudopolymorphism) or due to packing differences between different conformational isomers of the same molecule (conformational pseudopolymorphism). The present application includes all polymorphs and pseudopolymorphs of the compounds of Formulae I, la, lb, II, Ila, lib, III, Ilia, Illb, or IIIc and pharmaceutically acceptable salts thereof.

[0175] The compounds disclosed herein (e.g., compounds of Formulae I, II, III, IV, V, Va, Vb, VI, Via, and VIb) and pharmaceutically acceptable salts thereof can also exist as amorphous solids. As used herein, an amorphous solid is a solid in which atomic positions are not long-range ordered. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to produce amorphous forms of the present application. The present application includes all amorphous forms of the compounds of Formulae I, II, III, IV, V, Va, Vb, VI, Via, and VIb and pharmaceutically acceptable salts thereof.

[0176] ​For therapeutic use, salts of the active ingredient of the compounds of the application will be pharmaceutically acceptable, i.e., they will be derived from pharmaceutically acceptable acids or bases. However, salts of acids or bases which are non-pharmaceutically acceptable can also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether or not derived from a pharmaceutically acceptable acid or base, are within the scope of the application.

[0177] It is also to be understood that the compositions herein include the compounds of the application in their non-ionized form, as well as in the zwitterionic form, in combination with stoichiometric amounts of water in the hydrate.

[0178] It is noted that the application encompasses all enantiomers, diastereomers and racemic mixtures of the compounds within the scope of Formula I, II, III, IV, V, Va, Vb, VI, Via, or VIb, as well as their pharmaceutically acceptable salts. All mixtures of such enantiomers and diastereomers are within the scope of the application.

[0179] The compounds of the application exemplified by Formula I, II, III, IV, V, Va, Vb, VI, Via, or VIb, can have chiral centers, e.g., chiral carbon or phosphorus atoms. Accordingly, the compounds of the application include all racemic, scalemic, and scalemic mixtures of the stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the application include optically active forms of the compounds that are enriched or resolved at any or all of the asymmetric, chiral atoms. In other words, chiral centers apparent from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and diastereomeric mixtures, as well as isolated or synthetic individual optical isomers substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the application. Racemic mixtures are separated into their individual, substantially optically pure isomers by appropriate techniques, such as, for example, separation of diastereomeric salts formed with an optically active base (e.g., an acid or a base), followed by conversion back to the optically active forms of the compounds. In most cases, the desired optical isomer is synthesized by a stereospecific reaction that

[0180] The stereochemical definitions and conventions used herein generally follow S. P. 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. McGraw-Hill Dictionary of Chemical Terms Stereochemistry of Organic " (1984) McGraw-Hill Book Company, New York; and Eliel, E and Wilen, S, "Stereochemistry of Organic Compounds" (1994) John Wiley & Sons, Inc., New York. Compounds IV. PHARMACEUTICAL FORMULATIONS(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. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1, D and L, or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, with S, (-), or 1 indicating a left-handed rotation, and R, (+), or d indicating a right-handed rotation. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0181] In certain instances, the compounds of the present application can also exist as tautomers. While only one tautomer can be depicted, all such forms are intended to be included within the scope of the present application. For example, for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazolyl systems, the enol-imine tautomer can exist, and all possible tautomeric forms are within the scope of the present application.

[0182] Any formula or structure given herein, including the compounds of Formulae I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be 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 I. Various isotopically labeled compounds of the present disclosure, for example, those into which radioactive isotopes such as 3 H, 13 C, and 14C incorporation. Such isotopically labeled compounds are useful in metabolic studies, in drug or substrate detection assays, in diagnostic assays and in radioactive treatment. Exemplary isotopes include18F,11C,10C,13N, and3H. Further, substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic index.

[0183] The present disclosure also includes compounds of Formula I, wherein from 1 to x hydrogens attached to a carbon atom are replaced with deuterium, wherein x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and, thus, can be used to prolong the half-life of any compound of Formula I when administered to a mammal, especially a human. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by methods known in the art, given the present disclosure, for example, by employing starting materials in which one or more hydrogens have been replaced with deuterium.

[0184] Deuterium labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic index. 18 F labeled compounds can be used in PET or SPECT studies. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent in a

[0185] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope means that the atom has any stable isotope of that atom. Unless otherwise indicated, when a position is designated specifically as“H” or“hydrogen,” that position is understood to have its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) means that the atom is deuterium.

[0186] Whenever a compound described herein is substituted with more than one of the same designated group (e.g.,“R” or“R”), then unless stated otherwise it is understood that the groups can be the same or different, i.e., each group is independently selected.

[0187] wavy line, indicates the position of covalent bond attachment to an adjacent substructure, group, moiety, or atom.

[0188] V. KITS

[0189] The compounds disclosed herein (e.g., compounds of Formulae I, II, III, IV, V, Va, Vb, VIa, and VIb) can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, glidants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration, generally will be isotonic. All formulations can optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. The pH of the formulations can range from about 3 to about 11, but typically will be from about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but typically will be from about 3 to 4.

[0190] While it is possible for the compounds of the present disclosure ("active ingredients") to be administered alone, it is preferable to present them as a pharmaceutical formulation. Both veterinary and human formulations of the present application comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefore and optionally other therapeutic ingredients, in particular those additional therapeutic ingredients discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject receiving the formulation.

[0191] These formulations include those suitable for the aforementioned routes of administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods known in the art of pharmacy. Techniques and formulations generally are found in "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with a carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0192] In some embodiments, the disclosed compounds have pharmacokinetic properties (e.g., good oral bioavailability) suitable for oral administration of the compounds. In some embodiments, the formulations of the present application are adapted for oral administration and exist as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary, or paste.

[0193] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide a slow or controlled release of the active ingredient therefrom.

[0194] For infections of the eye or other external tissues (e.g., mouth and skin), formulations are applied as a topical ointment or cream containing an amount of the active ingredient sufficient to deliver a dose of 0.075 to 20% w / w (including active ingredients ranging from 0.1% and 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2% w / w to 15% w / w, and most preferably 0.5% w / w to 10% w / w, when the disorder is treated for short periods of time. When the formulations are to be administered for long periods of time, it is preferable to administer them topically in dosage units containing amounts of active ingredient in the range of 0.001 to 1% w / w. When formulated in an ointment, the active ingredient can be employed in combination with one or more of the following: a petrolatum base or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water emulsion base or a water-in-oil emulsion base.

[0195] If desired, the water phase of the cream base can include, for example, at least 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. The topical formulation can desirably include a compound that enhances 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 analogs.

[0196] The oil phase of the emulsions of the present application can be constructed in known manner from known ingredients. While this phase can include only emulsifiers (or emulsifying agents), it desirably includes a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included along with a lipophilic emulsifier which acts as a stabilizer. It is also preferable to include both an oil and a fat. The emulsifiers with or without stabilizers together constitute a so-called emulsifying wax, and the wax together with the oil and fat constitute a so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulation.

[0197] Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present application include 60、 80, cetyl stearyl alcohol, benzyl alcohol, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate. Other emulsifiers and emulsion stabilizers suitable for use in the formulations of the present application include 80.

[0198] Suitable oils or fats for the formulation are those of either vegetable or animal origin and include

[0199] Pharmaceutical formulations according to the present application comprise a compound according to the present application together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral use the active ingredient will be present in a tablet, troche, lozenge, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended to be administered orally are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient are also acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, alginic acid or alginates; binding agents, such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. Examples of coating agents include polymeric substances such as hydroxypropylmethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyethyleneglycol, ethylcellulose, hydroxypropylmethylcellulose acetate succinate, and methacrylic acid copolymers. The tablets can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, time delay material such as glyceryl monostearate or glyceryl distearate can be employed alone or with a wax.

[0200] Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0201] Aqueous suspensions according to the application contain the active material in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents, such as a naturally occurring phosphatide (for example, soy lecithin), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of an alkylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyoxyethylene

[0202] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (such as liquid paraffin). Oral suspensions can contain suspending agents such as acacia, tragacanth, or soy lecithin. Sweetening agents (such as those set forth above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0203] Dispersible powders and granules of the present application suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring, and coloring agents, can also be present.

[0204] The pharmaceutical compositions of this application can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil (such as olive oil or arachis oil), a mineral oil (such as liquid paraffin), or a mixture of these. Suitable emulsifying agents include naturally occurring gums such as acacia, and gum tragacanth, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, sorbitol, or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring, or coloring agent.

[0205] The pharmaceutical compositions of this application can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Acceptable solvents and vehicles that can be employed include water, Ringer's solution, isotonic sodium chloride solution, and high- sodium chloride solution.

[0206] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans can contain approximately 1 mg to 1000 mg of the active material compounded with an appropriate and convenient amount of carrier material to make a dosage unit form that is suitably adapted for ingestion, the carrier material being present in about 5 to about 95% (w / w) of the total composition. The pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain from about 3 to 500 μg of the active ingredient per milliliter of the solution, in order that infusion of an appropriate amount (e.g., having a dose of from about 3 to 500 μg) with an appropriate rate can be effected.

[0207] Formulations suitable for topical application to the eye also include drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient preferably is present in such formulations in a concentration of from 0.5% to 20%, advantageously from 0.5% to 10%, and especially about 1.5% w / w.

[0208] Formulations suitable for topical application to the eye also include drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient preferably is present in such formulations in a concentration of from 0.5% to 20%, advantageously from 0.5% to 10%, and especially about 1.5% w / w.

[0209] Formulations for rectal administration can be presented as a suppository, with a suitable base, including for example, cocoa butter or salicylates.

[0210] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or intranasal administration have, for example, a particle size that is in the range of from about 0.1 to 500 microns, such as 0.5, 1, 30, 35, or the like, which are administered by rapid inhalation delivery through the nasal passage or by inhalation into the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oil-based solutions of the active ingredient. Formulations suitable for administration by aerosol or dry powder can be prepared according to conventional methods and can deliver other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as a dry powder. In some embodiments, the compounds used herein are formulated and administered as an aerosolized 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 a face mask inhaler.

[0211] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0212] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

[0213] Formulations are presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above described, in an amount suitable for the subject to be treated.

[0214] It will be appreciated that, in addition to ingredients particularly mentioned herein, the formulations of the application can include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration can include flavouring agents.

[0215] The present application further provides veterinary compositions comprising at least one active ingredient as defined above and a veterinary carrier.

[0216] Veterinary carriers are materials which can be used to administer a composition and can be solid, liquid or gaseous materials which are otherwise inert and acceptable to a veterinary art and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route.

[0217] The compounds of the present application are used to provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more compounds of the present application as active ingredients, wherein the release of the active ingredients is controlled and regulated to allow less frequent dosaging or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0218] VI. ADMINISTRATION

[0219] Also provided herein are kits comprising a compound disclosed herein (e.g., a compound of Formula I, II, III, IV, V, Va, Vb, VI, Via, or VIb), a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. In some embodiments, the kits described herein can include a label and / or instructions for using the compound to treat a disease or condition in a subject (e.g., a human) in need thereof. In some embodiments, the disease or condition is a viral infection.

[0220] In some embodiments, the kit can further include one or more additional therapeutic agents and / or instructions for using the additional therapeutic agent(s) in combination with the compound of Formula I to treat a disease or condition in a subject (e.g., a human) in need thereof.

[0221] In some embodiments, the kits provided herein include a separate dosage unit of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. Examples of separate dosage units can include pills, tablets, capsules, pre-filled syringes or cartridges, IV bags, inhalers, nebulizers, etc., each of which includes a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. In some embodiments, the kit can contain a single dosage unit, and in other embodiments there are multiple dosage units, such as the number of dosage units required for a specified regimen or cycle.

[0222] Also provided are articles of manufacture comprising: a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof; and a container. In some embodiments, the container of the article of manufacture is a vial, jar, ampule, pre-filled syringe, blister pack, can, flask, bottle, box, intravenous bag, inhaler, or nebulizer.

[0223] VII. METHODS OF USE

[0224] The compound(s) of the application are administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) etc. In some embodiments, the compounds disclosed herein are administered by inhalation or intravenously. It will be appreciated that the preferred route can vary with, for example, the condition of the recipient.

[0225] In the methods of the application for treating viral infections, the compounds of the application can be administered to a person who can be exposed to a virus or who already has a viral infection at any time. In some embodiments, the compounds of the application can be administered prophylactically to a person who is in contact with or at risk of being in contact with a person who has a viral infection, for example a healthcare provider. In some embodiments, administration of the compounds of the application can be to a person who tests positive for a viral infection but has not yet shown symptoms of the viral infection. In some embodiments, the compounds of the application can be administered to a person at the onset of symptoms of a viral infection.

[0226] In some embodiments, the methods disclosed herein comprise event- driven administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject.

[0227] As used herein, the term “event-driven” or “event-driven administration” refers to administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, (1) prior to an event that will expose the individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection); and / or (2) during an event (or more than one repeated event) that will expose the individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection); and / or (3) after an event (or after the final event in a series of repeated events) that will expose the individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection). In some embodiments, event-driven administration occurs prior to exposure of the subject to a virus. In some embodiments, event-driven administration occurs after exposure of the subject to a virus. In some embodiments, event-driven administration occurs both prior to and after exposure of the subject to a virus.

[0228] In certain embodiments, the methods disclosed herein involve administration prior to and / or after an event that will expose the individual to a virus or otherwise increase the risk of the individual acquiring a viral infection, e.g., as pre-exposure prophylaxis (PrEP) and / or as post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein comprise pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein comprise post-exposure prophylaxis (PEP).

[0229] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered prior to exposure of the subject to a virus.

[0230] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered prior to and after exposure of the subject to a virus.

[0231] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered after exposure of the subject to a virus.

[0232] An example of an event-driven dosing regimen includes administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to a virus, followed by administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, every 24 hours during exposure, followed by further administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the last exposure, and a final administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0233] Another example of an event-driven dosing regimen includes administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 hours prior to a virus exposure, followed by daily administration during exposure, followed by a final administration about 24 hours after the last exposure (which can be an increased dose, such as a double dose).

[0234] The effective dosage of active ingredient depends on the nature of the condition being treated, the toxicity, whether the compound is used prophylactically or to combat an active viral infection, the method of delivery and the pharmaceutical formulation, and will be determined by the clinician using routine dose escalation studies. The dosage can be expected to be from about 0.0001 mg / kg body weight to about 100 mg / kg body weight per day; typically from about 0.01 mg / kg body weight to about 10 mg / kg body weight per day; more typically from about 0.01 mg / kg body weight to about 5 mg / kg body weight per day; most typically from about 0.05 mg / kg body weight to about 0.5 mg / kg body weight per day. For example, a candidate daily dosage for an adult human weighing about 70 kg would range from 1 mg to 1000 mg, preferably from 5 mg to 500 mg, and can take the form of a single dose or multiple doses.

[0235] Any suitable period of time for administering the compounds of the application is contemplated. For example, administration can be for 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. Administration can also be for 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer periods of administration are also contemplated.

[0236] 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.

[0237] In some embodiments, one or more of the compounds disclosed herein are administered once a day. The once daily dose can be administered for as long as needed, for example, for up to 5 days, for up to 7 days, for up to 10 days, for up to 15 days, for up to 20 days, for up to 25 days, for up to one month, or longer. In some embodiments, the once daily dose is administered for up to 20 days, for up to 15 days, for up to 14 days, for up to 13 days, for up to 12 days, for up to 10 days, for up to 8 days, for up to 6 days, for up to 4 days, for up to 3 days, for up to 2 days, or for 1 day.

[0238] In some embodiments, one or more compounds disclosed herein are administered once a day for about 6 to 12 days, for example, for about 8 to 10 days. In some embodiments, the one or more compounds are administered once a day for about 9 days. In some embodiments, the one or more compounds are administered once a day for about 10 days. In some embodiments, about 50 mg to 150 mg of one or more compounds disclosed herein are administered once a day for about 5 to 12 days, for example, for about 10 days. In some embodiments, about 100 mg of one or more compounds disclosed herein are administered once a day for about 5 to 12 days, for example, for about 10 days.

[0239] VIII. COMBINATION THERAPIES

[0240] The present disclosure also provides methods of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound described herein.

[0241] In some embodiments, the present disclosure provides methods of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound described herein.

[0242] In some embodiments, the present disclosure provides methods of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0243] In some embodiments, the present disclosure provides methods of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0244] In some embodiments, the present disclosure provides methods of inhibiting viral polymerase in a cell, comprising contacting a cell infected with a virus with a compound disclosed herein, thereby inhibiting viral polymerase.

[0245] In some embodiments, the present disclosure provides methods of inhibiting viral polymerase in a cell, comprising contacting a cell infected with a virus with a compound disclosed herein and at least one additional active therapeutic agent, thereby inhibiting viral polymerase.

[0246] Also provided herein are uses of a compound disclosed herein for treating or preventing a viral infection in a subject in need thereof. For example, provided herein are uses of a compound disclosed herein for treating a viral infection in a subject in need thereof.

[0247] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Thus, in some embodiments, the present disclosure provides a method for treating a Paramyxoviridae infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles, mumps, and parainfluenza viruses. In some embodiments, the Paramyxoviridae virus is a Soavevirus.

[0248] In some embodiments, the viral infection is a Pneumoviridae virus infection. Thus, in some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound provided herein. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. 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.

[0249] In some embodiments, the present disclosure provides a compound disclosed herein for use in treating a Pneumoviridae virus infection in a human 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.

[0250] In some embodiments, the present disclosure provides a method for treating an RSV infection in a human in need thereof, the method comprising administering to the human a compound provided herein. In some embodiments, the human has a chronic respiratory syncytial virus infection. In some embodiments, the human has an acute RSV infection.

[0251] In some embodiments, a method of inhibiting RSV replication is provided, wherein the method comprises administering to a human in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0252] In some embodiments, the present disclosure provides a method for reducing viral load associated with an RSV infection, wherein the method comprises administering to a human infected with RSV a compound disclosed herein.

[0253] In some embodiments, the viral infection is a picornaviridae virus infection. Accordingly, in some embodiments, the disclosure provides a method of treating a picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound of the disclosure. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), nonparalytic poliomyelitis-like syndrome, epidemic myalgia (usually an acute, febrile, infectious illness occurring in epidemics), hand-foot-and-mouth syndrome, 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, the picornaviridae virus infection is selected from the group consisting of: a coxsackie A virus infection, a coxsackie A virus infection, an enterovirus D68 infection, an enterovirus B69 infection, an enterovirus D70 infection, an enterovirus A71 infection, and a poliovirus infection.

[0254] In some embodiments, the disclosure provides a compound for use in treating a picornaviridae virus infection in a human in need thereof. In some embodiments, the picornaviridae virus infection is a human rhinovirus infection.

[0255] In some embodiments, the viral infection is a flaviviridae virus infection. Accordingly, in some embodiments, the disclosure provides a method of treating a flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative flaviviridae viruses include, but are not limited to, dengue, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the flaviviridae virus infection is a dengue virus infection. In some embodiments, the flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the flaviviridae virus infection is a West Nile virus infection. In some embodiments, the flaviviridae virus infection is a Zika virus infection. In some embodiments, the flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the flaviviridae virus infection is a hepatitis C virus infection.

[0256] In some embodiments, the disclosure provides a compound disclosed herein for use in treating a flaviviridae virus infection in a human in need thereof. In some embodiments, the flaviviridae virus infection is a dengue virus infection. In some embodiments, the flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the flaviviridae virus infection is a West Nile virus infection. In some embodiments, the flaviviridae virus infection is a Zika virus infection. In some embodiments, the flaviviridae virus infection is a hepatitis C virus infection.

[0257] In some embodiments, the viral infection is a Filoviridae virus infection. Thus, in some embodiments, provided herein are methods of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (variant Zaire, Bundibugio, Sudan, Tai Forest, or Reston) and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0258] In some embodiments, the present disclosure provides compounds for use in treating a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0259] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, provided herein are methods of treating a coronavirus infection in a human in need thereof, wherein the method comprises administering to the human a compound provided herein. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, a zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus having at least 70% sequence homology 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.

[0260] In some embodiments, the present disclosure provides compounds for use in treating a coronavirus infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, a zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0261] In some embodiments, the viral infection is an arenavirus infection. Accordingly, in some embodiments, the disclosure provides methods of treating an arenavirus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the arenavirus infection is a Lassa virus infection or a Junin virus infection.

[0262] In some embodiments, the disclosure provides compounds for use in treating an arenavirus infection in a human in need thereof. In some embodiments, the arenavirus infection is a Lassa virus infection or a Junin virus infection.

[0263] In some embodiments, the viral infection is a orthomyxovirus infection, e.g., an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0264] In some embodiments, the viral infection is a nairovirus infection. Accordingly, in some embodiments, the disclosure provides methods of treating a nairovirus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the nairovirus infection is a Crimean-Congo hemorrhagic fever virus infection. In some embodiments, the nairovirus infection is a Hazara virus infection.

[0265] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a virus along with one or more additional therapeutic agents. The additional therapeutic agent(s) can be administered to the infected individual simultaneously with, or prior to, or following administration of the compound of the disclosure.

[0266] 1. Combination therapies for the treatment of the family of pneumoviridae

[0267] The compounds described herein can also be used in combination with one or more additional therapeutic or prophylactic agents. Accordingly, also provided herein are methods for treating a viral infection in a subject in need thereof, wherein the methods comprise administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents. In some embodiments, the methods comprise administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic agents.

[0268] In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2'-deoxyuridine analogs, nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogs, acyclic nucleoside phosphonate analogs, HCV NS5A / NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulants, oligonucleotides, antimitotic inhibitors, and combinations thereof.

[0269] 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 iododeoxyuridine, trifluorouridine, bromovinyldeoxyuridine (BVDU), and combinations thereof.

[0270] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, beta-D-N4-hydroxycytidine, or combinations thereof.

[0271] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0272] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0273] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0274] 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, 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 voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, glecaprevir, ribavirin, danoprevir, fidaxomir, velpatasvir, sovaprevir, deldeprefir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, glecaprevir, and combinations thereof.

[0275] 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.

[0276] 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, ibalizumab, fosfestavir, leronlimab, ibalizumab, fosfestavir, leronlimab, palivizumab, intravenous respiratory syncytial virus immunoglobulin [RSV-IGIV], varicella zoster immunoglobulin [VariZIG], varicella zoster immunoglobulin [VZIG]), and combinations thereof.

[0277] In some embodiments, the additional therapeutic agent is an acyclic guanosine analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valganciclovir), valganciclovir, peniclovir, famciclovir, and combinations thereof.

[0278] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, lifamavir, 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, tenofovir, TDF, and combinations thereof.

[0279] 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 protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5B polymerase inhibitor of the nucleoside / nucleotide type. In some embodiments, the additional therapeutic agent is an NS5B polymerase inhibitor of the non-nucleoside type. 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.

