Phospholipid compounds and methods for producing and using same

Abstract

Disclosed are phospholipid compounds and methods of using the phospholipid compounds alone or in combination with additional agents, as well as pharmaceutical formulations of the compounds for the treatment of viral infections.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 63 / 234,515, filed August 18, 2021, and 63 / 313,633, filed February 24, 2022, both of which are incorporated herein in their entirety for all purposes. Sequence Listing

[0002] The instant application contains an electronically submitted Sequence Listing, which is hereby incorporated by reference in its entirety. [Background technology]

[0003] There is a need for compounds, pharmaceutical formulations, and methods for treating viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, and Orthomyxovirus families. Embodiments of the present disclosure can address these and other needs. Summary of the Invention [Means for solving the problem]

[0004] Disclosed herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof; R 1 is C3~C 10 Cycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl containing 1, 2 or 3 N; R 1 is R 1A and -NR 13A R 14Aand optionally substituted with 1, 2, or 3 groups independently selected from Each R 1A are independently halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O; Each R 13A are independently H or C1-C3 alkyl, Each R 14A are independently H or C1-C3 alkyl, R 2 is H or C1-C3 alkyl, R 3 is a C1-C3 alkyl, Each R 4 are independently a bond, H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; Each R 5 are independently a bond or H, Two or more adjacent (CR 4 R 5 ) groups are optionally connected via a double bond, R 6 is H or —C(O)C1-C6 alkyl, R 7 is H or —C(O)C1-C6 alkyl, m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21; L is -O-, -(CR 12A R 12B ) n -, -O-(CR 12A R 12B ) n -, -(CR 12A R 12B ) n -O-, or -(CR 12A R 12B ) n -O-(CR 12A R 12B ) n - and Each R 12A are independently H or C1-C6 alkyl, Each R 12B are independently H or C1-C6 alkyl, n is 1 or 2, Q is a bond or phenylene; T is a bond or —O—; X is a bond or C1-C3 alkylene; Z is -O-, -O-(C1-C6)-alkylene or NR 15 -(C1-C6)-alkylene, R 15 is H or C1-C3 alkyl.

[0005] Also disclosed herein are compounds of subformulas of Formula I, such as Formulas Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIa, XIb, XII, XIIa, XIIb, XIII, XIIIa, and XIIIb.

[0006] Disclosed herein are pharmaceutical formulations comprising a pharmaceutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0007] Also disclosed herein is a method of treating or preventing a viral infection in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0008] Further disclosed herein is a method of treating or preventing a viral infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0009] The present disclosure provides a method for manufacturing a medicament for treating or preventing a viral infection in a subject in need thereof, wherein a compound disclosed herein or a pharmaceutically acceptable salt thereof is used.

[0010] The present disclosure provides a method for manufacturing a medicament for treating or preventing a viral infection in a human in need thereof, wherein a compound disclosed herein or a pharmaceutically acceptable salt thereof is used.

[0011] The present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0012] I. Overview The present disclosure broadly relates to methods and compounds for treating or preventing viral infections, such as infections of the Paramyxoviridae, Pneumoviridae, Pneumoviridae, Flaviviridae, Filoviridae, and Orthomyxoviridae families. The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the disclosure, but instead is provided as a description of exemplary embodiments. II. Definition

[0013] As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0014] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. Dashes at the front or end of a chemical group are for convenience, and chemical groups may be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0015] For example, a squiggly line over a chemical group such as shown below, e.g. [ka] indicates a point of attachment, i.e., it indicates a broken bond where a group is attached to another described group.

[0016] As used herein, "a compound of the disclosure" can mean a compound of any of Formulas I-XIIIb or a pharmaceutically acceptable salt thereof. Similarly, the phrase "a compound of formula (number)" means a compound of formula (number) and its pharmaceutically acceptable salts.

[0017] "C u ~C v The prefix "" indicates that the following group has carbon atoms u through v. For example, "C 1~ "C8 alkyl" indicates that the alkyl group has from 1 to 8 carbon atoms.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1 to C6). 20The alkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (- CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 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), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3). Other alkyl groups include, but are not limited to, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0019] "Alkylene" refers to unbranched and branched divalent saturated hydrocarbon chains. As used herein, alkylene refers to alkylenes having 1 to 20 carbon atoms (i.e., C 1~20 alkylene), 1 to 12 carbon atoms (i.e., C 1~12 alkylene), 1 to 8 carbon atoms (i.e., C 1~8 alkylene), 1 to 6 carbon atoms (i.e., C 1~6 alkylene), 1 to 4 carbon atoms (i.e., C 1~4 alkylene), 1 to 3 carbon atoms (i.e., C 1~3 alkylene), or 1 to 2 carbon atoms (i.e., C 1~2 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0020] "Alkenyl" refers to an unbranched or branched hydrocarbon chain containing at least two carbon atoms and at least one carbon-carbon double bond. As used herein, alkenyl refers to an alkyl group having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4Alkenyl can have C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 Alkenyl groups can contain any number of carbons, such as 1, 2, 3, 4, 5, or any range in between. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0021] "Alkoxy" means a group having the formula -O-alkyl, where an alkyl group, as defined above, is attached to the parent molecule through an oxygen atom. The alkyl portion of the alkoxy group contains 1 to 20 carbon atoms (i.e., C1 to C6). 20 alkoxy), 1 to 12 carbon atoms (i.e., C1 to C 12The alkoxy group may have 1 to 8 carbon atoms (i.e., C1-C8 alkoxy), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy), or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), isopropoxy (-O-CH(CH3)2), t-butoxy (-OC(CH3)3 or -OtBu), and the like. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. The alkoxy group may be substituted or unsubstituted.

[0022] A "haloalkyl" is an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group are replaced with a halogen atom. The alkyl portion of a haloalkyl group has 1 to 20 carbon atoms (i.e., C1 to C6). 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0023] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (I).

[0024] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms of the alkoxy group are replaced by a halogen atom. The alkoxy portion of the haloalkoxy group has 1 to 20 carbon atoms (i.e., C1 to C6). 20 haloalkoxy), 1 to 12 carbon atoms (i.e., C1 to C 12haloalkoxy), 1 to 8 carbon atoms (i.e., C1-C8 haloalkoxy), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy), or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Examples of suitable haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2, -OCFH2, -OCH2CF3, and the like.

[0025] "Hydroxy" refers to --OH.

[0026] "Aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have from 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, biphenyl, and the like.

[0027] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having one or more rings, including fused, bridged, and spiro ring systems. As used herein, cycloalkyl refers to a group having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups also include partially unsaturated ring systems containing one or more double bonds, and include fused ring systems having one aromatic ring and one non-aromatic ring, but not entirely aromatic.

[0028] "Heteroaryl" refers to aromatic groups, including groups having aromatic tautomers or resonance structures, having monocyclic, polycyclic, or multiple fused rings with at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the nitrogen or sulfur can be oxidized. Thus, the term includes rings having one or more cyclic O, N, S, S(O), S(O)2, and N-oxide groups. The term includes rings having one or more cyclic C(O) groups. As used herein, heteroaryl includes groups having 5 to 20 ring atoms (i.e., 5-20-membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, as well as oxidized forms of the heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyridin-2(1H)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass and does not overlap with aryl, as defined above.

[0029] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heterocyclyl can be monocyclic or polycyclic, and polycyclic rings can be fused, bridged, or spiro. As used herein, a heterocyclyl has 3 to 20 ring atoms (i.e., 3-20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3-12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3-10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3-8-membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., 4-12-membered heterocyclyl), 4 to 8 ring atoms (i.e., 4-8-membered heterocyclyl), or 4 to 6 ring atoms (i.e., 4-6-membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

[0030] The term "optionally substituted" with respect to a particular moiety in a compound disclosed herein (e.g., an optionally substituted aryl group) refers to a moiety where all of the substituents are hydrogen, or where one or more of the hydrogens on the moiety can be replaced with the listed substituents.

[0031] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, formulations, dosage forms, and other substances that are useful in preparing pharmaceutical formulations suitable for veterinary or human pharmaceutical use.

[0032] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that possesses the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne, hexyne-1,4-diol, hexyne-2 ... 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0033] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. +(X is C1-C4 alkyl). Base addition salts such as sodium or potassium salts are also included.

[0034] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom can be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can have enhanced resistance to metabolism and thus can be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium. The compounds disclosed herein can be deuterated at various positions, including (but not limited to) the following positions: [ka]

[0035] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123I, and 125 I can also be mentioned. 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of Formulas I-XIIIb can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples below, using the appropriate isotopically labeled reagents in place of conventionally employed unlabeled reagents.

[0036] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, with respect to absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that embodiments are directed to either the specific diastereomerically or enantiomerically enriched form, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0037] The term "prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. The term "prevention" or "preventing" also encompasses administering a compound or composition according to the embodiments disclosed herein after a subject has been exposed to a virus but before symptoms of the disease appear and / or before the virus is detectable in the blood, to prevent symptoms of the disease from appearing and / or the virus from reaching detectable levels in the blood, and administering a compound or composition according to the embodiments disclosed herein to a mother before birth and to a child within the first few days of life, to prevent perinatal transmission of a viral infection from mother to infant.

[0038] A "racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0039] "Stereoisomer" and "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric forms if they possess one or more asymmetric centers or double bonds with asymmetric substitution and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley & Sons, New York, 1992).

[0040] "Subject" or "patient" is meant to describe a vertebrate, including a human or dog, cat, pocket pet, marmoset, horse, cow, pig, sheep, goat, elephant, giraffe, chicken, lion, monkey, owl, rat, squirrel, slender loris, and mouse. "Pocket pet" refers to the group of vertebrates that can fit into a commodity coat pocket, such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits, and sugar gliders.

[0041] "Tautomer" refers to alternative forms of a compound that differ in the location of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms attached to both the -NH- and =N- rings, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the front or end of chemical groups are for convenience; chemical groups may be designated with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied in the order in which chemical groups are written or their point of attachment to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be attached in either direction. Similarly, for example, an "arylalkyl" group can be attached to the rest of the molecule at either the aryl or alkyl portion of the group. "C u~v " or (C u ~C v ) indicates that the following group has u to v carbon atoms. For example, "C 1~6Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "x- to y-membered" ring, where x and y are numerical ranges (e.g., "3- to 12-membered heterocyclyl") refers to a ring having x to y atoms (e.g., 3 to 12), up to 80% of which may be heteroatoms such as N, O, S, etc., and the remaining atoms are carbon.

[0043] Unless otherwise specified, the carbon atoms of the compounds of Formulas I-XIIIb are intended to have a valence of 4. If a carbon atom in some chemical structure representation does not have a sufficient number of variables to produce a valence of 4, the remaining carbon substituents necessary to provide a valence of 4 should be assumed to be hydrogen.

[0044] As used herein, the terms "treating" and "treatment" are intended to mean administering a compound or composition according to an embodiment disclosed herein to reduce or eliminate symptoms of a viral infection and / or reduce viral load in a subject.

[0045] As used herein, the term "therapeutically effective amount" refers to the amount of a compound disclosed herein present in a formulation described herein required to provide a desired level of drug in the subject's secretions and airway and lung tissues, or alternatively, in the bloodstream of a treated subject, that will produce an expected physiological response or desired biological effect when such formulation is administered via a selected route of administration. The exact amount will depend on numerous factors, including the specific compound disclosed herein, the specific activity of the formulation, the delivery device used, the physical properties of the formulation, its intended use, and subjective considerations such as the severity of the disease state and the patient's cooperation, and can be readily determined by one of skill in the art based on the information provided herein. The term "therapeutically effective amount" or "effective amount" also refers to an amount that eliminates or reduces a subject's viral load and / or viral reservoir.

[0046] As used herein, the term "adjacent carbons" refers to consecutive carbon atoms that are directly bonded to each other. For example, [ka] In the formula, 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. [ka] In the example, C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, C4 and C5 are adjacent carbons, C5 and C6 are adjacent carbons, and C6 and C1 are adjacent carbons.

[0047] As used herein, "solvate" refers to the result of the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0048] As used herein, "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted into the parent drug through some chemical or enzymatic pathway.

[0049] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include, but are not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and combinations thereof. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Except as long as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulation. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. III.Compound

[0050] Provided herein are compounds of formula I [ka] or a pharmaceutically acceptable salt thereof; R 1 is C3~C 10 Cycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl containing 1, 2 or 3 N; R 1 is R 1A and -NR 13A R 14A and optionally substituted with 1, 2, or 3 groups independently selected from Each R 1A are independently halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O; Each R 13A are independently H or C1-C3 alkyl, Each R 14A are independently H or C1-C3 alkyl, R 2 is H or C1-C3 alkyl, R 3 is a C1-C3 alkyl, Each R 4 are independently a bond, H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; Each R 5 are independently a bond or H, Two or more adjacent (CR 4 R 5 ) groups are optionally connected via a double bond, R 6 is H or —C(O)C1-C6 alkyl, R 7 is H or —C(O)C1-C6 alkyl, m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21; L is -O-, -(CR 12A R 12B ) n -, -O-(CR 12A R 12B ) n -, -(CR 12A R 12B ) n -O-, or -(CR 12A R 12B ) n -O-(CR 12A R 12B ) n - and Each R 12A are independently H or C1-C6 alkyl, Each R 12B are independently H or C1-C6 alkyl, n is 1 or 2, Q is a bond or phenylene; T is a bond or —O—; X is a bond or C1-C3 alkylene; Z is -O-, -O-(C1-C6)-alkylene or NR 15 -(C1-C6)-alkylene, R 15 is H or C1-C3 alkyl.

[0051] In some embodiments, R 1 is C6~C 10 aryl, and R 2 is H and R 3 is methyl, and each R 4 is H, and each R 5 is H, and L is -O- or -O(CR 12A R 12B ) n -, X is -CH2-, T is -O-, and Q is a bond, then R 1 is 1 to 3 R 1A In some embodiments, the compounds disclosed herein and pharmaceutically acceptable salts thereof are the following compounds and pharmaceutically acceptable salts thereof: [ka] Does not include.

[0052] R 1 is C3~C 10 Cycloalkyl, C6-C 10 R can be aryl or 5-10 membered heteroaryl containing 1 or 2 N. 1 is R 1A and -NR 13A R 14A In some embodiments, R 1 is unsubstituted. In some embodiments, R 1 is R 1A and -NR 13A R 14A In some embodiments, R 1 is one R 1A In some embodiments, R 1 is one -NR 13A R 14A In some embodiments, R 1 is R 1A and -NR 13A R 14A In some embodiments, R 1 is R 1A In some embodiments, R 1 is -NR 13A R 14A In some embodiments, R 1 is R 1A and -NR 13A R 14A In some embodiments, R 1 is R 1A In some embodiments, R 1 is -NR 13A R 14AIn some embodiments, R 1 is one R 1A and one -NR 13A R 14A In some embodiments, R 1 is one R 1A and two -NR 13A R 14A In some embodiments, R 1 is two R 1A and one -NR 13A R 14A In some embodiments, R 1 is one, two or three R 1A Each R is replaced by 1A is independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A Each R is replaced by 1A is independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 (e.g., 5, 6, 7, 8, 9, or 10) membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A Each R is replaced by 1A is independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A Each R is replaced by 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1is one R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl; 1A In some embodiments, R 1 is two R 1A Each R is replaced by 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is three R 1A Each R is replaced by 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 The cycloalkyl, aryl, or heteroaryl of 1A In some embodiments, R 1 The cycloalkyl, aryl, or heteroaryl of 1A In some embodiments, R 1 The cycloalkyl, aryl, or heteroaryl of 1A is replaced by .

[0053] In some embodiments, R 1 is C3~C 10 (For example, C3~C4, C3~C5, C3~C6, C3~C7, C3~C8, C3~C9, C4~C5, C4~C6, C4~C7, C4~C8, C4~C9, C4~C 10 , C5~C6, C5~C7, C5~C8, C5~C9, C5~C 10 , C6~C7, C6~C8, C6~C9, C6~C 10 , C7~C8, C7~C9, C7~C 10 , C8~C9, C8~C 10 or C9~C 10 ) cycloalkyl. In some embodiments, R 1is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, C8 cycloalkyl, C9 cycloalkyl, or C 10 In some embodiments, C3 to C6 10 Cycloalkyl is saturated. In some embodiments, C3-C 10 Cycloalkyl is partially saturated. In some embodiments, C3-C 10 The cycloalkyl has a single ring (i.e., the cycloalkyl is a monocyclic cycloalkyl). In some embodiments, C3-C 10 Cycloalkyls have multiple rings (e.g., 2 rings, 3 rings, 4 rings, 5 rings, or 6 rings). In some embodiments, C3 to C 10 Cycloalkyls have multiple rings, including fused ring systems, bridged ring systems, spiro ring systems, or combinations thereof. In some embodiments, C3-C 10 Cycloalkyl has two fused rings. In some embodiments, C3-C 10 Cycloalkyl includes partially unsaturated ring systems containing one or more (e.g., 1, 2, 3, or 4) double bonds. In some embodiments, C3-C 10 Cycloalkyl includes fused ring systems having one aromatic ring and one non-aromatic ring. C3-C 10 Cycloalkyl does not include completely aromatic ring systems. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0054] C3~C 10 Cycloalkyl is R 1A and -NR 13A R 14A In some embodiments, C3 to C6 are optionally substituted with 1, 2, or 3 groups independently selected from 10 The cycloalkyl is unsubstituted. In some embodiments, C3-C 10 Cycloalkyl is R 1A and -NR 13A R14A In some embodiments, C3 to C6 are substituted with one group selected from 10 Cycloalkyl is a group containing one R 1A In some embodiments, C3 to C 10 Cycloalkyl is one -NR 13A R 14A In some embodiments, C3 to C 10 Cycloalkyl is R 1A and -NR 13A R 14A In some embodiments, the alkyl group is substituted with two groups independently selected from C3 to C 10 Cycloalkyl is R 1A In some embodiments, the alkyl group is substituted with two groups independently selected from C3 to C 10 Cycloalkyl is -NR 13A R 14A In some embodiments, the alkyl group is substituted with two groups independently selected from C3 to C 10 Cycloalkyl is R 1A and -NR 13A R 14A In some embodiments, the alkyl group is substituted with three groups independently selected from C3 to C 10 Cycloalkyl is R 1A In some embodiments, the alkyl group is substituted with three groups independently selected from C3 to C 10 Cycloalkyl is -NR 13A R 14A In some embodiments, the alkyl group is substituted with three groups independently selected from C3 to C 10 Cycloalkyl is unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl, unsubstituted cycloheptyl, or unsubstituted cyclooctyl. In some embodiments, C3-C 10 Cycloalkyl is R 1A and -NR 13A R 14AIn some embodiments, C3-C4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl substituted with 1, 2, or 3 groups independently selected from 10 Cycloalkyl is R 1A and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl substituted with 1, 2, or 3 groups independently selected from:

[0055] In some embodiments, R 1 is one, two or three R 1A C3~C substituted with 10 (For example, C3, C4, C5, C6, C7, C8, C9, C 10 ) cycloalkyl, and each R 1A is independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A C3~C substituted with 10 (For example, C3, C4, C5, C6, C7, C8, C9, C 10 ) cycloalkyl, and each R 1A is independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 (e.g., 5, 6, 7, 8, 9, or 10) membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A C3~C substituted with 10 (For example, C3, C4, C5, C6, C7, C8, C9, C 10 ) cycloalkyl, and each R 1Ais independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A C3~C substituted with 10 (For example, C3, C4, C5, C6, C7, C8, C9, C 10 ) cycloalkyl, and each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is one R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl; 1A C3~C substituted with 10 (For example, C3, C4, C5, C6, C7, C8, C9, C 10 ) cycloalkyl. In some embodiments, R 1 is two R 1A C3~C substituted with 10 (For example, C3, C4, C5, C6, C7, C8, C9, C 10 ) cycloalkyl, and each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is three R 1A C3~C substituted with 10 (For example, C3, C4, C5, C6, C7, C8, C9, C 10 ) cycloalkyl, and each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0056] In some embodiments, R 1 C6~C 10 In some embodiments, R 1 is C aryl (e.g., phenyl), or C 10aryl (e.g., naphthyl). In some embodiments, R 1 is phenyl. In some embodiments, C6-C 10 Aryl is phenyl. In some embodiments, C6-C 10 Aryl is naphthyl.