[0280] 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, memantine, 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, memantine, ribavirin, umifenovir, baloxavir marboxil, oseltamivir, peramivir, inosine monophosphate dehydrogenase, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of: amantadine, memantine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0281] In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa 1b, pegylated interferon alfa 2a (PegIFN alpha-2a) and PegIFN alpha-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFN alpha-2a) and PegIFN alpha-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, pegylated interferon alfa 2a (PegIFN alpha-2a), PegIFN alpha-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or combinations thereof.

[0282] In some embodiments, the additional therapeutic agent is an immune stimulator. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is an anti-mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: formivirsen, pudafloxane, imiquimod, resiquimod, and combinations thereof.

[0283] In some embodiments, the additional therapeutic agent is selected from the group consisting of: becilamaf, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0284] In some embodiments, the additional therapeutic agent is an agent for treating RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or pritelivir. For example, in some embodiments, the antiviral agent is ALS-8112 or pritelivir.

[0285] In some embodiments, the additional therapeutic agent is an agent for treating picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of: hydantoin, guanidine hydrochloride, L-methionine 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 rupintrivir.

[0286] In some embodiments, the additional therapeutic agent is an agent for treating malaria. In some embodiments, the additional therapeutic agent is chloroquine.

[0287] In some embodiments, the additional therapeutic agent is selected from the group consisting of: hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, dihydroartemisinin, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artemisinin, ganaplacide, DSM-265, sipankalim, artemotil, and combinations thereof.

[0288] In some embodiments, the additional therapeutic agent is an agent for treating coronavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of: IFX-1, FM-201, CYNK-001, DPP4-Fc, celgosivir, nafamostat, LB-2, AM-1, antiviral pore protein, and combinations thereof.

[0289] In some embodiments, the additional therapeutic agent is an agent for treating Ebola virus. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: ribavirin, ZMab, motavizumab, RSV-IGIV MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5- (hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N- bis[3-(dimethylamino)propyl]-3,9-dimethylquinolo[8,7-h]quinolin-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenoviral 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, the additional therapeutic agent is ZMapp, mAB 114, REGEN-EB3, and combinations thereof.

[0290] In some embodiments, the additional therapeutic agent is an agent for treating 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, radalbuvir, 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, such as GS-9256, veldolpavir, voxilaprevir, and combinations thereof.

[0291] 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.

[0292] 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, but are not limited to, a-hydroxytopiketone, amdoxovir, andrographolide, b-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicroside (gentiopicroside), HH-003, heprapide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotide, mivitript, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, carotene, 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, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007, sofosbuvir, ledipasvir, UB-551, and ZH-2N, as well as the compounds disclosed in US20150210682 (Roche), US 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir emtricitabine Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide diterpenoid, tenofovir alafenamide diterpenoid, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir Entecavir maleate, telbivudine Felosivir, Pradefovir, Clavudine, Ribavirin, Lamivudine Azidoxime, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate aspartate, tenofovir disoproxil fumarate orotate, and HS-10234. In some implementations, the additional treatment agent is an HBV capsid inhibitor.

[0293] In some embodiments, the adjunctive therapeutic agent is a pharmaceutical agent used to treat HIV. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogs, and combinations thereof.

[0294] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), and cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0295] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0296] In some embodiments, the additional therapeutic agent is an HIV combination drug. Examples of HIV combination drugs include, but are not limited to (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Bictegravir, Emtricitabine, and Tenofovir alafenamide); (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); (Tenofovir disoproxil fumarate and Emtricitabine; TDF + FTC); (Tenofovir alafenamide and Emtricitabine); (Tenofovir alafenamide, Emtricitabine, and Rilpivirine); (Tenofovir alafenamide, Emtricitabine, Cobistat, and Etravirine); (Darunavir, Tenofovir alafenamide hemifumarate, Emtricitabine, and Cobistat); SYMFI TM (Efavirenz, Lamivudine, and Tenofovir disoproxil fumarate); CIMDU TM (Lamivudine and Tenofovir disoproxil fumarate); Tenofovir and Lamivudine; Tenofovir alafenamide and Emtricitabine; Tenofovir alafenamide hemifumarate and Emtricitabine; Tenofovir alafenamide hemifumarate, Emtricitabine, and Rilpivirine; Tenofovir alafenamide hemifumarate, Emtricitabine, Cobistat, and Etravirine; (Zidovudine and Lamivudine; AZT + 3TC); (Efavirenz, Lamivudine, and Tenofovir disoproxil fumarate); (Abacavir sulfate and Lamivudine; ABC + 3TC); (Efavirenz, Lamivudine, and Tenofovir disoproxil fumarate); (Lopinavir and Ritonavir); (Dolutegravir, Abacavir, and Lamivudine); (abcam, zidovudine, and lamivudine; 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 fumarate; dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, efavirenz + emtricitabine + tenofovir disoproxil fumarate, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine.

[0297] 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, cobicistat. In some embodiments, the additional therapeutic agent is selected from the group consisting of amprenavir, atazanavir, brecanavir, 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.

[0298] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. 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 selected from the group consisting of bictegravir, elvitegravir, curcumin, a derivative of curcumin, chlorogenic acid, a derivative of chlorogenic acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurogygones tricarboxylic acid, a derivative of aurogygones tricarboxylic acid, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrosine kinase inhibitor, a derivative of a tyrosine kinase inhibitor, quercetin, a derivative of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injectable), diketquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0299] In some embodiments, the additional therapeutic agent is an HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Other examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adatatribe (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 plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0300] 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.

[0301] In some embodiments, the additional therapeutic agent is an HIV nucleoside or nucleotide reverse transcriptase inhibitor. For example, the additional therapeutic agent is selected from the group consisting of adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (ddl), abacavir, abacavir sulfate, alovudine, alitaskin, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapiyvirine, doravirine, eduvirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rofavirine-ethavirine amide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0302] In some embodiments, the additional therapeutic agent is an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor. For example, the additional agent is selected from the group consisting of dapiyvirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, eduvirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, efavirenz rilp (VM-1500), and combinations thereof.

[0303] In some embodiments, the additional therapeutic agent is selected from (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (etravirine, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); (Tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (Dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; (Dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; (Lopinavir and ritonavir); (Zidovudine and lamivudine; AZT + 3TC); (Zidovudine and lamivudine; AZT + 3TC); (Zidovudine and lamivudine; AZT + 3TC); (Zidovudine and lamivudine; 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; pritelivir; fosamprenavir; fosamprenavir calcium efavirenz; efcavirenz; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptor alcohol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0304] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, valrubicin, ibutilide, betahistine, epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, plazidox, bictegravir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, dexzopiclone, and zopiclone.

[0305] In some implementations, the adjunctive therapeutic agent is an inhibitor of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). For example, in some implementations, the adjunctive therapeutic agent is selected from the group consisting of: (S)-6-amino-9-(1-(but-2-ethynyl)pyrrolidone-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (ibubrutinib (evobr) The adjunctive therapy includes teirabrutinib (ONO-4059), sipetinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, acalabrutinib, danvastatin, and combinations thereof. In some embodiments, the adjunctive therapy is selected from the group consisting of teirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the adjunctive therapy is selected from the group consisting of teirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the adjunctive therapy is a tyrosine kinase inhibitor A9 (A9).

[0306] In some embodiments, the adjunctive therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0307] In some embodiments, the adjunctive therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is carfilzomib.

[0308] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the 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 a live attenuated RSV vaccine MEDI-559, an anti-RSV human monoclonal antibody REGN2222, palivizumab, respiratory syncytial virus immune globulin, respiratory syncytial virus immune globulin intravenous [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, such as pediarix, engerix-B, and recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, such as zostavax and varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, such as cervarix, gardasil9, and gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine. For example, (i) an influenza A monovalent vaccine (e.g., influenza A [H5N1] virus monovalent vaccine and influenza A [H1N1] 2009 virus monovalent vaccine), (ii) an influenza A and B trivalent vaccine (e.g., Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) an influenza A and B quadrivalent vaccine (FluMist, Fluarix, Fluzone, and FluLaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., Adenovirus types 4 and 7 vaccine, 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., M-M-RII and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., M-M-R II and ProQuad).In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., M-M-R II 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 (variola) 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.

[0309] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an anti-2019-nCov antibody selected from the group consisting of: a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting SARS-CoV-2 spike protein, an antibody that can neutralize 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 a PD-1 antibody. In some embodiments, the additional therapeutic agent is REGN-COV2. In some embodiments, the additional therapeutic agent is LY-CoV555.

[0310] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0311] 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, pimodivir, and combinations thereof.

[0312] In some embodiments, the additional therapeutic agent is selected from the group consisting of: lopinavir, ritonavir, interferon alpha-2b, ritonavir, arbidol, hydroxychloroquine, delaviradine, and combivir, arbidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0313] In some embodiments, the additional therapeutic agent is selected from the group consisting of 6'-fluorinated mannoquin analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASC09F, GC376, GC813, phenylisoserine derivatives, neuraminidase inhibitor analogs, pyrithioxate derivatives, pannatin and 5-hydroxychromone derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thiophene-4-azaspiro[4.5]decane-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, alisporivir, imatinib mesylate, dasatinib, semetitinib, trametinib, rapamycin, serabtinib, chlorpromazine, triflupromazine, fluphenazine, thioridazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivatives N30, mycophenolic acid, silvestrol, and combinations thereof.

[0314] 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 2019-nCoV viral antibody.

[0315] In some embodiments, the additional therapeutic agent is a steroid, for example, a corticosteroid. In some embodiments, the additional therapeutic agent is dexamethasone.

[0316] The compositions of the present application are also used in combination with other active ingredients. For the treatment of 2019-nCoV viral infection, preferably the other active therapeutic agent has activity against coronavirus infection, for example activity against 2019-nCoV viral infection. The compounds and compositions of the present application are also intended for use in the general care of patients with 2019-nCoV viral infection, including parenteral fluids (including dextrose saline and Ringer’s lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal agents, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory drugs (e.g., interferons), other small molecule or biologic antiviral agents targeting 2019-nCoV (such as but not limited to lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, pain medications, and medications for other common diseases in the patient population, such as anti-malarial agents (including artemether and artemisinin-lumefantrine combination therapy), typhoid fever vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or Shigella disease vaccines. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine.

[0317] In some embodiments, the additional therapeutic agent is an immunomodulator. Examples of immune-based therapies include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; the polymer polyethylenimine (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, Noviladim, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent refers to fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0318] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example tocilizumab, sarilumab, or a combination thereof.

[0319] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For example, the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0320] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example the additional therapeutic agent is baricitinib, filgotinib, baricinib, or a combination thereof.

[0321] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, for example pirfenidone.

[0322] In some embodiments, the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia. For example, the additional therapeutic agent is a macrolide antibiotic (e.g., azithromycin, clarithromycin, and mycoplasma pneumoniae), a fluoroquinolone (e.g., ciprofloxacin and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof.

[0323] In some embodiments, the compounds disclosed herein are used in combination with standard of care for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (October 1)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment will depend on several factors, including the type and severity of the pneumonia, the age and overall health of the individual. Options include: (i) antibiotics, (ii) cough medicine, and (iii) fever / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant.

[0324] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from convalescing COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusion. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0325] In some embodiments, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, rintatlimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod. RO-7020531.

[0326] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurizan, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, serazide, clevidipine, atorvastatin, cinoxolone, clofazimine, fosaprepitant, and combinations thereof.

[0327] In some embodiments, the additional therapeutic agent is canfosfamide, suramin, triazirine, dipyridamole, bevacizumab, mepolizumab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0328] In some embodiments, the additional therapeutic agent is an antiviral pore protein therapeutic. 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. Other examples of additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.

[0329] Any of the compounds of the present disclosure can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0330] Co-administration of a compound of the present disclosure with one or more other active therapeutic agents generally refers to the administration of a compound of the present disclosure and one or more other active therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of both the compound of the present disclosure and the one or more other active therapeutic agents are present in the patient's body.

[0331] Co-administration includes administration of a unit dose of a compound of the present disclosure prior to or following administration of a unit dose of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administration of the one or more other active therapeutic agents. For example, a unit dose of a compound of the present disclosure can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a compound of the present disclosure. In some cases, it can be desirable to administer a unit dose of a compound of the present disclosure first, followed by administration of a unit dose of one or more other active therapeutic agents several hours (e.g., 1 to 12 hours) later. In other cases, it can be desirable to administer a unit dose of one or more other active therapeutic agents first, followed by administration of a unit dose of a compound of the present disclosure several hours (e.g., 1 to 12 hours) later.

[0332] Combination therapy can provide "synergy" and "potentiation" such that the effect of the active ingredients when used together is greater than the sum of the effects of the compounds when given alone. A synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation, a synergistic effect can be attained when, for example, the compounds are delivered on different, but overlapping, time schedules. Typically, in alternation therapy, an effective dosage of each active ingredient is administered in sequence (i.e., sequentially) without these compounds being present in the regimen at the same time. In contrast, in combination therapy, an effective dosage of two or more active ingredients are presented together at the same time. A synergistic antiviral effect means that the antiviral effect is greater than the predicted pure additive effect of the compounds in the combination.

[0333] 2. Combination therapies for the treatment of the family of picornaviridae

[0334] The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Pneumoviridae virus infections, preferably the other active therapeutic agents have activity against Pneumoviridae virus infections, in particular respiratory syncytial virus infection and / or metapneumovirus infection. Non-limiting examples of these other active therapeutic agents with activity against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents with activity against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and pritelivir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAbs; viral replication inhibitors such as nitazoxanide.

[0335] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0336] Non-limiting examples of other active therapeutic agents active against metapneumovirus infection include sialidase modulators such as DAS-181; RNA polymerase inhibitors such as ALS-8112; and antibodies for treating metapneumovirus infection such as EV-046113.

[0337] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccine.

[0338] 3. Combination therapies for the treatment of respiratory infections

[0339] The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Picornaviridae virus infection, preferably the other active therapeutic agent has activity against Picornaviridae virus infection, in particular enterovirus infection. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase proteins such as DAS-181; capsid protein VP1 inhibitors such as VVX-003 and AZN-001; viral protease inhibitors such as CW-33; phosphatidylinositol 4 kinase beta inhibitors such as GSK-480 and GSK-533; anti-EV71 antibodies.

[0340] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing Picornaviridae virus infection, including but not limited to EV71 vaccine, TAK-021, and EV-D68 adenoviral vector-based vaccine.

[0341] Glucocorticoids

[0342] Many infections of Pneumoviridae and Picornaviridae viruses are respiratory tract infections. Thus, additional active therapeutic agents for treating respiratory symptoms and sequelae of infection can be used in combination with the compounds provided herein. The additional therapeutic agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents for treating viral respiratory infections in combination with the compounds provided herein include, but are not limited to, bronchodilators and corticosteroids.

[0343] Anti-inflammatory agents

[0344] Glucocorticoids, first introduced as a therapy for asthma in 1950 (Carryer, Journal of Allergy, vol. 21, pp. 282-287, 1950), remain the most effective and consistently effective therapy for this disease, but their mechanism of action is not fully understood (Morris, J. Allergy Clin. Immunol., vol. 75 (1 Pt) pp. 1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with serious adverse side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001). A solution to the systemic side effects is to deliver the steroid drug directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to reduce the serious side effects of oral steroids. Non-limiting examples of corticosteroids that can be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, flurandrenolide, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, flurandrenolide-21 -butylacetate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide; or a pharmaceutically acceptable salt thereof.

[0345] Beta2-adrenergic receptor agonist bronchodilators

[0346] Other anti-inflammatory agents that act through anti-inflammatory cascades can also be used as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. The use of "anti-inflammatory signal transduction modulators" (referred to herein as AISTMs) such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., block NFκB through IKK inhibition), or kinase inhibitors (e.g., block P38 MAP, JNK, PI3K, EGFR, or Syk) is a logical approach to cut off inflammation because these small molecules target a limited number of common intracellular pathways (these signal transduction pathways are the key points for anti-inflammatory therapeutic intervention) (see review by P.J. Barnes, 2006). These non-limiting additional therapeutic agents include: 5-(2,4-difluoro-phenoxy)-l-isobutyl-lH-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-l-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[l-(4-fluorobenzyl)-5-hydroxy-lH-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-l-oxo-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-lH-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-l-(3-phenylpropyl)-5-pyridin-4-yl-lH-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast, PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (Gefitinib, EGFR inhibitor); and 4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (Imatinib, EGFR inhibitor).

[0347] Anticholinergic agents

[0348] Combinations comprising inhaled beta2-adrenergic receptor agonist bronchodilators such as formoterol, salbutamol or salmeterol in combination with the compounds provided herein are also suitable, but not limiting, combinations useful for treating respiratory viral infections.

[0349] Combinations of inhaled beta2-adrenergic receptor agonist bronchodilators such as formoterol or salmeterol in combination with ICS are also used to treat bronchoconstriction and inflammation (respectively and ). Combinations comprising these ICS and beta2-adrenergic receptor agonist combinations in combination with the compounds provided herein are also suitable, but not limiting, combinations useful for treating respiratory viral infections.

[0350] Other examples of beta2 adrenergic receptor agonists are bevonol, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arformoterol, levalbuterol, fenoterol and TD-5471.

[0351] Mucolytic agents

[0352] Anticholinergic agents have potential use for the treatment or prevention of bronchoconstriction in the lungs and thus can be used in combination with the compounds provided herein as an additional therapeutic agent for the treatment of viral respiratory infections.These anticholinergic agents include, but are not limited to, antagonists of muscarinic receptors (particularly the M3 subtype) that have proven therapeutic efficacy in humans for the control of cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)-propionyl]-pyrrolidine-2-carbonyl}- pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino- acetyloxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonio-bicyclo[3.2.1]octane (isopropylamine-N,N-diethylglycine); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solfenazin); 2-hydroxymethyl-4-methane-sulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (revatropate); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (darifenacin); 4-azepan-1-yl-2,2-diphenyl-butyramide (buzepide); 7-[3-(2-diethylamino-acetyloxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonio- tricyclo[3.3.1.02,4]nonane (oxitropium-N,N-diethylglycine); 7-[2-(2-diethylamino-acetyloxy)-2,2-di-thiophen-2-yl-acetyloxy]-9,9-dimethyl-3-oxa-9-azonio- tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycine); dimethylamino-acetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycine); 3-[4,4-bis-(4-fluorophenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl- ethyl)-pyrrolidinium; 1-[1-(3-fluorobenzyl)-piperidin-4-yl]-4,4-bis-(4-fluorophenyl)- imidazolidin-2-one; 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1- ol; 3-[2-(2-diethylamino-acetyloxy)-2,2-dithiophen-2-yl-acetyloxy]-1-(3-phenoxy-propyl)-1-azonio-bicyclo[2.2.2]octane (atropine-N,N-diethylglycine); or (2-diethylamino-acetyloxy)-dithiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; rafenamin, glycopyrronium, umclidinium, tiotropium, aclidinium, benzquinonium.

[0353] 4. Combination therapies for the treatment of flaviviridae viral infections

[0354] The compounds provided herein can also be combined with mucolytic agents to treat infections and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds can be combined with expectorants to treat infections and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0355] Aerosolized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung disease (Kuzik, Pediatrics 2007, 266). Accordingly, the compounds provided herein can also be combined with aerosolized hypertonic saline, particularly when the viral infection is complicated by bronchiolitis. The combination of the compounds provided herein with hypertonic saline can also include any of the additional agents discussed above. In some embodiments, about 3% hypertonic saline is used.

[0356] 5. Combination therapies for the treatment of filoviridae viral infections

[0357] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Flaviviridae viral infections, preferably the other active therapeutic agent has activity against Flaviviridae viral infections.

[0358] For the treatment of dengue viral infections, non-limiting examples of other active therapeutic agents are host cytokine modulators such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors such as celgosivir; platelet-activating factor receptor (PAFR) antagonists such as modipafant; cadherin-5 / factor la 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.

[0359] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of dengue, including but not limited to TetraVax-DV, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2delta30-7169, and DENV-1 PIV.

[0360] IX. COMPOUND PREPARATION

[0361] The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Filoviridae virus infections, preferably the other active therapeutic agents have activity against Filoviridae virus infections, in particular Marburg virus, Ebola virus, and Quelea virus infections. Non-limiting examples of these other active therapeutic agents are: ribavirin, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5- (hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9- dimethylquinolo[8,7-h]quinolin-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as Galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cytokine modulators such as GMV-006; Cadherin-5 / Factor la modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0362] Non-limiting active therapeutic agents with activity against Ebola include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cytokine modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick Cl 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).

[0363] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing Ebola, including but not limited to VRC-EBOADC076-00-VP, an adenovirus-based Ebola vaccine, 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-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0364] The compounds provided herein can 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 duplexes with specific RNA sequences. Examples of PMOs include, but are not limited to, AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0365] The compounds provided herein are also intended for use with the general care provided to patients infected with an Orthomyxoviridae virus, including parenteral fluids (including dextrose saline and Ringer’s lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common ailments in the patient population, such as anti-malarial agents (including artemether and artemether-lumefantrine combination therapy), typhoid fever vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or Shigella disease vaccines.

[0366] X. EXAMPLES

[0367] In some embodiments, the present disclosure provides processes and intermediates useful for making the compounds provided herein, or pharmaceutically acceptable salts thereof.

[0368] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase as well as ion resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0369] During any of the processes for preparation of the compounds provided herein, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 4th edition, Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known from the art.

[0370] Exemplary chemical entities of the methods useful in embodiments will now be described by reference to the general preparations herein and the illustrative synthetic schemes of the specific examples below. The skilled person will recognize that, in order to obtain the various compounds herein, the starting materials can be appropriately chosen such that the reaction scheme, with or without protection as appropriate, will carry the ultimately desired substituents to yield the desired product. Alternatively, it can be necessary or desirable to employ suitable groups in place of the ultimate desired substituents, which suitable groups can be carried through the reaction scheme and replaced with the desired substituents as appropriate. Furthermore, the skilled person will recognize that the transformations shown in the schemes below can be carried out in any order that is compatible with the functionality of the particular side groups.

[0371] The methods of the present disclosure generally provide a particular enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer is not determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that particular stereocenter, even though the compound can be substantially enantiomerically or diastereomerically pure.

[0372] Representative syntheses of the compounds of the present disclosure are described in the following schemes, as well as in the specific examples that follow.