[0057] R 1 C6~C 10 Aryl is R 1A and -NR 13A R 14A In some embodiments, C6 to C6 are optionally substituted with 1, 2, or 3 groups independently selected from 10 The aryl is unsubstituted. In some embodiments, the aryl is C6-C 10 Aryl is R 1A and -NR 13A R 14A In some embodiments, C6 to C 10 Aryl is one R 1A In some embodiments, C6 to C 10 Aryl is one -NR 13A R 14A In some embodiments, C6 to C 10 Aryl is R 1A and -NR 13A R 14A In some embodiments, the alkyl group is substituted with two groups independently selected from C6 to C 10 Aryl is R 1A In some embodiments, the alkyl group is substituted with two groups independently selected from C6 to C 10 Aryl is -NR 13A R 14A In some embodiments, the alkyl group is substituted with two groups independently selected from C6 to C 10 Aryl is R 1A and -NR 13A R 14A In some embodiments, the alkyl group is substituted with three groups independently selected from C6 to C 10 Aryl is R 1AIn some embodiments, the alkyl group is substituted with three groups independently selected from C6 to C 10 Aryl is -NR 13A R 14A In some embodiments, R 1 is an unsubstituted C aryl (e.g., phenyl), or an unsubstituted C 10 aryl (e.g., naphthyl). In some embodiments, R 1 is R 1A and -NR 13A R 14A C aryl (e.g., phenyl) or C substituted with 1, 2, or 3 groups independently selected from 10 aryl (e.g., naphthyl). In some embodiments, C6-C 10 The aryl is unsubstituted phenyl. In some embodiments, C-C 10 Aryl is R 1A and -NR 13A R 14A In some embodiments, C6-C 10 Aryl is R 1A In some embodiments, C6-C 10 Aryl is one R 1A and one -NR 13A R 14A In some embodiments, C6-C 10 Aryl is one R 1A and two -NR 13A R 14A In some embodiments, C6-C 10 Aryl is a group consisting of two R 1A and one -NR 13A R 14A is phenyl substituted with

[0058] In some embodiments, R 1 is one, two or three R 1AC6~C substituted with 10 aryl, and each R 1A is independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A C6~C substituted with 10 aryl, and each R 1A is independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A C6~C substituted with 10 aryl, and each R 1A is independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A C6~C substituted with 10 aryl, and each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is one R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl; 1A C6~C substituted with 10 In some embodiments, R 1 is two R 1A C6~C substituted with 10 aryl, and each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is three R 1AC6~C substituted with 10 aryl, and each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0059] In some embodiments, R 1 is a 5-10 membered heteroaryl containing one or two N. In some embodiments, the 5-10 membered heteroaryl contains one N. In some embodiments, the 5-10 membered heteroaryl contains two N. In some embodiments, the 5-10 membered heteroaryl has one ring (i.e., the 5-10 membered heteroaryl is a monocyclic heteroaryl). In some embodiments, the 5-10 membered heteroaryl has two or more rings (e.g., two rings, three rings, or four rings). In some embodiments, the 5-10 membered heteroaryl contains two fused rings. In some embodiments, the 5-10 membered heteroaryl is pyridinyl. In some embodiments, the 5-10 membered heteroaryl is pyrimidinyl.

[0060] R 1 is R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing one or two Ns is unsubstituted. In some embodiments, the 5-10 membered heteroaryl containing one or two Ns is optionally substituted with one, two, or three groups independently selected from R 1A and -NR 13A R 14A In some embodiments, a 5-10 (e.g., 5, 6, 7, 8, 9, 10) membered heteroaryl containing one or two N is substituted with one group selected from R 1A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with one -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with R1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with two groups independently selected from R 1A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with two groups independently selected from -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with two groups independently selected from R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with 3 groups independently selected from R 1A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with 3 groups independently selected from: 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with 3 groups independently selected from R 1A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with 1 or 2 groups independently selected from 1A and one -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with one R 1A and two -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing 1 or 2 N is substituted with two R 1A and one -NR 13A R 14A is replaced by .

[0061] In some embodiments, R 1 is one, two or three R 1A and each R is a 5- to 10-membered heteroaryl containing one or two N groups substituted with1A is independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A and each R is a 5- to 10-membered heteroaryl containing one or two N groups substituted with 1A is independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 (e.g., 5, 6, 7, 8, 9, or 10) membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A and each R is a 5- to 10-membered heteroaryl containing one or two N groups substituted with 1A is independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A and each R is a 5- to 10-membered heteroaryl containing one or two N groups substituted with 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is one R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl; 1A In some embodiments, R is a 5-10 membered heteroaryl containing 1 or 2 N substituted with 1 is two R 1A and each R is a 5- to 10-membered heteroaryl containing one or two N groups substituted with 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is three R 1Aand each R is a 5- to 10-membered heteroaryl containing one or two N groups substituted with 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0062] R 1 is R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing one N is unsubstituted. In some embodiments, the 5-10 membered heteroaryl containing one N is optionally substituted with 1, 2, or 3 groups independently selected from R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing one N is substituted with one group selected from R 1A In some embodiments, the 5-10 membered heteroaryl containing one N is substituted with one —NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing one N is substituted with R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing one N is substituted with two groups independently selected from R 1A In some embodiments, the 5-10 membered heteroaryl containing one N is substituted with two groups independently selected from -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing one N is substituted with two groups independently selected from R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing one N is substituted with three groups independently selected from R 1AIn some embodiments, the 5-10 membered heteroaryl containing one N is substituted with three groups independently selected from -NR 13A R 14A is substituted with three groups independently selected from

[0063] R 1 is R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing one N is unsubstituted. In some embodiments, the 5-10 membered heteroaryl containing two N is optionally substituted with 1, 2, or 3 groups independently selected from R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing two Ns is substituted with one group selected from R 1A In some embodiments, the 5-10 membered heteroaryl containing two Ns is substituted with one -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing two Ns is substituted with R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing two Ns is substituted with two groups independently selected from R 1A In some embodiments, the 5-10 membered heteroaryl containing two Ns is substituted with two groups independently selected from -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing two Ns is substituted with two groups independently selected from R 1A and -NR 13A R 14A In some embodiments, the 5-10 membered heteroaryl containing two Ns is substituted with three groups independently selected from R 1AIn some embodiments, the 5-10 membered heteroaryl containing two Ns is substituted with three groups independently selected from -NR 13A R 14A is substituted with three groups independently selected from

[0064] In some embodiments, the 5-10 membered heteroaryl is pyridinyl. Pyridinyl is R 1A and -NR 13A R 14A In some embodiments, the pyridinyl is optionally substituted with 1, 2, or 3 groups independently selected from R 1A and -NR 13A R 14A In some embodiments, the pyridinyl is substituted with one group selected from 1A In some embodiments, the pyridinyl is substituted with one —NR 13A R 14A In some embodiments, pyridinyl is substituted with R 1A and -NR 13A R 14A In some embodiments, pyridinyl is substituted with two groups independently selected from R 1A In some embodiments, pyridinyl is substituted with two groups independently selected from -NR 13A R 14A In some embodiments, pyridinyl is substituted with two groups independently selected from R 1A and -NR 13A R 14A In some embodiments, pyridinyl is substituted with 3 groups independently selected from R 1A In some embodiments, pyridinyl is substituted with 3 groups independently selected from -NR 13A R 14A In some embodiments, the pyridinyl is substituted with three groups independently selected from one R 1A and one -NR 13A R 14AIn some embodiments, pyridinyl is substituted with one R 1A and two -NR 13A R 14A In some embodiments, pyridinyl is substituted with two R 1A and one -NR 13A R 14A is replaced by .

[0065] In some embodiments, R 1 is one, two or three R 1A and each R is a pyridinyl substituted with 1A are independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, pyridinyl is selected from 1, 2, or 3 R 1A Each R is replaced by 1A are independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 (e.g., 5, 6, 7, 8, 9, or 10) membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, pyridinyl is selected from 1, 2, or 3 R 1A Each R is replaced by 1A are independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, pyridinyl is selected from 1, 2, or 3 R 1A Each R is replaced by 1A are independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, pyridinyl is substituted with one R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1A In some embodiments, pyridinyl is substituted with two R 1A Each R is replaced by 1Aare independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, pyridinyl is selected from three R 1A Each R is replaced by 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0066] In some embodiments, the 5-10 membered heteroaryl is pyridin-2-yl. 1A and -NR 13A R 14A In some embodiments, the pyridin-2-yl is optionally substituted with 1, 2, or 3 groups independently selected from: 1A and -NR 13A R 14A In some embodiments, pyridin-2-yl is substituted with one group selected from 1A In some embodiments, the pyridin-2-yl is substituted with one —NR 13A R 14A In some embodiments, pyridin-2-yl is substituted with R 1A and -NR 13A R 14A In some embodiments, pyridin-2-yl is substituted with two groups independently selected from R 1A In some embodiments, pyridin-2-yl is substituted with two groups independently selected from -NR 13A R 14A In some embodiments, pyridin-2-yl is substituted with two groups independently selected from R 1A and -NR 13A R 14A In some embodiments, pyridin-2-yl is substituted with three groups independently selected from R 1A In some embodiments, pyridin-2-yl is substituted with three groups independently selected from -NR 13A R 14AIn some embodiments, pyridin-2-yl is substituted with three groups independently selected from one R 1A and one -NR 13A R 14A In some embodiments, pyridin-2-yl is substituted with one R 1A and two -NR 13A R 14A In some embodiments, pyridin-2-yl is substituted with two R 1A and one -NR 13A R 14A is replaced by .

[0067] In some embodiments, R 1 is one, two or three R 1A and each R is a pyridin-2-yl substituted with 1A are independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, pyridin-2-yl is selected from 1, 2, or 3 R 1A Each R is replaced by 1A are independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 (e.g., 5, 6, 7, 8, 9, or 10) membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, pyridin-2-yl is selected from 1, 2, or 3 R 1A Each R is replaced by 1A are independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, pyridin-2-yl is selected from 1, 2, or 3 R 1A Each R is replaced by 1Aare independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, pyridin-2-yl is selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1A In some embodiments, pyridin-2-yl is substituted with two R 1A Each R is replaced by 1A are independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, pyridin-2-yl is a group having three R 1A Each R is replaced by 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0068] In some embodiments, the 5- to 10-membered heteroaryl is pyridin-3-yl. 1A and -NR 13A R 14A In some embodiments, the pyridin-3-yl is optionally substituted with 1, 2, or 3 groups independently selected from: 1A and -NR 13A R 14A In some embodiments, pyridin-3-yl is substituted with one group selected from 1A In some embodiments, the pyridinyl is substituted with one —NR 13A R 14A In some embodiments, pyridin-3-yl is substituted with R 1A and -NR 13A R 14A In some embodiments, pyridin-3-yl is substituted with two groups independently selected from R 1A In some embodiments, pyridin-3-yl is substituted with two groups independently selected from -NR 13A R 14AIn some embodiments, pyridin-3-yl is substituted with two groups independently selected from R 1A and -NR 13A R 14A In some embodiments, pyridin-3-yl is substituted with three groups independently selected from R 1A In some embodiments, pyridin-3-yl is substituted with three groups independently selected from -NR 13A R 14A In some embodiments, pyridin-3-yl is substituted with three groups independently selected from one R 1A and one -NR 13A R 14A In some embodiments, pyridin-3-yl is substituted with one R 1A and two -NR 13A R 14A In some embodiments, pyridin-3-yl is substituted with two R 1A and one -NR 13A R 14A is replaced by .

[0069] In some embodiments, the 5-10 membered heteroaryl is pyrimidinyl. Pyrimidinyl is R 1A and -NR 13A R 14A In some embodiments, pyrimidinyl is optionally substituted with 1, 2, or 3 groups independently selected from R 1A and -NR 13A R 14A In some embodiments, the pyrimidinyl is substituted with one group selected from 1A In some embodiments, the pyrimidinyl is substituted with one —NR 13A R 14A In some embodiments, pyrimidinyl is substituted with R 1A and -NR 13A R 14AIn some embodiments, pyrimidinyl is substituted with two groups independently selected from R 1A In some embodiments, pyrimidinyl is substituted with two groups independently selected from -NR 13A R 14A In some embodiments, pyrimidinyl is substituted with two groups independently selected from R 1A and -NR 13A R 14A In some embodiments, pyrimidinyl is substituted with 3 groups independently selected from R 1A In some embodiments, pyrimidinyl is substituted with 3 groups independently selected from -NR 13A R 14A In some embodiments, the pyrimidinyl is substituted with three groups independently selected from one R 1A and one -NR 13A R 14A In some embodiments, the pyrimidinyl is substituted with one R 1A and two -NR 13A R 14A In some embodiments, the pyrimidinyl is substituted with two R 1A and one -NR 13A R 14A is replaced by .

[0070] In some embodiments, R 1 is one, two or three R 1A and each R is a pyrimidinyl substituted with 1A is independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A and each R is a pyrimidinyl substituted with 1Ais independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-10 (e.g., 5, 6, 7, 8, 9, or 10) membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A and each R is a pyrimidinyl substituted with 1A is independently selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, R 1 is one, two or three R 1A and each R is a pyrimidinyl substituted with 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is one R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl; 1A In some embodiments, R is pyrimidinyl substituted with 1 is two R 1A and each R is a pyrimidinyl substituted with 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1 is three R 1A and each R is a pyrimidinyl substituted with 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0071] R 1 is R 1A and -NR 13A R 14A In some embodiments, at least one R 1A is halo. In some embodiments, at least one R 1Ais fluoro. In some embodiments, at least one R 1A is chloro. In some embodiments, at least one R 1A In some embodiments, halo is iodo. In some embodiments, at least one R 1A is cyano.

[0072] In some embodiments, at least one R 1A is C1-C3 alkyl (for example, methyl, ethyl, n-propyl, isopropyl).

[0073] In some embodiments, at least one R 1A is C1-C3 alkoxy (for example, methoxy, ethoxy, n-propoxy, isopropoxy).

[0074] In some embodiments, at least one R 1A is C1-C3 haloalkoxy. In some embodiments, at least one R 1A is C1-C3 fluoroalkoxy (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, fluoro-n-propoxy, difluoro-n-propoxy, trifluoro-n-propoxy, tetrafluoro-n-propoxy, pentafluoro-n-propoxy, hexafluoro-n-propoxy, heptafluoro-n-propoxy, fluoroisopropoxy, difluoroisopropoxy, trifluoroisopropoxy, tetrafluoroisopropoxy, heptafluoroisopropoxy, hexafluoroisopropoxy, or heptafluoroisopropoxy). In some embodiments, at least one R 1Ais C1-C3 chloroalkoxy (e.g., chloromethoxy, dichloromethoxy, trichloromethoxy, chloroethoxy, dichloroethoxy, trichloroethoxy, tetrachloroethoxy, pentachloroethoxy, chloro-n-propoxy, dichloro-n-propoxy, trichloro-n-propoxy, tetrachloro-n-propoxy, pentachloro-n-propoxy, hexachloro-n-propoxy, heptachloro-n-propoxy, chloroisopropoxy, dichloroisopropoxy, trichloroisopropoxy, tetrachloroisopropoxy, heptachloroisopropoxy, hexachloroisopropoxy, or heptachloroisopropoxy). In some embodiments, at least one R 1A is C1-C3 bromoalkoxy (e.g., bromomethoxy, dibromomethoxy, tribromomethoxy, bromoethoxy, dibromoethoxy, tribromoethoxy, tetrabromoethoxy, pentabromoethoxy, bromo-n-propoxy, dibromo-n-propoxy, tribromo-n-propoxy, tetrabromo-n-propoxy, pentabromo-n-propoxy, hexabromo-n-propoxy, heptabromo-n-propoxy, bromoisopropoxy, dibromoisopropoxy, tribromoisopropoxy, tetrabromoisopropoxy, heptabromoisopropoxy, hexabromoisopropoxy, or heptabromoisopropoxy). In some embodiments, at least one R 1A is C1 to C3 iodoalkoxy (e.g., iodomethoxy, diiodomethoxy, triiodomethoxy, iodoethoxy, diiodoethoxy, triiodoethoxy, tetraiodoethoxy, pentaiodoethoxy, iodo-n-propoxy, diiodo-n-propoxy, triiodo-n-propoxy, tetraiodo-n-propoxy, pentaiodo-n-propoxy, hexaiodo-n-propoxy, heptaiodo-n-propoxy, iodoisopropoxy, diiodoisopropoxy, triiodoisopropoxy, tetraiodoisopropoxy, heptaiodoisopropoxy, hexaiodoisopropoxy, or heptaiodoisopropoxy).

[0075] In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O. In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing one N. In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing two N. In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing 3 N. In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing one O. In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing two O. In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing 3 O. In some embodiments, at least one R 1A is a 5-10 membered heteroaryl containing one N and one O. In some embodiments, at least one R 1A is a 5-6 membered heteroaryl containing one N. In some embodiments, at least one R 1A is a 5-6 membered heteroaryl containing two N. In some embodiments, at least one R 1A is a 5-6 membered heteroaryl containing 3 N. In some embodiments, at least one R 1A is a 5-6 membered heteroaryl containing one O. In some embodiments, at least one R 1A is a 5-6 membered heteroaryl containing one N and one O. In some embodiments, at least one R 1A is a 5-6 membered heteroaryl containing two N and one O. In some embodiments, at least one R 1Ais a 5-6 membered heteroaryl having one ring (i.e., the 5-10 membered heteroaryl is a monocyclic heteroaryl). In some embodiments, at least one R 1A is a 5-10 membered heteroaryl having two or more rings (e.g., two rings, three rings, or four rings). In some embodiments, at least one R 1A is a 5-10 membered heteroaryl comprising two fused rings. In some embodiments, the 5-10 membered heteroaryl is triazolyl. In some embodiments, the 5-10 membered heteroaryl is oxadiazolyl.

[0076] R 1 is 1, 2 or 3 NRs 13A R 14A and each R 13A are independently H or C1-C3 alkyl, and each R 14A is independently H or C1-C3 alkyl. In some embodiments, at least one R 13A is H. In some embodiments, at least one R 13A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, at least two R 13A is H. In some embodiments, at least two R 13A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, three R 13A is H. In some embodiments, three R 13A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, at least one R 14A is H. In some embodiments, at least one R 14A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, at least two R 14A is H. In some embodiments, at least two R 14Ais C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, three R 14A is H. In some embodiments, three R 14A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, at least one NR 13A R 14A is R 13A is H and R 14A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, at least two NR 13A R 14A is R 13A is H and R 14A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, three NR 13A R 14A is R 13A is H and R 14A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, at least one NR 13A R 14A is R 13A is H and R 14A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), and at least one NR 13A R 14A NH 2 In some embodiments, one NR 13A R 14A is R 13A is H and R 14A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), and two NR 13A R 14A is NH. In some embodiments, two NR 13A R 14A is R 13A is H and R 14A is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), and one NR13A R 14A is NH. In some embodiments, at least one NR 13A R 14A is NH. In some embodiments, at least two NR 13A R 14A is NH. In some embodiments, three NR 13A R 14A is NH2.

[0077] In some embodiments, R 1 is C3~C 10 Cycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl containing 1, 2 or 3 N; R 1 The cycloalkyl and heteroaryl of R 1A and -NR 13A R 14A and the aryl is optionally substituted with 1, 2, or 3 groups independently selected from R 1A and -NR 13A R 14A In some embodiments, R 1 is R 1A and -NR 13A R 14A In some embodiments, R is phenyl substituted with 1, 2, or 3 groups independently selected from 1 is one R 1A In some embodiments, R 1 is two R 1A In some embodiments, R 1A is halo or cyano. In some embodiments, R 1A is chloro or cyano. In some embodiments, R 1A is fluoro or cyano.

[0078] In some embodiments, R 1is unsubstituted cyclohexyl, unsubstituted phenyl, phenyl substituted with 1, 2, or 3 substituents independently selected from cyano, halo, methoxy, isopropoxy, trifluoromethoxy, triazolyl, and oxadiazolyl, pyridinyl substituted with 1, 2, or 3 substituents independently selected from cyano and halo, or pyrimidinyl substituted with cyano. In some embodiments, R 1 is cyclohexyl, phenyl, cyano-substituted phenyl, cyano- and fluoro-substituted phenyl, cyano- and chloro-substituted phenyl, cyano- and methoxy-substituted phenyl, cyano- and isopropoxy-substituted phenyl, cyano- and trifluoromethoxy-substituted phenyl, cyano- and two methoxy-substituted phenyl, cyano- and triazolyl-substituted phenyl, fluoro- and oxadiazolyl-substituted phenyl, cyano-substituted pyridinyl, chloro-substituted pyridinyl, or cyano-substituted pyrimidinyl. In some embodiments, R 1 teeth, [ka] is.

[0079] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0080] R 2 can be H or C1-C3 alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is C1-C3 alkyl (for example, methyl, ethyl, n-propyl, isopropyl).

[0081] R 3 can be C1-C3 alkyl (eg, methyl, ethyl, n-propyl, isopropyl).

[0082] (CR 4 R 5 ) m In some embodiments, m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21. In some embodiments, m is 16. In some embodiments, m is 17. In some embodiments, m is 18. In some embodiments, m is 19, and in some embodiments, m is 20. In some embodiments, m is 21. In some embodiments, (CR 4 R 5 ) m is C 10 ~C 21 In some embodiments, (CR 4 R 5 ) m is the unsubstituted C 10 ~C 21 In some embodiments, (CR 4 R 5 ) m is a linear C 10 ~C 21 In some embodiments, (CR 4 R 5 ) m is an unsubstituted linear C 10 ~C 21 In some embodiments, (CR 4 R 5 ) m is branch C 10 ~C 21 In some embodiments, (CR 4 R 5 ) m is C 10 ~C 21 In some embodiments, (CR 4 R 5 )m is the unsubstituted C 10 ~C 21 In some embodiments, (CR 4 R 5 ) m is a linear C 10 ~C 21 In some embodiments, (CR 4 R 5 ) m is an unsubstituted linear C 10 ~C 21 In some embodiments, (CR 4 R 5 ) m is branch C 10 ~C 21 In some embodiments, R is alkenylenyl. 3 (CR 4 R 5 ) m is C 11 ~C 24 In some embodiments, R 3 (CR 4 R 5 ) m is the unsubstituted C 11 ~C 24 In some embodiments, R 3 (CR 4 R 5 ) m is a substitution C 11 ~C 24 In some embodiments, R 3 (CR 4 R 5 ) m is branch C 11 ~C 24 In some embodiments, R 3 (CR 4 R 5 ) m is a linear C 11 ~C 24 In some embodiments, R 3 (CR 4 R 5 ) m is an unsubstituted linear C11 ~C 24 In some embodiments, R 3 (CR 4 R 5 ) m is octadecanyl. In some embodiments, R 3 (CR 4 R 5 ) m is nonadecanyl. In some embodiments, R 3 (CR 4 R 5 ) m is eicosanyl. In some embodiments, R 3 (CR 4 R 5 ) m is heneicosanil.

[0083] Each R 4 may independently be a bond, H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, at least one R 4 is a bond. In some embodiments, R 4 In some embodiments, 10 to 21 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21) of R are H. 4 is halo (e.g., chloro, bromo, fluoro, or iodo). In some embodiments, at least one R 4 is C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, R 4 10 to 21 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21) of R are C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, at least one R 4 is C1-C3 haloalkyl (e.g., halomethyl, haloethyl, halo-n-propyl, haloisopropyl). In some embodiments, R 410 to 21 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21) of the above are C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). Exemplary C1-C3 haloalkyl include fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, or iodoisopropyl.

[0084] Each R 5 may independently be a bond or H. In some embodiments, at least one R 5 is a bond. In some embodiments, R 5 In some embodiments, only one of R 5 In some embodiments, 10 to 21 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21) of R are H. 5 is H.

[0085] In some embodiments, each R 4 and each R 5 is H. In some embodiments, two or more adjacent (CR 4 R 5 ) groups are optionally connected through a double bond. In some embodiments, the (CR 4 R 5 ) m has one double bond. In some embodiments, (CR 4 R 5 ) m has at least one double bond (eg, 2, 3, 4, or 5 double bonds).

[0086] R 6 can be H or —C(O)C1-C6 alkyl. In some embodiments, R 6 is H. In some embodiments, R6 is -C(O)C1-C6 (for example, -C(O)C1, -C(O)C2, -C(O)C3-C(O)C4, -C(O)C5, -C(O)C6) alkyl, -C(O)methyl, -C(O)ethyl, -C(O)-n-propyl, -C(O)isopropyl, -C(O)-n-butyl, -C(O)isobutyl, -C(O)-s-butyl, -C(O)-t-butyl, -C(O)-n-pentyl, -C(O)-2-pentyl, -C(O)-3-pentyl, -C(O)-2-methyl-2-butyl, -C(O)-3-methyl-2-butyl, and -C(O)-2,3-dimethyl-2-butyl, -C(O)-3-methyl-1-butyl, -C(O)-2-methyl-1-butyl, -C(O)-1-hexyl, -C(O)-2-hexyl, -C(O)-3-hexyl, -C(O)-2-methyl-2-pentyl, -C(O)-3-methyl-2-pentyl, -C(O)-4-methyl-2-pentyl, -C(O)-3-methyl-3-pentyl, -C(O)-2-methyl-3-pentyl, -C(O)-2,3-dimethyl-2-butyl, or -C(O)-3,3-dimethyl-2-butyl.

[0087] R 7 can be H or —C(O)C1-C6 alkyl. In some embodiments, R 7 is H. In some embodiments, R 7is -C(O)C1-C6 (for example, -C(O)C1, -C(O)C2, -C(O)C3-C(O)C4, -C(O)C5, -C(O)C6) alkyl, -C(O)methyl, -C(O)ethyl, -C(O)-n-propyl, -C(O)isopropyl, -C(O)-n-butyl, -C(O)isobutyl, -C(O)-s-butyl, -C(O)-t-butyl, -C(O)-n-pentyl, -C(O)-2-pentyl, -C(O)-3-pentyl, -C(O)-2-methyl-2-butyl, -C(O)-3-methyl-2-butyl, and -C(O)-2,3-dimethyl-2-butyl, -C(O)-3-methyl-1-butyl, -C(O)-2-methyl-1-butyl, -C(O)-1-hexyl, -C(O)-2-hexyl, -C(O)-3-hexyl, -C(O)-2-methyl-2-pentyl, -C(O)-3-methyl-2-pentyl, -C(O)-4-methyl-2-pentyl, -C(O)-3-methyl-3-pentyl, -C(O)-2-methyl-3-pentyl, -C(O)-2,3-dimethyl-2-butyl, or -C(O)-3,3-dimethyl-2-butyl.

[0088] In some embodiments, R 6 and R 7 are both H. 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)methyl, —C(O)ethyl, —C(O)-n-propyl, —C(O)isopropyl, —C(O)-n-butyl, —C(O)isobutyl, —C(O)-s-butyl, or —C(O)-t-butyl. 6 is —C(O)C1-C6 alkyl, and R 7 is H. In some embodiments, R 6 is —C(O)methyl, —C(O)ethyl, —C(O)-n-propyl, —C(O)isopropyl, —C(O)-n-butyl, —C(O)isobutyl, —C(O)-s-butyl, or —C(O)-t-butyl; R 7 is H. In some embodiments, R 6 and R7 are each independently selected from —C(O)methyl, —C(O)ethyl, —C(O)-n-propyl, —C(O)isopropyl, —C(O)-n-butyl, —C(O)isobutyl, —C(O)-s-butyl, and —C(O)-t-butyl. 6 =R 7 In some embodiments, R 6 and R 7 are both -C(O)isopropyl.

[0089] L is -O-, -(CR 12A R 12B ) n -, -O-(CR 12A R 12B ) n -, -(CR 12A R 12B ) n -O- or -(CR 12A R 12B ) n -O-(CR 12A R 12B ) n -, where n is 1 or 2. In some embodiments, L is -O-. In some embodiments, L is -(CR 12A R 12B )-or-(CR 12A R 12B )-(CR 12A R 12B In some embodiments, L is -O-(CR 12A R 12B )- or -O-(CR 12A R 12B )(CR 12A R 12B In some embodiments, L is -(CR 12A R 12B )-O- or -(CR 12A R 12B )(CR 12A R 12B In some embodiments, L is -(CR 12A R 12B )-O-(CR 12A R 12B)-or-(CR 12A R 12B )(CR 12A R 12B )-O-(CR 12A R 12B )(CR 12A R 12B )-.

[0090] Each R 12A may be independently selected from H and C1-C6 alkyl. In some embodiments, at least one R 12A is H. In some embodiments, at least one R 12A and C1-C6 (e.g., C1, C2, C3, C4, C5 or C6) alkyl is methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl.

[0091] Each R 12B may be independently selected from H and C1-C6 alkyl. In some embodiments, at least one R 12B is H. In some embodiments, at least one R 12Band C1 to C6 (e.g., C1, C2, C3, C4, C5 or C6) alkyl is methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl.

[0092] In some embodiments, R 12A =R 12B In some embodiments, each R 12A and each R 12B is H. In some embodiments, R 12A and R 12B are each independently selected from C1-C6 alkyl. In some embodiments, L is -O-, -O-CH2-, -CH2-O-, -CH2-O-CH2-, -O-CH2-CH2-, -CH2-CH2-O-, or -CH2-CH2-. In some embodiments, L is O. In some embodiments, L is -O-CH2- or -CH2-O-.

[0093] Q can be a bond or phenylene. In some embodiments, Q is a bond. In some embodiments, Q is phenylene. In some embodiments, Q is [ka] is.

[0094] T can be a bond or -O-. In some embodiments, T is a bond. In some embodiments, T is -O-.

[0095] X can be a bond or a C1-C3 alkylene. In some embodiments, X is a bond. In some embodiments, X is methylene, ethylene, n-propylene, or isopropylene.

[0096] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is [ka] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is [ka] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is [ka] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is [ka] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is [ka] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is [ka] is.

[0097] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is [ka] is.

[0098] Z is -O-, -O-(C1-C6)-alkylene, or NR 15 -(C1-C6)-alkylene, R 15 is H or C1-C3 alkyl. In some embodiments, Z is -O-. In some embodiments, Z is -O-(C1-C6-alkylene, where (C1-C6)-alkylene is methylene, ethylene, -n-propylene, isopropylene, -n-butylene, isobutylene, -s-butylene, -t-butylene, -n-pentylene, -2-pentylene, -3-pentylene, -2-methyl-2-butylene, -3-methyl-2-butylene, -3- methyl-1-butylene, -2-methyl-1-butylene, -1-hexylene, -2-hexylene, -3-hexylene, -2-methyl-2-pentylene, -3-methyl-2-pentylene, -4-methyl-2-pentylene, -3-methyl-3-pentylene, -2-methyl-3-pentylene, -2,3-dimethyl-2-butylene, or -3,3-dimethyl-2-butylene.

[0099] In some embodiments, Z is NH-(C1-C6)-alkylene, N-methyl-(C1-C6)-alkylene, N-ethyl-(C1-C6)-alkylene, Nn-propyl-(C1-C6)-alkylene, or N-isopropyl-(C1-C6)-alkylene, wherein (C1-C6)-alkylene is methylene, ethylene, -n-propylene, isopropylene, -n-butylene, isobutylene, -s-butylene, -t-butylene, -n-pentylene, -2-pentylene, -2-pentylylene, -2-pentyl-2-methyl ... In some embodiments, Z is -O-CH2-, -NH-CH2-, or -N(CH3)-CH2-.

[0100] In some embodiments, R 1 is cyclohexyl, phenyl, cyano-substituted phenyl, cyano- and fluoro-substituted phenyl, cyano- and chloro-substituted phenyl, cyano- and methoxy-substituted phenyl, cyano- and isopropoxy-substituted phenyl, cyano- and trifluoromethoxy-substituted phenyl, cyano- and two methoxy-substituted phenyl, cyano- and triazolyl-substituted phenyl, fluoro- and oxadiazolyl-substituted phenyl, cyano-substituted pyridinyl, chloro-substituted pyridinyl, or cyano-substituted pyrimidinyl; R 2 is H or methyl, and R 3 is methyl, ethyl, or n-propyl, and each R 4 and R 5 are independently H or a bond, and R 6 is H and R 7is H; m is 11, 12, 13, 14, 15, 16, 17, or 18; L is -O-, -O-CH-, -CH-O-, -CH-O-CH-, -O-CH-CH-, -CH-CH-O-, or -CH-CH-; Q is a bond or phenylene; T is a bond or -O-; X is a bond, -CH-, -CH-CH-, or -CH(CH)-; and Z is -O-CH-, -NH-CH-, or -N(CH)-CH-.

[0101] In some embodiments, R 1 is unsubstituted cyclohexyl, unsubstituted phenyl, phenyl substituted with 1, 2, or 3 substituents independently selected from cyano, halo, methoxy, isopropoxy, trifluoromethoxy, triazolyl, and oxadiazolyl, pyridinyl substituted with 1, 2, or 3 substituents independently selected from cyano and halo, or pyrimidinyl substituted with cyano; R 2 is H or methyl, and R 3 is methyl, ethyl, or n-propyl, and each R 4 and R 5 are independently H or a bond, and R 6 is H and R 7 is H; m is 11, 12, 13, 14, 15, 16, 17, or 18; L is -O-, -O-CH-, -CH-O-, -CH-O-CH-, -O-CH-CH-, -CH-CH-O-, or -CH-CH-; Q is a bond or phenylene; T is a bond or -O-; X is a bond, -CH-, -CH-CH-, or -CH(CH)-; and Z is -O-CH-, -NH-CH-, or -N(CH)-CH-. In some embodiments, R 1 -L is [ka] is.

[0102] Those skilled in the art will recognize the groups disclosed herein (e.g., R 1) each and every embodiment of the remaining groups (e.g., R 2 , R 3 , R 4 , R 5 , R 6 It is recognized that each of the above-described embodiments (e.g., methyl ...

[0103] In some embodiments, the compounds of Formula I and pharmaceutically acceptable salts thereof include the compounds of Table 1 and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula I and pharmaceutically acceptable salts thereof include the compounds of Table 1A and pharmaceutically acceptable salts thereof. Tables 1 and 1A provide some of the compounds disclosed herein, along with compound numbers and corresponding structures. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1A-1] [Table 2-2]

[0104] In some embodiments, the compound of Formula I has Formula Ia: [ka] It has.

[0105] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, and m) apply to formula Ia.

[0106] In some embodiments, the compounds of Formula Ia and pharmaceutically acceptable salts thereof include the compounds of Table 2 and pharmaceutically acceptable salts thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0107] In some embodiments, the compound of Formula I has Formula Ib: [ka] It has.

[0108] Substituents of Formula I (e.g., R1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, and m) apply to Formula Ib. In some embodiments, compounds and pharmaceutically acceptable salts of Formula Ib include compounds and pharmaceutically acceptable salts thereof in Table 3. [Table 3-1] [Table 3-2]

[0109] In some embodiments, the compound of formula I has formula II: [ka] It has.

[0110] Substituents of Formula I (e.g., R 1 , R 6 , R 7 , L, and m) apply to Formula II. In some embodiments, compounds and pharmaceutically acceptable salts of Formula II include compounds in Table 4 and pharmaceutically acceptable salts thereof. [Table 4-1] [Table 4-2] [Table 4-3]

[0111] In some embodiments, the compound of formula I has formula IIa [ka] It has.

[0112] Substituents of Formula I (e.g., R1 , R 6 , R 7 , L, and m) apply to Formula IIa.

[0113] In some embodiments, the compounds of Formula IIa and pharmaceutically acceptable salts thereof include the compounds of Table 5 and pharmaceutically acceptable salts thereof. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0114] In some embodiments, the compound of Formula I has Formula IIb: [ka] It has.

[0115] Substituents of Formula I (e.g., R 1 , R 6 , R 7 , L, and m) apply to Formula IIb. In some embodiments, compounds and pharmaceutically acceptable salts of Formula IIb include compounds in Table 6 and pharmaceutically acceptable salts thereof. [Table 6]

[0116] In some embodiments, the compound of formula I has formula III: [ka] It has.

[0117] Substituents of Formula I (e.g., R 1A , R 6 , R 7 , m, and n) apply to Formula III.

[0118] In some embodiments, the compounds of Formula III and pharmaceutically acceptable salts thereof include the compounds of Table 7 and pharmaceutically acceptable salts thereof. [Table 7-1] [Table 7-2] [Table 7-3]

[0119] In some embodiments, the compound of Formula I has Formula IIIa: [ka] It has.

[0120] Substituents of Formula I (e.g., R 1A , R 6 , R 7 The descriptions of m, m, and n) apply to Formula IIIa. In some embodiments, compounds and pharmaceutically acceptable salts of Formula IIIa include compounds and pharmaceutically acceptable salts thereof in Table 8. [Table 8-1] [Table 8-2]

[0121] In some embodiments, the compound of Formula I has Formula IIIb: [ka] It has.

[0122] Substituents of Formula I (e.g., R 1A , R 6 , R 7 , m, and n) apply to Formula IIIb. In some embodiments, compounds and pharmaceutically acceptable salts of Formula IIIb include compounds and pharmaceutically acceptable salts thereof in Table 9. [Table 9]

[0123] In some embodiments, the compound of formula I has formula IV: [ka] It has.

[0124] Substituents of Formula I (e.g., R 1 , R 6 , R 7 , L, and m) apply to Formula IV. In some embodiments, compounds and pharmaceutically acceptable salts of Formula IV include compounds in Table 10 and pharmaceutically acceptable salts thereof. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0125] In some embodiments, the compound of formula I has formula IVa: [ka] It has.

[0126] Substituents of Formula I (e.g., R 1 , R 6 , R7 The descriptions of , L, and m) apply to Formula IVa. In some embodiments, compounds and pharmaceutically acceptable salts of Formula IVa include compounds in Table 11 and pharmaceutically acceptable salts thereof. [Table 11-1] [Table 11-2] [Table 11-3]

[0127] In some embodiments, the compound of Formula I has Formula IVb: [ka] It has.

[0128] Substituents of Formula I (e.g., R 1 , R 6 , R 7 The descriptions of , L, and m) apply to Formula IVb. In some embodiments, compounds and pharmaceutically acceptable salts of Formula IVb include compounds in Table 12 and pharmaceutically acceptable salts thereof. [Table 12]

[0129] In some embodiments, the compound of formula I has formula V: [ka] It has.

[0130] Substituents of Formula I (e.g., R 1A , R 6 , R 7 , m, and n) apply to Formula V. In some embodiments, compounds and pharmaceutically acceptable salts of Formula V include compounds in Table 13 and pharmaceutically acceptable salts thereof. [Table 13-1] [Table 13-2] [Table 13-3]

[0131] In some embodiments, the compound of formula I has formula Va: [ka] It has.

[0132] Substituents of Formula I (e.g., R 1A , R 6 , R 7 , m, and n) apply to Formula Va. In some embodiments, compounds and pharmaceutically acceptable salts of Formula Va include compounds in Table 14 and pharmaceutically acceptable salts thereof. [Table 14-1] [Table 14-2]

[0133] In some embodiments, the compound of formula I has formula Vb: [ka] It has.

[0134] Substituents of Formula I (e.g., R 1A , R 6 , R 7 , m, and n) apply to Formula Vb. In some embodiments, compounds and pharmaceutically acceptable salts of Formula Vb include compounds in Table 15 and pharmaceutically acceptable salts thereof. [Table 15]

[0135] In some embodiments, the compound of formula I has formula VI: [ka] It has.

[0136] Substituents of Formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, m, and n) apply to Formula VI. In some embodiments, compounds and pharmaceutically acceptable salts of Formula VI include compounds in Table 16 and pharmaceutically acceptable salts thereof. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7] [Table 16-8] [Table 16-9]

[0137] In some embodiments, the compound of formula I has formula VIa: [ka] It has.

[0138] Substituents of Formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, m, and n) apply to Formula VIa. In some embodiments, compounds and pharmaceutically acceptable salts of Formula VIa include compounds and pharmaceutically acceptable salts thereof in Table 17. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6]

[0139] In some embodiments, the compound of formula I has formula VIb: [ka] It has.

[0140] Substituents of Formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, m and n) apply to Formula VIb.

[0141] In some embodiments, the compounds of Formula VIb and pharmaceutically acceptable salts thereof include the compounds of Table 18 and pharmaceutically acceptable salts thereof. [Table 18-1] [Table 19-2]

[0142] In some embodiments, the compound of formula I has formula VII: [ka] It has.