[0373] Intermediate 1-2: (R)-2-(benzyloxy)-3-(octadecyloxy)propyl bis(4-nitrophenyl) phosphate

[0374] Intermediate 1-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)-3- (octadecyloxy)propyl)(4-nitrophenyl) phosphate

[0375] 4-Nitrophenyl dichlorophosphate (1.41 g, 5.52 mmol) was dissolved in DCM (36 mL). The resulting solution was cooled in an ice bath, and a separate solution of 1-O-octadecyl-2-O-benzyl-sn-glycerol (intermediate 1-1, 2 g, 4.6 mmol) in DCM (10 mL) was added. Triethylamine (1.12 g, 11 mmol) was then added dropwise. The ice bath was then removed. After 1 hour and 45 minutes, additional triethylamine (0.239 g, 2.35 mmol) was added, followed by 4-nitrophenol. The reaction progress was monitored by LC / MS and TLC. The reactants were diluted with Et2O, and the resulting solids were removed by filtration. The filtrate was concentrated, and intermediates 1-2 were separated by silica gel column chromatography (25 g loading cartridge, 120 g Combiflash HP Gold column, eluent gradient of 100% hexane to 30% EtOAc / hexane).

[0376] 1 ¹H NMR (400MHz, chloroform-d) δ 8.21–8.08 (m, 4H), 7.38–7.21 (m, 9H), 4.66–4.55 (m, 2H), 4.52 (ddd, J = 10.5, 7.1, 3.2Hz, 1H), 4.38 (ddd, J = 10.8, 8.5, 5.5Hz, 1H), 3.83–3.76 (m, 1H), 3.57–3.46 (m, 2H), 3.39 (t, J = 6.6Hz, 2H), 1.57–1.46 (m, 2H), 1.33–1.17 (m, 30H), 0.90–0.80 (m, 3H).

[0377] 31 P NMR (162MHz, chloroform-d) δ -19.447.

[0378] Intermediate 1-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)-3- (octadecyloxy)propyl) hydrogen phosphate Intermediate 1-6: (R)-2-(benzyloxy)-3-(octadecyloxy)propyl (2-chlorophenyl) triethylammonium phosphate Intermediate 1-7: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)-3- (octadecyloxy)propyl)(2-chlorophenyl) phosphate

[0379]

[0380] Intermediate 1-2 (0.503 g, 0.664 mmol) and Intermediate 1-3 (J. Med. Chem., 2017, Vol. 60, No. 5, p. 1648; 0.2 g, 0.604 mmol) were dissolved in THF. MgCl2(0.287 g, 3.02 mmol) was added in one portion at room temperature. The reaction was placed in a 50 °C bath and stirred for 10 minutes. To the resulting mixture was added DIPEA in a dropwise fashion. The reaction progress was monitored by LC / MS. The reaction was cooled to room temperature and concentrated. The resulting residue was taken up in DCM using sonication and Intermediate 1-4 was isolated by silica gel column chromatography (12 g loading cartridge, 40 g Combiflash HP Gold column, eluent gradient 100% hexanes to 100% EtOAc).

[0381] 1 H NMR (400 MHz, Chloroform-d) δ 7.93 – 7.86 (m, 1H), 7.84 – 7.77 (m, 2H), 7.30 – 7.18 (m, 5H), 7.18 – 7.08 (m, 2H), 6.89 (t, J = 4.8 Hz, 1H), 6.53 (dd, J = 6.7, 4.6 Hz, 1H), 6.01 (br s, 2H), 5.40 (dd, J = 13.8, 6.9 Hz, 1H), 4.87 (ddd, J = 10.9, 6.9, 4.3 Hz, 1H), 4.64 – 4.48 (m, 3H), 4.43 (ddd, J = 10.8, 6.8, 4.0 Hz, 1H), 4.39 – 2.27 (m, 2H), 4.25 – 4.14 (m, 1H), 3.78 – 3.68 (m, 1H), 3.53 – 3.40 (m, 2H), 3.36 (td, J = 6.7, 2.2 Hz, 2H), 1.70 (s, 3H), 1.55 – 1.42 (m, 2H), 1.33 (d, J = 3.8 Hz, 3H), 1.30 – 1.14 (m, 30H), 0.83 (t, J = 6.7 Hz, 3H).

[0382] 31 P NMR (162 MHz, Chloroform-d) δ -7.275 (s), -7.608 (s).

[0383] MS m / z = 949.10 [M+1]

[0384] Intermediate 1-5— ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)- 3-(octadecyloxy)propyl) hydrogen phosphate Example 1: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-3-(octadecyloxy)propyl) hydrogen phosphate (1) ​

[0385]

[0386] Intermediate 1-4 (0.169 g, 0.178 mmol) was dissolved in THF (4 mL). To this solution was added IN NaOH aqueous solution (0.0249 g, 0.623 mmol) dropwise. After the NaOH solution was completely added, the reaction was placed in a 50 °C bath. The reaction progress was monitored by LC / MS. After the consumption of intermediate 1-4, the reaction was cooled in an ice bath. 2N HC1 aqueous solution was added until the reaction pH reached about 4. The reaction was concentrated and the resulting residue was taken up in DCM with sonication. Intermediate 1-5 was isolated by silica gel column chromatography (12 g loading cartridge, 24 g Combiflash HP Gold column, eluent gradient 100% DCM to 20% MeOH / DCM).

[0387] 1 H NMR (400 MHz, MeOH-d3) δ 7.86 (s, 1H), 7.35 - 7.15 (m, 5H), 6.93 - 6.85 (m, 2H), 5.32 (d, J = 6.6 Hz, 1H), 5.00 (dd, J = 6.6, 3.1 Hz, 1H), 4.64 - 4.51 (m, 3H), 4.03 (t, J = 5.4 Hz, 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, 1.6 Hz, 2H), 1.69 (s, 3H), 1.51 (pent, J = 6.7 Hz, 2H), 1.39 (s, 3H), 1.36 - 1.21 (m, 30H), 0.92 - 0.86 (m, 3H).

[0388] 31 P NMR (162 MHz, MeOH-d3) δ 2.852 - -0.151 (br s).

[0389] MS m / z = 828.69 [M+1], 1656.24 [2M+1]

[0390] ​

[0391]

[0392] At 0 °C, 1,2,4-triazole (1.33 g, 19.3 mmol) and triethylamine (2.69 mL, 19.3 mmol) were sequentially added to a stirred solution of 2-chlorophenyl dichlorophosphate (1.45 mL, 8.97 mmol) in acetonitrile (30 mL), and the resulting mixture was heated to room temperature. After 40 minutes, a solution of intermediate 1-1 (3.90 g, 8.97 mmol) in pyridine (40 mL) was slowly added via a tube. After 5 hours, triethylamine (5.0 mL) and water (1.5 mL) were added sequentially. After 25 minutes, a saturated aqueous solution of sodium bicarbonate was added. After 10 minutes, a saturated aqueous solution of sodium bicarbonate was added, and the aqueous layer was extracted with dichloromethane (4 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 1-6.

[0393] LCMS:623.3[M-C6H 16 N] - .

[0394] ​ ​ ​

[0395]

[0396] At room temperature, 1-(trimethylbenzenesulfonyl)-3-nitro-1H-1,2,4-triazole (4.02 g, 13.6 mmol), intermediate 1-3 (3.00 g, 9.05 mmol), and 1-methylimidazole (1.08 mL, 13.6 mmol) were sequentially added to a pyridine-stirred solution of intermediate 1-6 (5.92 g, 8.15 mmol). After 4 hours, the resulting mixture was cooled to 0 °C, and saturated aqueous sodium bicarbonate solution and brine were added sequentially. The aqueous layer was extracted with dichloromethane (2 × 400 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 100% ethyl acetate in hexane) to give intermediate 1-7.

[0397] LCMS: 938.5.

[0398] ​ ​ ​

[0399]

[0400] Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 12.8 mL, 13 mmol) was added via syringe to a stirred mixture of intermediate 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 h, the resulting mixture was cooled to 0 °C. Saturated aqueous sodium bicarbonate 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 aqueous hydrogen chloride (2.0 M) was added until the pH of the aqueous layer was 3. The aqueous layer was extracted with dichloromethane (4 times). The combined organic layers were washed with a mixture of brine and saturated aqueous sodium bicarbonate solution (pH = 8, 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 20% methanol in dichloromethane) to give intermediate 1-5. LCMS: 828.5.

[0401] ​ ​

[0402]

[0403] 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 reaction was stirred vigorously. The reaction progress was monitored by LC / MS. After consumption of intermediate 1-5, the reaction was concentrated. The residue was taken up in a mixture of MeOH, DCM and concentrated. The resulting residue was taken up in DCM and compound 1 was isolated by silica gel column chromatography (12 g loading cartridge, 24 g Combiflash HP Gold column, eluent gradient 100% DCM to 20% MeOH / DCM).

[0404] 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,2H),4.37–4.31(m,1H),4.22(t,J=5.5H z,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)]

[0405] Intermediate 2-1 : (R)-(2-([1,1 '-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propoxy)(tert- butyl)dimethylsilane Intermediate 2-2: (S)-2-([1,1 '-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propan-1 -ol

[0406]

[0407] At 0°C, (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop-2-ol (159 mg, 347 μmol) was administered via cannulation. A solution of tetrahydrofuran (2.0 mL) was added to a mixture of sodium hydride (60 wt% dispersion in mineral oil, 46.6 mg, 1.22 mmol) in tetrahydrofuran (3.0 mL) under vigorous stirring. After 30 minutes, 4-(bromomethyl)-1,1'-biphenyl (300 mg, 1.22 mmol) was added, and the resulting mixture was heated to room temperature. After 21 hours, saturated aqueous ammonium chloride 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 silica gel rapid column chromatography (0 to 5% ethyl acetate in hexane) to give intermediate 2-1.

[0408] 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).

[0409] Intermediate 2-3: (R)-2-([1,1 '-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propyl bis(4- nitrophenyl) phosphate

[0410]

[0411] Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 756 μL, 760 μmol) was added via syringe to a stirred solution of Intermediate 2-1 (200 mg, 320 μmol) in tetrahydrofuran (3.0 mL) at room temperature. After 85 min, saturated aqueous ammonium chloride solution (1.0 mL) and diethyl ether (30 mL) were added sequentially. The organic layer was washed with water (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 30% ethyl acetate in hexanes) to give Intermediate 2-2.

[0412] LCMS: 533.4 [M+Na] + .

[0413] 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]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)(4-nitrophenyl) phosphate 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]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methyl) hydrogen phosphate

[0414]

[0415] Triethylamine (10.8 μL, 77.8 μmol) was added via syringe to a stirred mixture of Intermediate 2-2 (33.1 mg, 64.8 μmol), 4-nitrophenyl phosphorodichloridate (19.9 mg, 77.8 μmol) and dichloromethane (3.0 mL) at 0 °C. After 60 min, the resulting mixture was allowed to warm to room temperature. After 30 min, 4-nitrophenyl phosphorodichloridate (20.0 mg, 78.1 μmol) and triethylamine (20.0 μL, 143 μmol) were added sequentially. After 60 min, 4-nitrophenyl phosphorodichloridate (60.0 mg, 234 μmol) and triethylamine (50.0 μL, 359 μmol) were added sequentially. After 70 min, 4-nitrophenol (150 mg, 1.08 mmol) and triethylamine (200 μL, 1.43 mmol) were added sequentially. After 50 min, diethyl ether (60 mL) and aqueous citric acid (10 wt%) (10 mL) were added sequentially. The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 30% ethyl acetate in hexanes) to give Intermediate 2-3.

[0416] LCMS: 855.4 [M+Na] + .

[0417] Intermediate 3-1 : (S)-2-(Cyclohexylmethoxy)-3-(octadecyloxy)propan-1 -ol Example 3: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1 -f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(cyclohexylmethoxy)-3- (octadecyloxy)propyl) hydrogen phosphate Intermediate 4-1 : (S)-2-(Cyclohexylmethoxy)-3-(octadecyloxy)propan-1 -ol

[0418]

[0419] A vigorously stirred mixture of Intermediate 2-3 (190 mg, 228 μmol), Intermediate 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 min, N,N-diisopropylethylamine (397 μL, 2.28 mmol) was added via syringe over 1 min. After 60 min, the resulting mixture was cooled to room temperature and a mixture of citric acid (726 mg), aqueous sodium hydroxide (2.0 M, 4 mL) and water (10 mL) was added. Ethyl acetate (60 mL) was added and the organic layer was washed with a mixture of water and brine (2:1 v:v, 30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 4.5% methanol in dichloromethane) to give Intermediate 2-4.

[0420] LCMS: 1025.5.

[0421] Example 4: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1 -f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(naphthalen-2-ylmethoxy)-3- (octadecyloxy)propyl) hydrogen phosphate (4) Intermediate 5-1 : (R)-3-(Hexadecyloxy)-2-hydroxypropyl 4-methylbenzenesulfonate Intermediate 5-2: (R)-2-(Benzyloxy)-3-(hexadecyloxy)propyl 4-methylbenzenesulfonate

[0422]

[0423] At room temperature, an aqueous sodium hydroxide solution (2.0 M, 276 μL, 552 μmol) was added via syringe to a vigorously stirred solution of intermediate 2-4 (162 mg, 158 μmol) in tetrahydrofuran (1.8 mL), and the resulting mixture was heated to 50 °C. After 60 min, an aqueous sodium hydroxide solution (2.0 M, 150 μL, 300 μmol) was added via syringe. After 150 min, the resulting mixture was cooled to room temperature. A mixture of aqueous hydrogen chloride solution (2.0 M, 400 μL), and citric acid (706 mg), aqueous sodium hydroxide solution (2.0 M, 3.67 mL), aqueous hydrogen chloride solution (2.0 M, 1.83 mL), water (5 mL), and brine (10 mL) was added sequentially. The aqueous layer was extracted with dichloromethane (3 x 30 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2.0 mL) and stirred vigorously at room temperature. Concentrated hydrogen chloride (625 μL, 7.5 mmol) was added via syringe. After 165 min, a mixture of citric acid (706 mg), aqueous sodium hydroxide solution (2.0 M, 1.83 mL), water (15 mL), aqueous sodium hydroxide solution (6.0 M, 250 μL), and brine (10 mL) was added. The aqueous layer was extracted sequentially with a mixture of dichloromethane and ethyl acetate (2:5 v:v, 70 mL), ethyl acetate (2 x 50 mL), and tetrahydrofuran (2 x 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 give compound 2.

[0424] 1 H NMR (400 MHz, DMSO-d6-methanol-d4) δ 7.92 (s, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.48 - 7.28 (m, 5H), 6.91 (d, J = 4.5 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 4.68 - 4.52 (m, 3H), 4.39 - 3.25 (m, 11H), 1.54 - 0.99 (m, 32H), 0.85 (t, J = 6.6 Hz, 3H). LCMS: 864.0.

[0425] Intermediate 5-3: (S)-2-(Benzyloxy)-3-(hexadecyloxy)propan-1 -ol

[0426]

[0427] A vigorously stirred mixture of (S)-3-(octadecyloxy)propane-1,2-diol (250 mg, 726 pmol), cyclohexanecarboxaldehyde (92.3 pL, 762 pmol), 4-methylbenzenesulfonic acid monohydrate (13.8 mg, 72.6 pmol), anhydrous magnesium sulfate (162 mg, 1.34 mmol), and dichloromethane (3.0 mL) was heated to 60 °C. After 80 min, the resulting mixture was cooled to room temperature and potassium carbonate (101 mg, 726 pmol) was added. After 10 min, the resulting mixture was filtered through celite and the filter cake was extracted with dichloromethane (8 mL). The combined filtrates were stirred and cooled to -40 °C. Diisobutylaluminum hydride solution (1.0 M in toluene, 5.80 mL, 5.8 mmol) was added via syringe and the resulting mixture was warmed to -10 °C over 145 min. The resulting mixture was warmed to room temperature. After 22 h, methanol (2.0 mL) was added slowly via syringe. Water (50 mL) and aqueous hydrogen chloride (2.0 M, 20 mL) were added sequentially and the aqueous layer was extracted with dichloromethane (2 x 60 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 10% ethyl acetate in hexanes) to give Intermediate 3-1.

[0428] Intermediate 5-4: (R)-2-(Benzyloxy)-3-(hexadecyloxy)propyl bis(4-nitrophenyl) phosphate Intermediate 5-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1 -f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)((R)-2-(benzyloxy)-3- (hexadecyloxy)propyl)(4-nitrophenyl) phosphate ​

[0429]

[0430] Compound 3 was synthesized in a similar manner to Compound 2 using (S)-2- (cyclohexylmethoxy)-3-(octadecyloxy)propan-1-ol in place of (S)-2-([1,1’-biphenyl]-4- ylmethoxy)-3-(octadecyloxy)propan-1-ol.

[0431] 1 H NMR (400 MHz, DMSO-d6 - Methanol-d4) d 7.94 (s, 1H), 6.93 (d, J = 4.5 Hz, 1H), 6.84 (d, J = 4.5 Hz, 1H), 4.65 (d, J = 4.9 Hz, 1H), 4.31 - 3.06 (m, 13H), 1.72 - 1.00 (m, 43H), 0.86 (t, J = 6.7 Hz, 3H). 31 P NMR (162 MHz, DMSO-d6) d -1.13 (s, 1P). LCMS: 794.1.

[0432] ​

[0433]

[0434] Intermediate 4-1 was synthesized in a similar manner to Intermediate 2-4 using 2- (bromomethyl)naphthalene instead of 4-(bromomethyl)-1,1'-biphenyl.

[0435] ​ ​ ​

[0436]

[0437] Sodium hydroxide aqueous solution (2.0 M, 800 μL, 1.6 mmol) was added via syringe to a vigorously stirred solution of Intermediate 4-1 (250 mg, 250 μmol) in tetrahydrofuran (1.8 mL) at room temperature and the resulting mixture was heated to 56 °C. After 186 min, the resulting mixture was cooled to room temperature. A mixture of hydrogen chloride aqueous solution (2.0 M, 800 μL) and citric acid (706 mg), sodium hydroxide aqueous solution (2.0 M, 1.83 mL), water (5 mL), and brine (10 mL) was added sequentially. The aqueous layer was extracted with 2-methyltetrahydrofuran (2 x 30 mL) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1.2 mL) and stirred vigorously at room temperature. Concentrated hydrogen chloride (250 μL, 3.0 mmol) was added via syringe. After 165 min, triethylamine (600 μL) was added via syringe and the resulting mixture was purified by reverse-phase preparative HPLC (2-propanol / water) to give Compound 4 as a triethylammonium salt. 1 H NMR (400 MHz, Methanol-d4) δ 7.86 (s, 1H), 7.84 - 7.75 (m, 4H), 7.52 - 7.40 (m, 3H), 7.00 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.6 Hz, 1H), 4.86 - 4.71 (m, 3H), 4.35 (t, J = 4.5 Hz, 1H), 4.25 (t, J = 5.4 Hz, 1H), 4.23 - 4.11 (m, 1H), 4.07 (dt, J = 11.4, 4.6 Hz, 1H), 3.92 (hept, J = 5.4 Hz, 2H), 3.83 - 3.75 (m, 1H), 3.52 (qd, J = 10.7, 5.1 Hz, 2H), 3.40 (t, J = 6.5 Hz, 2H), 3.22 (q, J = 7.3 Hz, 6H), 1.60 - 1.18 (m, 41H), 0.97 - 0.86 (m, 3H). LCMS: 838.1.

[0438] ​

[0439]

[0440] (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 with hexanes to afford Intermediate 5-1.

[0441] 1 H NMR (400 MHz, Chloroform-d) δ 7.83 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 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 = 6.6 Hz, 3H).

[0442] MS m / z = 471.0

[0443] ​

[0444]

[0445] Intermediate 5-1 (216 mg, 0.459 mmol) was dissolved in dioxane (4 mL) and treated with benzyl 2,2,2-trichloroacetimidate (0.175 mL, 0.942 mmol) followed by a few drops of trifluoromethanesulfonic acid. The reaction mixture was stirred for 90 minutes at which point additional benzyl 2,2,2-trichloroacetimidate (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-trichloroacetimidate (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 aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered, and evaporated under reduced pressure. Intermediate 5-2 was isolated from the resulting residue by silica gel column chromatography (elution gradient 0-20% EtOAc:hexanes).

[0446] 1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 8.3 Hz, 2H), 7.45 - 7.24 (m, 7H), 4.22 (dd, J = 10.4, 4.1 Hz, 1H), 4.11 (dd, J = 10.4, 5.8 Hz, 1H), 3.78 (qd, J = 5.5, 4.1 Hz, 1H), 3.48 (dd, J = 5.3, 4.1 Hz, 2H), 3.38 (t, J = 6.7 Hz, 2H), 2.46 (s, 3H), 1.51 (t, J = 6.7 Hz, 2H), 1.29 (s, 28H), 0.91 (t, J = 6.7 Hz, 3H).

[0447] ​

[0448]

[0449] Intermediate 5-2 (257 mg, 0.458 mmol) was dissolved in DMSO (10 mL) and treated with sodium nitrite (976 mg, 14.1 mmol) and heated to 40 °C for 18 h at which point the reaction mixture was diluted with water, extracted into dichloromethane, dried over sodium sulfate, filtered and evaporated under reduced pressure. Intermediate 5-3 was isolated from the resulting residue by column chromatography on silica gel (elution gradient 0-25% EtOAc:hexanes).

[0450] 1 H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 8.3 Hz, 2H), 7.45 - 7.24 (m, 7H), 4.22 (dd, J = 10.4, 4.1 Hz, 1H), 4.11 (dd, J = 10.4, 5.8 Hz, 1H), 3.78 (qd, J = 5.5, 4.1 Hz, 1H), 3.48 (dd, J = 5.3, 4.1 Hz, 2H), 3.38 (t, J = 6.7 Hz, 2H), 2.46 (s, 3H), 1.51 (t, J = 6.7 Hz, 2H), 1.29 (s, 28H), 0.91 (t, J = 6.7 Hz, 3H).

[0451] MS m / z = 406.9

[0452] ​

[0453]

[0454] 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-nitrophenyldichlorophosphine (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-nitrophenyldichlorophosphine (100 mg, 0.391 mmol) were added and stirring was continued for 1 hour. Triethylamine (0.100 mL, 0.717 mmol) and 4-nitrophenol (160 mg, 1.15 mmol) were added sequentially and stirring was continued for 20 minutes at which point the reaction mixture was diluted with diethyl ether and filtered to remove solids and the filtrate was evaporated under reduced pressure. Intermediate 5-4 was isolated from the resulting residue by silica gel column chromatography (elution gradient 0-20% EtOAc:hexanes).

[0455] 1 H NMR (400 MHz, Chloroform-d) δ 8.26 - 8.10 (m, 4H), 7.45 - 7.21 (m, 9H), 4.68 (d, J = 11.5 Hz, 1H), 4.64 - 4.53 (m, 2H), 4.45 (ddd, J = 10.8, 8.4, 5.5 Hz, 1H), 3.86 (ddt, J = 5.0, 3.3, 1.7 Hz, 1H), 3.60 (dd, J = 10.1, 4.9 Hz, 1H), 3.54 (dd, J = 10.1, 6.5 Hz, 1H), 3.44 (t, J = 6.7 Hz, 2H), 1.56 (t, J = 7.0 Hz, 2H), 1.27 (d, J = 2.9 Hz, 28H), 0.90 (t, J = 6.8 Hz, 3H).