[0143] Substituents of Formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, L, m and n) apply to Formula VII.

[0144] In some embodiments, the compounds of Formula VII and pharmaceutically acceptable salts thereof include the compounds of Table 19 and pharmaceutically acceptable salts thereof. [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5]

[0145] In some embodiments, the compound of Formula I has Formula VIIa: [ka] It has.

[0146] Substituents of Formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, L, m, and n) apply to Formula VIIa. In some embodiments, compounds and pharmaceutically acceptable salts of Formula VIIa include compounds and pharmaceutically acceptable salts thereof in Table 20. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4]

[0147] In some embodiments, the compound of Formula I has Formula VIIb: [ka] It has.

[0148] Substituents of Formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, L, m, and n) apply to Formula VIIb. In some embodiments, compounds and pharmaceutically acceptable salts of Formula VIIb include compounds in Table 21 and pharmaceutically acceptable salts thereof. [Table 21]

[0149] In some embodiments, the compound of formula I has formula VIIc: [ka] It has.

[0150] Substituents of Formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, L, m, and n) apply to Formula VIIc. In some embodiments, compounds and pharmaceutically acceptable salts of Formula VIIc include compounds in Table 22 and pharmaceutically acceptable salts thereof. [Table 22]

[0151] In some embodiments, the compound of formula I has formula VIII: [ka] It has.

[0152] Substituents of Formula I (e.g., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, and m) apply to Formula VIII.

[0153] In some embodiments, compounds of Formula VIII and pharmaceutically acceptable salts thereof include compounds in Table 23 and pharmaceutically acceptable salts thereof. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5]

[0154] In some embodiments, the compound of Formula I has Formula VIIIa: [ka] It has.

[0155] Substituents of Formula I (e.g., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, and m) apply to Formula VIIIa.

[0156] In some embodiments, the compounds of Formula VIIIa and pharmaceutically acceptable salts thereof include the compounds of Table 24 and pharmaceutically acceptable salts thereof. [Table 24-1] [Table 24-2] [Table 24-3]

[0157] In some embodiments, the compound of Formula I has Formula VIIIb: [ka] It has.

[0158] Substituents of Formula I (e.g., R 2 , R 3 , R4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, and m) apply to Formula VIIIb.

[0159] In some embodiments, the compounds of Formula VIIIb and pharmaceutically acceptable salts thereof include the compounds of Table 25 and pharmaceutically acceptable salts thereof. [Table 25]

[0160] In some embodiments, the compound of Formula I has Formula VIIIc: [ka] It has.

[0161] Substituents of Formula I (e.g., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, T, X, Z, L, and m) apply to Formula VIIIc.

[0162] In some embodiments, compounds of Formula VIIIc and pharmaceutically acceptable salts thereof include compounds in Table 26 and pharmaceutically acceptable salts thereof. [Table 26]

[0163] In some embodiments, the compound of formula I has formula IX: [ka] It has.

[0164] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R 7 , Q, X, L, and m) apply to Formula IX.

[0165] In some embodiments, the compounds of Formula IX and pharmaceutically acceptable salts thereof include the compounds of Table 27 and pharmaceutically acceptable salts thereof. [Table 27-1] [Table 27-2] [Table 27-3] [Table 27-4] [Table 27-5]

[0166] In some embodiments, the compound of formula I has formula IXa: [ka] It has.

[0167] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, L, and m) apply to Formula IXa.

[0168] In some embodiments, the compounds of Formula IXa and pharmaceutically acceptable salts thereof include the compounds of Table 28 and pharmaceutically acceptable salts thereof. [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4]

[0169] In some embodiments, the compound of formula I has formula IXb: [ka] It has.

[0170] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, L, and m) apply to formula IXb.

[0171] In some embodiments, the compounds of Formula IXb and pharmaceutically acceptable salts thereof include the compounds of Table 29 and pharmaceutically acceptable salts thereof. [Table 29]

[0172] In some embodiments, the compound of formula I has formula IXc: [ka] It has.

[0173] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, L, and m) apply to formula IXc.

[0174] In some embodiments, the compounds of Formula IXc and pharmaceutically acceptable salts thereof include the compounds of Table 30 and pharmaceutically acceptable salts thereof. [Table 30]

[0175] In some embodiments, the compound of formula I has formula X: [ka] It has.

[0176] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 The descriptions in m) and m) apply to formula X. In some embodiments, compounds of formula X and pharmaceutically acceptable salts thereof include compounds in Table 31 and pharmaceutically acceptable salts thereof. [Table 31-1] [Table 31-2] [Table 31-3] [Table 31-4]

[0177] In some embodiments, the compound of formula I has formula Xa: [ka] It has.

[0178] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 The explanations in m) and m) apply to formula Xa.

[0179] In some embodiments, the compounds of Formula Xa and pharmaceutically acceptable salts thereof include the compounds of Table 32 and pharmaceutically acceptable salts thereof. [Table 32-1] [Table 32-2] [Table 32-3]

[0180] In some embodiments, the compound of formula I has formula Xb: [ka] It has.

[0181] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 The explanations in (a) and (b) apply to formula Xb.

[0182] In some embodiments, compounds of Formula Xb and pharmaceutically acceptable salts thereof include compounds in Table 33 and pharmaceutically acceptable salts thereof. [Table 33]

[0183] In some embodiments, the compound of formula I has formula XI: [ka] It has.

[0184] Substituents of Formula I (e.g., R 1 , R 3 , R 4 , and R 5) applies to Formula XI. In some embodiments, compounds of Formula XI and pharmaceutically acceptable salts thereof include compounds of Table 34 and pharmaceutically acceptable salts thereof. [Table 34-1] [Table 34-2] [Table 34-3] [Table 34-4]

[0185] In some embodiments, the compound of formula I has formula XIa: [ka] It has.

[0186] Substituents of Formula I (e.g., R 1 , R 3 , R 4 and R 5 ) applies to formula XIa.

[0187] In some embodiments, the compounds of Formula XIa and pharmaceutically acceptable salts thereof include the compounds of Table 35 and pharmaceutically acceptable salts thereof. [Table 35-1] [Table 35-2]

[0188] In some embodiments, the compound of formula I has formula XIb: [ka] It has.

[0189] Substituents of Formula I (e.g., R 1 , R 3 , R 4 and R 5 ) applies to formula XIb.

[0190] In some embodiments, the compounds of Formula XIb and pharmaceutically acceptable salts thereof include the compounds of Table 36 and pharmaceutically acceptable salts thereof. [Table 36]

[0191] In some embodiments, the compound of formula I has formula XII: [ka] and wherein w+v is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19.

[0192] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, and L) apply to Formula XII.

[0193] In some embodiments, the compounds of Formula XII and pharmaceutically acceptable salts thereof include the compounds of Table 37 and pharmaceutically acceptable salts thereof. [Table 37]

[0194] In some embodiments, the compound of Formula I has Formula XIIa: [ka] and wherein w+v is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19.

[0195] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, and L) apply to formula XIIa.

[0196] In some embodiments, the compounds of Formula XIIa and pharmaceutically acceptable salts thereof include the compounds in Table 37 and pharmaceutically acceptable salts thereof.

[0197] In some embodiments, the compound of Formula I has Formula XIIb: [ka] and wherein w+v is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19.

[0198] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, and L) apply to formula XIIb.

[0199] In some embodiments, the compound of formula I has formula XIII: [ka] It has.

[0200] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, Z, L, and m) apply to Formula XIII.

[0201] In some embodiments, the compounds of Formula XIII and pharmaceutically acceptable salts thereof include the compounds of Table 38 and pharmaceutically acceptable salts thereof. [Table 38-1] [Table 38-2] [Table 38-3] [Table 38-4]

[0202] In some embodiments, the compound of Formula I has Formula XIIIa: [ka] It has.

[0203] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, Z, L, and m) apply to Formula XIIIa. In some embodiments, compounds and pharmaceutically acceptable salts of Formula XIIIa include compounds in Table 39 and pharmaceutically acceptable salts thereof. [Table 39-1] [Table 39-2] [Table 39-3]

[0204] In some embodiments, the compound of Formula I has Formula XIIIb: [ka] It has.

[0205] Substituents of Formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q, X, Z, L, and m) apply to formula XIIIb.

[0206] In some embodiments, the compounds of Formula XIIIb and pharmaceutically acceptable salts thereof include the compounds of Table 40 and pharmaceutically acceptable salts thereof. [Table 40]

[0207] In vivo metabolic products of the compounds described herein are also within the scope of the present invention, so long as such products are novel and unobvious over the prior art. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily through enzymatic processes. Thus, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield metabolic products. Such products are typically radiolabeled (e.g., 14 C or 3H) Compounds are prepared and identified by administering them at detectable doses (e.g., greater than about 0.5 mg / kg) to animals, such as rats, mice, guinea pigs, monkeys, or humans, allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and isolating the transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding to epitopes surviving in the metabolites). The structures of the metabolites are determined by conventional methods, such as MS or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism studies. Transformation products are useful in diagnostic assays for therapeutic administration of compounds, even if they do not possess their own HSV antiviral activity unless otherwise found in vivo.

[0208] Recipes and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as stable in the gastrointestinal tract if less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal or gastric fluids when incubated at 37°C for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. Prodrugs are typically stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive lumen, liver, lungs, or other metabolic organs, or generally within cells. As used herein, a prodrug is understood to be a compound chemically designed to efficiently release the parent drug after overcoming a biological barrier to oral delivery. IV. Pharmaceutical Preparations

[0209] Also disclosed herein are pharmaceutical formulations comprising a pharmaceutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIa, XIb, XII, XIII, XIIIa, or XIIIb) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Also provided herein are pharmaceutical formulations comprising a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0210] The compounds disclosed herein can be formulated with conventional carriers and excipients. Tablets can include, for example, excipients, glidants, fillers, binders, or combinations thereof. Aqueous formulations are prepared in sterile form and, if intended for delivery by other than oral administration, are generally isotonic. Exemplary excipients include, but are not limited to, those listed in the "Handbook of Pharmaceutical Excipients" (1986). Excipients can include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and combinations thereof. In some embodiments, the formulation is basic. In some embodiments, the formulation is acidic. In some embodiments, the formulation has a neutral pH. In some embodiments, the pH of the formulation is 2 to 11 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 4 to 11, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 7 to 8, 7 to 9, 7 to 10, 7 to 11, 8 to 9, 8 to 10, 8 to 11, 9 to 10, or 9 to 11).

[0211] In some embodiments, the compounds disclosed herein have pharmacokinetic properties (e.g., oral bioavailability) suitable for oral administration of the compounds. Formulations suitable for oral administration can be presented, for example, 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 suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be administered, for example, as a bolus, electuary, or paste.

[0212] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may 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, surfactant, dispersant, or a combination thereof. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets may optionally be coated or scored, and may optionally be formulated to provide slow or controlled release of the active ingredient therefrom.

[0213] For infections of the eye or other external tissues (e.g., mouth and skin), formulations may be applied as a topical ointment or cream containing the active ingredient in an amount, for example, 0.075-20% w / w (including active ingredient in ranges of 0.1% to 20% in 0.1% w / w increments, such as 0.6% w / w, 0.7% w / w, etc.), 0.2-15% w / w, or 0.5-10% w / w. When formulated in an ointment, the active ingredient may, in some embodiments, be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

[0214] In some embodiments, the aqueous phase of the cream base may comprise, for example, 30% to 90% (e.g., 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%) w / w of a polyhydric alcohol, 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. In some embodiments, the cream base may include, for example, 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, but are not limited to, dimethyl sulfoxide and related analogs. In some embodiments, the cream or emulsion does not contain water.

[0215] The oily phase of the emulsion can be composed of known ingredients in a known manner. In some embodiments, the phase comprises only an emulsifier (otherwise known as an emulgent). In some embodiments, the phase comprises a mixture of at least one emulsifier with a fat, an oil, or a combination thereof. In some embodiments, a hydrophilic emulsifier is included along with a lipophilic emulsifier that functions as a stabilizer. Taken together, the emulsifiers, with or without stabilizers, constitute the so-called emulsifying waxes, which, together with oils and fats, constitute the so-called emulsifying ointment bases that can form the oily dispersed phase of a cream formulation.

[0216] Emulgents and emulsion stabilizers suitable for use in the formulation may include, for example, but are not limited to, TWEEN® 60, TWEEN® 80, SPAN® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, and combinations thereof.

[0217] The selection of suitable oils or fats for the formulation can be based on achieving the desired aesthetic properties. In some embodiments, the cream can be a non-greasy, non-staining, and washable product with a suitable consistency to avoid leakage from tubes or other containers. In some embodiments, the ester can include, for example, linear or branched, mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, CRODAMOL® CAP, or a blend of branched esters known as such, or a combination thereof. In some embodiments, a high-melting lipid, such as white soft paraffin and / or liquid paraffin or other mineral oil, can be included.

[0218] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered in a pharmaceutical formulation. In some embodiments, the pharmaceutical formulation is for veterinary use. In some embodiments, the pharmaceutical formulation is for human use. In some embodiments, the pharmaceutical formulation disclosed herein comprises at least one additional therapeutic agent.

[0219] The pharmaceutical formulations disclosed herein may be in any form suitable for the intended method of administration. The pharmaceutical formulations disclosed herein may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Exemplary techniques and formulations may be found, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods may include the step of bringing into association the compounds disclosed herein with the carrier, which constitutes one or more accessory ingredients. In general, the formulations may be prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0220] For oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs can be prepared. Preparations intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical preparations, and such preparations can contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, for example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0221] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0222] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoates, one or more coloring agents, one or more flavoring agents, one or more sweeteners (e.g., sucrose or saccharin), or mixtures thereof. Further non-limiting examples of suspending agents include cyclodextrins, hi some embodiments, the suspending agent is sulfobutylether beta-cyclodextrin (SEB-beta-CD), such as CAPTISOL®.

[0223] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, coconut oil, or a combination thereof) or in a mineral oil such as liquid paraffin, or a combination thereof. Oral suspensions can contain a thickening agent such as, for example, beeswax, hard paraffin, cetyl alcohol, or a combination thereof. In some embodiments, sweetening agents, such as those set forth above, and / or flavoring agents can be added to provide a palatable oral preparation. In some embodiments, the formulations disclosed herein are preserved by the addition of an antioxidant, such as ascorbic acid.

[0224] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, a preservative, or combinations thereof. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, can also be present.

[0225] Pharmaceutical preparations can be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavoring agents. Syrups and elixirs can be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such preparations can also contain, for example, demulcents, preservatives, flavorings, coloring agents, or combinations thereof.

[0226] Pharmaceutical preparations may be in the form of sterile injectable or intravenous preparations, such as sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable or intravenous preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or may be prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, solid oils may be used as solvents or suspending media. For this purpose, any solvent-free solid oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables. Acceptable vehicles and solvents that may be used include, but are not limited to, water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0227] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 1000 mg of active ingredient, compounded with an appropriate amount of carrier material, which may vary from 5 to 95% (weight:weight) of the total formulation. Pharmaceutical formulations can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain 3 μg to 500 μg of active ingredient per milliliter of solution to allow infusion of a suitable volume at a rate of about 30 mL / hour.

[0228] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. In some embodiments, the compounds disclosed herein are included in the pharmaceutical formulations disclosed herein at a concentration of 0.5% to 20% (e.g., 0.5% to 10%, 1.5% w / w).

[0229] Formulations suitable for topical administration to the mouth include lozenges, which may contain the active ingredient (i.e., a compound disclosed herein and / or additional therapeutic agent) in a flavored base, usually sucrose and acacia or tragacanth; pastilles, which contain the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes, which contain the active ingredient in a suitable liquid carrier.

[0230] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0231] Formulations suitable for vaginal administration may 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.

[0232] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0233] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a 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 described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0234] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents standard in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0235] Additionally, there is provided a veterinary formulation comprising a compound disclosed herein together with a carrier for veterinary use.

[0236] A veterinary carrier is a substance useful for the purpose of administering the formulation and may be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary formulations may be administered orally, parenterally, or by any other desired route.

[0237] The compounds herein are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") comprising one or more of the compounds as active ingredients, the release of which can be controlled and regulated to allow for less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0238] The effective dose of active ingredient will depend, at least in part, on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (low doses) or against an active viral infection, the delivery method, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose-escalation studies. In some embodiments, the dose is 0.0001 to 100 mg / kg body weight per day, e.g., about 0.01 to about 10 mg / kg body weight per day, 0.01 to 5 mg / kg body weight per day, or 0.05 to 0.5 mg / kg body weight per day. For example, the daily candidate dose for an adult weighing approximately 70 kg can range from 1 mg to 1000 mg (e.g., 5 mg to 500 mg) and can take the form of a single or multiple doses. V. Kit

[0239] Also provided herein are kits comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof. In some embodiments, the kits described herein may include a label and / or instructions for using the compound in treating 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.

[0240] In some embodiments, the kit may also include one or more additional therapeutic agents and / or instructions for using the additional therapeutic agents in combination with the compounds disclosed herein in the treatment of a disease or condition in a subject (e.g., a human) in need thereof.

[0241] In some embodiments, the kits provided herein contain individual dosage units of a compound described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. Examples of individual dosage units may include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective amount of the compound of interest, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. In some embodiments, the kit may contain a single dosage unit and other multiple dosage units, such as the number of dosage units required for a particular regimen or time period.

[0242] Also provided is an article of manufacture comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and a container. In some embodiments, the article of manufacture container is a vial, bottle, ampoule, pre-filled syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or nebulizer. VI. Administration

[0243] One or more compounds of the present disclosure 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 understood that the route may vary depending, for example, on the condition of the recipient.

[0244] In the disclosed methods for treating a viral infection, the compounds of the present disclosure can be administered at any time to a subject who may have come into contact with the virus or who already has the viral infection. In some embodiments, the compounds of the present disclosure can be administered prophylactically to a subject who comes into contact with a subject who has a viral infection or who is at risk of coming into contact with a subject who has a viral infection, such as a healthcare provider. In some embodiments, the administration of the compounds of the present disclosure can be to a subject who has tested positive for a viral infection but has not yet shown symptoms of the viral infection. In the disclosed methods for treating a viral infection, the compounds of the present disclosure can be administered prophylactically to a person who may have come into contact with the virus or who already has the viral infection, such as a healthcare provider. In some embodiments, the compounds of the present disclosure can be administered prophylactically to a person who comes into contact with a person who has a viral infection or who is at risk of coming into contact with a person who has a viral infection, such as a healthcare provider. In some embodiments, the administration of the compounds of the present disclosure can be to a person who has tested positive for a viral infection but has not yet shown symptoms of the viral infection. In some embodiments, compounds of the present disclosure can be administered to a human at the onset of symptoms of a viral infection.

[0245] In some embodiments, the methods disclosed herein comprise event-driven administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject.

[0246] As used herein, the term "event-driven" or "event-driven administration" refers to administering a compound of any one of Formulas I-XIIIb, or a pharmaceutically acceptable salt thereof, (1) before an event (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event) that exposes the subject to the virus (or otherwise increases the subject's risk of being infected with the virus), and / or (2) during an event (or two or more recurring events) that exposes the subject to the virus (or otherwise increases the subject's risk of being infected with the virus), and / or (3) after an event (or after the last event in a series of recurring events) that exposes the subject to the virus (or otherwise increases the subject's risk of being infected with the virus). In some embodiments, event-driven administration occurs before the subject's exposure to the virus. In some embodiments, event-driven administration occurs after the subject's exposure to the virus. In some embodiments, event-driven administration occurs before the subject's exposure to the virus and after the subject's exposure to the virus.

[0247] In certain embodiments, the methods disclosed herein include administering a therapeutic agent before and / or after an event that exposes a subject (e.g., a human) to the virus or that otherwise increases the subject's (e.g., a human's) risk of becoming infected with the virus, e.g., as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0248] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered prior to the subject's exposure to the virus.

[0249] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered before and after exposure of the subject to a virus.

[0250] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered after the subject's exposure to the virus.

[0251] An example of an event-driven dosing regimen includes administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, within 24 hours to 2 hours prior to the virus, followed by administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, every 24 hours for the duration of exposure, followed by another administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, after the final exposure, and finally another administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0252] A further example of an event-driven dosing regimen includes administering a compound of any one of Formulas I-XIIIb, or a pharmaceutically acceptable salt thereof, within 24 hours before exposure to the virus, followed by daily dosing for the duration of exposure, followed by a final dose (which may be an increased dose, such as a double dose) approximately 24 hours after the last exposure.