[0456] 31 P NMR (162 MHz, Chloroform-d) δ 13.36 (t, J = 7.9 Hz).

[0457] ​ ​ ​

[0458]

[0459] 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 an additional 2 hours. The solvent was removed under reduced pressure and Intermediate 5-5 was isolated from the resulting residue by silica gel column chromatography (elution gradient 0-5% MeOH:DCM).

[0460] 1 H NMR (400 MHz, Chloroform-d) δ 8.00 - 7.81 (m, 3H), 7.37 - 7.26 (m, 5H), 7.19 (dd, J = 15.2, 9.0 Hz, 2H), 6.99 (dd, J = 7.6, 4.6 Hz, 1H), 6.60 (t, J = 4.9 Hz, 1H), 5.77 (s, 2H), 5.46 (dd, J = 15.5, 6.9 Hz, 1H), 4.94 (ddd, J = 11.3, 6.9, 4.3 Hz, 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 = 6.7 Hz, 2H), 1.77 (s, 3H), 1.55 (t, J = 6.9 Hz, 2H), 1.40 (d, J = 3.8 Hz, 3H), 1.27 (s, 28H), 0.90 (t, J = 6.7 Hz, 3H).

[0461] 31 P 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

[0462] Example 5: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano -3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-3-(hexadecyloxy)propyl) hydrogen phosphate (5)

[0463]

[0464] Intermediate 5-5 (13.0 mg, 0.0141 mmol) was dissolved in THF (1 mL THF), treated with 2 M aqueous NaOH (0.075 mL, 0.15 mmol), and heated to 50 °C. The reaction solution was stirred for 2 h at which point the reaction flask was placed in an ice bath and acidified with concentrated aqueous HC1. The reaction solution was warmed to room temperature and stirred for 18 h at which point triethylamine was added dropwise until the solution remained yellow, at which point the solvent was removed under reduced pressure. The resulting residue was taken up in 4: 1 MeOH:dioxane, and compound 5 was isolated as the triethylammonium salt by preparative HPLC (eluent gradient 60-100% water:i-PrOH).

[0465] 1 H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.35 - 7.19 (m, 5H), 6.90 (d, J = 4.5 Hz, 1H), 6.85 (d, J = 4.6 Hz, 1H), 4.65 - 4.51 (m, 3H), 3.95 (dd, J = 6.4, 4.9 Hz, 1H), 3.75 (s, 2H), 3.64 (dd, J = 5.8, 4.1 Hz, 1H), 3.49 - 3.26 (m, 6H), 3.17 - 3.04 (m, 7H), 1.45 (t, J = 6.8 Hz, 2H), 1.31 - 1.14 (m, 34H), 0.89 - 0.81 (m, 3H). MS m / z = 760.2

[0466] Example 6: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano -3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-3-(heptadecyloxy)propyl) hydrogen phosphate

[0467]

[0468] Compound 6 was synthesized as the triethylammonium salt in a similar manner to compound 5 using 1-heptadecanol instead of 1-hexadecanol.

[0469] 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.35 - 7.18 (m, 5H), 6.90 (d, J = 4.6 Hz, 1H), 6.84 (d, J = 4.4 Hz, 1H), 4.57 (d, J = 7.5 Hz, 1H), 4.18 - 3.12 (m, 13H), 3.09 (q, J = 7.3 Hz, 6H), 1.45 (p, J = 6.9 Hz, 2H), 1.32 - 1.13 (m, 37H), 0.85 (t, J = 6.6 Hz, 3H).

[0470] MS m / z = 774.0.

[0471] Example 7: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-3-(nonadecyloxy)propyl) hydrogen phosphate (7)

[0472]

[0473] Compound 7 was synthesized as a triethylammonium salt in a similar manner to compound 5 using 1-nonadecanol instead of 1-hexadecanol.

[0474] 1 H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.36 - 7.20 (m, 5H), 6.90 (d, J = 4.5 Hz, 1H), 6.84 (d, J = 4.5 Hz, 1H), 4.64 - 4.50 (m, 3H), 3.94 (dd, J = 6.5, 4.9 Hz, 1H), 3.83 (q, J = 5.9 Hz, 1H), 3.72 (t, J = 5.7 Hz, 2H), 3.67 - 3.59 (m, 1H), 3.49 - 3.28 (m, 8H), 3.16 - 3.02 (m, 5H), 1.44 (q, J = 6.7 Hz, 2H), 1.23 (d, J = 5.8 Hz, 32H), 1.17 (t, J = 7.3 Hz, 9H), 0.89 - 0.81 (m, 3H).

[0475] MS m / z = 802.2

[0476] Example 8: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano -3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-3-(eicosyloxy)propyl) hydrogen phosphate

[0477]

[0478] Compound 8 was synthesized as a triethylammonium salt in a similar manner to compound 5 using 1-eicosanol instead of 1-hexadecanol.

[0479] 1 H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.35 - 7.18 (m, 5H), 6.90 (d, J = 4.5 Hz, 1H), 6.85 (d, J = 4.5 Hz, 1H), 4.64 - 4.51 (m, 3H), 4.15 (t, J = 5.2 Hz, 1H), 3.94 (dd, J = 6.5, 4.9 Hz, 1H), 3.85 (d, J = 5.7 Hz, 1H), 3.74 (d, J = 6.1 Hz, 2H), 3.66 - 3.27 (m, 7H), 3.13 (td, J = 3.2, 1.6 Hz, 2H), 3.08 (t, J = 7.3 Hz, 3H), 1.31 - 1.14 (m, 45H), 0.89 - 0.81 (m, 3H).

[0480] MS m / z = 816.2

[0481] Intermediate 9-1: (S)-3-(octadecyloxy)propane-1,2-diol [1-O-octadecyl-sn-glycerol]

[0482]

[0483] A mixture of (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (6.68 g, 50.6 mmol), powdered potassium hydroxide (10 g, 178 mmol) and 1 -bromooctadecane (16.9 g, 50.6 mmol) in benzene (100 mL) was stirred at reflux for 15 hours, while removing the water formed by azeotropic distillation. The reaction mixture was then cooled to room temperature, filtered and the volume of solvent was then reduced to half. Water (100 mL) was added and then the mixture was extracted with diethyl ether (3 x 100 mL), the combined organic phases were combined, dried over Na2S04, filtered and the solvent was then removed under reduced pressure to give the intermediate. 1 H NMR (400 MHz, Chloroform-d) δ 4.29 (p, J = 6.0 Hz, 1H), 4.08 (dd, J = 8.3, 6.4 Hz, 1H), 3.75 (dd, J = 8.2, 6.4 Hz, 1H), 3.60 - 3.37 (m, 4H), 1.58 (q, J = 7.1 Hz, 2H), 1.45 (s, 3H), 1.39 (s, 3H), 1.27 (s, 30H), 0.90 (t, J = 6.7 Hz, 3H).

[0484] To a solution of the above crude intermediate (5 g, 13 mmol) in methanol (80 mL) was added a 2M HCI solution (13 mL, 26 mmol) and the solution was heated to reflux for 4 hours. After cooling to room temperature, the mixture was poured into water, the organic layer was extracted with diethyl ether, dried over Na2S04and the solvent was removed under vacuum to give a small volume, the product was precipitated from hexane to give the intermediate 9-1.

[0485] 1 H 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).

[0486] Intermediate 9-2: 1-O-octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol

[0487]

[0488] 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), CH2CI2(5 mL) and DMF (5 mL) was added tert-butyldimethylsilyl chloride (1.44 g, 9.58 mmol) at 0 °C. After stirring at room temperature for 5 h, the reaction mixture was diluted with water (10 mL), then extracted with CH2CI2and dried over Na2S04. The solvent was evaporated and the residue was purified by flash chromatography (0-30% EtOAc in hexanes) to give the product.

[0489] 1 H NMR (400 MHz, Chloroform-d) δ 3.93 - 3.77 (m, 1 H), 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 = 11.7 Hz, 6H).

[0490] Intermediate 9-3: (R)-4-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2- yl)oxy)methyl)benzonitrile

[0491]

[0492] NaH (60% dispersion in oil, 143 mg, 3.74 mmol) was suspended in THF (8 ml) and cooled to 0 °C. A solution of 1-O-octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol (350 mg, 0.763 mmol) in THF (3 ml) was added over 30 seconds. After 30 minutes, a solution of 4-(bromomethyl)benzonitrile (493 mg, 2.52 mmol) in THF (3 ml) was added at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (15 ml). The mixture was extracted with EtOAc. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-30% EtOAc in hexanes) to give the product.

[0493] 1 H NMR (400 MHz, Chloroform-d) δ 7.77 - 7.58 (m, 2H), 7.58 - 7.42 (m, 2H), 4.79 (s, 1 H), 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).

[0494] Intermediate 9-4: (S)-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile

[0495]

[0496] To a solution of silyl-protected compound 9-3 (480 mg, 0.836 mmol) in THF (3.6 mL) at 0 °C was added 1 M TBAF in THF (1 mL, 1 mmol) and stirred for 1 h. It was diluted with water (3 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (2 x 5 mL), brine, dried over Na2S04, evaporated, and the residue was purified by column chromatography (silica gel, 0-60% ethyl acetate in hexanes) to give the product.

[0497] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.54 (q, J = 8.1 Hz, 2H), 4.81 - 4.62 (m, 3H), 3.60 - 3.39 (m, 6H), 1.46 (q, J = 6.7 Hz, 2H), 1.23 (m, 30H), 0.95 - 0.72 (m, 3H).

[0498] Intermediate 9-5: tert-butyl (7-((3aR,4R,6R,6aR)-6-((((2-chlorophenoxy)((R)-2-((4- cyano benzyl)oxy)-3-(octadecyloxy)propoxy)phosphoryl)oxy)methyl)-4-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate Example 9: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano -3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (9)

[0499]

[0500] To 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 added a solution of 2-chlorophenyldichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). The mixture was stirred for 30 min and then filtered. To the filtrate was added additional THF (1.2 mL), the nucleoside (100 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol) sequentially. After 1 h, (S)-4-(((1-hydroxy-3- (octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile (107 mg, 0.232 mmol) was added to the mixture and stirred at room temperature overnight. The solvent was evaporated and the residue was purified by silica gel flash chromatography (0-15% MeOH in CH2Cl2) to give the compound (136 mg, 55%).

[0501] 1H NMR (400 MHz, Chloroform-d) δ 8.35 - 8.10 (m, 1H), 7.65 (d, 2H), 7.58 (m, 1H), 7.49 (d, J = 8.0 Hz, 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 = 6.7 Hz, 3H).

[0502] 31 P NMR (162 MHz, Chloroform-d) δ -6.94 (m).

[0503] Example 10: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano -3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-methoxybenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (10) ​

[0504]

[0505] 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 eq) was added. The mixture was stirred at 50 °C for 4 h. The reaction progress was monitored by TLC. After consumption of the intermediate, the mixture was neutralized with 1 N HC1 at 0 °C. The mixture was diluted with buffer solution (pH 3) and brine and extracted twice with a mixture of DCM and MeOH. The combined organic layers were combined, dried over anhydrous Na2S04, filtered and evaporated to give a residue.

[0506] The residue was dissolved in THF (0.6 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HC1 (0.12 mL) was added. The cold bath was removed and the reaction was stirred vigorously for 3 h. The mixture was neutralized with Na2C03, diluted with MeOH and filtered. The filtrate was evaporated to give a residue which was purified by preparative HPLC (Gemini column, 50% - 100% isopropanol in H20) to give compound 9.

[0507] 1H NMR (400 MHz, Methanol-d4) δ 8.07 - 8.21 (d, 1H), 7.63 (dd, J = 8.2, 1.7 Hz, 2H), 7.53 (dd, J = 10.5, 8.2 Hz, 2H), 7.31 (dd, J = 7.4, 4.8 Hz, 1H), 7.21 (dd, J = 14.6, 4.8 Hz, 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 = 6.8 Hz, 3H).

[0508] 31 P NMR (162 MHz, Methanol-d4) δ 0.16.

[0509] ​ ​ ​

[0510]

[0511] Compound 10 was synthesized in a similar manner to compound 9 using 4- methoxybenzyl bromide instead of 4-cyanobenzyl bromide.

[0512] 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (m, 2H, 1 proton D2O exchangeable), 7.26 - 7.18 (m, 2H), 6.90 (d, J = 4.5 Hz, 1H), 6.85 (m, 3H), 6.34 (d, J = 6.1 Hz, 1H, D2O exchangeable), 4.64 (t, J = 5.3 Hz, 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 = 6.9 Hz, 2H), 1.22 (d, J = 7.9 Hz, 30H), 0.93 - 0.78 (m, 3H).

[0513] 31 P NMR (162 MHz, DMSO-d6) δ -1.09.

[0514] Example 11 : ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-((4- (trifluoromethyl)benzyl)oxy)propyl) hydrogen phosphate (11) Example 11 : ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-((4- (trifluoromethyl)benzyl)oxy)propyl) hydrogen phosphate (11) Example 11 : ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-((4- (trifluoromethyl)benzyl)oxy)propyl) hydrogen phosphate (11)

[0515]

[0516] Compound 11 was synthesized in a similar manner to compound 9 using 4- trifluoromethylbenzyl bromide instead of 4-cyanobenzyl bromide.

[0517] 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (m, 3H, 2 proton D2O exchangeable), 7.66 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 4.5 Hz, 1H), 6.84 (d, J = 4.5 Hz, 1H), 6.35 (d, J = 6.0 Hz, 1H, D2O exchangeable), 4.75 - 4.59 (m, 3H), 4.17 (m, 2H), 3.94 (m, 4H), 3.70 (m, 1H), 3.44 (m, 4H), 1.42 (m, 2H), 1.21 (m, 30H), 0.93 - 0.79 (m, 3H).

[0518] 31 P NMR (162 MHz, DMSO-d6) δ -1.10 (m).

[0519] Intermediate 12-1 : (R)-2-(benzyloxy)-3-(octadecyloxy)propyl (2-chlorophenyl) triethylammonium phosphate

[0520]

[0521] Dissolve 2-chlorophenyl phosphorodichloridate (2.2 g, 8.97 mmol) in acetonitrile (30 mL) and cool to 0 °C. To this solution, add 1,2,4-triazole (1.33 g, 19.3 mmol) followed by slow addition of TEA (2.69 mL, 19.3 mmol). Remove the cold bath and stir at room temperature for 45 min. To the stirring mixture, slowly add a solution of (S)-2-(benzyloxy)-3-(octadecyloxy)propan-1-ol (3.9 g, 8.97 mmol) in pyridine (40 mL) and stir at room temperature for 4 h. To the mixture, add TEA (2.69 mL) followed by water (1.5 mL), stir for 25 min, then add saturated NaHCO3(20 mL) and stir for another 10 min. Dilute with more saturated NaHCO3, then extract with DCM (2 x 100 mL). Dry the combined organic layers over Na2SO4, concentrate, co-evaporate with toluene (50 mL x 2), and dry under high vacuum. Dissolve the crude product in 5% MeOH / DCM, load onto a 220 g gold cartridge, elute with 0-40% MeOH, elute the product with 20% MeOH / DCM in two broad peaks (long tailing peaks), combine the pure fractions (checked by TLC / LCMS), and concentrate to give intermediate 12-1.

[0522] MS m / z = 625.4 [M+1]

[0523] 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.62 (dd, J = 8.4, 1.4 Hz, 1H), 7.39 - 7.22 (m, 6H), 7.15 (td, J = 8.3, 7.8, 1.7 Hz, 1H), 6.94 (td, J = 7.7, 1.5 Hz, 1H), 4.56 (d, J = 2.4 Hz, 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, 4.5 Hz, 5H), 1.43 (q, J = 6.6 Hz, 2H), 1.23 (d, J = 2.6 Hz, 32H), 1.16 (t, J = 7.3 Hz, 9H), 0.90 - 0.81 (m, 3H).

[0524] 31 P NMR (162 MHz, DMSO-d6) δ -5.82.

[0525] Intermediate 12-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)- 3-(octadecyloxy)propyl) (2-chlorophenyl) phosphate Intermediate 12-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)- 3-(octadecyloxy)propyl) (2-chlorophenyl) phosphateIntermediate 12-3: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-3- (octadecyloxy)propyl) (2-chlorophenyl) phosphate.

[0526]

[0527] Intermediate 12-1 (3.0 g, 9.05 mmol) was dissolved in pyridine (80 mL). To this solution was added l-(mesitylene-2-sulfonyl)-3-nitro-l,2,4-triazole (4.02 g, 13.6 mmol) followed by Intermediate 1-3 (3.0 g, 9.05 mmol). To this solution was added NMI (1.12 mL, 13.6 mmol) and the reaction was stirred at room temperature for 4 hours. The reaction was cooled in an ice bath and quenched by slow addition of saturated aqueous NaHC03solution. The aqueous layer was diluted with a 1:1:1 mixture of water, saturated aqueous NaHC03solution, and brine. The aqueous layer was extracted with DCM (2 x 400 mL) and the combined organics were dried over Na2S04, which was removed by filtration. The filtrate was concentrated and Intermediate 12-2 was isolated by silica gel column chromatography (220 g, Combi flash HP Gold column, eluent gradient 0-100% EtOAc / hexanes).

[0528] MS m / z = 938.3 [M+l]

[0529] Compound 12 Compound 13 Intermediate 14-0: (2R)-1-[tert-butyl(dimethyl)silyl]oxy-3-octadecyloxy-propan-2-ol

[0530]

[0531] Intermediate 12-2 (0.5 g, 0.533 mmol) was dissolved in THF (20 mL). To this solution was added concentrated HC1 (3.32 mL, 50.6 mmol) dropwise at 0 °C. The reaction was warmed and stirred at room temperature for 4 hours or more. Upon completion, the reaction was concentrated and the residue was co-evaporated with THF (2 x 30 mL) and DCM (2 x 30 mL). The resulting residue was taken up in DCM and Intermediate 12-3 was isolated by silica gel column chromatography (40 g Combi flash HP Gold column, eluent gradient 0-40% MeOH / DCM).

[0532] MS m / z = 898.4 [M+l]

[0533] Intermediate 12-4: (2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-2- (((((R)-2-(benzyloxy)-3-(octadecyloxy)propoxy)(2-chlorophenoxy)phosphoryl)oxy)methyl)- 5-cyano-4-hydroxytetrahydrofuran-3-yl isobutyrate.

[0534] Intermediate 13-4: (2R, 3R, 4R, 5R)-2-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5- (((((R)-2-(benzyloxy)-3-(octadecyloxy)propoxy)(2-chlorophenoxy)phosphoryl)oxy)methyl)- 2-cyanotetrahydrofuran-3, 4-diyl bis(2-methylpropanoate).

[0535]

[0536] 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 in one portion. The resulting mixture was stirred at room temperature for 1.2 h. The reaction was diluted with DCM and washed with water, followed by saturated ammonium chloride solution, dried over sodium sulfate, concentrated and dried under high vacuum. The obtained crude residue contained intermediate 12-4 and intermediate 13-4, which were confirmed by LCMS and used for the next step.

[0537] Intermediate 12-4: MS m / z = 968.5 [M+1]

[0538] Intermediate 13-4: MS m / z = 1038.7 [M+1]

[0539] Example 12: (2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-2- (((((R)-2-(benzyloxy)-3-(octadecyloxy)propoxy)(hydroxy)phosphoryl)oxy)methyl)-5- cyano-4-hydroxytetrahydrofuran-3-yl isobutyrate (12)

[0540] Example 13: (2R, 3R, 4R, 5R)-2-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5- (((((R)-2-(benzyloxy)-3-(octadecyloxy)propoxy)(hydroxy)phosphoryl)oxy)methyl)-2- cyanotetrahydrofuran-3, 4-diyl bis(2-methylpropanoate) (13)

[0541]

[0542] The crude mixture of intermediate 12-4 and intermediate 13-4 (0.5 g, 0.451 mmol) was dissolved in THF (10.2 mL) and pyridine (1.25 mL) was added followed by water (1.25 mL). To the resulting clear homogeneous solution was added a 1 M solution of TBAF in THF (1.8 mL, 0.43 mmol). The reaction was stirred at room temperature for over 3 hours. After confirming completion of the reaction by LCMS, the reaction was cooled in an ice bath and quenched with saturated aqueous NaHC03solution (5 mL). The reaction was concentrated to remove most of the volatiles and partitioned between DCM and water. To the stirring solution was added 2N HC1 dropwise to adjust the pH to about 3 and extracted with DCM (2 x 100 mL). The combined organic phase was washed once with brine (pH adjusted to 8 with saturated aqueous NaHC03solution) and dried over Na2S04, which was removed by filtration. The filtrate was concentrated and the crude product was dissolved in a mixture of MeOH / dioxane / water (about 6:1:0.1 mL), sonicated to completely dissolve, filtered and purified by preparative HPLC (Gemini, 10 μM, NX-C18, 250 mm x 30 mm column, gradient 60% - 100% in 16 minutes, acetonitrile / water, and 100% acetonitrile for 16 minutes to give compounds 12 and 13. 250 mm x 30 mm column, gradient 60% - 100% in 16 minutes, acetonitrile / water, and 100% acetonitrile for 16 minutes to give compounds 12 and 13.

[0543] Intermediate 14-1 : tert-butyl-[(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy- propoxy]-dimethyl-silane

[0544] MS m / z = 858.5 [M+1]

[0545] 1 H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.28 (s, 5H), 6.94 (d, J = 4.6 Hz, 1H), 6.64 (d, J = 4.7 Hz, 1H), 6.27 (d, J = 5.9 Hz, 1H), 5.61 (s, 2H), 5.53 (dd, J = 5.9, 4.2 Hz, 1H), 4.65 (q, J = 4.1 Hz, 1H), 4.41 (qd, J = 12.3, 4.1 Hz, 2H), 4.28 - 4.03 (m, 1H), 4.02 - 3.84 (m, 1H), 3.87 - 3.59 (m, 2H), 3.58 - 3.22 (m, 1H), 2.80 - 2.48 (m, 3H), 1.48 (d, J = 32.7 Hz, 2H), 1.39 - 1.04 (m, 38H), 0.93 (dt, J = 23.4, 7.1 Hz, 3H).

[0546] Intermediate 14-2: (2S)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy-propan-1-ol

[0547] MS m / z = 928.5 [M+1]

[0548] 1 H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.34 - 7.17 (m, 5H), 6.92 (s, 2H), 6.90 (d, J = 4.8 Hz, 1H), 6.68 (d, J = 4.7 Hz, 1H), 6.23 (d, J = 6.0 Hz, 1H), 5.46 (dd, J = 6.0, 4.2 Hz, 1H), 5.08 (t, J = 2.8 Hz, 1H), 4.72 - 4.49 (m, 2H), 4.30 (qd, J = 10.9, 4.5 Hz, 1H), 4.19 (ddd, J = 11.9, 7.8, 4.2 Hz, 1H), 4.06 (dq, J = 12.9, 6.7 Hz, 1H), 3.75 (td, J = 8.7, 8.1, 3.2 Hz, 2H), 3.65 (dt, J = 11.6, 3.0 Hz, 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 = 6.7 Hz, 3H).