[0253] The effective dose of active ingredient will depend, at least, on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically or against an active viral infection, the delivery method, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose-escalation studies. It may be expected to be between 0.0001 mg / kg and 100 mg / kg of body weight per day (e.g., 0.01 mg / kg and 10 mg / kg of body weight per day, 0.01 mg / kg and 5 mg / kg of body weight per day, 0.05 mg / kg and 0.5 mg / kg of body weight per day). In some embodiments, the daily candidate dose for an adult weighing approximately 70 kg will be between 1 mg and 2000 mg (e.g., 5 mg and 500 mg, 500 mg and 1000 mg, 1000 mg and 1500 mg, 1500 mg and 2000 mg), and may take the form of a single dose or multiple doses (e.g., twice-daily doses, three-daily doses). For example, the daily candidate dose for an adult human weighing approximately 70 kg will range from 1 mg to 1000 mg (eg, 5 mg to 500 mg) and may take the form of a single dose or multiple doses.

[0254] Any suitable period for administering the compounds of the present disclosure is contemplated. For example, administration can be from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. Administration can also be from 1 week to 15 weeks, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks. Longer administration periods are also contemplated.

[0255] In some embodiments, the compounds disclosed herein are administered once a day. In some embodiments, the compounds disclosed herein are administered twice a day. 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.

[0256] In some embodiments, one or more compounds disclosed herein are administered once daily. A single daily dose can be administered as needed, for example, for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to one month or more. In some embodiments, a single daily dose is administered for up to 20 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6 days, up to 4 days, up to 3 days, up to 2 days, or 1 day.

[0257] In some embodiments, one or more compounds disclosed herein are administered once daily for 6 to 12 days, e.g., 8 to 10 days. In some embodiments, one or more compounds are administered once daily for 9 days. In some embodiments, one or more compounds are administered once daily for 10 days. In some embodiments, 50 to 150 mg of one or more compounds disclosed herein are administered once daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days. In some embodiments, 100 mg of one or more compounds disclosed herein are administered once daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days. In some embodiments, 500-2000 mg (e.g., 500-1000 mg, 1000-1500 mg) of one or more compounds disclosed herein is administered once daily for 5-12 days, e.g., 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days.

[0258] In some embodiments, one or more compounds disclosed herein are administered twice daily. The twice-daily dose can be administered as needed, for example, for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to one month or more. In some embodiments, the twice-daily dose is administered for up to 20 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6 days, up to 4 days, up to 3 days, up to 2 days, or 1 day.

[0259] In some embodiments, one or more compounds disclosed herein are administered twice daily for 6 to 12 days, e.g., 8 to 10 days. In some embodiments, one or more compounds are administered twice daily for 9 days. In some embodiments, one or more compounds are administered twice daily for 10 days. In some embodiments, 1 to 1000 mg of one or more compounds disclosed herein are administered twice daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days. In some embodiments, 500 to 1500 mg (e.g., 500 to 1000 mg, 1000 to 1500 mg) of one or more compounds disclosed herein are administered twice daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days. VII.How to use

[0260] The present disclosure also provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound described herein.

[0261] In some embodiments, the disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject in need thereof a compound described herein.

[0262] In some embodiments, the present disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0263] In some embodiments, the present disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0264] In some embodiments, the present disclosure provides a method of inhibiting a viral polymerase in a cell, the method comprising contacting a cell infected with a virus with a compound disclosed herein, thereby inhibiting the viral polymerase.

[0265] In some embodiments, the present disclosure provides a method of inhibiting a viral polymerase in a cell, the method comprising contacting a virally infected cell with a compound disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0266] Also provided is the use of a compound disclosed herein for use in treating or preventing a viral infection in a subject in need thereof. For example, provided herein is the use of a compound disclosed herein for use in treating a viral infection in a subject in need thereof. A. Paramyxoviridae

[0267] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method for treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein. In some embodiments, the Paramyxoviridae virus comprises a BSL4 pathogen. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus.

[0268] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Paramyxoviridae virus infection in a subject (e.g., a human).

[0269] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof. B. Pneumoviridae

[0270] In some embodiments, the viral infection is a Pneumoviridae virus infection. 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 subject (e.g., human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus (RSV) and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus (RSV) infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0271] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Pneumoviridae virus infection in a subject (e.g., a human) in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Pneumoviridae virus infection in a subject (e.g., a human). 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.

[0272] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Pneumoviridae virus infection in a human in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a Pneumoviridae virus infection in a human. In some embodiments, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a Pneumoviridae virus infection in a human. 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.

[0273] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, 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 (RSV) infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0274] In certain embodiments, the present disclosure provides a method for treating a respiratory syncytial virus infection, comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject (e.g., a human) infected with a respiratory syncytial virus. In some embodiments, the human is suffering from a chronic respiratory syncytial virus infection. In some embodiments, the human is acutely infected with RSV.

[0275] In certain embodiments, methods are provided for inhibiting RSV replication, comprising administering to a subject (e.g., a human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0276] In certain embodiments, the present disclosure provides a method for reducing the viral load associated with a RSV infection, the method comprising administering to a subject (e.g., a human) infected with RSV a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to reduce the RSV viral load in the subject.

[0277] As described in more detail herein, the compounds of the present disclosure can be administered to a subject (e.g., a human) infected with RSV along with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected subject (e.g., a human) simultaneously with the compounds of the present disclosure, or before or after administration of the compounds of the present disclosure.

[0278] In certain embodiments, compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are provided for use in treating or preventing a RSV infection. In certain embodiments, compounds of the present disclosure (e.g., compounds of Formulas I-XIIIb), or pharmaceutically acceptable salts thereof, are provided for the manufacture of a medicament for treating or preventing a RSV infection.

[0279] In some embodiments, a method of inhibiting RSV replication is provided, comprising administering to a subject (e.g., a human) in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0280] In some embodiments, the present disclosure provides a method for reducing the viral load associated with a RSV infection, the method comprising administering to a human infected with RSV a compound disclosed herein. C. Picornaviridae

[0281] In some embodiments, the viral infection is a Picornaviridae virus infection. 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 subject (e.g., a human) a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections, including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic polio-like syndrome, epidemic pleurodynia (an acute, febrile, infectious illness that typically occurs during epidemics), hand, foot, and mouth disease, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection. In some embodiments, the Picornaviridae virus infection is an enterovirus infection. In some embodiments, the Picornaviridae virus infection is selected from the group consisting of Coxsackie A virus infection, Coxsackie A virus infection, Enterovirus D68 infection, Enterovirus B69 infection, Enterovirus D70 infection, Enterovirus A71 infection, and Poliovirus infection. In some embodiments, the Picornaviridae virus is foot and mouth disease virus (FMDV).

[0282] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Picornaviridae virus infection in a subject (e.g., a human) in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Picornaviridae virus infection in a subject (e.g., a human). In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection.

[0283] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Picornaviridae virus infection in a subject (e.g., a human) in need thereof, in some embodiments, the Picornaviridae virus infection is a human rhinovirus infection. D. Flaviviridae

[0284] In some embodiments, the viral infection is a Flaviviridae virus infection. In some embodiments, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to a subject (e.g., a human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Representative Flaviviridae viruses include, but are not limited to, dengue, yellow fever, West Nile, Zika, Japanese encephalitis virus, tick-borne encephalitis virus (TBEV), and hepatitis C (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 tick-borne encephalitis virus (TBEV) infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection. In some embodiments, the Flaviviridae virus infection is a bovine viral diarrhea virus (BVDV). In some embodiments, the Flaviviridae virus infection is a swine fever virus (SFV) infection.

[0285] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Flaviviridae virus infection in a subject (e.g., a human) in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Flaviviridae virus infection in a subject (e.g., a human). 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.

[0286] In some embodiments, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, 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. E. Filoviridae

[0287] In some embodiments, the viral infection is a Filoviridae virus infection. 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 subject (e.g., human) a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. Representative Filoviridae viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Tai Forest, or Reston variant) 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.

[0288] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Filoviridae virus infection in a human in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Filoviridae virus infection in a human. In some embodiments, the Filoviridae virus infection is an Ebola virus infection.

[0289] In some embodiments, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Filoviridae virus infection in a subject (e.g., 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. VIII. Combination Therapy

[0290] 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 of treating a viral infection in a subject in need thereof, comprising 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 method comprises administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the compounds disclosed herein are combined with at least one other active therapeutic agent, and the combination is used to treat a viral infection in a subject in need thereof. In some aspects, the combination can be used to treat multiple separate viral infections (e.g., RSV and HIV) in a single subject. In some embodiments, the compounds disclosed herein are combined with at least one other active therapeutic agent to cover a broader spectrum of respiratory viruses in a single treatment, without the need for diagnosis.

[0291] In some embodiments, the combination can be used to treat the same virus (e.g., RSV) in a single subject. Active therapeutic agents include, but are not limited to, approved drugs, therapeutic agents currently in clinical trials, therapeutic agents that have demonstrated efficacy in animal models, therapeutic agents that have demonstrated efficacy in in vitro assays, or any of the above.

[0292] In some embodiments, the additional therapeutic agent comprises 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 a 5-substituted 2'-deoxyuridine analog, a nucleoside analog, a pyrophosphate analog, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, an entry inhibitor, an acyclic guanosine analog, an acyclic nucleoside phosphonate analog, an HCV NS5A / NS5B inhibitor, an influenza virus inhibitor, an interferon, an immunostimulant, an oligonucleotide, a mitotic inhibitor, and combinations thereof.

[0293] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog, e.g., in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0294] 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, β-D-N4-hydroxycytidine, or a combination thereof.

[0295] 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.

[0296] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, hi some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0297] 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.

[0298] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, bedroprevir, sovaprevir, deldeprevir, naraprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.

[0299] 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.

[0300] 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, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), varicella-zoster immunoglobulin (VariZIG), varicella-zoster immune globulin (VZIG), and combinations thereof.

[0301] In some embodiments, the additional therapeutic agent is an acyclic guanosine analog, for example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0302] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof.

[0303] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0304] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0305] 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 (PegIFNα-2a), and PegIFNα-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 (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof.

[0306] In some embodiments, the additional therapeutic agent is an immunostimulant. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is a mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechin, and combinations thereof.

[0307] In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0308] In some embodiments, the additional therapeutic agent is an agent for the treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir.

[0309] In some embodiments, the additional therapeutic agent is an agent for the treatment of picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-buthionine 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.

[0310] In some embodiments, the additional therapeutic agent is an agent for the treatment of malaria, hi some embodiments, the additional therapeutic agent is chloroquine.

[0311] In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomer mesylate, ganaplacid, DSM-265, cypargamine, artemisone, and combinations thereof.

[0312] In some embodiments, the additional therapeutic agent is an agent for the treatment of coronavirus. In some aspects, the additional therapeutic agent is an agent for the treatment of COVID-19 (coronavirus disease 2019, a disease caused by a virus designated SARS-CoV-2). In some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporin, remdesivir, VV116, GS-441524, GS-5245, and combinations thereof.

[0313] In some embodiments, the additional therapeutic agent is an agent for the treatment of Ebola virus. For example, in some embodiments, the additional therapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma, or the like. 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-dimethylquinolin[8,7 [-h]quinolone-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 inhibitor (NPC1 inhibitor), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0314] In some embodiments, the additional therapeutic agent is an agent for the treatment of HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, ladarbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of GS-9256, vedroprevir, voxilaprevir, and combinations thereof.

[0315] In some embodiments, the additional therapeutic agent is an NS5A inhibitor, e.g., in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0316] 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 alpha-hydroxytropolone, amdoxovir, antroquinonol, beta-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, 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, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sofosbuvir, ledipasvir, UB-551, and ZH-2N, as well as U.S. Patent Application Publication Nos. 20150210682 (Roche), 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), WO 2015252057(B) (Roche), WO 2015252057(C) (Roche), WO 2015252057(D) (Roche), WO 2015252057(E) (Roche), WO 2015252057(F) (Roche), WO 2015252057(G) (Roche), WO 2015252057(H) (Roche), WO 2015252057(I ... Examples of therapeutic agents include, but are not limited to, compounds disclosed in Publication Nos. 16128335(A1) (Roche), 16120186(A1) (Roche), U.S. Patent Application Publication Nos. 2016237090(A) (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), U.S. Patent Application Publication Nos. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), U.S. Patent Application Publication Nos. 2016220586(A) (Roche), and 2015031687(A) (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. HBVExamples of DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, bicifovir, and entecavir. In some embodiments, the additional therapeutic agent includes, but is not limited to, HBV capsid inhibitors, including, but not limited to, HBV capsid inhibitors ...

[0317] In some embodiments, the additional therapeutic agent is an agent for the treatment of HIV, hi some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, an HIV integrase inhibitor, an entry inhibitor, an HIV nucleoside reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, an acyclic nucleoside phosphonate analog, and combinations thereof.

[0318] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modulating agents, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), and cell therapy (e.g., chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0319] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other drugs for treating 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 reactivators, capsid inhibitors, immune system therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0320] In some embodiments, the additional therapeutic agent is an HIV combination medication. Examples of HIV combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine). TRUVADA® (tenofovir disoproxil fumarate and emtricitabine, TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine) , and cobicistat; SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™ (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, cobicistat, and ervivir Tegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®, lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; 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; dapivirine and levonorgestrel, dolutegravir and lamivudine, dolutegravir and emtricitabine and tenofovir alafena These include, but are not limited to, elsulfavirine + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine;

[0321] In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor (lenacapavir).

[0322] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and cobicistat. In some embodiments, 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.

[0323] 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 bictegravir, elvitegravir, curcumin, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, A Selected from the group consisting of VX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0324] 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. Further examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (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).

[0325] 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.

[0326] In some embodiments, the additional therapeutic agent is a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, for example, adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0327] In some embodiments, the additional therapeutic agent is a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, for example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, elsulfavirin rilp (VM-1500), and combinations thereof.

[0328] In some embodiments, the additional therapeutic agent is ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); TDF+FT C); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir, adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; T RIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®, lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine, AZT+3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine, ABC+3TC); TRIZIVIR® (abacavir sulfate) acid salt, zidovudine, and lamivudine, ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine;Selected from stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0329] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, barbicin, icatibant, bepotastine, epirubicin, epoprocetonol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegovyne, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0330] In some embodiments, the additional therapeutic agent is combined with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, dambatrisen, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9).

[0331] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of MRTX-849(G12C) and KRAS(G12D) selective inhibitory peptides, including AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602 (Ras GTP), RT11, KRpep-2(Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0332] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib.

[0333] 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, a human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pedialix, Engelix-B, and RecombiVax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, e.g., Zostavix and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, e.g., cervical, Gardasil 9, and Gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine, such as (i) a monovalent influenza A vaccine (e.g., an influenza A [H5N1] virus monovalent vaccine and an influenza A [H1N1] 2009 virus monovalent vaccine), (ii) a trivalent vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Fluud, Fluarix, Flublox, Flucervax, Flulaval, Fluvirin, and Fluzone), and (iii) a quadrivalent vaccine for influenza A and B viruses (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., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a variola virus (smallpox) 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 SARS-COV-2 vaccine.

[0334] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an antibody against SARS-CoV-2 selected from the group consisting of a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting the SARS-CoV-2 spike protein, an antibody capable of neutralizing SARS-CoV-2 (a 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 an aPD-1 antibody.

[0335] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0336] 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.

[0337] In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0338] In some embodiments, the additional therapeutic agent is a 6'-fluorinated aristemicin analog, an acyclovir fleximer analog, disulfiram, a thiopurine analog, ASC09F, GC376, GC813, a phenylisoserine derivative, a neuroimidase inhibitor analog, a pyrithiobac derivative, a vananin and a 5-hydroxychromone derivative, SSYA10-001, a griffithsin, a HR2P-M1, a HR2P-M2, a P21S10, dihydrotanshinone E-64-C and E-64-D, an OC43-HR2P, a MERS-5HB, a 229E-HR1P, a 229E-HR2P, a resveratrol, rol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporin A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0339] 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, e.g., an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is a SARS-COV-2 virus antibody.

[0340] The formulations of the present disclosure may also be used in combination with other active ingredients. For the treatment of SARS-COV-2 viral infection, in some embodiments, the other active therapeutic agent is active against coronavirus infection, e.g., SARS-COV-2 viral infection. The compounds and formulations of the present disclosure may also be used in combination with parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory agents (e.g., interferons), other small molecule or biological antivirals targeting SARS-COV-2, and the like. The additional therapeutic agent is intended for use in conjunction with the general care provided to patients with SARS-COV-2 virus infection, including, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, vaccines, analgesics, and drugs for other common illnesses in the target population, such as antimalarials (including artemether and artemether-lumefantrine combination therapy), typhoid (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine.

[0341] In some embodiments, the additional therapeutic agent is an immune modulator. Examples of immune system 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 (MPA). mofetil, MMF), ribavirin, polymer polyethyleneimine (PEI), gepon, IL-12, WF-10, VGV-1, MOR-22, BMS-936559, CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, pegylated interferon alfa-2a, pegylated interferon 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 is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0342] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, or a combination thereof.

[0343] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor, e.g., the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0344] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, Olumiant, or a combination thereof.

[0345] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, eg, pirfenidone.

[0346] 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.

[0347] In some embodiments, the compounds disclosed herein are used in combination with standard treatments for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (1 October)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment depends on several factors, including the type and severity of the pneumonia, the age, and the overall health of the subject. Options include: (i) antibiotics; (ii) cough suppressants; and (iii) antipyretics / 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.

[0348] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from a cured COVID-19 subject. 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.

[0349] 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, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, and RO-7020531.

[0350] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, crividipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.

[0351] In some embodiments, the additional therapeutic agent is kalimycin, suramin, triazavirine, dipyridamole, bevacizumab, meplasmab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketoamine. 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).

[0352] In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic agent. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those described in WO 2004112687, WO 2006135978, WO 2018145148, and WO 2009018609.

[0353] Any compound 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 subject. The combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0354] Co-administration of a compound of the present disclosure with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the present disclosure with one or more other active therapeutic agents such that therapeutically effective amounts of both the compound of the present disclosure and the one or more other active therapeutic agents are present in the body of a subject.

[0355] Co-administration includes administration of a unit dose of a compound of the present disclosure before or after administration of a unit dose of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administration of a compound of the present disclosure. 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 may be desirable to administer a unit dose of a compound of the present disclosure first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of one or more other active therapeutic agents. In other embodiments, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of a compound of the present disclosure.

[0356] Combination therapy can provide "synergistic" and "synergistic" effects, i.e., effects achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by separate tablets, pills, capsules, or different injections in separate syringes. Generally, during alternation therapy, effective dosages of each active ingredient are administered sequentially, i.e., consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect indicates an antiviral effect that is greater than the expected purely additive effect of the individual compounds of the combination. A. Combination Therapy for the Treatment of Pneumoviridae Virus Infections

[0357] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.A herein. In some embodiments, the other active therapeutic agent is active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. As described in more detail herein, the compounds of the present disclosure can be administered to a subject (e.g., a human) infected with RSV along with one or more additional therapeutic agents. Furthermore, in certain embodiments, when used to treat or prevent RSV, the compounds of the disclosure are selected from the group consisting of RSV combination drugs, RSV vaccines, RSV RNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, respiratory syncytial surface antigen inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, RSV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, farnesoid X receptor agonists, RSV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase inhibitors, and the like. The therapeutic agent may be administered with one or more (e.g., 1, 2, 3, 4 or more) additional therapeutic agents selected from the group consisting of: a PI3K inhibitor, an indoleamine-2,3-dioxygenase (IDO) pathway inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a recombinant thymosin alpha-1 agonist, a Bruton's tyrosine kinase (BTK) inhibitor, a KDM inhibitor, an RSV replication inhibitor, an arginase inhibitor, and other RSV drugs.