[0549] Intermediate 14-3: [(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy-propyl] bis(4-nitrophenyl) phosphate

[0550]

[0551] A solution of tert-butyldimethylsilyl chloride (350 mg, 2.32 mmol) in dichloromethane (2 mL) was added to a solution of (2S)-3-octadecyloxypropane-1,2-diol (500 mg, 1.45 mmol) and imidazole (198 mg, 2.90 mmol) in dichloromethane (5 mL) at 0 °C over 1 minute. After 2 hours, the ice bath was removed. After 3 hours, the reaction was washed with water (5 mL). The aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-30% ethyl acetate / hexanes). Fractions containing the product were combined and the solvent was removed under reduced pressure to give Intermediate 14-0.

[0552] 1H NMR (400 MHz, Chloroform-d) δ 3.83 (p, J = 5.4 Hz, 1H), 3.74 - 3.62 (m, 2H), 3.50 - 3.42 (m, 4H), 1.58 (q, J = 7.0 Hz, 2H), 1.27 (m, 30H), 0.91 (m, 12H), 0.09 (s, 6H).

[0553] Intermediate 14-4: [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl [(2R)-2- [(3,4-difluorophenyl)methoxy]-3-octadecyloxy-propyl] (4-nitrophenyl) phosphate Intermediate 12-3: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-3- (octadecyloxy)propyl) (2-chlorophenyl) phosphate.

[0554]

[0555] Sodium hydride, 60% 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 (320 mg, 0.697 mmol) in tetrahydrofuran (2 mL) was added over 30 seconds. After 30 minutes, a solution of 4-(bromomethyl)-1,2-difluoro-benzene (178 μL, 1.39 mmol) in tetrahydrofuran (2 mL) was added. The ice bath was removed. After 16 hours, the reaction was judged complete by TLC (15% ethyl acetate / hexanes). The reaction was quenched with water (10 mL) at 0 °C. The mixture was extracted with ethyl acetate (3 x 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 (0-20% ethyl acetate / hexanes using ELSD detection). Fractions containing product were combined and the solvent was removed under reduced pressure to give intermediate 14-1.

[0556] 1 H NMR (400 MHz, Chloroform-d) δ 7.25 (dd, J = 7.4, 4.8 Hz, 1H), 7.18 - 7.03 (m, 2H), 4.67 (s, 2H), 3.71 (d, J = 6.0 Hz, 2H), 3.63 (p, J = 5.3 Hz, 1H), 3.56 (dd, J = 10.3, 4.2 Hz, 1H), 3.50 (dd, J = 10.3, 5.8 Hz, 1H), 3.45 (t, J = 6.8 Hz, 2H), 1.58 (q, J = 7.2 Hz, 2H), 1.27 (s, 30H), 0.91 (d, J = 5.7 Hz, 12H), 0.08 (s, 6H).

[0557] 19 F NMR (376 MHz, Chloroform-d) δ -138.62 - -138.83 (m), -140.54 - -140.77 (m).

[0558] Example 11 : ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-((4- (trifluoromethyl)benzyl)oxy)propyl) hydrogen phosphate (11)

[0559]

[0560] A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.995 mL, 0.995 mmol) was added to a solution of Intermediate 14-1 (194 mg, 0.332 mmol) in tetrahydrofuran (5 mL). After 45 minutes, the reaction was diluted with ethyl acetate (20 mL). The organic phase was washed with water (3 x 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 (0-20% ethyl acetate / hexanes using ELSD). Fractions containing product were combined and the solvent was removed under reduced pressure to give Intermediate 14-2.

[0561] Example 11 : ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-((4- (trifluoromethyl)benzyl)oxy)propyl) hydrogen phosphate (11) Example 11 : ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-((4- (trifluoromethyl)benzyl)oxy)propyl) hydrogen phosphate (11)

[0562]

[0563] A solution of Intermediate 14-2 (143 mg, 0.304 mmol) in dichloromethane (2 mL) was added to a solution of 4-nitrophenyldichlorophosphate (93.5 mg, 0.365 mmol) in dichloromethane (5 mL) at 0 °C. 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 was diluted with ethyl acetate (20 mL) and washed with water (2 x 5 mL) and brine (5 mL). The residue was subjected to flash chromatography (0-50% ethyl acetate / hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure to give Intermediate 14-3.

[0564] 1 H NMR (400 MHz, Chloroform-d) δ 8.30 - 8.19 (m, 4H), 8.13 (d, J = 9.1 Hz, 0.41H), 7.46 - 7.35 (m, 4H), 7.23 - 7.14 (m, 1H), 7.10 (dt, J = 10.1, 8.1 Hz, 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 = 6.6 Hz, 2H), 1.55 (q, J = 6.8 Hz, 2H), 1.26 (m, 30H), 0.89 (t, J = 6.7 Hz, 3H). 19 F NMR (376 MHz, Chloroform-d) δ -137.88 (ddd, J = 21.0, 11.1, 8.0 Hz), -139.15 - -139.37 (m).

[0565] 31P NMR (162 MHz, Chloroform-d) δ -13.10 (t, J = 8.0 Hz).

[0566] ​ ​ ​

[0567] Magnesium chloride (31.3 mg, 0.329 mmol) was 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). The mixture was stirred at 50 °C for 15 minutes. The mixture was briefly cooled and N,N-diisopropylethylamine (0.057 mL, 0.329 mmol) was added. After 2 hours, the reaction was quenched with water (5 mL) and brine (5 mL). The mixture was extracted with 2-methyltetrahydrofuran (3 x 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 (0-10% methanol / dichloromethane). Fractions containing product were combined and the solvent was removed under reduced pressure to give Intermediate 14-4.

[0568] 1 H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 9.1 Hz, 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, 4.6 Hz, 1H), 6.59 (t, J = 4.6 Hz, 1H), 5.85 (m, 2H), 5.48 (dd, J = 9.2, 6.9 Hz, 1H), 4.95 (m, 1H), 4.65 - 4.55 (m, 3H), 4.52 (m, 1H), 4.48 - 4.42 (m, 1H), 4.42 - 4.31 (m, 1H), 4.25 (m, 1H), 3.83 - 3.71 (m, 1H), 3.50 (m, 2H), 3.42 (td, J = 6.7, 3.6 Hz, 2H), 1.76 (s, 3H), 1.54 (q, J = 6.8 Hz, 2H), 1.40 (d, J = 3.9 Hz, 3H), 1.37 - 1.20 (m, 30H), 0.95 - 0.86 (m, 3H). MS m / z [M+1]=985.35

[0569] 19 F NMR (377 MHz, Chloroform-d) δ -137.94 - -138.19 (m), -139.46 - -139.82 (m). 31P NMR (162 MHz, chloroform-d) δ -7.15 (p, J = 7.4 Hz), -7.51 (p, J = 7.4 Hz).

[0570] ​ ​ ​

[0571]

[0572] Sodium hydroxide solution (1 N, 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 heated at 50 °C. After 2 hours, residual starting material was present. After 5 hours, the reaction mixture was cooled and diluted with 2-methyltetrahydrofuran (10 mL) and hydrochloric acid (1 N, 0.3 mL, 0.3 mmol). The aqueous phase was extracted with 2-methyltetrahydrofuran (2 x 10 mL). The combined organic phases were washed with brine (10 mL) and dried over sodium sulfate. The residue was subjected to flash chromatography (0-20% methanol / dichloromethane). Fractions containing product were combined and the solvent was removed under reduced pressure to give [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl [(2R)-2-[(3,4-difluorophenyl)methoxy]-3-octadecyloxy-propyl] hydrogen phosphate.

[0573] MS m / z [M+1] = 864.28

[0574] Concentrated hydrochloric acid (12 N, 0.30 mL, 3.69 mmol) was added to a solution of [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyl-6,6a- dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl [(2R)-2-[(3,4-difluorophenyl)methoxy]-3- octadecoxy-propyl] hydrogen phosphate (24.5 mg, 0.0295 mmol). After 2 hours, triethylamine (0.51 mL, 3.69 mmol) was added. A small amount of methanol was added to the mixture to dissolve any solids. The solution was subjected to preparative HPLC (50%-100% isopropanol / water over 20 minutes). Fractions containing product were combined and the isopropanol was removed under reduced pressure. The residue was taken up in 1,4-dioxane (5 mL) and lyophilized. Further purification was required. The product was subjected to preparative HPLC (50%-100% isopropanol / water over 20 minutes). Fractions containing product were combined and the isopropanol was removed under reduced pressure. The residue was taken up in 1,4-dioxane (5 mL) and lyophilized to give Compound 14.

[0575] 1 H NMR (400 MHz, DMSO-d6) δ 12.13 - 12.04 (m, 0.15 H), 8.12 - 7.67 (m, 3 H), 7.42 - 7.24 (m, 2 H), 7.18 - 7.10 (m, 1 H), 6.94 - 6.74 (m, 2 H), 6.27 - 6.20 (m, 1 H), 5.92 - 5.83 (m, 1 H), 4.67 - 4.48 (m, 3 H), 4.24 - 4.10 (m, 1 H), 4.03 - 3.89 (m, 1 H), 3.89 - 3.77 (m, 1 H), 3.72 (q, J = 4.9 Hz, 1 H), 3.68 - 3.57 (m, 3 H), 3.57 - 3.40 (m, 2 H), 3.40 - 3.27 (m, 2 H / 7 H), 1.45 (p, J = 6.7 Hz, 2 H), 1.22 (d, J = 7.6 Hz, 30 H), 0.90 - 0.81 (m, 3 H). * peak overlaps with water.

[0576] 19 F NMR (376 MHz, DMSO-d6) δ -139.77 (dddd, J = 33.5, 25.3, 11.7, 8.2 Hz), -141.80 (dddt, J = 37.3, 23.1, 11.8, 4.8 Hz).

[0577] 31P NMR (162 MHz, DMSO-d6) δ 0.26 - -0.34 (m).

[0578] MS m / z [M+1] = 824.18

[0579] ​ Base-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl [(2R)-2-[(3,5-difluorophenyl)methoxy]-3- octadecoxy-propyl] hydrogen phosphate (15) Example 16: [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxy-tetrahydrofuran-2-yl]methyl [(2R)-2-[(3-cyano-5-fluoro-phenyl)methoxy]-3- octadecoxy-propyl] hydrogen phosphate (16)

[0580]

[0581] Compound 15 was synthesized in a similar manner to compound 14 using 5- (bromomethyl)-1,3-difluoro-benzene instead of 4-(bromomethyl)-1,2-difluoro-benzene.

[0582] 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 6.98 (d, J = 4.6 Hz, 1H), 6.96 - 6.91 (m, 2H), 6.89 (d, J = 4.6 Hz, 1H), 6.75 (tt, J = 9.2, 2.5 Hz, 1H), 4.84 (d, J = 5.4 Hz, 1H), 4.72 - 4.55 (m, 2H), 4.44 - 4.36 (m, 1H), 4.27 (t, J = 5.5 Hz, 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 = 6.6 Hz, 3H).

[0583] 19 F NMR (377 MHz, Methanol-d4) δ -112.53 (t, J = 8.3 Hz).

[0584] 31 P NMR (162 MHz, Methanol-d4) δ -0.65.

[0585] MS m / z [M+1] = 824.17

[0586] Example 17: [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxy-tetrahydrofuran-2-yl]methyl [(2R)-2-[(3-cyano-5-fluoro-phenyl)methoxy]-3- octadecoxy-propyl] hydrogen phosphate (17) Intermediate 18-1: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecoxy)propan-2-ol Intermediate 18-2: [(2S)-2-benzyloxy-3-octadecoxy-propoxy]-tert-butyl-dimethyl-silane

[0587]

[0588] Compound 16 was synthesized in a similar manner to compound 14 using 5- (bromomethyl)-l-cyano-3-fluoro-benzene instead of 4-(bromomethyl)-l,2-difluoro- benzene.

[0589] 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.52 (s, 1H), 7.44 (dd, J = 9.6, 2.5 Hz, 1H), 7.36 (d, J = 8.3, 2.5 Hz, 1H), 6.98 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.6 Hz, 1H), 4.85 (d, J = 5.5 Hz, 1H), 4.78 - 4.60 (m, 2H), 4.42 - 4.33 (m, 1H), 4.27 (t, J = 5.5 Hz, 1H), 4.22 - 4.13 (m, 1H), 4.13 - 4.03 (m, 1H), 4.00 - 3.83 (m, 2H), 3.79 - 3.63 (m, 1.7H), 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 = 6.6 Hz, 3H).

[0590] 19 F NMR (377 MHz, Methanol-d4) δ -112.78 (t, J = 8.8 Hz).

[0591] 31 P NMR (162 MHz, Methanol-d4) δ -0.47.

[0592] MS m / z [M+1] = 831.21.

[0593] Intermediate 18-3: (2R)-2-benzyloxy-3-octadecoxy-propan-1-ol Intermediate 18-4: [(2S)-2-benzyloxy-3-octadecoxy-propyl] bis(4-nitrophenyl) phosphate Intermediate 18-5: [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl [(2S)-2-benzyloxy- 3-octadecoxy-propyl] (4-nitrophenyl) phosphate

[0594]

[0595] Compound 17 was synthesized in a similar manner to compound 14 using 4- (bromomethyl)-2-chloro-l-fluoro-benzene instead of 4-(bromomethyl)-l,2-difluoro- benzene.

[0596] 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.44 (dd, J = 7.2, 2.1 Hz, 1H), 7.30 - 7.22 (m, 1H), 7.12 (t, J = 8.8 Hz, 1H), 6.99 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.85 (d, J = 5.4 Hz, 1H), 4.68 - 4.50 (m, 2H), 4.41 - 4.34 (m, 1H), 4.27 (t, J = 5.4 Hz, 1H), 4.24 - 4.13 (m, 1H), 4.13 - 4.03 (m, 1H), 3.97 - 3.83 (m, 2H), 3.77 - 3.62 (m, 2H), 3.59 - 3.42 (m, 2H), 3.39 (td, J = 6.5, 2.4 Hz, 2H), 1.59 - 1.47 (m, 2H), 1.39 - 1.20 (m, 30H), 0.91 (t, J = 6.7 Hz, 3H).

[0597] 19 F NMR (377 MHz, Methanol-d4) δ -120.49 (td, J = 8.4, 4.9 Hz).

[0598] 31 P NMR (162 MHz, Methanol-d4) δ -0.26.

[0599] MS m / z [M+1] = 840.18

[0600] Example 18: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxy-tetrahydrofuran-2-yl)methyl ((S)-2-(benzyloxy)-3-(octadecoxy)propyl) hydrogen phosphate

[0601]

[0602] At 0 °C, a solution of octadecan-1-ol (10.1 g, 37.4 mmol) in tetrahydrofuran (30 mL) was added by cannula to a vigorously stirring mixture of sodium hydride (1.50 g, 39.1 mmol). The reaction mixture was equipped with a reflux condenser and heated to 80 °C. After 2 h, tert-butyl-dimethyl-[[(2S)-oxiranyl-2-yl]methoxy]silane (4.70 g, 25.0 mmol) was added by syringe. After 17 h, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (50 mL), water (100 mL), and diethyl ether (200 mL) were added sequentially. The organic layer was extracted with water, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to give Intermediate 18-1.

[0603] Intermediate 19-0: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2, 2-dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-6-(prop-1-en-2-yl)-2-sulfooxyhexahydrobenzo[d][1,3, 2]oxathiazol-2-yl)oxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile

[0604]

[0605] A solution of intermediate 18-1 (300 mg, 650 μmol) in tetrahydrofuran (3.0 mL) was added via syringe to a vigorously stirring mixture of sodium hydride (50 mg, 1.3 mmol) in tetrahydrofuran (6.0 mL) at 0 °C. After 45 min, a solution of bromomethylbenzene (280 mg, 1.6 mmol) in tetrahydrofuran (3.0 mL) was added via syringe. The reaction mixture was warmed to room temperature. After 16 h, the reaction 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 x 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 silica gel flash column chromatography (0 to 20% ethyl acetate in hexanes) to give intermediate 18-2.

[0606] Intermediate 19-2: (S)-2-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)-3-(octadecoxy)propan-1- ol

[0607]

[0608] A solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 623 μL, 623 μmol) was added via syringe to a stirred solution of intermediate 18-2 (114 mg, 208 μmol) in tetrahydrofuran (3.0 mL). After 45 min, ethyl acetate (10 mL) and water (10 mL) were added sequentially. The organic layer was washed with water (10 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0 to 20% ethyl acetate in hexanes) to give intermediate 18-3.

[0609] Example 19: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxy-tetrahydrofuran-2-yl)methyl ((S)-2-(benzyloxy)-3-(octadecoxy)propyl) hydrogen phosphate

[0610]

[0611] Intermediate 18-4 was prepared in a manner similar to intermediate 2-3 using intermediate 18-3 in place of intermediate 2-2.

[0612] ​ ​ ​

[0613]

[0614] Intermediate 18-5 was prepared in a manner similar to intermediate 2-4 using intermediate 18-4 in place of intermediate 2-3.

[0615] ​ ​ (18)

[0616]

[0617] 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 min, the resulting mixture was cooled to room temperature. A few drops of concentrated hydrochloric acid were added until the resulting mixture had a pH < 1. After 16 h, triethylamine was added until the mixture had a pH > 7, as indicated by the persistent yellow color. The mixture was purified by reverse-phase preparative HPLC (2-propanol / water) to give compound 18 as a complex with triethylamine.

[0618] 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.34 (d, J = 7.5 Hz, 2H), 7.28 (t, J = 7.4 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.83 (d, J = 5.2 Hz, 2H), 4.66 (d, J = 11.8 Hz, 1H), 4.62 - 4.52 (m, 2H), 4.34 (s, 1H), 4.26 (t, J = 5.3 Hz, 1H), 4.17 - 3.98 (m, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.71 (d, J = 6.2 Hz, 1H), 3.47 - 3.42 (m, 1H), 3.39 (d, J = 2.1 Hz, 1H), 1.51 (d, J = 6.8 Hz, 2H), 1.29 (d, J = 7.3 Hz, 30H), 0.92 (t, J = 6.7 Hz, 3H).

[0619] LCMS: 788.305.

[0620] ​ ​ ​

[0621]

[0622] At room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (609 μL, 4.07 mmol) was added via syringe over 2 minutes to a vigorously stirred mixture of intermediate 1-3 (1.00 g, 3.02 mmol), (2R,3aR,6S,7aR)-3a-methyl-2-((perfluorophenyl)thio)-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphonyl 2-sulfide (1.75 g, 3.92 mmol), and acetonitrile (24.0 mL). After 10 minutes, saturated ammonium chloride aqueous solution (10 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with water (70 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 10% methanol in dichloromethane) to give intermediate 19-0. LCMS: 578.2.

[0623] Intermediate 19-1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-2-oxo-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphatidyl-2-yl)oxy)methyl)tetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-carboxynitrile

[0624]

[0625] Selenium dioxide (316 mg, 2.84 mmol) was added to a vigorously stirred solution of intermediate 19-0 (1.57 g, 2.71 mmol) in acetonitrile (23.5 mL) and water (8.9 mL) at room temperature. After 60 minutes, ethyl acetate (250 mL) was added, and the resulting suspension was filtered through diatomaceous earth. The organic layer of the filtrate was washed with a mixture of water and brine (1:1 v:v, 120 mL), and the aqueous layer was extracted with ethyl acetate (75 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 10% methanol in dichloromethane) to give intermediate 19-1. LCMS: 562.2.

[0626] ​

[0627]

[0628] Potassium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran, 382 μL, 380 μmol) was added via syringe over 1 min at 0 °C to a vigorously stirred solution of (R)-1- ((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (159 mg, 347 μmol) in tetrahydrofuran (1.0 mL) at 0 °C. After 10 min, 1-(bromomethyl)-3-fluoro-5- (trifluoromethyl)benzene (223 mg, 869 μmol) was added and the resulting mixture was allowed to warm to room temperature. After 50 min, concentrated hydrochloric acid (300 μL, 3.60 mmol) and methanol (0.3 mL) were added sequentially and the resulting biphasic mixture was stirred vigorously. After 60 min, saturated aqueous sodium bicarbonate 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 hexanes) to give intermediate 19-2. LCMS: 543.4 [M+Na] + .

[0629] ​ (R)-3-(octadecyloxy)-2-(thiophen-3-ylmethoxy)propyl) hydrogen phosphate (20) Example 20: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-(thiophen-3-ylmethoxy) propyl) hydrogen phosphate (20)

[0630]

[0631] 1,8-Diazabicyclo[5.4.0]undec-7-ene (10.7 μL, 71.2 μmol) was added via syringe over 1 min at room temperature to a vigorously stirred mixture of intermediate 19-2 (18.5 mg, 35.6 μmol), intermediate 19-1 (20.0 mg, 35.6 μmol) and tetrahydrofuran (0.7 mL). After 18 min, water (50 μL) and concentrated hydrochloric acid (300 μL, 3.60 mmol) were added sequentially. After 120 min, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 19. 1H NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.49 (s, 1H), 7.43 (d, J = 9.3 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.20 (d, J = 4.8 Hz, 1H), 4.97 - 4.68 (m, 3H), 4.40 - 4.31 (m, 1H), 4.25 (t, J = 5.5 Hz, 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 = 6.6 Hz, 3H). 31 P NMR (162 MHz, Methanol-d4) δ 0.19. LCMS: 872.4 [M-H] - .

[0632] Intermediate 21-1: (R)-triisopropyl ((2-methyloxetan-2-yl)methoxy)silane Intermediate 21-2: (R)-2-methyl-1-(octadecyloxy)-3-((triisopropylsilyl)oxy)propan-2- ol Example 21: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)-2-methyl-3-(octadecyloxy) propyl) hydrogen phosphate (21)

[0633]

[0634] Compound 20 was synthesized in a similar manner to Compound 4 using 3- (bromomethyl)thiophene instead of 2-(bromomethyl)naphthalene. 1 H NMR (400 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.34 - 7.27 (m, 2H), 7.07 (dd, J = 4.9, 1.4 Hz, 1H), 7.04 (d, J = 4.6 Hz, 1H), 6.96 (d, J = 4.6 Hz, 1H), 4.83 - 4.79 (m, 1H), 4.69 - 4.57 (m, 2H), 4.39 - 4.31 (m, 1H), 4.26 (t, J = 5.4 Hz, 1H), 4.14 (dt, J = 11.5, 4.3 Hz, 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 = 7.3 Hz, 6H), 1.61 - 1.42 (m, 2H), 1.38 - 1.19 (m, 39H), 0.94 - 0.86 (m, 3H). LCMS: 794.1.