[0358] Non-limiting examples of these other active therapeutic agents active against RSV include active monoclonal antibody and nanobody therapeutic agents, agents active against RSV infection, respiratory syncytial virus protein F inhibitors, viral replication inhibitors, RNA polymerase inhibitors, siRNA-based therapies, and combinations thereof. Non-limiting examples of active monoclonal antibody and nanobody therapeutic agents include palivizumab, RSV-IGIV (RESPIGAM®), MEDI-557 (motavizumab), MEDI8897 (nirsevimab), MK-1654, ALX-0171, A-60444 (also known as RSV604), anti-RSV G protein antibodies, and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as MDT-637, BMS-433771, AK-0529, RV-521 (cisnatovir), JNJ-53718678 (lilematovir), BTA-585 and presatovir, RNA polymerase inhibitors (e.g., ribavirin, A-60444 (also known as RSV604), JNJ-64417184, ALS-8112 (JNJ-64041575, lumicitabine)), and ALS-8112 (the parent nuc of lumicitabine), and viral replication inhibitors such as EDP-938 and nitazoxanide, siRNA-based therapies such as ALN-RSV01, and combinations thereof.

[0359] In some embodiments, the other active therapeutic agent may 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.

[0360] 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 the treatment of metapneumovirus infection such as EV-046113.

[0361] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines. B. Combination Therapies for the Treatment of Picornaviridae Virus Infections

[0362] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.B herein. In some embodiments, the other active therapeutic agent is active against Picornaviridae virus infections, particularly Enterovirus infections. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors, e.g., pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (U.S. Pat. No. 7,078,403) and Watson (U.S. Pat. No. 7,166,604), fusion sialidase proteins such as DAS-181, capsid protein VP1 inhibitors such as VVX-003 and AZN-001, viral protease inhibitors such as CW-33, phosphatidylinositol 4 kinase beta inhibitors such as GSK-480 and GSK-533, and anti-EV71 antibodies.

[0363] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Picornaviridae virus infection, including but not limited to, EV71 vaccine, TAK-021, and EV-D68 adenovector-based vaccine. C. Combination Therapy for the Treatment of Respiratory Infections

[0364] The compounds disclosed herein and their pharmaceutically acceptable salts can be used in combination with any of the active therapeutic agents discussed in Section VIII of the present specification and / or other active therapeutic agents specifically discussed in Section VIII.C of the present specification. Many infections caused by Pneumoviridae and Picornaviridae viruses are respiratory infections. Therefore, additional active therapeutic agents used to treat respiratory symptoms and sequelae of infection can be used in combination with the compounds provided herein. The additional agents can be administered orally or by direct inhalation. For example, other additional therapeutic agents that can be combined with the compounds provided herein to treat viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids. Glucocorticoids

[0365] Glucocorticoids, first introduced as an asthma treatment in 1950 (Carryer, Journal of Allergy, 21, 282–287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75(1 Pt)1–13, 1985). Unfortunately, oral glucocorticoid therapy is associated with significant undesirable side effects, including truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term treatments (Goodman and Gilman, 10th edition, 2001). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. To mitigate the severe adverse effects of oral steroids, inhaled corticosteroids (ICS) have been developed. 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, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide, or a pharmaceutically acceptable salt thereof. anti-inflammatory agents

[0366] Other anti-inflammatory agents that act through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents combined with the compounds provided herein for the treatment of viral respiratory infections.The application of "anti-inflammatory signaling modulators" (referred to herein as AISTMs), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB through IKK inhibition), or kinase inhibitors (e.g., P38 MAP, JNK, PI3K, EGFR, or Syk), is a logical approach to stop inflammation because these small molecules target a limited number of common intracellular pathways, i.e., signaling pathways that are key points for anti-inflammatory therapeutic intervention (see review by PJBarnes, 2006).These non-limiting additional therapeutic agents include 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 MAP kinase inhibitor ARRY-797), 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor roflumilast), 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840), N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast), N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281), 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591), 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850), 4-[4-(4-fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657), 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-2-diethylcyclohexanecarboxylate 2-diethyl-ethyl ester prodrug of cilomilast, a PDE-4 inhibitor), (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefinib, an EGFR inhibitor), and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor). Beta-2 adrenergic receptor agonist bronchodilators

[0367] Combinations including an inhaled β2-adrenergic receptor agonist bronchodilator, such as formoterol, albuterol, or salmeterol, together with a compound provided herein are also suitable, but non-limiting, combinations useful for treating respiratory viral infections.

[0368] Combinations of inhaled beta-2 adrenergic receptor agonist bronchodilators, such as formoterol or salmeterol, with ICS are also used to treat both bronchial constriction and inflammation (SYMBICORT® and ADVAIR®, respectively). Combinations including these ICS and beta-2 adrenergic receptor agonists with compounds provided herein are also suitable, but not limited to, combinations useful for treating respiratory viral infections.

[0369] Other examples of beta2 adrenergic receptor agonists include, but are not limited to, bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abesiterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471. Anticholinergic drugs

[0370] Anticholinergic agents may be useful for the treatment or prevention of pulmonary bronchoconstriction and are therefore useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergic agents include muscarinic receptor antagonists (especially of the M3 subtype) that have shown therapeutic efficacy in humans for controlling cholinergic tone in COPD (Witek, 1999), such as 1-{4-hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide, 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycinate), 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solifenacin), and 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solifenacin). ), 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (levatropate), 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-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (oxitropium-N,N-diethylglycinate), 7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycinate), dimethylaminoacetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycinate), 3-[4,4-bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium, 1-[1-(3-fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one, 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2] These include, but are not limited to, oct-3-yl)-1-phenyl-prop-2-yn-1-ol, 3-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (acridinium-N,N-diethylglycinate), or (2-diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester, rebefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, and bencycloquidium bromide. mucolytics

[0371] The compounds provided herein can also be combined with mucolytic agents to treat both the infection 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 both the infection and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0372] Nebulized hypertonic saline is used to improve the immediate and long-term clearance of small airways in subjects with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds provided herein can also be combined with nebulized hypertonic saline, especially when viral infections are coexisting with bronchiolitis. The combination of the compounds provided herein and hypertonic saline can also include any of the additional agents discussed above. In some embodiments, 3% hypertonic saline is used. D. Combination Therapy for the Treatment of COPD

[0373] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of respiratory exacerbations of COPD, specifically discussed in Section VIII.D herein. In some embodiments, the other active therapeutic agents include other active agents for COPD.Non-limiting examples of these other active therapeutic agents include anti-IL5 antibodies such as benralizumab and mepolizumab, dipeptidyl peptidase I (DPP1) inhibitors such as AZD-7986 (INS-1007), DNA gyrase inhibitors / topoisomerase IV inhibitors such as ciprofloxacin hydrochloride, MDR-related protein 4 / phosphodiesterase (PDE) 3 and 4 inhibitors such as RPL-554, CFTR stimulators such as ivacaftor and QBW-251, MMP-9 / MMP-12 inhibitors such as RBx-10017609, adenosine A1 receptor antagonists such as PBF-680, GATA3 transcription factor inhibitors such as SB-010, and muscarinic receptor modulators / nicotinic acetylcholine receptor agonists such as ASM-024. agonists, MARCKS protein inhibitors, e.g., KIT tyrosine kinase / PDGF inhibitors such as BIO-11006 and masitinib, phosphodiesterase (PDE) 4 inhibitors such as roflumilast and CHF-6001, phosphoinositide-3 kinase delta inhibitors such as nemiralisib, 5-lipoxygenase inhibitors such as TA-270, muscarinic receptor antagonists / beta-2 adrenergic agonists such as butefenterol succinate, AZD-887, and ipratropium bromide, elastase inhibitors such as TRN-157 and erdosteine, metalloproteinase-12 inhibitors such as FP-025, interleukin-18 ligand inhibitors such as tadekinig alpha, skeletal muscle troponin activators such as CK-2127107, and p38 inhibitors such as akmapimod These include MAP kinase inhibitors, IL-17 receptor modulators, e.g., CNTO-6785, CXCR2 chemokine antagonists such as danilixin, leukocyte elastase inhibitors such as POL-6014, epoxide hydrolase inhibitors such as GSK-2256294, HNE inhibitors, e.g., CHF-6333, VIP agonists such as aviptadil, phosphoinositide-3 kinase delta / gamma inhibitors such as RV-1729, complement C3 inhibitors such as APL-1, and G protein-coupled receptor-44 antagonists such as AM-211.

[0374] Other non-limiting examples of active therapeutic agents include budesonide, adipocytes, nitric oxide, PUR-1800, YLP-001, LT-4001, azithromycin, Gamnex, QBKPN, sodium pyruvate, MUL-1867, mannitol, MV-130, MEDI-3506, BI-443651, VR-096, OPK-0018, TEV-48107, doxofylline, TEV-46017, OligoG-COPD-5 / 20, STEMPEUCEL®, ZP-051, lysine acetylsalicylate.

[0375] In some embodiments, the other active therapeutic agent may be a vaccine that is active against COPD, including but not limited to MV-130 and GSK-2838497A. E. Combination Therapy for the Treatment of Flaviviridae Virus Infections

[0376] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.E herein. In some embodiments, the other active therapeutic agent is active against Flaviviridae virus infections.

[0377] Non-limiting examples of other active therapeutic agents for the treatment of Flaviviridae infections are host cell factor modulators such as GBV-006, alpha-glucosidase 1 inhibitors such as fenretinide ABX-220, BRM-211, celgosivir, platelet activating factor receptor (PAFR) antagonists such as modipafant, cadherin-5 / factor Ia modulators such as FX-06, NS4B inhibitors, e.g., JNJ-8359, viral RNA splicing modulators such as ABX-202, NS5 polymerase inhibitors, NS3 protease inhibitors, and TLR modulators.

[0378] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of dengue fever, including, but not limited to, TETRAVAX-DV, DENGVAXIA®, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2 delta30-7169, and DENV-1 PIV. F. Combination Therapy for the Treatment of Filoviridae Virus Infections

[0379] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.F herein. In some embodiments, the other active therapeutic agent is active against Filoviridae virus infections (e.g., Marburg virus, Ebola virus, Sudan virus, and Cueva virus infections). Non-limiting examples of these other active therapeutic agents include: MR186-YTE, remdesivir, ribavirin, palivizumab, motavizumab, RSV-IGIV (RESPIGAM®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T- 705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir, galidesivir, favipiravir (also known as T-705 or Avigan), RNA polymerase inhibitors such as JK-05, host cell factor modulators such as GMV-006, cadherin-5 / factor Ia modulators such as FX-06, and antibodies for the treatment of Ebola such as INMAZEB (atortivimab, maftivimab, and odesivimab), ZMapp, and mAb114 (EBANGA).

[0380] Other non-limiting active therapeutic agents active against Ebola include, but are not limited to, alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 binding nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists HLA class II antigen modulators, host cell factor modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0381] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, and may include, but is not limited to, VRC-EBOADC076-00-VP, 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.

[0382] 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-pair duplexes with specific RNA sequences. Examples of PMOs include, but are not limited to, AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002 and AVI-6003.

[0383] The compounds provided herein are also intended for use in combination with the general care provided to subjects with Filoviridae virus infections, including parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and medications for other common illnesses in the subject population, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. Combination Therapy for the Treatment of G. Influenza

[0384] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII of the present specification and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.G of the present specification. In some embodiments, the compounds provided herein are also used in combination with other active therapeutic agents for the treatment of influenza virus infections. The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In some embodiments, the compounds provided herein can also be combined with influenza therapeutic agents. In some embodiments, the compounds provided herein are used in conjunction with influenza therapeutic agents when treating influenza viruses. In some embodiments, the compounds provided herein are used in conjunction with influenza therapeutic agents to treat a broader spectrum of respiratory viruses, such as those disclosed herein. In some embodiments, the influenza therapeutic agent is a neuraminidase (NA) inhibitor. In some embodiments, the influenza therapeutic agent is an M2 inhibitor.Examples of influenza therapeutic agents include AB-5080, ALS-1, amantadine (GOCOVRI®), AV-001, AV-5124, AVM-0703, baloxavir marboxil (XOFLUZA®), CB-012, CC-42344, CD-388, CT-P27, Codivir, DAS-181, DNK-651, ENOB-FL-01, ENOB-FL-11, favipiravir, GP-584, GP-681, H-015, HC-imAb, HEC-116094HCl·3H2O, HNC-042, histamine glutarimide, IFV-PA, Ingavirin, INI-2004, INNA-051, and KYA. These include, but are not limited to, H01-2019-121, laninamivir, molnupiravir, niclosamide, nitazoxanide, norketotifen, NX-2016, oseltamivir phosphate (TAMIFLU®), peramivir (RAPIVAB®), REVTx-99, rimantadine, S-416, SAB-176, STP-702, T-705IV, TG-1000, TJ-27, TSR-066, 7HP-349, VIR-2482, VIS-410, VIS-FLX, XC-221, zanamivir (RELENZA®), zanamivir-dinitrophenyl conjugate, ZSP-1273, and ZX-7101A. IX. Compound Preparation

[0385] In some embodiments, the present disclosure provides processes and intermediates useful for preparing the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0386] The compounds disclosed herein can be purified by any of the means known in the art, including, but not limited to, chromatographic means 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, but not limited to, normal and reverse phase and ionic resins. In some embodiments, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0387] During any of the processes for the preparation of the compounds provided herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is further discussed in T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," 4 th This can be achieved by conventional protecting groups, as described in standard works such as "Protective Groups for the Synthesis of Novel Compounds," ed., Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0388] Exemplary chemicals useful in the methods of the embodiments are illustrated by reference to exemplary synthetic schemes for their general preparation herein and the specific examples below. To obtain the various compounds herein, those skilled in the art will recognize that starting materials can be appropriately selected to obtain the desired product, such that the ultimately desired substituents are carried through the reaction scheme, with or without protection as necessary. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is carried through the reaction scheme and can be appropriately replaced with the desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular pendant groups.

[0389] Although the methods of the present disclosure generally provide a specific enantiomer or diastereomer as the desired product, the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is derived without indicating the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0390] Representative syntheses of compounds of the present disclosure are described in the following schemes and specific examples below. [ka]

[0391] Scheme 1 shows a general synthesis of compounds, beginning with the addition of alcohol S1a1 to epoxide S1b1 using PG (e.g., Tr, TBDPS) under basic conditions (e.g., KOtBu or NaH) to give alcohol S1c. Alternatively, addition of alcohol S1b2 to alkyl halide S1a2 (e.g., Br) under basic conditions (e.g., NaH), followed by acetonide removal under acidic conditions (e.g., HCl) and protection of the primary alcohol under basic conditions (e.g., TBDPSCl, TEA) gives S1c. Substitution reaction with halide S1d (e.g., Br) under basic conditions (e.g., KOtBu or NaH) and removal of PG (e.g., HCl or TBAF) gives alcohol S1e. Coupling of alcohol S1e and nucleoside S1f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) affords S1g. Removal of 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl) affords final compounds of type S1h (e.g., compounds 1, 3-10, 12-20, 22, 53, 55, 61, 63, 66, 67, 68, 73, and 75 in Table 1). [ka]

[0392] Scheme 2 shows a general synthesis of compounds, beginning with the addition of an alkyl Grignard S2a to an epoxide S2b with PG (e.g., Tr, TBDPS) to give alcohol S2c. Substitution with a halide S2d (e.g., Br) under basic conditions (e.g., KOtBu) and removal of PG (e.g., HCl or TBAF) affords alcohol S2e. Coupling of alcohol S2e and nucleoside S2f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) affords S2g. Removal of 2-Cl-phenols (e.g., CsF, DMAP) and acetonides (e.g., HCl) affords final compounds of type S2h (e.g., compounds 2, 11, 25–37, 56, 62, 70, 74, and 76 in Table 1). [ka]

[0393] Scheme 3 shows a general synthesis of compounds, beginning with the addition of alcohol S3a to epoxide S3b using PG (e.g., Tr, TBDPS) under basic conditions (e.g., KOtBu) to give alcohol S3c. Substitution reaction (e.g., KOtBu) or Ullmann CO coupling with halide S3d (e.g., Br) under basic conditions (e.g., CuI, CsCO, MePhen), followed by removal of PG (e.g., HCl or TBAF), gives alcohol S3e. Coupling of alcohol S3e and nucleoside S3f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine) gives S3g. Removal of the 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl) affords final compounds of type S3g (e.g., compounds 21, 23, 24-50, 59, 69, 71, 72, and 77 in Table 1). [ka]

[0394] Scheme 4 shows a general synthesis of compounds starting from the addition of an alkyl Grignard S4a1 to an epoxide S4b using PG (e.g., Tr, TBDPS) under basic conditions (e.g., KOtBu) to give an alcohol S4c. Alternatively, dihydroxylation (CR) of a terminal alkene S4a2 can be performed. 4 R 5 (The group is not linked via a double bond), followed by protection of the primary alcohol (e.g., TrCl or TBDPSCl) provides alcohol S4c. Substitution reaction (e.g., KOtBu) or Ullmann CO coupling (e.g., CuI, CsCO, MePhen) with halide S4d (e.g., Br) under basic conditions, followed by removal of PG (e.g., HCl or TBAF) provides alcohol S4e. Coupling of alcohol S4e and nucleoside S4f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) provides S4g. Removal of 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl) provides final compounds of type S4g (e.g., compounds 38-40, 51, and 60 in Table 1). [ka]

[0395] Scheme 5 shows a general synthesis of compounds, starting with the substitution reaction of alcohol S5a with halide S5b under basic conditions (e.g., NaH), followed by acetonide cleavage under acidic conditions (e.g., HCl) and protection of the alcohol (e.g., TBDPSCl) to give alcohol S5c. Substitution reaction with alkyl halide S5d (e.g., Br) under basic conditions (e.g., NaH), followed by removal of the protecting group (e.g., TBAF), gives alcohol S5e. Coupling of alcohol S4e and nucleoside S4f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) gives S5g. Removal of 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl) gives final compounds of type S5h (e.g., compounds 41 and 42, Table 1). [ka]

[0396] Scheme 6 shows a general synthesis of compounds, starting with a substitution reaction (e.g., NaH) or Ullmann CO coupling (e.g., CuI, CsCO, MePhen) of alcohol S6a with a halide S6b (e.g., Br) under basic conditions, followed by acetonide cleavage (e.g., HCl) and protection of the alcohol (e.g., TBDPSCl) under acidic conditions to give alcohol S6c. Substitution reaction with an alkyl halide S6d (e.g., Br) under basic conditions (e.g., NaH), followed by removal of the protecting group (e.g., TBAF), gives alcohol S6e. Coupling of alcohol S6e and nucleoside S6f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) gives alcohol S6g. Removal of the 2-Cl-phenol (eg, CsF, DMAP) and acetonide (eg, HCl) affords final compounds of type S6h (eg, compounds 43 and 65, Table 1). [ka]

[0397] Scheme 7 shows a general synthesis of compounds, beginning with a substitution reaction of alkyl halide S7b under basic conditions (e.g., NaH), followed by acetonide cleavage under acidic conditions (e.g., HCl) and alcohol protection (e.g., TBDPSCl) to give alcohol S7c. Substitution reaction (e.g., NaH) or Ullmann CO coupling (e.g., CuI, CsCO, MePhen) with halide S7d (e.g., Br) under basic conditions, followed by removal of the protecting group (e.g., TBAF) gives alcohol S7e. Coupling of alcohol S7e and nucleoside S7f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) gives S7g. Removal of the 2-Cl-phenol (eg, CsF, DMAP) and acetonide (eg, HCl) affords final compounds of type S7h (eg, compound 44, Table 1). [ka]

[0398] Scheme 8 shows a general synthesis of compounds, beginning with the tosylation of an alcohol (e.g., S1e or S2e), followed by displacement with sodium azide and treatment with triphenylphosphine to give amine S8a. Amine S8a and nucleoside S8b are coupled with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) to give S8c. Removal of 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl) affords final compounds of type S8d (e.g., compounds 45 and 46, Table 1). [ka]

[0399] Scheme 9 shows a general synthesis of compounds beginning with sulfonylation (e.g., 2-nitrobenzenesulfonyl chloride) of amine S8a (e.g., X=O or CH), followed by Mitsunobu reaction (e.g., MeOH, PPh, DEAD) and desulfonylation (e.g., PhSH) to give amine S9a. Amine S9a and nucleoside S9b are coupled with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) to give S9c. Removal of 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl) affords final compounds of type S9d (e.g., compounds 57 and 58, Table 1). [ka]

[0400] Scheme 10 shows a general synthesis of compounds, starting with coupling of Grignard S10a with S10b (e.g., [1,1-bis(diphenylphosphino)ferrocene]dichloronickel(II)) to give S10c. Metallation of aryl halide S10c (e.g., Mg, CuI) and addition of epoxide S10d with PG (e.g., Tr, TBDPS) gives alcohol S10e. Substitution reaction with halide S10f (e.g., Br) under basic conditions (e.g., KOtBu) and removal of PG (e.g., HCl or TBAF) gives alcohol S10g. Coupling of alcohol S10g and nucleoside S10h with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) gives S10i. Removal of the 2-Cl-phenol (eg, CsF, DMAP) and acetonide (eg, HCl) affords final compounds of type S10j (eg, compound 54, Table 1). [ka]

[0401] Scheme 11 shows a general synthesis of compounds, starting with protection of primary alcohol S11a (e.g., TrCl) to give S11b. S11b is then cross-coupled to Grignard S11c using a metal catalyst (e.g., [1,1-bis(diphenylphosphino)ferrocene]-dichloronickel(II)) to give S11d. Substitution reaction with a halide S11e (e.g., Br) under basic conditions (e.g., KOtBu) and removal of the protecting group under acidic conditions (e.g., HCl) gives alcohol S11f. Coupling of alcohol S11f and nucleoside S11g with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) gives S11h. Removal of the 2-Cl-phenol (eg, CsF, DMAP) and acetonide (eg, HCl) affords final compounds of type S11i (eg, compound 47, Table 1). [ka]

[0402] Scheme 12 shows a general synthesis of compounds, starting with the addition of alcohol S12b to S12a under acidic conditions (e.g., TsOH, MgSO4, Servi, SJ Org. Chem. 1985, 50, 5865) to give alcohol S12c. Substitution with S12d under acidic conditions (e.g., TsOH) and reduction of the ester (e.g., LiAlH4) affords alcohol S12e. Coupling of alcohol S12e and nucleoside S1f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF) affords S12g. Removal of 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl) affords final compounds of type S12h (e.g., compound 64, Table 1). [ka]

[0403] Scheme 13 shows a general synthesis of compounds, starting with allylation of the alcohol S13a, followed by dihydroxylation (e.g., OsO, NMNO) and cleavage of the vincadiol (e.g., NaIO) to give the aldehyde S13b. Addition of a Grignard reagent to the aldehyde gives the secondary alcohol, which is deoxygenated (e.g., Br2PPh3, Bu3SnH, AIBN, Bu4NF), followed by removal of the protecting group (e.g., TBAF) to give S13c. Coupling of the alcohol S13c and the nucleoside S13d with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF) gives S13e. Removal of the 2-Cl-phenol (eg, CsF, DMAP) and acetonide (eg, HCl) affords final compounds of type S13f (eg, compound 48, or compound 49, Table 1). [ka]

[0404] Scheme 14 shows a general synthesis of compounds, starting with the substitution reaction of malonate S14b with alkyl halide S14a under basic conditions (e.g., NaH), followed by reduction (e.g., LiAlH) to give S14c. Substitution reaction of alcohol S14c with alkyl halide (e.g., Br) S14d under basic conditions (e.g., NaH) gives S14e (Subba Reddy et al., Eur. J. Org. Chem 2013, 10, 1993-1999). Coupling of alcohol S14e and nucleoside S14f with 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CHCN, pyridine, or THF) gives S14e. Removal of the 2-Cl-phenol (eg, CsF, DMAP) and acetonide (eg, HCl) affords final compounds of type S14f (eg, compound 52, Table 1). [ka]

[0405] Scheme 15 shows a general synthesis of compounds, starting with acetonide cleavage under acidic conditions (e.g., HCl), followed by esterification of the 2'- and 3'-ribose alcohols with anhydride reagents under basic conditions (e.g., DMAP). Removal of the 2-Cl-phenol (e.g., CsF, DMAP) affords final compounds of type S15b. [Example]

[0406] A. Abbreviation Certain abbreviations and acronyms are used in describing the experimental details. While most of these will be understood by those skilled in the art, Table 41 contains a list of some of these abbreviations and acronyms. [Table 41] B.Intermediates Intermediate I-1: (S)-1-O-trityl-3-(heptadecyloxy)propane-1,2-diol [ka]

[0407] Potassium tert-butoxide (18.7 mmol) and hexadecanol (8.42 mmol) were added to a solution of (S)-O-trityloxiran-2-ylmethanol (4.68 mmol) in DMF (40 mL). The resulting mixture was stirred at 100° C. for 2 h, cooled to room temperature, diluted with ether (300 mL), washed with brine (100 mL × 2), dried over sodium sulfate, and purified by silica gel column chromatography (0% to 20% EtOAc in hexane) to give intermediate I-1. 1H NMR(400MHz,DMSO-d6)δ 7.50-7.10(m,15H),4.86(d,J=5.4Hz,1H),3.76(q,J=5.4Hz,1H),3.38(m,2H),3. 33(s,2H),2.95(m,2H),1.41(m,2H),1.22(d,J=11.2Hz,28H),0.89-0.79(m,3H). Intermediate I-2: (R)-3-fluoro-5-(((1-(heptadecyloxy)-3-(trityloxy)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0408] To a solution of intermediate I-1 (1.52 mmol) in THF (8 mL) was added potassium tert-butoxide (3.04 mL, 1.0 M, 3.04 mmol). The mixture was stirred for 20 minutes, and 3-(bromomethyl)-5-fluoro-benzonitrile (3.04 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours, diluted with water (50 mL), and extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (50 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to give intermediate I-2. 1 H NMR (400 MHz, DMSO-d₆) δ 7.77 (d, J = 8.9 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 9.6 Hz, 1H), 7.43-7.16 (m, 15H), 4.68 (s, 2H), 3.77-3.66 (m, 1H), 3.50 (m, 2H), 3.32 (m, 2H, buried solvent peak), 3.15 (dd, J = 10.1, 3.8 Hz, 1H), 3.07 (dd, J = 10.1, 5.7 Hz, 1H), 1.42 (s, 2H), 1.34-1.00 (m, 28H), 0.85 (t, J = 6.6 Hz, 3H). Intermediate I-3: (S)-3-fluoro-5-(((1-(heptadecyloxy)-3-hydroxypropan-2-yl)oxy)methyl)benzonitrile [ka]

[0409] To a solution of intermediate I-2 (1.42 mmol) in THF-iPrOH-MeOH (1.4:1.4:1.4 mL) was added 25% HCl (0.7 mL). The resulting mixture was heated at 65 °C for 45 min, cooled, and saturated NaHCO3 (10 mL) was added. After stirring for 5 min, the mixture was extracted with EtOAc (100 mL × 2). The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0 to 40% EtOAc in hexanes) to give intermediate I-3. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.61 (s, 1H), 7.50 (dd, J = 9.6, 2.4 Hz, 1H), 7.44 (dt, J = 8.5, 1.8 Hz, 1H), 4.73 (s, 2H), 3.68-3.50 (m, 5H), 3.43 (m, 2H), 2.84 (t, J = 5.7 Hz, 1H), 1.55 (m, 2H), 1.39-1.21 (m, 28H), 0.91 (t, J = 6.7 Hz, 3H). Intermediate I-3a1: (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ka]

[0410] Intermediate I-3a1 was prepared according to WO 2015 / 069939. For example, pages 127-138 of WO 2015 / 069939 provide a process for preparing this compound (identified as compound 14k in WO 2015 / 069939). Intermediate I-3a: (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ka]

[0411] Intermediate I-3a1 (18.87 mmol) was dissolved in THF (100 mL). TBAF 1.0 M in THF (28.31 mmol) was added in one portion at ambient temperature. Stirred at ambient temperature for 10 minutes. The reaction was determined to be complete by LCMS. The reaction mixture was quenched with water and the organics were removed under reduced pressure. The crude material was partitioned between EtOAc and water. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and dried over sodium sulfate. The solids were filtered off and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography on a 120 g column using 0% to 10% CHOH in CH2Cl2 to give intermediate I-3a. LC / MS: R = 0.76 min, MS m / z = 332.14 [M+1]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50 × 3.00 mm; Solvent: acetonitrile with 0.1% formic acid, water with 0.1% formic acid. Gradient: 2-100% ACN from 0 min to 2.4 min, 100% ACN from 2.4 min to 2.80 min, 100% ACN from 2.8 min to 2.85 min, 2% ACN from 2.85 min to 3.0 min, at 1.8 mL / min. 1 H NMR(400MHz,DMSO-d6)δ 7.87-7.80(m,3H),6.85(d,J=4.5Hz,1H),6.82(d,J=4.5Hz,1H),5.74(t,J=5.8Hz,1H),5.52(d,J=4.2Hz,1H ),5.24(dd,J=6.8,4.2Hz,1H),4.92(d,J=6.8Hz,1H),3.65(dd,J=6.1,1.7Hz,2H),1.61(s,3H),1.33(s,3H). Intermediate I-4: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(heptadecyloxy)propyl)phosphate [ka]

[0412] To a solution of 1H-1,2,4-triazole (0.844 mmol) and TEA (0.118 mL, 0.844 mmol) in ACN (0.5 mL)-pyridine (0.2 mL) was added 2-chlorophenylphosphorodichloridate (0.065 mL, 0.392 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and intermediate I-3a (0.392 mmol) was added, followed by 1-methylimidazole (0.0631 mL, 0.792 mmol). The resulting mixture was stirred at room temperature for 1 hour, and intermediate I-3 (0.430 mmol) was added. The resulting reaction mixture was stirred for 2 hours and 30 minutes, concentrated in vacuo, and purified by silica gel column chromatography (0% to 100% MeOH in DCM) to give intermediate I-4. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.86 (d, J = 3.5 Hz, 1H), 7.54-7.29 (m, 5H), 7.26-7.05 (m, 2H), 6.83-6.63 (m, 2H), 6.26 (s, 2H), 5.67 (m, 1H), 5.34-5.22 (m, 1H), 5.14-5.06 (m, 1H), 4.67-4.42 (m, 4H), 4. 41-4.28(m,1H),4.27-4.16(m,1H),3.75(m,1H),3.53-3.42(m,2H),3.42-3.28(m, 2H),1.72(s,3H),1.58-1.44(m,2H),1.38(s,3H),1.35-1.17(m,28H),0.90(m,3H). 19 F NMR (376 MHz, acetonitrile-d3) δ -112.78, -112.79. 31P NMR (162 MHz, acetonitrile-d3) δ -7.31, -7.36. MS m / z [M+1] = 967. Intermediate I-5: (R)-3-((1-(octadecyloxy)-3-(trityloxy)propan-2-yl)oxy)benzonitrile [ka]

[0413] To a solution of intermediate I-128 (1.14 mmol) in DMF (10 mL) was added NaH (60% in mineral oil) at room temperature. The mixture was stirred at room temperature for 1 hour, and 3-fluorobenzonitrile (115 mg, 0.950 mmol) was added. The resulting mixture was then heated at 60 °C for 30 minutes, diluted with EtOAc (100 mL), and the reaction was quenched by adding water (10 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-10% EtOAc in hexanes) to give intermediate I-5. 1H NMR(400MHz,DMSO-d6)δ 7.77(d,J=8.9Hz,1H),7.66(s,1H),7.58(d,J=9.6Hz,1H),7.43-7.16(m,16H),4.68(s,2H),3.77-3.66(m,1H),3.56-3.43, (m,2H),3.15(dd,J=10.1,3.8Hz,1H),3.07(dd,J=10.1,5.7Hz,1H),1.42(s,2H),1.34-1.00(m,30H),0.85(t,J=6.6Hz,3H). Intermediate I-6: (S)-3-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)benzonitrile [ka]

[0414] To a solution of intermediate I-5 (0.469 mmol), prepared, for example, as described above, in THF-iPrOH-MeOH (1.5:1.5:1.5 mL) was added 25% HCl (0.3 mL). The resulting mixture was heated at 65 °C for 45 min, cooled, and saturated NaHCO3 (10 mL) was added. After stirring for 5 min, it was extracted with EtOAc (50 mL × 2). The aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0–40% EtOAc in hexanes) to give intermediate I-6. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.48-7.42 (m, 1H), 7.37 (m, 1H), 7.34-7.27 (m, 2H), 4.51 (ddd, J = 10.1, 5.7, 4.3 Hz, 1H), 3.78-3.54 (m, 4H), 3.44 (m, 2H), 2.98 (t, J = 6.1 Hz, 1H), 1.51 (m, 2H), 1.38-1.19 (m, 30H), 0.91 (m, 3H). Intermediate I-7: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-(3-cyanophenoxy)-3-(octadecyloxy)propyl)phosphate [ka]

[0415] To a solution of 1H-1,2,4-triazole (1.00 mmol) in THF (2 mL), TEA (0.139 mL, 1.00 mmol) and 2-chlorophenylphosphorodichloridate (0.0807 mL, 0.49 mmol) were added at room temperature and stirred for 30 min. To this mixture, intermediate I-3a (0.38 mmol) was added in one portion, followed by 1-methylimidazole (0.0391 mL, 0.49 mmol). The resulting mixture was stirred for 30 min, and then intermediate I-6 (0.38 mmol) in THF (2 mL) was added dropwise. After stirring at room temperature for 15 h, the mixture was concentrated in vacuo and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give intermediate I-7. 1 H NMR (400 MHz, methanol-d4) δ 7.83(m,1H),7.55-7.05(m,8H),6.83-6.72(m,2H),5.68(m,1H),5.33-5.2 9(m,1H),5.16(d,J=6.6Hz,0.5H),5.11(d,J=6.6Hz,0.5H),4.71-4.64(m,1 H),4.60-4.37(m,4H),3.63-3.51(m,2H),3.46-3.34(m,2H),1.73(s,3H), 1.53-1.42(m,2H),1.38(s,3H),1.34-1.17(m,30H),0.89(t,J=6.7Hz,3H). 31 P NMR (162 MHz, methanol-d₄) δ −6.46, −6.48. MS m / z [M+1] = 949. Intermediate I-8: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-(3-cyanophenoxy)-3-(octadecyloxy)propyl)hydrogenphosphate [ka]

[0416] Intermediate I-7 (0.179 mmol) was dissolved in THF-ACN (2:1 mL), and CsF (1.55 mmol) in water (0.2 mL) was added, followed by DMAP (0.66 mmol). The resulting mixture was heated at 80 °C for 3.5 h. After dilution with PBS buffer pH 7 (10 mL), the mixture was partitioned between brine (20 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were dried under sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0–50% MeOH in DCM) to give intermediate I-8. MS m / z [M+1] = 839. Intermediate I-9: (R)-2-chloro-4-(((1-(octadecyloxy)-3-(trityloxy)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0417] To a solution of intermediate I-128 (2.56 mmol) in THF (20 mL) was added sodium tert-butoxide powder (5.11 mmol). The solution was stirred at room temperature for 40 minutes. 4-(Bromomethyl)-2-chloro-benzonitrile (5.11 mmol) in THF (5 mL) was added dropwise, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (50 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to give intermediate I-9. 1 H NMR(400MHz,chloroform-d)δ 7.62(d,J=8.0Hz,1H),7.58(d,J=1.4Hz,1H),7.49-7.42(m,6H),7.37-7.24(m,10H),4.73(s,2H),3.74(m,1H),3.60 (d,J=5.2Hz,2H),3.44(t,J=6.6Hz,2H),3.26(m,2H),1.64-1.52(m,2H),1.43-1.06(s,30H),0.91(t,J=6.7Hz,3H). Intermediate I-10: (S)-2-chloro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile [ka]

[0418] To a solution of intermediate I-9 (0.815 mmol) in THF-iPrOH-MeOH (3:3:3 mL) was added 25% HCl (0.5 mL). The resulting mixture was heated at 65 °C for 45 min, cooled, and 10 mL of saturated NaHCO was added. After stirring for 5 min, it was extracted with EtOAc (40 mL × 3). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel chromatography (0 to 40% EtOAc in hexanes) to give intermediate I-10. 1H NMR (400 MHz, acetonitrile-d3) δ 7.77 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.47 (dd, J = 8.0, 1.4 Hz, 1H), 4.75 (s, 2H), 3.67-3.48 (m, 5H), 3.42 (m, 2H), 2.83 (t, J = 5.7 Hz, 1H), 1.54 (m, 2H), 1.40-1.22 (m, 30H), 0.96-0.86 (m, 3H). Intermediate I-11: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3-chloro-4-cyanobenzyl)oxy)-3-(octadecyloxy)propyl)(2-chlorophenyl)phosphate [ka]

[0419] 1H-1,2,4-Triazole (0.664 mmol) was dissolved in THF (2 mL) and TEA (0.09 mL, 0.664 mmol) was added at room temperature. 2-Chlorophenylphosphorodichloridate (0.081 mL, 0.501 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 30 minutes. Intermediate I-3a (0.251 mmol) was added in one portion, and the mixture was stirred at room temperature for 15 minutes. Intermediate I-10 (0.275 mmol) in THF (2 mL) was added, and 1-methylimidazole (0.04 mL, 0.506 mmol) was added at room temperature. The resulting mixture was stirred for 1 hour, concentrated in vacuo, and purified by silica gel (0% to 10% MeOH in DCM) to give Intermediate I-11. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.86 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 6.1 Hz, 1H), 7.48-7.40 (m, 1H), 7.39-7.29 (m, 2H), 7.24-7.12 (m, 2H), 6.80-6.67 (m, 2H), 6.38 (s, 2H), 5.69-5.65 (m, 1H), 5.32-5.24 (m, 1H), 5.13-5.01 (m, 1H), 4.65 ( s,1H),4.60(s,1H),4.58-4.44(m,2H),4.40-4.30(m,1H),4.29-4.17(m,1H),3.76(m,1H),3.51-3.41(m, 2H),3.42-3.30(m,2H),1.72(s,3H),1.49(m,2H),1.37(s,3H),1.34-1.06(m,30H),0.89(t,J=6.7Hz,3H). 31 P NMR (162 MHz, acetonitrile-d3) δ -7.32, -7.38. MS m / z [M+1] = 997. Intermediate I-12: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3-chloro-4-cyanobenzyl)oxy)-3-(octadecyloxy)propyl)hydrogenphosphate [ka]

[0420] Intermediate I-11 (0.179 mmol) was dissolved in THF-ACN (2:1 mL), and CsF (1.46 mmol) in water (0.2 mL) was added, followed by DMAP (0.621 mmol). The resulting mixture was heated at 80 °C for 4 h. After dilution with citrate-NaOH buffer (pH 4, 10 mL), the mixture was partitioned between brine (20 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were dried under sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 50% MeOH in DCM) to give intermediate I-12. MS m / z [M+1] = 887. Intermediate I-14: (R)-docosane-1,2-diol [ka]

[0421] AD-mix-β (28 g) was dissolved in t-butanol (100 mL) and water (100 mL) and cooled to 0 °C. Then, 1-docosene (6.2 g, 20.1 mmol) in THF (100 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 48 h, and NaSO (30 g) was added. The mixture was extracted with EtOAc (150 mL × 3), and the extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0% to 50% EtOAc in hexane) to give intermediate I-14. 1 H NMR(400MHz,DMSO-d6)δ 4.39(t,J=5.7Hz,1H),4.31(d,J=4.9Hz,1H),3.41-3.33(m,1H),3.23(m,2H),1.39(m,2H),1.24(s,36H),0.92-0.79(m,3H). Intermediate I-15: (R)-1-(trityloxy)docosan-2-ol [ka]

[0422] Intermediate I-14 (60% purity, 4.3 mmol) was dissolved in DCM (20 mL) and TEA (1.5 mL, 10.8 mmol) was added. The resulting mixture was stirred for 5 min, and TrCl (4.30 mmol) in DCM (10 mL) was added dropwise at room temperature. The resulting mixture was stirred for 20 h, and hexane (20 mL) was added. The solid was filtered off, and the filtrate was concentrated in vacuo and purified by silica gel column chromatography (0% to 20% EtOAc in hexane) to give intermediate I-15. 1 H NMR(400MHz,chloroform-d)δ 7.46(dd,J=7.7,1.8Hz,6H),7.33(dd,J=8.4,6.6Hz,6H),7.29-7.23(m,2H),3.78(m,1H),3.20(dd,J= 9.4,3.2Hz,1H),3.04(dd,J=9.3,7.6Hz,1H),1.56(s,1H),1.48-1.19(m,36H),0.90(t,J=6.7Hz,3H). Intermediate I-16: (R)-3-((1-(triphenyl-14-oxidanyl)docosan-2-yl)oxy)benzonitrile [ka]