[0635] Intermediate 22-1: (R)-(4-(benzyloxy)-3-((octadecyloxy)methyl)butyl)benzene

[0636]

[0637] Triisopropylchlorosilane (5.38 mL, 25.2 mmol) was added via syringe over 2 minutes to a stirred mixture of (S)-(2-methyloxirane-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) at 0 °C. After 8 minutes, the resulting mixture was allowed to warm to room temperature. After 20 hours, the resulting mixture was poured into a biphasic mixture of ethyl ether (100 mL), aqueous citric acid (10% wt / v, 10 mL) and water (80 mL) at 0 °C. The resulting 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 silica gel flash column chromatography (0 to 4% ethyl acetate in hexanes) to give Intermediate 21-1. LCMS: 245.2.

[0638] Intermediate 22-2: (S)-2-((octadecyloxy)methyl)-4-phenylbutan-1-ol Example 22: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((octadecyloxy)methyl)-4-phenylbutyl) hydrogen phosphate (22)

[0639]

[0640] At room temperature, 1-octadecanol (2.13 g, 7.88 mmol) was added to a vigorously stirred mixture of sodium hydride (60 wt% dispersion in mineral oil, 311 mg, 8.12 mmol) in 2-methyltetrahydrofuran (20 mL) and the resulting mixture was heated to 85 °C. After 80 minutes, a solution of Intermediate 21-1 (1.47 g, 6.01 mmol) in N,N-dimethylformamide (10 mL) was added via cannula and the resulting mixture was heated to 90 °C. After 17 hours, the resulting mixture was cooled to room temperature and saturated aqueous ammonium chloride (10 ml) and ethyl ether (500 mL) were added sequentially. The organic layer was washed with water (2 x 500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 100% dichloromethane in hexanes, then 0 to 2% ethyl acetate in dichloromethane) to give Intermediate 21-2. LCMS: 515.5.

[0641] Intermediate 23-1: (S)-2-chloro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl) benzonitrile Intermediate 23-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-chloro-4- cyano benzyl)oxy)-3-(octadecyloxy)propyl)(2-chlorophenyl) phosphate

[0642] Example 23: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-chloro-4-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (23)

[0643]

[0644] Compound 21 was synthesized in a manner similar to Compound 4 using benzyl bromide in place of 2-(bromomethyl)naphthalene and intermediate 21-2 in place of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol. 1 HNMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.29 - 7.23 (m, 2H), 7.23 - 7.16 (m, 1H), 7.07 (d, J = 4.7 Hz, 1H), 7.03 (d, J = 4.7 Hz, 1H), 4.80 (d, J = 5.3 Hz, 1H), 4.56 (s, 2H), 4.34 (d, J = 4.8 Hz, 1H), 4.26 (t, J = 5.4 Hz, 1H), 4.16 (dt, J = 11.6, 4.2 Hz, 1H), 4.07 (dt, J = 10.3, 4.1 Hz, 1H), 3.93 (dd, J = 10.3, 3.9 Hz, 1H), 3.85 (dd, J = 10.3, 4.1 Hz, 1H), 3.56 - 3.37 (m, 3H), 3.23 (q, J = 7.3 Hz, 6H), 1.62 - 1.49 (m, 2H), 1.45 - 1.08 (m, 42H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 800.3 [M-H] - .

[0645] Intermediate 24-1: (S)-2-(benzyloxy)-3-((15-methylhexadecyloxy)propyl)-1-ol

[0646]

[0647] Sodium hydride (60 wt% dispersion in mineral oil, 186 mg, 4.64 mmol) was added to a vigorously stirred solution of (R)-2-((benzyloxy)methyl)-4-phenylbutan-1-ol (419 mg, 1.55 mmol) (Muehlman, A.; Lindberg, J.; Classon, B.; Unge, T.; Hallberg, A.; Samuelsson, B. J. Med. Chem., 2001, vol. 44, p. 3407) in N,N-dimethylformamide (2.5 mL) at room temperature. After 40 min, 1-bromooctadecane (1.32 mL, 3.87 mmol) and tetrahydrofuran (1.0 mL) were added sequentially. After 140 min, the resulting mixture was heated to 80 °C. After 16.5 h, the resulting mixture was cooled to room temperature and saturated aqueous ammonium chloride solution (5.0 mL) and diethyl ether (100 mL) were added sequentially. The organic layer was washed with water (2 x 100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 20% ethyl acetate in hexanes) to give intermediate 22-1. LCMS: 545.4 [M+Na] + .

[0648] Example 24: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((15-methylhexadecyloxy)propyl)-4- phenylbutyl) hydrogen phosphate (24)

[0649]

[0650] A vigorously stirred mixture of intermediate 22-1 (535 mg, 1.02 mmol), palladium (10 wt% on carbon, 109 mg, 102 μmol), tetrahydrofuran (3.0 mL) and ethanol (3.0 mL) was placed under a hydrogen atmosphere (balloon) at room temperature. After 13 h, the resulting mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give intermediate 22-2. LCMS: 455.4 [M+Na] + .

[0651] ​ ​

[0652] ​

[0653]

[0654] Compound 22 was synthesized in a similar manner to compound 2 using intermediate 22-2 in place of intermediate 2-2. 1HNMR (400 MHz, Methanol-d4) δ 7.95 (s, 1H), 7.27 - 7.06 (m, 7H), 4.82 (d, J = 5.2 Hz, 1H), 4.37 (d, J = 4.6 Hz, 1H), 4.28 (t, J = 5.4 Hz, 1H), 4.16 (dt, J = 11.5, 4.3 Hz, 1H), 4.11 - 3.74 (m, 3H), 3.53 - 3.28 (m, 4H), 3.23 (q, J = 7.3 Hz, 6H), 2.73 - 2.53 (m, 2H), 1.83 (h, J = 6.6 Hz, 1H), 1.66 (dd, J = 14.3, 7.4 Hz, 2H), 1.59 - 1.41 (m, 2H), 1.41 - 1.09 (m, 39H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 784.3 [M-H] - .

[0655] ​

[0656]

[0657] Intermediate 23-1 was synthesized in a similar manner to Intermediate 2-2 using 4-(bromomethyl)-2-chlorobenzonitrile instead of 4-(bromomethyl)-1,1'-biphenyl. LCMS: 516.3 [M+Na] + .

[0658] ​ ​ ​

[0659]

[0660] At room temperature, 2-chlorophenyldichlorophosphine (33.3 μL, 206 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (28.6 mg, 414 μmol), triethylamine (57.8 μL, 414 μmol), and tetrahydrofuran (0.4 mL). After 40 min, 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 min, 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 added. After 15 h, saturated aqueous sodium bicarbonate (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 5% methanol in dichloromethane) to give Intermediate 23-2. LCMS: 997.4.

[0661] ​ ​ ​

[0662]

[0663] At room temperature, 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). After 4 h, trimethylchlorosilane (58.0 μL, 457 μmol) and concentrated hydrochloric acid (300 μL, 3.60 mmol) were added sequentially. After 150 min, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in 2-propanol / water) to give Compound 23. 1H NMR (400 MHz, Methanol-d4) d 8.08 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 1.4 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.8 Hz, 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 [M-H] - .

[0664] ​

[0665]

[0666] Intermediate 24-1 was synthesized in a similar manner to 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] + .

[0667] ​ (R)-2-(benzyloxy)-3-((15-methylhexadecyl)oxy)propyl ((2R,3S,4R,5R)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl Phosphonate (24)

[0668]

[0669] Compound 24 was synthesized in a similar manner to Compound 19 using Intermediate 24-1 instead of Intermediate 19-2. 1HNMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.36 - 7.32 (m, 2H), 7.32 - 7.26 (m, 2H), 7.26 - 7.19 (m, 2H), 7.17 (d, J = 4.8 Hz, 1H), 4.78 (d, J = 5.2 Hz, 1H), 4.66 (d, J = 11.9 Hz, 1H), 4.61 (d, J = 11.9 Hz, 1H), 4.39 - 4.31 (m, 1H), 4.26 (t, J = 5.4 Hz, 1H), 4.17 (dq, J = 12.8, 4.4 Hz, 1H), 4.13 - 4.02 (m, 1H), 4.01 - 3.86 (m, 2H), 3.75 (q, J = 5.2 Hz, 1H), 3.61 - 3.38 (m, 4H), 1.69 - 1.47 (m, 3H), 1.40 - 1.08 (m, 24H), 0.98 - 0.81 (m, 6H). LCMS: 772.4 [M-H] - .

[0670] Example 25: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3,5-dicyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (26) Phosphonate (24)

[0671]

[0672] Compound 25 was synthesized in a similar manner to Compound 55 using 1,4-butanediol instead of 1,3-propanediol and 1-bromohexadecane instead of 1-bromohexadecane. 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (s, 1H), 6.98 (d, J = 4.6 Hz, 1H), 6.93 (d, J = 4.6 Hz, 1H), 4.95 - 4.83 (m, 1H), 4.38 (t, J = 4.4 Hz, 1H), 4.28 (t, J = 5.4 Hz, 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.

[0673] Intermediate 26-1: (R)-5-(((1-((tert-butyldimethylsilyl)oxy)-3- (octadecyloxy)propan-2-yl)oxy)methyl)isophthalonitrile Intermediate 26-2: (S)-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)isophthalonitrile

[0674]

[0675] To a stirred solution of (R)-3-(octadecyloxy)-2-((trimethylsilyl)oxy)propyl acetate (Intermediate 26-4, 150 mg, 227 μmol) in tetrahydrofuran (0.5 mL) at 0 °C was added via syringe a solution of potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 230 μL, 230 μmol). After 5 min, a solution of 5-(bromomethyl)isophthalonitrile (Intermediate 26-5, 100 mg, 363 μmol) in tetrahydrofuran (1.0 mL) was added via syringe and the resulting mixture was allowed to warm to room temperature. After 16 h, saturated aqueous ammonium chloride 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 (0 to 10% ethyl acetate in hexanes) to give Intermediate 26-6. LCMS: 621.5 [M+Na] + .

[0676] Intermediate 26-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl)((R)- 2-((3,5-dicyanobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate

[0677]

[0678] Intermediate 26-2 was synthesized in a similar manner to Intermediate 2-2 using Intermediate 26-1 in place of Intermediate 2-1. LCMS: 507.4 [M+Na] + .

[0679] Phosphonate (24) Example 26: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3,5-dicyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (26) Phosphonate (24)

[0680]

[0681] Intermediate 26-3 was synthesized in a similar manner to Intermediate 23-2 using Intermediate 26-2 in place of Intermediate 23-1. LCMS: 988.4.

[0682] Intermediate 27-1: tert-butyldimethyl ((2R)-3-(octadecyloxy)-2-(1- phenylethoxy)propoxy)silane Intermediate 27-2: (2S)-3-(octadecyloxy)-2-(1-phenylethoxy)propan-1-ol (faster eluting diastereomer on silica gel) Intermediate 28-1: (2S)-3-(octadecyloxy)-2-(1-phenylethoxy)propan-1-ol (slower eluting diastereomer on silica gel)

[0683]

[0684] Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 300 pL, 300 pmol) was added via syringe to a vigorously stirring mixture of intermediate 26-3 (23.6 mg, 23.9 pmol), 4-(dimethylamino)pyridine (29.2 mg, 239 pmol), water (45.0 pL, 2.50 mmol), and tetrahydrofuran (0.1 mL) at room temperature. After 82 min, trimethylsilyl chloride (38.2 pL, 301 pmol) and concentrated hydrochloric acid (300 pL, 3.60 mmol) were added sequentially. After 140 min, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 26. 1 H NMR (400 MHz, Methanol-d4) d 8.07 (s, 1H), 8.01 (s, 3H), 7.31 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 4.8 Hz, 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 = 5.0 Hz, 1H), 3.63 - 3.41 (m, 4H), 1.65 - 1.51 (m, 2H), 1.38 - 1.22 (m, 30H), 0.95 - 0.86 (m, 3H). LCMS: 836.4 [M-H] - .

[0685] Example 27: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((2R)-3-(octadecyloxy)-2-(1- phenylethoxy)propyl) hydrogen phosphate (27) Phosphonate (24)

[0686]

[0687] Intermediate 27-1 was synthesized as a 1 : 1 mixture of diastereomers in a similar manner to 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 (WO 2011059021) instead of benzyl 2,2,2-trichloroacetimidate. LCMS: 585.6 [M+Na] + .

[0688] Example 28: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((2R)-3-(octadecyloxy)-2-(1- phenylethoxy)propyl) hydrogen phosphate (28) Intermediate 29-1: 2,2-dimethyl-5-(phenoxymethyl)-1,3-dioxane

[0689] Intermediate 29-2: 2-(phenoxymethyl)propane-1,3-diol ​

[0690]

[0691] Intermediate 27-2 and Intermediate 28-1 were synthesized in a similar manner to Intermediate 2-2 using Intermediate 27-1 instead of Intermediate 2-1. The diastereomers were separated by silica gel flash column chromatography (0 to 9% ethyl acetate in hexanes) to give Intermediate 27-2 (faster eluting diastereomer) and Intermediate 28-1 (slower eluting diastereomer). Intermediate 27-2: LCMS: 471.4 [M+Na] + . Intermediate 28-1: LCMS: 471.4 [M+Na] + .

[0692] ​ ​

[0693] ​

[0694]

[0695] Compound 27 was synthesized in a similar manner to Compound 26 using Intermediate 27-2 instead of Intermediate 26-2. 1 HNMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.40 - 7.19 (m, 6H), 7.17 (d, J = 4.8 Hz, 1H), 4.83 - 4.69 (m, 2H), 4.36 - 4.28 (m, 1H), 4.22 (t, J = 5.4 Hz, 1H), 4.16 - 4.05 (m, 1H), 4.05 - 3.94 (m, 1H), 3.83 - 3.76 (m, 2H), 3.75 - 3.43 (m, 5H), 1.66 - 1.50 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H), 1.37 - 1.21 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 800.3 [M-H] - .

[0696] ​ ​ ​

[0697]

[0698] Compound 28 was synthesized in a similar manner to Compound 26 using Intermediate 28-1 instead of Intermediate 26-2. 1HNMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.40 - 7.34 (m, 2H), 7.34 - 7.28 (m, 3H), 7.25 (d, J = 7.1 Hz, 1H), 7.21 (d, J = 4.8 Hz, 1H), 4.81 - 4.70 (m, 2H), 4.41 - 4.33 (m, 1H), 4.30 - 4.16 (m, 2H), 4.16 - 4.06 (m, 1H), 4.05 - 3.85 (m, 2H), 3.62 - 3.53 (m, 1H), 3.42 - 3.22 (m, 4H), 1.51 - 1.40 (m, 2H), 1.38 (d, J = 6.5 Hz, 3H), 1.35 - 1.21 (m, 30H), 0.91 (t, J = 6.8 Hz, 3H). LCMS: 800.3 [M-H] - .

[0699] ​

[0700]

[0701] Methanesulfonyl chloride (1.53 mL, 19.8 mmol) was added to a stirred mixture of (2,2-dimethyl-l,3-dioxan-5-yl)methanol (2.41 g, 16.5 mmol), triethylamine (3.21 mL, 23.1 mmol) and dichloromethane (35 mL) at 0 °C over 3 minutes and the resulting mixture was allowed to warm to room temperature. After 4 hours, diethyl ether (200 mL) was added. The organic layer was washed successively with a mixture of aqueous phosphoric acid (85% wt / wt, 1.13 mL) in water (100 mL) and a mixture of water and saturated aqueous sodium bicarbonate solution (5: 1 v:v, 60 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (25 mL) at room temperature and the resulting solution was stirred vigorously. Phenol (2.47 g, 26.2 mmol) and potassium carbonate (6.39 g, 45.9 mmol) were added successively and the resulting mixture was heated to 95 °C. After 18.5 hours, the resulting mixture was cooled to room temperature and saturated aqueous ammonium chloride solution (25 mL) and diethyl ether (500 mL) were added successively. The organic layer was washed with water (2 x 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 to 100% ethyl acetate in hexanes) to give Intermediate 29-1. LCMS: 245.1 [M+Na] + .

[0702] ​

[0703]

[0704] Concentrated hydrochloric acid (387 μί, 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 h, sodium bicarbonate (1.02 g, 12.1 mmol) was added and the resulting mixture was stirred vigorously. After 10 min, 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 to 100% ethyl acetate in hexanes) to give intermediate 29-2. LCMS: 183.0.

[0705] Intermediate 29-3: 3-(octadecyloxy)-2-(phenoxymethyl)propan-1-ol

[0706]

[0707] Potassium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran, 2.63 mL, 2.6 mmol) was added via syringe to a vigorously stirred solution of intermediate 29-2 (400 mg, 2.20 mmol) in N,N-dimethylformamide (6.0 mL) at 0 °C over 1 min and the resulting mixture was allowed to warm to room temperature. After 5 min, 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 h, the resulting mixture was allowed to cool to room temperature over 40 min. Methanol (8.0 mL) and concentrated hydrochloric acid (723 μί, 8.78 mmol) were added sequentially. After 180 min, diethyl ether (125 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 x 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 to 25% ethyl acetate in hexanes) to give intermediate 29-3. LCMS: 435.1.

[0708] Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34) Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34) (29)

[0709]

[0710] Compound 29 was synthesized as a 1 : 1 mixture of diastereomers in a similar manner to compound 26 using intermediate 29-3 in place of intermediate 26-2. 1H NMR (400 MHz, Methanol-d4) δ 8.00 (s, 0.5H), 7.99 (s, 0.5H), 7.24 (d, J = 4.8 Hz, 1H), 7.22 - 7.14 (m, 3H), 6.89 - 6.80 (m, 3H), 4.73 (d, J = 5.1 Hz, 1H), 4.35 - 4.26 (m, 1H), 4.22 (t, J = 5.5 Hz, 1H), 4.19 - 4.09 (m, 1H), 4.10 - 3.91 (m, 5H), 3.57 - 3.48 (m, 2H), 3.39 (t, J = 6.4 Hz, 2H), 2.37 - 2.22 (m, 1H), 1.57 - 1.45 (m, 2H), 1.36 - 1.17 (m, 30H), 0.88 (t, J = 6.6 Hz, 3H). LCMS: 786.4 [M-H] - .

[0711] Intermediate 30-1: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-yl 4- methylbenzenesulfonate Intermediate 30-2: (S)-3-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)benzonitrile

[0712]

[0713] Intermediate 30-1. LCMS: 635.4 [M+Na] At 0 °C, 4-toluenesulfonyl chloride (929 mg, 4.87 mmol) was added to a stirred mixture of Intermediate 18-1 (1.40 g, 3.04 mmol), N,N-diisopropylethylamine (848 μL, 4.87 mmol), 4-(dimethylamino)pyridine (37.2 mg, 304 μmol), and dichloromethane (7.0 mL). After 2 min, the resulting mixture was warmed to room temperature. After 170 min, 4-(dimethylamino)pyridine (67.0 mg, 548 μmol) was added. After 30 min, the resulting mixture was heated to 65 °C. After 17 h, the resulting mixture was cooled to room temperature, and ethyl ether (120 mL), ethyl acetate (20 mL), and aqueous hydrogen chloride (2.0 M, 5 mL) were added sequentially. The organic layer was washed sequentially with water (100 mL), and a mixture of water and saturated aqueous sodium bicarbonate (5:1 v:v, 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 50% dichloromethane in hexanes) to afford Intermediate 30-1. LCMS: 635.4 [M+Na] + .

[0714] Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34)

[0715]

[0716] Potassium tert-pentoxide solution (1.7 M in toluene, 461 μL, 783 μmol) was added 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 over 1 min via syringe and the resulting mixture was heated to 90 °C. After 55 min, the resulting mixture was heated to 130 °C. After 1 h, the resulting mixture was cooled to room temperature. After 14 h, diethyl ether (40 mL), saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 x 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. Tetra- butylammonium fluoride solution (1.0 M in tetrahydrofuran, 1.07 mL, 1.1 mmol) was added via syringe. After 60 min, saturated aqueous ammonium chloride solution (10 mL), diethyl ether (40 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (40 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 30% ethyl acetate in hexanes) to give a mixture of intermediate 30-2. The mixture was purified by flash column chromatography on basic alumina (0 to 15% ethyl acetate in hexanes) to give intermediate 30-2. LCMS: 468.4 [M+Na] + .

[0717] Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34) Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34) Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34)

[0718]

[0719] Compound 30 was synthesised in a similar manner to compound 19 using intermediate 30-2 in place of intermediate 19-2. 1HNMR(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(dd,J=10.8, 6.1Hz,1H),3.53–3.41(m,2H),1.58–1.46(m,2H),1.40–1.20(m,30H),0.92(t,J=6.8Hz,3H).LCMS:797.4[MH] - .

[0720] Intermediate 34-1: (R)-1-((tert-butyldimethylsilyl)oxy)-3-(heptadecyloxy)propan-2-ol Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34) Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34)

[0721]

[0722] Compound 31 was synthesized in a manner similar to that of Compound 30, using 3-fluoro-5-hydroxybenzyl nitrile instead of 3-hydroxybenzyl nitrile. 1 H 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] - .

[0723] Example 29: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34) ​ ​

[0724]

[0725] Compound 32 was synthesized in a manner similar to Compound 19 using 1- (bromomethyl)-3-(difluoromethyl)benzene instead of 1-(bromomethyl)-3-fluoro-5- (trifluoromethyl)benzene. 1 H NMR (400 MHz, DMSO-d6) d 7.94 (s, 1H), 7.53 - 7.41 (m, 4H), 7.18 - 6.74 (m, 3H), 4.73 - 4.54 (m, 3H), 4.18 (ddt, J = 30.5, 6.1, 3.0 Hz, 2H), 4.08 - 3.85 (m, 4H), 3.77 - 3.66 (m, 1H), 1.44 (q, J = 6.7 Hz, 2H), 1.22 (d, J = 9.8 Hz, 28H), 0.93 - 0.79 (m, 3H). LCMS: 838.2.

[0726] ​ ​ ​

[0727]

[0728] Compound 33 was synthesized in a manner similar to Compound 19 using 1- (bromomethyl)-4-(difluoromethyl)benzene instead of 1-(bromomethyl)-3-fluoro-5- (trifluoromethyl)benzene. 1 H NMR (400 MHz, DMSO-d6) d 7.95 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.1 Hz, 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, 1.9 Hz, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.13 (p, J = 1.6 Hz, 1H), 1.44 (t, J = 6.8 Hz, 2H), 1.22 (d, J = 8.0 Hz, 32H), 0.96 - 0.78 (m, 3H). LCMS: 838.2.

[0729] ​

[0730]

[0731] Intermediate 34-1 was synthesized in a manner similar to Intermediate 9-2 using (S)-3-(heptadecyloxy)propane-1,2-diol instead of (S)-3-(octadecyloxy)propane- 1,2-diol. 1H NMR (400 MHz, Chloroform-d) δ 3.82 (q, J = 5.3 Hz, 1H), 3.72 - 3.61 (m, 2H), 3.47 (td, J = 6.7, 6.3, 1.4 Hz, 4H), 1.59 (t, J = 7.1 Hz, 2H), 1.28 (s, 30H), 0.92 (s, 9H), 0.10 (s, 6H).

[0732] ​ ​ ​

[0733]

[0734] Compound 34 was synthesized in a manner similar to Compound 19 using 3- (bromomethyl)benzonitrile instead of l-(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 (400 MHz, DMSO-d6, drop CD3OD) δ 7.96 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 4.5 Hz, 1H), 6.86 (t, J = 3.5 Hz, 1H), 4.66 (t, J = 10.0 Hz, 4H), 4.23 (s, 2H), 3.76 - 3.55 (m, 4H), 3.44 (t, J = 3.2 Hz, 2H), 3.36 (d, J = 13.3 Hz, 5H), 3.08 (dd, J = 25.4, 13.0 Hz, 3H), 2.80 (s, 4H), 1.45 (t, J = 6.8 Hz, 3H), 1.22 (d, J = 8.1 Hz, 33H), 0.85 (t, J = 6.5 Hz, 3H). LCMS: 799.3.

[0735] ​ ​ ​

[0736]

[0737] Compound 35 was synthesized in a manner similar to Compound 19 using 3- (bromomethyl)-5-fluorobenzonitrile instead of l-(bromomethyl)-3-fluoro-5- (trifluoromethyl)benzene and Intermediate 34-1 instead of (R)-1-((tert- butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol. 1H NMR (400 MHz, DMSO-d6, drop CD3OD) δ 7.92 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 9.7 Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 6.84 (d, J = 3.5 Hz, 1H), 4.72 - 4.56 (m, 2H), 3.71 (s, 1H), 3.47 - 3.38 (m, 2H), 3.33 (d, J = 7.2 Hz, 2H), 3.13 (s, 2H), 1.45 (t, J = 6.9 Hz, 2H), 1.22 (d, J = 9.0 Hz, 29H), 0.85 (t, J = 6.7 Hz, 3H). LCMS: 817.3.

[0738] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0739]

[0740] Compound 36 was synthesized in a manner similar to Compound 19 using 4- (bromomethyl)benzonitrile instead of l-(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 (400 MHz, DMSO-d6) δ 7.93 (d, J = 2.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 7.7 Hz, 2H), 6.91 (d, J = 3.4 Hz, 1H), 6.85 (d, J = 3.7 Hz, 1H), 4.66 (dt, J = 9.0, 3.5 Hz, 3H), 3.77 - 3.66 (m, 1H), 3.62 (d, J = 12.3 Hz, 1H), 3.49 - 3.40 (m, 2H), 3.35 (q, J = 9.5, 7.5 Hz, 3H), 3.10 (d, J = 24.5 Hz, 1H), 2.81 (d, J = 2.7 Hz, 1H), 1.43 (d, J = 7.3 Hz, 2H), 1.22 (d, J = 9.3 Hz, 26H), 0.85 (t, J = 6.1 Hz, 3H). LCMS: 799.3.

[0741] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0742] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0743]

[0744] Compound 37 was synthesized in a manner similar to Compound 19 using 1- (bromomethyl)-4-methoxybenzene in place of 1-(bromomethyl)-3-fluoro-5- (trifluoromethyl)benzene and Intermediate 34-1 in place of (R)-1-((tert- butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol. 1 H NMR (400 MHz, DMSO-d6, drop CD3OD) δ 7.93 (d, J = 2.8 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 6.98 - 6.74 (m, 4H), 4.66 (d, J = 4.6 Hz, 1H), 4.49 (d, J = 4.8 Hz, 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 = 5.5 Hz, 29H), 0.85 (d, J = 7.5 Hz, 3H). LCMS: 804.2.

[0745] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0746]

[0747] Triphenylphosphine (80.0 mg, 0.305 mmol) was added to a 0 °C cooled 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 (2 mL), THF. The reaction mixture was gradually warmed to room temperature and stirred for 24 h, at which point the solvent was removed under reduced pressure, and the crude product was adsorbed onto silica gel, which was purified by silica gel flash column chromatography (0 to 10% ethyl acetate in hexanes) to give (S)-tert-butyldimethyl(3-(octadecyloxy)-2- phenyloxypropoxy)silane. 1 H NMR (400 MHz, Chloroform-d) δ 7.33 - 7.22 (m, 2H), 7.03 - 6.90 (m, 3H), 4.43 (q, J = 5.1 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.67 (qd, J = 10.4, 4.9 Hz, 2H), 3.49 (td, J = 6.5, 1.9 Hz, 2H), 1.63 - 1.53 (m, 2H), 1.27 (s, 30H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H).

[0748] 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- phenyloxypropoxy)silane (84.0 mg, 0.157 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred for one hour at which point the reaction mixture was diluted with ethyl acetate and washed sequentially with 3* water followed by saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 20% ethyl acetate in hexanes) to give intermediate 38-1. 1 HNMR (400 MHz, Chloroform-d) δ 7.38 - 7.29 (m, 2H), 7.04 - 6.86 (m, 3H), 4.19 (s, 1H), 4.05 (dd, J = 5.5, 2.8 Hz, 2H), 3.62 (qd, J = 9.7, 5.2 Hz, 2H), 3.51 (td, J = 6.6, 1.8 Hz, 2H), 1.59 (d, J = 12.7 Hz, 2H), 1.28 (s, 30H), 0.96 - 0.85 (m, 3H).

[0749] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0750]

[0751] Compound 38 was synthesized in a manner similar to Compound 2 using intermediate 38-1 in place of intermediate 2-2. 1 HNMR (400 MHz, Chloroform-d) δ 7.38 - 7.29 (m, 2H), 7.04 - 6.86 (m, 3H), 4.19 (s, 1H), 4.05 (dd, J = 5.5, 2.8 Hz, 2H), 3.62 (qd, J = 9.7, 5.2 Hz, 2H), 3.51 (td, J = 6.6, 1.8 Hz, 2H), 1.59 (d, J = 12.7 Hz, 2H), 1.28 (s, 30H), 0.96 - 0.85 (m, 3H).

[0752] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0753]

[0754] Compound 39 was synthesized in a manner similar to Compound 16 using 3- (bromomethyl)benzonitrile in place of 3-(bromomethyl)-5-fluorobenzonitrile as a 1:1 mixture of diastereomers. 1H NMR (400 MHz, Methanol-d4) δ 7.89 (s, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 4.6 Hz, 1H), 6.93 (d, J = 4.6 Hz, 1H), 4.83 (d, J = 5.4 Hz, 1H), 4.76 - 4.62 (m, 2H), 4.40 - 4.33 (m, 1H), 4.25 (t, J = 5.5 Hz, 1H), 4.23 - 4.14 (m, 1H), 4.14 - 4.05 (m, 1H), 4.00 - 3.85 (m, 2H), 3.79 - 3.70 (m, 1H), 3.57 - 3.44 (m, 2H), 3.44 - 3.37 (m, 2H), 3.18 (q, J = 7.3 Hz, 2H), 1.59 - 1.49 (m, 2H), 1.39 - 1.20 (m, 30H), 0.91 (t, J = 6.7 Hz, 3H).

[0755] 31 P NMR (162 MHz, Methanol-d4) δ -0.41.

[0756] LCMS: 813.25 [M+H] +

[0757] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0758]

[0759] Compound 40 was synthesized as a 1 : 1 mixture of diastereomers in a similar manner to Compound 16, replacing 3-(bromomethyl)-5-fluorobenzonitrile with 1- (bromomethyl)-4-methylbenzene. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.19 (d, J = 7.7 Hz, 2H), 7.07 (d, J = 7.7 Hz, 2H), 6.98 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.83 (d, J = 5.3 Hz, 1H), 4.62 - 4.52 (m, 2H), 4.42 - 4.35 (m, 1H), 4.27 (t, J = 5.5 Hz, 1H), 4.24 - 4.13 (m, 1H), 4.13 - 4.04 (m, 1H), 3.98 - 3.85 (m, 2H), 3.76 - 3.66 (m, 1H), 3.58 - 3.42 (m, 2H), 3.38 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H), 1.57 - 1.45 (m, 2H), 1.42 - 1.17 (m, 30H), 0.91 (t, J = 6.7 Hz, 3H).

[0760] 31 P NMR (162 MHz, Methanol-d4) δ -0.57.

[0761] LCMS: 802.12 [M+H] +

[0762] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36) Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0763] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-5-cyano- 3, 4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyanobenzyl)oxy)-3- (heptadecyloxy)propyl) hydrogen phosphate (36)

[0764]

[0765] Compound 41 was synthesized as a 1 : 1 mixture of diastereomers in a similar manner to Compound 16, replacing 3-(bromomethyl)-5-fluorobenzonitrile with 1- (bromomethyl)-4-chlorobenzene. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.84 (d, J = 5.4 Hz, 1H), 4.67 - 4.53 (m, 2H), 4.42 - 4.34 (m, 1H), 4.27 (t, J = 5.5 Hz, 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, 1.9 Hz, 2H), 1.59 - 1.46 (m, 2H), 1.41 - 1.17 (m, 30H), 0.91 (t, J = 6.7 Hz, 3H). 31 P NMR (162 MHz, Methanol-d4) δ -0.62.

[0766] LCMS: 822.16 [M+H] +

[0767] Example 36: ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2, 1-f][1, 2, 4]triazin-7- ​

[0768] ​

[0769]

[0770] Compound 42 was synthesized as a 1 : 1 mixture of diastereomers in a similar manner to Compound 16, replacing 3-(bromomethyl)-5-fluorobenzonitrile with 1- (bromomethyl)-2-fluorobenzene. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.52 - 7.45 (m, 1H), 7.30 - 7.22 (m, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.99 (d, J = 4.4 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.84 (d, J = 5.3 Hz, 1H), 4.76 - 4.67 (m, 2H), 4.41 - 4.33 (m, 1H), 4.27 (t, J = 5.4 Hz, 1H), 4.19 - 4.11 (m, 1H), 4.11 - 4.04 (m, 1H), 3.98 - 3.86 (m, 2H), 3.79 - 3.62 (m, 2H), 3.60 - 3.51 (m, 1H), 3.51 - 3.43 (m, 1H), 3.39 (td, J = 6.6, 2.5 Hz, 2H), 1.58 - 1.47 (m, 2H), 1.39 - 1.22 (m, 30H), 0.91 (t, J = 6.7 Hz, 3H).

[0771] 31 P NMR (162 MHz, Methanol-d4) δ -0.01.

[0772] 19 F NMR (376 MHz, Methanol-d4) δ -121.40 (dt, J = 12.1, 6.1 Hz).

[0773] LCMS: 806.19 [M+H] +

[0774] ​ ​ ​

[0775]

[0776] Compound 43 was synthesized as a 1 : 1 mixture of diastereomers in a similar manner to Compound 16, replacing 3-(bromomethyl)-5-fluorobenzonitrile with 2- (bromomethyl)-l,3-difluorobenzene. 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 = 6.6 Hz, 1H), 1.59 - 1.40 (m, 2H), 1.40 - 1.13 (m, 30H), 0.91 (t, J = 6.6 Hz, 3H).

[0777] 31 P NMR (162 MHz, Methanol-d4) δ -0.93.

[0778] 19 F NMR (376 MHz, Methanol-d4) δ -117.21 (t, J = 6.9 Hz).

[0779] LCMS: 824.19 [M+H] +

[0780] Example 44: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-methoxy-3-(octadecyloxy)propyl) hydrogen phosphate (44) Example 44: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-methoxy-3-(octadecyloxy)propyl) hydrogen phosphate (44)

[0781]

[0782] Compound 44 was synthesized as a 1 : 1 mixture of diastereomers in a similar manner to compound 16, replacing 3-(bromomethyl)-5-fluorobenzonitrile with iodomethane. 1 H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 7.00 (d, J = 4.6 Hz, 1H), 6.92 (d, J = 4.6 Hz, 1H), 4.88 - 4.79 (m, 1H), 4.42 - 4.35 (m, 1H), 4.28 (t, J = 5.3 Hz, 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 = 6.8 Hz, 3H).

[0783] 31P NMR (162 MHz, Methanol-d4) δ -0.09.

[0784] LCMS: 712.16 [M+H] +

[0785] Example 44: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-methoxy-3-(octadecyloxy)propyl) hydrogen phosphate (44) Example 44: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-methoxy-3-(octadecyloxy)propyl) hydrogen phosphate (44)

[0786] Intermediate 46-1: (R)-tert-butyldimethyl (2-((2-methylallyl)oxy)-3- (octadecyloxy)propoxy)silane

[0787]

[0788] Compound 45 was synthesized as a 1 : 1 mixture of diastereomers in a similar manner to Compound 16, replacing 3-(bromomethyl)-5-fluorobenzonitrile with 1- (bromomethyl)-3-fluorobenzene. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.28 (td, J = 8.0, 5.7 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.99 (d, J = 4.6 Hz, 1H), 6.94 (td, J = 8.5, 2.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.84 (d, J = 5.4 Hz, 1H), 4.72 - 4.54 (m, 2H), 4.45 - 4.33 (m, 1H), 4.27 (t, J = 5.4 Hz, 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 = 6.7 Hz, 3H).

[0789] 31 P NMR (162 MHz, Methanol-d4) δ 0.17.

[0790] 19 F NMR (377 MHz, Methanol-d4) δ -116.09 (td, J = 9.3, 5.7 Hz).

[0791] LCMS: 806.20 [M+H] +

[0792] Intermediate 46-2: (S)-2-((2-methylallyl)oxy)-3-(octadecyloxy)propan-1-ol Intermediate 46-3: (S)-2-isobutoxy-3-(octadecyloxy)propan-1-ol

[0793]

[0794] Intermediate 46-1 was prepared in a similar manner to Intermediate 2-1 using 3-bromo-2-methylpropene in place of 4-(bromomethyl)-1,1’-biphenyl. 1 H NMR (400 MHz, Chloroform-d) δ 5.02–4.98 (m, 1H), 4.89 (m, 1H), 4.06 (s, 2H), 3.69 (dd, J = 5.1, 1.6 Hz, 1H), 3.58–3.51 (m, 2H), 3.50–3.40 (m, 4H), 1.77 (s, 3H), 1.56 (m, 2H), 1.28 (s, 30H), 0.91 (m, 12H), 0.09 (m, 6H).

[0795] Intermediate 46-4: (R)-2-isobutoxy-3-(octadecyloxy)propyl bis(4-nitrophenyl) phosphate

[0796]

[0797] A solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.05 mL, 1.05 mmol) was added via syringe to a stirred solution of 46-1 (179 mg, 359 µmol) in tetrahydrofuran (10 mL) at room temperature. After 150 min, 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 silica gel flash chromatography (0 to 25% ethyl acetate in hexanes) to afford Intermediate 46-2. 1 H NMR (400 MHz, Chloroform-d) δ 5.00 (m, 1H), 4.92–4.86 (m, 1H), 4.06 (s, 2H), 3.69 (dd, J = 5.1, 1.6 Hz, 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).

[0798] Intermediate 46-5: ((3aR,4R,6R,6aR)-6-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-isobutoxy- 3-(octadecyloxy)propyl)(4-nitrophenyl) phosphate

[0799]

[0800] A vigorously stirred mixture of Intermediate 46-2 (140 mg, 351 µmol), platinum (10 wt% on carbon, 193 mg, 98.0 µmol), tetrahydrofuran (1.5 mL), and ethanol (4.5 mL) was placed under a hydrogen atmosphere (balloon) at room temperature. After 16 h, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford Intermediate 46-3. 1H NMR (400 MHz, Chloroform-d) δ 3.80 - 3.72 (m, 1H), 3.65 (dd, J = 11.4, 4.9 Hz, 1H), 3.59 - 3.38 (m, 4H), 3.31 (dd, J = 9.1, 6.6 Hz, 1H), 1.88 (p, J = 6.7 Hz, 1H), 1.63 - 1.52 (m, 2H), 1.28 (s, 30H), 0.99 - 0.83 (m, 6H).

[0801] Example 44: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-methoxy-3-(octadecyloxy)propyl) hydrogen phosphate (44)

[0802]

[0803] Intermediate 46-4 was prepared in a manner similar to Intermediate 2-3 using 46-3 instead of Intermediate 2-2. LCMS: 722.9.

[0804] Example 44: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-methoxy-3-(octadecyloxy)propyl) hydrogen phosphate (44) Intermediate 47-1: (R)-2,2-dimethyl-4-((octadecyloxy)methyl)-1,3-dioxolane Intermediate 47-2: (S)-2-isopropoxy-3-(octadecyloxy)propan-1-ol

[0805]

[0806] Intermediate 46-5 was prepared in a manner similar to Intermediate 2-4 using 46-4 instead of Intermediate 2-3. LCMS: 915.3.

[0807] Intermediate 47-3: (R)-2-isopropoxy-3-(octadecyloxy)propyl bis(4-nitrophenyl) phosphate Intermediate 47-4: ((3aR,4R,6R,6aR)-6-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-isopropoxy- 3-(octadecyloxy)propyl)(4-nitrophenyl) phosphate (46)

[0808]

[0809] Compound 46 was prepared in a manner similar to Compound 18 using 46-5 instead of Intermediate 18-5. 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (s, 1H), 7.01 (d, J = 4.6 Hz, 1H), 6.94 (d, J = 4.6 Hz, 1H), 5.08 (m, 1H), 4.59 (s, 1H), 4.27 (t, J = 5.3 Hz, 1H), 4.20 - 4.11 (m, 1H), 4.11 - 3.97 (m, 1H), 3.82 (t, J = 5.5 Hz, 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.

[0810] Example 44: ((2R,3S,4R,5R)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-methoxy-3-(octadecyloxy)propyl) hydrogen phosphate (44)

[0811]

[0812] Acetone (458 μL, 6.18 mmol) was added via syringe to a rapidly stirred mixture of p-toluenesulfonic acid monohydrate (11.8 mg, 61.8 μmol) and (S)-3-(octadecyloxy)propane-1,2-diol (213 mg, 618 μmol) in dichloromethane (10 mL) at room temperature. After 90 min, the reaction mixture was heated to 50 °C. After 30 min, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (0 to 30% ethyl acetate in hexanes) to give Intermediate 47-1. 1 H NMR (400 MHz, Chloroform-d) δ 4.33 - 4.23 (m, 1H), 4.08 (dd, J = 8.3, 6.4 Hz, 1H), 3.75 (dd, J = 8.2, 6.4 Hz, 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).

[0813] ​

[0814]

[0815] Dichloroborane methyl sulfide complex (52 μL, 380 μmol) was added via syringe to a rapidly stirred mixture of Intermediate 47-1 (149 mg, 387 μmol) in tetrahydrofuran (750 μL) at -60 °C. The reaction was allowed to warm to room temperature over 15 min. After 16 h, 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 silica gel flash chromatography (0 to 30% ethyl acetate in hexanes) to give Intermediate 47-2. 1 H NMR (400 MHz, Chloroform-d) δ 3.80 (p, J = 6.1 Hz, 1H), 3.71 (dd, J = 10.1, 3.4 Hz, 1H), 3.67 - 3.56 (m, 2H), 3.52 (dd, J = 9.8, 4.8 Hz, 1H), 3.49 - 3.41 (m, 3H), 1.58 (m, 2H), 1.28 (d, J = 1.9 Hz, 30H), 1.20 (dd, J = 6.1, 0.9 Hz, 6H), 0.94 - 0.85 (m, 3H).

[0816] ​

[0817]

[0818] Intermediate 47-3 was prepared in a similar manner to 46-4 using 47-2 in place of 46-3. LCMS: 731.2 [M+Na] + .

[0819] ​ ​ ​

[0820]

[0821] Intermediate 47-4 was prepared in a similar manner to 46-5 using 47-3 in place of 46-4. LCMS: 923.4 [M+Na] + .

[0822] ​ ​ (47)

[0823]

[0824] Potassium trimethylsilanolate (9.8 mg, 77 μmol) was added to a rapidly stirring mixture of 47-4 (23.0 mg, 25.5 μmol) in tetrahydrofuran (800 μL) at room temperature. After 45 min, potassium trimethylsilanolate (27 mg, 210 μmol) was added. After 45 min, concentrated hydrochloric acid (200 μL) was added. After 90 min, triethylamine was added until the mixture had a pH > 7, as indicated by the persistent yellow color. The mixture was purified by reverse-phase preparative HPLC (2-propanol / water) to give compound 47 as a salt with triethylamine. 1 HNMR (400 MHz, Methanol-d4) δ 7.98 (s, 1H), 7.11 (s, 2H), 4.82 (d, J = 5.3 Hz, 1H), 4.36 (d, J = 4.7 Hz, 1H), 4.27 (t, J = 5.4 Hz, 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, 4.9 Hz, 1H), 3.54 (d, J = 6.0 Hz, 1H), 3.47 - 3.39 (m, 2H), 1.56 (m, 2H), 1.30 (m, 30H), 1.12 (dd, J = 6.1, 1.7 Hz, 6H), 0.96 - 0.88 (m, 3H). LCMS: 738.4 [M-H] - .

[0825] Intermediate 48-1: (R)-tert-butyldimethylsilanediyl bis(2-((3,4-dichlorobenzyl)oxy)-3- (octadecyloxy)propyl) oxide Methylsilane

[0826]

[0827] Sodium hydride (60 wt% dispersion in mineral oil, 74 mg, 1.94 mmol) was added to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3- (octadecyloxy)propan-2-ol (335 mg, 730 μmol) in tetrahydrofuran (6 mL) at 0 °C. After 30 min, 4-(bromomethyl)-1,2-dichlorobenzene (438 mg, 1.83 mmol) was added, 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 x 20 mL). The combined organic fractions were then washed with brine (25 mL) and dried over magnesium sulfate. Filtration and concentration followed by purification of the crude residue by silica gel flash column chromatography (0 to 20% ethyl acetate in hexanes) afforded Intermediate 48-1. 1 H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 1.9 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.21 (dd, J = 8.2, 2.0 Hz, 1H), 4.68 (s, 2H), 3.71 (d, J = 5.9 Hz, 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).

[0828] Intermediate 48-2: (S)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propan-1-ol

[0829]

[0830] Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.63 mL, 0.63 mmol) was added to a stirred solution of Intermediate 48-1 (323 mg, 523 μmol) in tetrahydrofuran (5 mL) at 0 °C. After 1 h, water (5 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were then washed with brine (25 mL) and dried over magnesium sulfate. Filtration and concentration followed by purification of the crude residue by silica gel flash column chromatography (0 to 50% ethyl acetate in hexanes) afforded Intermediate 48-2. 1H NMR (400 MHz, Chloroform-d) δ 7.49 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.20 (dd, J = 8.2, 2.0 Hz, 1H), 4.66 (q, J = 12.3 Hz, 2H), 3.83 - 3.64 (m, 3H), 3.59 (qd, J = 10.0, 5.0 Hz, 2H), 3.46 (td, J = 6.7, 1.9 Hz, 2H), 2.11 (t, J = 6.0 Hz, 1H), 1.65 - 1.55 (m, 2H), 1.28 (s, 30H), 0.90 (t, J = 6.7 Hz, 3H).

[0831] Intermediate 48-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3,4-dichlorobenzyl)oxy)- 3-(octadecyloxy)propyl)(2-chlorophenyl) phosphate Methylsilane Intermediate 48-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3,4-dichlorobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate

[0832]

[0833] At room temperature, 2-chlorophenyl phosphorodichloridate (64.6 μL, 392 μmol) was added via syringe to a vigorously stirring mixture of 1,2,4-triazole (54.3 mg, 786 μmol), triethylamine (110 μL, 786 μmol), and tetrahydrofuran (0.6 mL). After 40 min, Intermediate 1-3 (97.5 mg, 294 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (31.3 μL, 313 μmol) were added sequentially. After 60 min, a solution of Intermediate 48-2 (148 mg, 294 μmol) in tetrahydrofuran (0.7 mL) was added via cannula. 1-Methylimidazole (20 μL, 392 μmol) was added. After 15 h, saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0 to 10% methanol in dichloromethane) to afford Intermediate 48-3. 1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 1.6 Hz, 1H), 7.45 - 7.34 (m, 4H), 7.21 - 7.06 (m, 3H), 7.01 (t, J = 4.6 Hz, 1H), 6.61 (dd, J = 10.3, 4.7 Hz, 1H), 5.62 (s, 2H), 5.44 (dd, J = 17.1, 6.8 Hz, 1H), 4.99 (ddd, J = 9.2, 6.8, 4.0 Hz, 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 = 2.7 Hz, 30H), 0.90 (t, J = 6.7 Hz, 3H).

[0834] Example 48: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3,4-dichlorobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (48) Intermediate 48-1: (R)-tert-butyldimethylsilanediyl bis(2-((3,4-dichlorobenzyl)oxy)-3- (octadecyloxy)propyl) oxide Methylsilane

[0835]

[0836] Sodium hydroxide (0.5 N, 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 h, concentrated hydrochloric acid (30 μL, 357 μmol) was added. The residue was then concentrated and purified by flash column chromatography on silica gel (0 to 30% methanol in dichloromethane) to give intermediate 48-4. 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.24 (dd, J = 8.2, 1.9 Hz, 1H), 6.93 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.6 Hz, 1H), 5.40 (d, J = 6.4 Hz, 1H), 5.03 (dd, J = 6.5, 3.2 Hz, 1H), 4.65 - 4.50 (m, 3H), 4.06 (d, J = 5.7 Hz, 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).

[0837] Intermediate 48-2: (S)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propan-1-ol Intermediate 48-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3,4-dichlorobenzyl)oxy)- 3-(octadecyloxy)propyl)(2-chlorophenyl) phosphate Methylsilane

[0838]

[0839] Concentrated hydrochloric acid (52.4 μL, 629 μmol) was added to a solution of 48-4 (47 mg, 52.4 μmol) in tetrahydrofuran (0.5 mL). After 3 h, sodium carbonate (67 mg, 629 μmol), methanol (10 mL), and magnesium sulfate were added sequentially and stirred at room temperature for 10 min. It was then filtered and concentrated, and the residue was purified by flash column chromatography on silica gel (0 to 50% methanol in dichloromethane) to give compound 48. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 4.5 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.95 - 4.75 (m, 1H), 4.60 (s, 2H), 4.39 - 4.33 (m, 1H), 4.20 (t, J = 5.8 Hz, 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 = 6.7 Hz, 3H).

[0840] Example 48: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3,4-dichlorobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (48) Intermediate 48-1: (R)-tert-butyldimethylsilanediyl bis(2-((3,4-dichlorobenzyl)oxy)-3- (octadecyloxy)propyl) oxide

[0841]

[0842] Intermediate 49-1 was prepared in a manner similar to Intermediate 2-1 using 4-(bromomethyl)-2-chloro-1-methoxy-benzene instead of 4-(bromomethyl)-1,1'-biphenyl. LCMS: 635.5 [M+Na] + .

[0843] Methylsilane

[0844]

[0845] Intermediate 49-2 was prepared in a manner similar to Intermediate 18-3 using 49-1 instead of Intermediate 18-2. LCMS: 522.1 [M+Na] + .

[0846] Intermediate 48-2: (S)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propan-1-ol Intermediate 48-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3,4-dichlorobenzyl)oxy)- 3-(octadecyloxy)propyl)(2-chlorophenyl) phosphate Methylsilane

[0847]

[0848] Intermediate 49-3 was prepared in a similar manner to 23-2 using 49-2 in place of 23-1. LCMS: 1024.5 [M+Na] + .

[0849] Example 48: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3,4-dichlorobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (48) Intermediate 48-1: (R)-tert-butyldimethylsilanediyl bis(2-((3,4-dichlorobenzyl)oxy)-3- (octadecyloxy)propyl) oxide Methylsilane

[0850]

[0851] Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 25 μL, 25 μmol) was added via syringe to a vigorously stirred mixture of intermediate 49-3, pyridine (3 μL, 40 μmol), water (3 μL, 200 μmol), and tetrahydrofuran (100 μL). After 4 h, an additional 25 μL (25 μmol) of tetrabutylammonium fluoride was added via syringe. After 16 h, trimethylsilyl chloride (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 (0.1% trifluoroacetic acid in methanol / water) to give compound 49. 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 4.5 Hz, 1H), 6.98 (s, 1H), 6.88 (d, J = 4.6 Hz, 1H), 5.19 (s, 1H), 4.59 (d, J = 4.7 Hz, 2H), 4.56 (s, 1H), 4.51 (s, 1H), 4.48 (s, 1H), 4.35 (s, 2H), 4.26 (t, J = 5.4 Hz, 1H), 4.08 (s, 1H), 3.87 (s, 3H), 3.78 - 3.63 (m, 2H), 3.59 (s, 1H), 1.53 (s, 2H), 1.30 (d, J = 10.7 Hz, 30H), 1.00 - 0.81 (m, 3H). LCMS: 850.5 [M-H] - .

[0852] Intermediate 48-2: (S)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propan-1-ol Intermediate 48-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3,4-dichlorobenzyl)oxy)- 3-(octadecyloxy)propyl)(2-chlorophenyl) phosphate

[0853]

[0854] Intermediate 50-1 was prepared in a similar manner to Intermediate 2-1 using 2- (bromomethyl)benzonitrile in place of 4-(bromomethyl)-1,1'-biphenyl. 1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 7.6, 1.2 Hz, 1H), 7.59 (td, J = 7.7, 1.3 Hz, 1H), 7.38 (td, J = 7.6, 1.2 Hz, 1H), 4.93 (s, 2H), 3.77 (d, J = 5.4 Hz, 2H), 3.71 (tt, J = 5.7, 4.4 Hz, 1H), 3.60 (qd, J = 10.3, 4.9 Hz, 2H), 3.46 (td, J = 6.6, 1.6 Hz, 2H), 1.58 (q, J = 7.1 Hz, 2H), 1.27 (s, 30H), 0.91 (d, J = 6.6 Hz, 12H), 0.09 (s, 6H).

[0855] ​

[0856]

[0857] Intermediate 50-2 was prepared in a manner similar to Intermediate 18-3 using 50-1 in place of Intermediate 18-2. 1 H NMR (400 MHz, Chloroform-d) δ 7.72 - 7.66 (m, 1H), 7.65 - 7.57 (m, 2H), 7.42 (ddd, J = 7.7, 6.0, 2.8 Hz, 1H), 4.91 (d, J = 12.2 Hz, 1H), 4.86 (d, J = 12.2 Hz, 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, 1.1 Hz, 2H), 1.67 - 1.49 (m, 2H), 1.28 (s, 30H), 0.90 (t, J = 6.7 Hz, 3H).

[0858] Intermediate 50-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)((R)- 2-((2-cyanobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate

[0859]

[0860] Intermediate 50-3 was prepared in a manner similar to 23-2 using 50-2 in place of 23-1. LCMS: 963.3.

[0861] Example 50: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((2-cyanobenzyl)oxy)-3-(octadecyloxy)propyl) hydrogen phosphate (50)

[0862]

[0863] Compound 50 was prepared in a manner analogous to 49 using intermediate 50-3 in place of 49-3. 1 HNMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.48 - 7.38 (m, 1H), 7.37 - 7.26 (m, 1H), 7.20 (d, J = 4.8 Hz, 1H), 4.78 (d, J = 5.1 Hz, 2H), 4.64 (d, J = 11.5 Hz, 1H), 4.35 (s, 2H), 4.26 (t, J = 5.4 Hz, 1H), 4.23 - 4.14 (m, 1H), 4.14 - 4.06 (m, 1H), 3.98 (qt, J = 11.1, 5.6 Hz, 2H), 3.83 (t, J = 5.1 Hz, 1H), 3.58 (qd, J = 10.6, 5.1 Hz, 2H), 3.45 (td, J = 6.5, 2.4 Hz, 1H), 1.54 (t, J = 7.0 Hz, 2H), 1.29 (d, J = 7.9 Hz, 30H), 0.92 (t, J = 6.5 Hz, 3H). LCMS: 813.2.

[0864] Intermediate 51-1: (R)-2-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop- 2-yl)oxy)methyl)-4-fluorobenzyl nitrile

[0865]

[0866] Intermediate 51-1 was prepared in a manner analogous to Intermediate 2-1 using 2- (bromomethyl)-4-fluoro-benzonitrile in place of 4-(bromomethyl)-1,1'-biphenyl. 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (dd, J = 8.6, 5.3 Hz, 1H), 7.52 (dd, J = 9.5, 2.6 Hz, 1H), 7.06 (td, J = 8.2, 2.6 Hz, 1H), 4.94 (s, 2H), 3.77 (d, J = 4.9 Hz, 2H), 3.72 (tt, J = 6.2, 4.5 Hz, 1H), 3.63 - 3.54 (m, 2H), 3.47 (tt, J = 5.6, 1.9 Hz, 2H), 1.65 - 1.52 (m, 2H), 1.40 - 1.19 (m, 30H), 0.96 - 0.84 (m, 12H), 0.09 (s, 6H).

[0867] Intermediate 51-2: (S)-4-fluoro-2-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)benzylnitrile

[0868]

[0869] Intermediate 51-2 was prepared in a similar manner to Intermediate 18-3 using 51-1 in place of Intermediate 18-2. 1 HNMR (400 MHz, Chloroform-d) δ 7.69 (dd, J = 8.6, 5.3 Hz, 1H), 7.39 (dd, J = 9.2, 2.6 Hz, 1H), 7.11 (td, J = 8.2, 2.6 Hz, 1H), 4.90 (d, J = 3.4 Hz, 2H), 3.85 (d, J = 9.0 Hz, 1H), 3.81 - 3.72 (m, 2H), 3.70 - 3.59 (m, 2H), 3.48 (td, J = 6.6, 1.5 Hz, 2H), 2.22 (s, 1H), 1.58 (d, J = 14.8 Hz, 2H), 1.28 (s, 30H), 0.94 - 0.86 (m, 3H).

[0870] 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)

[0871]

[0872] Compound 51 was prepared in a similar manner to Compound 19 using 51-2 in place of 19-2. 1 HNMR (400 MHz, Chloroform-d) δ 7.69 (dd, J = 8.6, 5.3 Hz, 1H), 7.39 (dd, J = 9.2, 2.6 Hz, 1H), 7.11 (td, J = 8.2, 2.6 Hz, 1H), 4.90 (d, J = 3.4 Hz, 2H), 3.85 (d, J = 9.0 Hz, 1H), 3.81 - 3.72 (m, 2H), 3.70 - 3.59 (m, 2H), 3.48 (td, J = 6.6, 1.5 Hz, 2H), 2.22 (s, 1H), 1.58 (d, J = 14.8 Hz, 2H), 1.28 (s, 30H), 0.94 - 0.86 (m, 3H). - .

[0873] Example 52: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((2,3-dihydro-1H-inden-5-yl)methoxy)-3-(octadecane) (52)Oxypropyl)hydrogen phosphate

[0874]

[0875] Compound 52 was prepared in a similar manner to Compound 19 using 5-(bromomethyl)-2,3-dihydro-1H-indene in place of 1-(bromomethyl)-3-fluoro-5- (trifluoromethyl)benzene. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.18 (s, 1H), 7.12 - 7.04 (m, 2H), 7.00 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.80 (d, J = 5.3 Hz, 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 = 7.4 Hz, 4H), 2.13 - 1.96 (m, 2H), 1.52 (t, J = 6.8 Hz, 2H), 1.38 - 1.24 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 828.2.

[0876] Intermediate 53-1: (R)-4-(((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)prop- 2-yl)oxy)methyl)-3-fluorobenzyl nitrile:

[0877]

[0878] NaH (60% dispersion in oil, 88 mg, 2.29 mmol, 3.5 eq) 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 eq) 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 was quenched with water (15 mL). The mixture was extracted with EtOAc. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-30% EtOAc in hexanes) to give the product.

[0879] Intermediate 53-2: (S)-3-fluoro-4-(((1-hydroxy-3-(octadecoxy)prop-2-yl)oxy)methyl)benzylnitrile :

[0880]

[0881] To a solution of the silyl protected compound (342 mg, 0.578 mmol) in THF (3.3 mL) at 0 °C was added 1 M TBAF in THF (1 mL, 1 mmol) and stirred for 1 h. It was diluted with water (3 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (2 x 5 mL), brine, dried over Na2S04, evaporated and the residue was purified by silica gel column chromatography (0-60% ethyl acetate in hexanes) to give the product. 1 H NMR (400 MHz, 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).

[0882] Intermediate 53-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 6-Cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(2-chlorophenyl)((R)- 2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate :

[0883]

[0884] To a solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 μί, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyldichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). The mixture was stirred for 30 min and then filtered. To the filtrate was added additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol) sequentially. After 1 h, (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 at room temperature overnight. The solvent was removed and the residue was purified by silica gel flash chromatography (0-15% MeOH in CH2CI2) to give the compound.

[0885] 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)

[0886]

[0887] The above 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 h. The reaction progress was monitored by TLC. After almost complete consumption of the intermediate, the mixture was neutralized with 4 N HC1 at 0 °C. The mixture was diluted with MeOH and Na2S04was added. The mixture was filtered and the filtrate was evaporated to give a residue.

[0888] The residue was dissolved in THF (1.5 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HC1 (0.3 mL) was added. The cold bath was removed and the reaction was stirred vigorously for 3 h. The mixture was neutralized with Na2C03, diluted with MeOH, and filtered. The filtrate was evaporated to give a residue, which was purified by silica gel column chromatography (0-40% MeOH in DCM) to give the product. 1 H NMR (400 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.54 - 7.39 (m, 2H), 7.04 (d, J = 4.7 Hz, 1H), 6.98 (d, J = 4.6 Hz, 1H), 4.85 - 4.72 (m, 2H), 4.36 (m, 1H), 4.27 (m, 1H), 4.18 (m, 1H), 4.09 (m, 1H), 3.92 (m, 1H), 3.78 (t, 1H), 3.63 - 3.35 (m, 4H), 1.51 (m, 2H), 1.28 (d, 30H), 1.01 - 0.84 (m, 3H). 31 P NMR (162 MHz, Methanol-d4) δ 0.28. MS: 831.22 (M+l).

[0889] Intermediate 54-1: (R)-4-(((1-((tert-butyldimethylsilyl)oxy)-3- (octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile Intermediate 54-2: (S)-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)- 2-methoxybenzonitrile :

[0890]

[0891] Intermediate 54-1 was synthesized in a manner similar to 53-1.

[0892] Intermediate 54-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl)((R)- 2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl) hydrogen phosphate Example 54: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl (3-(decyloxy)propyl) hydrogen phosphate (56)

[0893]

[0894] Intermediate 54-2 was synthesized in a manner similar to 53-2. 1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 7.9 Hz, 1H), 7.04 (s, 1H), 6.98 (d, J = 8.0 Hz, 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 = 6.9 Hz, 2H), 1.26 (s, 30H), 0.88 (t, J = 6.7 Hz, 3H).

[0895] Intermediate 55-1: Preparation of 3-(heptadecyloxy)propan-1-ol Intermediate 55-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl)(3- (heptadecyloxy)propyl) hydrogen phosphate Example 55: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl (3-(heptadecyloxy)propyl) hydrogen phosphate (55)

[0896]

[0897] To 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 added a solution of 2-chlorophenyldichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). The mixture was stirred for 30 min and then filtered. To the filtrate was added additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol) sequentially. After 1 h, (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 at room temperature overnight. The solvent was removed and the residue was purified by silica gel flash chromatography (0-15% MeOH in CH2Cl2) to give the compound.

[0898] Intermediate 56-1: 3-Decyloxypropan-1-ol Intermediate 56-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl)(3- (decyloxy)propyl) hydrogen phosphate Example 56: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl (3-(decyloxy)propyl) hydrogen phosphate (56)

[0899]

[0900] 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 h. The reaction progress was monitored by TLC. After almost complete consumption of the intermediate, the mixture was neutralized with 4 N HCl at 0 °C. The mixture was diluted with methanol and Na2SO4was added. The mixture was filtered and the filtrate was evaporated to give a residue.

[0901] The residue was dissolved in THF (1.5 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HC1 (0.3 mL) was added. The cold bath was removed and the reaction was stirred vigorously for 3 hours. The mixture was neutrali...

Claims

1. A compound of formula I: Or its pharmaceutically acceptable salt, wherein: Z 1 It is -CH2- or –CH2-CH2-; Z 2 It is -CH2- or –CH2-CH2-; X represents a chemical bond, -O-, or -(CR). 12A R 12B ) q -、-O(CR 12A R 12B ) q -or-OCR 12A R 12B -(CR 13 =CR 14 )-;in Each R 12A Independently H or C1-C6 alkyl; Each R 12B Independently H or C1-C6 alkyl; or R on the same carbon 12A and R 12B They are linked together to form C3-C6 cycloalkylene groups; R 13 It is H, C1-C6 alkyl or phenyl; R 14 It is H, C1-C6 alkyl or phenyl; and q is 1 or 2; R 1 For C6-C 10 Aryl; wherein R 1 The group is surrounded by one or two R 1A Group substitution; Each R 1A Independently, it is a C1-C3 alkyl, phenyl, haloyl, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; or two Rs on the same or adjacent carbons thereon. 1A Linked together to form a 3- to 6-membered cycloalkyl group or a 4- to 6-membered heterocyclic ring containing one, two or three heteroatoms selected from N, S and O; R 2 It is H or C1-C3 alkyl; Y is absent, or is a phenylene or a C3-C6 cycloalkylene group; R 3 It can be H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; Each R 4 Independently, it is H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R 4 The group and the R of an adjacent carbon atom 4 The groups together form a double bond; Each R 5 It can be independently H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl; R 6 It is H or -C(O)C1-C6 alkyl; R 7 It is H or -C(O)C1-C6 alkyl; and m is an integer from 10 to 21.

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

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 For -CH2- and Z 2 It is -CH2-.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula III: Where n is an integer from 8 to 19.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Y is absent.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula IV: Where n is an integer from 8 to 19.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For H.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a C1-C3 alkyl group.

10. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has formula V:

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula Va:

12. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula Vb:

13. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein each R 5 It is independently H or C1-C3 alkyl.

14. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein each R 5 For H.

15. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 It is H, C1-C3 alkyl or C3-C6 cycloalkyl.

16. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 It can be H, methyl, ethyl, isopropyl, or cyclopropyl.

17. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein each R 4 It can be independently H, C1-C3 alkyl, halogroup, C1-C3 haloalkyl or C3-C6 cycloalkyl.

18. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein each R 4 It can be H, methyl, or ethyl independently.

19. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein n is an integer from 11 to 18.

20. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 1 for Each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 Independently, it is H, C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein R 1A2 R 1A3 and R 1A4 At least one of them is CN, and R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 At least three of them are H.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 It can be H, a halogenated group, or a cyano group independently.

22. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 4 For H and R 5 For H.

23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R 6 For H and R 7 For H.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 3 It is H, C1-C3 alkyl or C3-C6 cycloalkyl.

25. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound has formula VI:

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the compound has formula VIa:

27. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula VIb:

28. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 1 For one or two R 1A A phenyl group substituted with a radical.

29. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein each R 1A It is independently a C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano or C1-C3 haloalkyl.

30. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein each R 1A It can be methyl, phenyl, chlorine, fluorine, methoxy, ethoxy, cyano, CHF2 or CF3 independently.

31. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein each R 1A It can be chlorine, fluorine, or cyanide on its own.

32. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein at least one R 1A It is a cyano group.

33. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein at least one R 1A It is cyano, and another R 1A If present, it is either cyano or halogroup.

34. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 1 for Each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 Independently, it is H, C1-C3 alkyl, phenyl, halogroup, C1-C3 alkoxy, cyano, or C1-C3 haloalkyl; wherein R 1A2 R 1A3 and R 1A4 At least one of them is CN, and R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 At least three of them are H.

35. The compound of claim 34 or a pharmaceutically acceptable salt thereof, wherein each R 1A1 R 1A2 R 1A3 R 1A4 and R 1A5 It can be H, a halogenated group, or a cyano group independently.

36. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein two Rs on the same or adjacent carbons are... 1A They are linked together to form 3 to 6-membered cycloalkyl groups.

37. A compound, said compound being selected from the group consisting of: Or their pharmaceutically acceptable salts.

38. The compound of claim 37, wherein the compound is selected from the group consisting of: Or their pharmaceutically acceptable salts.

39. The compound of claim 37, wherein the compound is selected from the group consisting of: Or their pharmaceutically acceptable salts.

40. The compound of claim 37, wherein the compound is selected from the group consisting of: Or their pharmaceutically acceptable salts 41. The compound according to claim 37, wherein the compound is: Or its pharmaceutically acceptable salt.

42. The compound according to claim 37, wherein the compound is: Or its pharmaceutically acceptable salt.

43. The compound according to claim 37, wherein the compound is: Or its pharmaceutically acceptable salt.

44. A pharmaceutical formulation comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

45. The pharmaceutical preparation of claim 44, wherein the pharmaceutical preparation is for oral administration.

46. ​​Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43 in the preparation of a medicament for treating coronavirus infection.

47. The use according to claim 46, wherein the coronavirus infection is a zoonotic coronavirus infection.

48. The use according to claim 46, wherein the coronavirus infection is SARS-CoV-2 infection.

49. The use according to claim 46, wherein the coronavirus infection is a SARS virus infection.

50. The use according to claim 46, wherein the coronavirus infection is a MERS virus infection.

51. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43 in the preparation of a medicament for infection with a pulmonary viral family virus.

52. The use according to claim 51, wherein the pulmonary virus infection is a respiratory syncytial virus infection.

53. The use according to claim 51, wherein the pulmonary virus infection is human metapneumovirus infection.

Images