[0423] To a solution of intermediate I-15 (75% pure, 1.71 mmol) in DMF (15 mL)-toluene (10 mL) was added NaH (60% in mineral oil, 2.85 mmol) at room temperature. The mixture was stirred at room temperature for 1 h, and 3-fluorobenzonitrile (0.238 mL, 2.22 mmol) was added. The resulting mixture was then heated at 60 °C for 18 h, cooled to room temperature, quenched with NH4Cl solution (20 mL), diluted with EtOAc (200 mL), washed with water (100 mL), dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% EtOAc in hexanes) to give intermediate I-16. 1H NMR(400MHz,chloroform-d)δ 7.42(d,J=7.4Hz,6H),7.38-7.14(m,13H),4.46-4.27(m,1H),3.36(dd,J=10.2,6.0Hz,1H),3 .26(dd,J=10.1,4.1Hz,1H),1.70(q,J=6.9Hz,2H),1.47-1.04(m,36H),0.91(t,J=6.7Hz,3H). Intermediate I-17: (R)-3-((1-hydroxydocosane-2-yl)oxy)benzonitrile [ka]

[0424] To a solution of intermediate I-16 (1.71 mmol) in toluene-MeOH (10:6 mL) was added 25% HCl (1.0 mL). The resulting mixture was heated at 65° C. for 90 min, cooled, and saturated NaHCO (50 mL) was added. After stirring for 5 min, it was extracted with EtOAc (150 mL × 2). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-40% EtOAc in hexanes) to give intermediate I-17. 1 H NMR (400 MHz, chloroform-d) δ 7.39 (t, J = 7.9 Hz, 1H), 7.29-7.25 (m, 1H), 7.24-7.17 (m, 2H), 4.39 (m, 1H), 3.92-3.72 (m, 2H), 1.75-1.61 (m, 2H), 1.56 (s, 1H), 1.49-1.21 (m, 36H), 0.98-0.83 (m, 3H). Intermediate I-18: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-(3-cyanophenoxy)docosyl)phosphate [ka]

[0425] 1H-1,2,4-Triazole (0.664 mmol) was dissolved in THF (2 mL) and TEA (0.09 mL, 0.664 mmol) was added at room temperature. 2-Chlorophenylphosphorodichloridate (0.081 mL, 0.501 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 30 minutes. Intermediate I-3a (0.251 mmol) was added in one portion, and the mixture was stirred at room temperature for 15 minutes. Intermediate I-17 (0.275 mmol) in THF (2 mL) was added, and 1-methylimidazole (0.04 mL, 0.506 mmol) was added at room temperature. The resulting mixture was stirred for 1 hour, concentrated in vacuo, and purified by silica gel (0% to 10% MeOH in DCM) to give intermediate I-18. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.87 (m, 1H), 7.52-7.09 (m, 8H), 6.79 (m, 1H), 6.77-6.68 (m, 1H), 6.31 (s, 2H), 5.68 (m, 1H), 5.34-5.26 (m, 1H), 5.15-5.06 (m, 1H), 4.59-4.42 (m, 3H), 4.40-4.17 (m, 2H), 1.72 (m, 3H), 1.59 (m, 2H), 1.40-1.18 (m, 39H), 0.96-0.84 (m, 3H). 31 P NMR (162 MHz, acetonitrile-d3) δ -7.54, -7.60. MS m / z [M+1] = 948. Intermediate I-19: ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(3-cyanophenoxy)docosyl)hydrogenphosphate [ka]

[0426] Intermediate I-18 (0.179 mmol) was dissolved in THF-ACN (2:1 mL), and CsF (1.46 mmol) in water (0.2 mL) was added, followed by DMAP (0.621 mmol). The resulting mixture was heated at 80 °C for 4 h. After dilution with citrate-NaOH buffer (pH 4, 10 mL), the mixture was partitioned between brine (20 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were dried under sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 50% MeOH in DCM) to give intermediate I-19. MS m / z [M+1] = 837. Intermediate I-21: (2R)-1-[tert-butyl(dimethyl)silyl]oxy-3-octadecoxy-propan-2-ol [ka]

[0427] A solution of t-butyldimethylsilyl chloride (2.32 mmol) in dichloromethane (2 mL) was added over 1 min to a solution of (2S)-3-octadecoxypropane-1,2-diol (1.45 mmol) and imidazole (2.90 mmol) in dichloromethane (5 mL) at 0 °C. After 2 h, the ice bath was removed. After 3 h, the reaction was washed with water (5 mL). The aqueous layer was extracted with dichloromethane (10 mL). The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0% to 30% ethyl acetate / hexane). The product-containing fractions were combined, and the solvent was removed under reduced pressure to give intermediate I-21. 1 H NMR (400MHz, chloroform-d) δ3.83(p, J=5.4Hz, 1H), 3.74-3.62(m, 2H), 3.50-3.42(m, 4H), 1.58(q, J=7.0Hz, 2H), 1.27(m, 30H), 0.91(m, 12H), 0.09(s, 6H). Intermediate I-22: 3-[[(1R)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-octadecoxy-ethoxy]methyl]-5-fluoro-benzonitrile [ka]

[0428] A 60% dispersion of sodium hydride in mineral oil (1.31 mmol) was suspended in tetrahydrofuran (5 mL) and cooled to 0 °C. A solution of intermediate I-21 (0.654 mmol) in tetrahydrofuran (2 mL) was added over 30 seconds. After 30 minutes, a solution of 3-(bromomethyl)-5-fluorobenzonitrile (1.44 mmol) in tetrahydrofuran (2 mL) was added. The ice bath was removed. After 16 hours, the reaction was quenched with water (10 mL) at 0 °C. Gas evolution was observed. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0% to 20% ethyl acetate / hexanes with ELSD detection). The product-containing fractions were combined, and the solvent was removed under reduced pressure to give intermediate I-22. 1 H NMR(400MHz,chloroform-d)δ 7.48(s,1H),7.41(m,1H),7.28-7.23(m,1H),4.77(s,2H),3.73(d,J=4.9Hz,2H),3.66(qd,J=5.7,4.1Hz,1H),3.55(qd, J=10.3,5.0Hz,2H),3.46(td,J=6.7,1.2Hz,2H),1.65-1.52(m,2H),1.28(s,30H),0.91(d,J=7.1Hz,13H),0.09(s,6H). 19 F NMR (376 MHz, chloroform-d) δ-110.67--110.85 (m). Intermediate I-23: 3-Fluoro-5-[[(1S)-1-(hydroxymethyl)-2-octadecoxy-ethoxy]methyl]benzonitrile [ka]

[0429] A solution of tetrabutylammonium fluoride (1.71 mL, 1.71 mmol) in tetrahydrofuran was added to a solution of intermediate I-22 (0.569 mmol) in tetrahydrofuran (5 mL). After 45 minutes, the reaction was diluted with ethyl acetate (20 mL). The organic layer was washed with water (3 × 5 mL) and brine (5 ml). The organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0% to 20% ethyl acetate / hexanes using ELSD). The product-containing fractions were combined, and the solvent was removed under reduced pressure to give intermediate I-23. 1H NMR (400 MHz, chloroform-d) δ 7.48 (s, 1H), 7.41-7.35 (m, 1H), 7.33-7.29 (m, 1H), 4.83-4.68 (m, 2H), 3.86-3.78 (m, 1H), 3.78-3.68 (m, 2H), 3.68-3.56 (m, 2H), 3.47 (td, J = 6.6, 2.2 Hz, 2H), 1.66-1.50 (m, 2H), 1.40-1.23 (m, 30H), 0.90 (t, J = 6.8 Hz, 3H). 19F NMR (376 MHz, chloroform-d) δ -110.36 (t, J = 8.4 Hz). Intermediate I-24: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)phosphate [ka]

[0430] To a solution of 1H-1,2,4-triazole (1.62 mmol) and TEA (0.226 mL, 1.62 mmol) in CH3CN (2.5 mL) and pyridine (2.5 mL) was added 2-chlorophenylphosphorodichloridate (0.124 mL, 0.755 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. A solution of intermediate I-23 (0.755 mmol) in MeCN (2.5 mL) and pyridine (2.5 mL) was added in one portion to the above reaction mixture under an Ar atmosphere and stirred vigorously for 90 min. To this mixture was added intermediate I-3a (0.755 mmol), followed by 1-methylimidazole (0.1 mL, 1.26 mmol) and stirred overnight. The mixture was concentrated to remove pyridine and coevaporated once with toluene (30 mL). To this mixture was added 10% citric acid (43 mL), followed by 1 N NaOH (7 mL), and water (20 mL) to complete the transfer. The aqueous layer was extracted with EtOAc (3 x 100 mL). The organic fractions were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0-20% MeOH in DCM) to give intermediate I-24. MS m / z [M+1] = 981.2. Intermediate I-25: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(octadecyloxy)propyl)hydrogenphosphate [ka]

[0431] Intermediate I-24 (0.458 mmol) was dissolved in 2:1 THF:ACN (6:3 mL). A solution of cesium fluoride (1.83 mmol) in water (0.578 mL) was added to the solution, followed by 4-(dimethylamino)pyridine (1.6 mmol). The reaction mixture was heated to 80 °C and stirred for 3 h. The reaction was cooled to room temperature and adjusted to pH 3-4 by adding 10% aqueous citric acid (20 mL) followed by 2 M NaOH. Extraction with EtOAc (50 mL × 2) was performed, and LCMS confirmed the absence of the desired product in the aqueous layer. The combined organic layers were washed once with brine, dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0%-50% MeOH in DCM) to give intermediate I-25. MS m / z [M+1] = 871.3. Intermediate I-26: (S)-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile [ka]

[0432] Intermediate I-26 was synthesized in a similar manner to intermediate I-23, using 5-(bromomethyl)-2-methoxybenzonitrile instead of 3-(bromomethyl)-5-fluorobenzonitrile. MS m / z[M+1]=490. Intermediate I-27: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)hydrogenphosphate [ka]

[0433] A 200 mL round-bottom flask equipped with a stir bar was charged with 1,2,4-triazole (26.2 mmol), THF (60 mL, 15 V), and TEA (3.65 mL, 26.2 mmol). The mixture was cooled to 0 °C and 2-chlorophenylphosphorodichloridate (1.96 mL, 12.1 mmol) was added dropwise over approximately 20 min (a white precipitate formed). The reaction mixture was warmed to room temperature and stirred for 1 h. To this mixture was added dry intermediate I-3a (12.1 mmol) in one portion. THF (30 mL) was used to remove the sticky solid around the flask. The reaction mixture was stirred for 1 h. The slurry was filtered, and the Et3N-HCl filter cake was rinsed with THF (approximately 3-5 volumes, 160 mL). The filtrate was concentrated under reduced pressure (approximately 25 mL, 3 volumes). To this mixture, 250 mL of 10% EtOAc and 250 mL of water were added and the mixture was transferred to a separatory funnel (approximately 100 mL of 100 mL of EtOAc / water). The pH of the solution was adjusted to 8-9 by adding saturated Na2CO3 solution (adding Na2CO4 is not necessary if the pH of the solution is already approximately 8). The aqueous layer contained the product, while the organic layer consisted of organic impurities with traces of the desired product. The aqueous layer was collected in a 500 mL RB flask, equipped with a stir bar, and 5% aqueous HCl was added dropwise over 30-40 minutes to reach a pH of approximately 3 (continue adding until no precipitate formed) until the slurry formed a solid. Solid formation occurred and disappeared, and after allowing it to stand for 1 hour, oily yellowish droplets formed (pure product). The mixture was transferred to a separatory flask and extracted with 3 x 200 mL of EtOAc and one x 100 mL of DCM / IPA (4:1). The combined organic layers were dried over Na2SO4 and the solvent was concentrated and dried to give intermediate I-27. 1H NMR(400MHz,DMSO-d6)δ 8.77(d,J=91.2Hz,2H),8.40(s,1H),8.07(s,1H),7.50(dd,J=19.3,8.1 Hz,2H),7.29-7.20(m,1H),7.15(d,J=4.5Hz,1H),7.10(t,J=7.7Hz,1H), 6.98(d,J=4.5Hz,1H),5.66(d,J=3.6Hz,1H),5.32(dd,J=6.6,3.8Hz,1H),5.12(d,J=6.6Hz,1H),4.31-4.13(m,2H),1.69(s,3H),1.39(s,3H).MS m / z[M+1]=522.0. Intermediate I-28: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-4-methoxybenzyl)oxy)-3-(octadecyloxy)propyl)phosphate. [ka]

[0434] Intermediate I-26 (0.041 mmol) and intermediate I-27 (0.061 mmol) were placed in a 20 mL vial and dried under vacuum (1 h). DCM (2 mL) was added, followed by NMI (13.4 μL, 0.163 mmol), TEA (11.5 μL, 0.081 mmol), and then Bop-Cl (10.4 mg, 0.04 mmol). The reaction was stirred at room temperature for 2 h. The solvent was concentrated under reduced pressure. The crude product was dissolved in DCM and loaded onto a 24 g column. The column was eluted with 100% Hex for 4 min, 0%–100% EtOAc for 6 min, and 100% EtOAc for 6 min. The product eluted with 100% EtOAc and the fractions containing pure product were combined and concentrated to give intermediate I-28. 1H NMR(400MHz,chloroform-d)δ 7.93(d,J=6.5Hz,1H),7.58-7.32(m,4H),7.23-7.02(m,2H),6.90(dd,J=8.6,5.0Hz,1H),6.72(d,J=4.5Hz,1H),6 .60(dd,J=6.8,4.5Hz,1H),5.77-5.61(m,2H),5.28(td,J=6.5,3.1Hz,1H),5.13(dd,J=15.1,6.6Hz,1H),4.68-4.4 1(m,5H),4.40-4.22(m,1H),3.91(s,3H),3.79(dp,J=22.7,5.1Hz,1H),3.51(dd,J=16.0,5.3Hz,2H),3.41(q,J=6 MS m / z[M+1]=993.3. Intermediate I-29: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3-cyano-4-methoxybenzyl)oxy)-3-(octadecyloxy)propyl)hydrogenphosphate [ka]

[0435] Intermediate I-28 (0.02 mmol) was dissolved in 2:1 THF:ACN (1:0.5 mL). A solution of cesium fluoride (0.101 mmol) in water (0.026 mL) was added to the solution, followed by 4-(dimethylamino)pyridine (0.08 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature and adjusted to pH 3–4 by adding 10% aqueous citric acid (20 mL) followed by 2 M NaOH. Extraction with EtOAc (50 mL × 2) was performed, and LCMS confirmed the absence of the desired product in the aqueous layer. The combined organic layers were washed once with brine, dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0%–50% MeOH in DCM) to give intermediate I-29. 1 H NMR(400MHz, methanol-d4)δ 7.85(s,1H),7.62-7.53(m,2H),7.11-7.00(m,1H),6.87(d,J=4.5Hz,1H),6.81(d,J=4.5Hz,1H),5.65( d,J=3.6Hz,1H),5.26(dd,J=6.6,3.7Hz,1H),5.15(d,J=6.6Hz,1H),4.66-4.49(m,2H),4.20-4.08(m,2H) ),3.95(t,J=5.4Hz,2H),3.92(s,3H),3.72(dt,J=9.1,4.7Hz,1H),3.56-3.36(m,4H),2.91-2.72(m,6H MS m / z[M+1]=883.2. Intermediate I-30: (S)-6-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)picolinonitrile [ka]

[0436] Intermediate I-30 was synthesized in a similar manner to intermediate I-16, using 6-fluoropicolinonitrile instead of 3-fluorobenzonitrile. MS m / z[M+1]=447.2. Intermediate I-31: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((6-cyanopyridin-2-yl)oxy)-3-(octadecyloxy)propyl)phosphate [ka]

[0437] Intermediate I-30 (0.119 mmol) and intermediate I-27 (0.178 mmol) were placed in a 20 mL vial and dried under vacuum (1 h). DCM (3 mL), NMI (38 μL, 0.476 mmol), TEA (33 μL, 0.238 mmol), followed by Bop-Cl (0.143 mmol) were added. The reaction was stirred at room temperature for 2 h. After 2 h, excess NMI (38 μL, 4 equiv.), TEA (35 μL, 2 equiv.) were added, followed by Bop-Cl (36 mg, 4 equiv.), and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure. The crude product was dissolved in DCM and loaded onto a 24 g column. The column was eluted with 100% Hex for 3 min, 0%–100% EtOAc for 6 min, and 100% EtOAc for 6 min. The product eluted with 100% EtOAc, fractions containing pure product were combined and concentrated to give intermediate I-31. 1H NMR (400 MHz, chloroform-d) δ 7.98-7.86 (m, 1H), 7.61 (dt, J = 21.6, 8.0 Hz, 1H), 7.44-7.22 (m, 3H), 7.20-7.00 (m, 2H), 6.98-6.88 (m, 1H), 6.72 (dd, J = 4.5, 2.5 Hz, 1H), 6.64-6.57 (m, 1H), 5.78 (s, 2H), 5.68 (dt, J = 8.0, 3.2 Hz, 1H), 5.48 (dt, J = 28.2, 4.8 Hz, 1H), 5.27 (ddd, J =12.0,6.8,3.1Hz,1H),5.14(ddd,J=19.1,11.5,6.6Hz,1H),4.72-4.36(m,4H),3.79-3.61(m,2H),3.55-3.33(m,2H),1 .78(d,J=5.4Hz,3H),1.54(dt,J=11.0,7.2Hz,2H),1.41-1.36(m,3H),1.26(d,J=6.0Hz,30H),0.90(t,J=6.7Hz,3H).MS m / z[M+1]=950.1. Intermediate I-32: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((6-cyanopyridin-2-yl)oxy)-3-(octadecyloxy)propyl)hydrogenphosphate [ka]

[0438] Intermediate I-31 (0.062 mmol) was dissolved in 2:1 THF:ACN (2:1 mL). A solution of cesium fluoride (0.311 mmol) in water (0.078 mL) was added to the solution, followed by 4-(dimethylamino)pyridine (0.249 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature and adjusted to pH 3–4 by adding 10% aqueous citric acid (20 mL) followed by 2 M NaOH. Extraction with MeTHF / EtOAc (3:2, 50 mL × 2) was performed, and LCMS confirmed the absence of the desired product in the aqueous layer. The combined organic layers were washed once with brine, dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0%–50% MeOH in DCM) to give intermediate I-32. 1 H NMR (400 MHz, chloroform-d) δ 7.85 (d, J = 6.6 Hz, 1H), 7.73 (q, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 14.6, 8.6 Hz, 1H), 6.83 (dt, J = 12.9, 5.0 Hz, 2H), 5.69-5.58 (m, 1H), 5.44 (t, J = 5.1 Hz, 1H), 5.27 (td, J = 8.1, 7.5, 3.8 Hz, 1H), 5.16(t,J=5.4Hz,1H),4.66-4.32(m,1H),4.22-4.03(m,3H),3.70-3.57(m,2H),3.51-3.34(m,2H),1. 69(s,3H),1.52-1.42(m,2H),1.38(d,J=2.9Hz,3H),1.26(d,J=17.7Hz,30H),0.90(t,J=6.6Hz,3H).MS m / z[M+1]=840.1. Intermediate I-33: (S)-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)picolinonitrile [ka]

[0439] Intermediate I-33 was synthesized in a similar manner to intermediate I-23, using 5-(bromomethyl)picolinonitrile instead of 3-(bromomethyl)-5-fluorobenzonitrile. MS m / z[M+1]=461.4. Intermediate I-34: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((6-cyanopyridin-3-yl)methoxy)-3-(octadecyloxy)propyl)phosphate [ka]

[0440] Intermediate I-33 (0.119 mmol) and intermediate I-27 (0.178 mmol) were placed in a 20 mL vial and dried under vacuum (1 h). DCM (3 mL), NMI (38 μL, 0.476 mmol), TEA (33 μL, 0.238 mmol), followed by Bop-Cl (0.143 mmol) were added. The reaction was stirred at room temperature for 2 h. After 2 h, excess NMI (38 μL, 4 equiv.), TEA (35 μL, 2 equiv.) were added, followed by Bop-Cl (36 mg, 4 equiv.), and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure. The crude product was dissolved in DCM and loaded onto a 24 g column. The column was eluted with 100% Hex for 3 min, 0%–100% EtOAc for 6 min, and 100% EtOAc for 6 min. The product eluted with 100% EtOAc, fractions containing pure product were combined and concentrated to give intermediate I-34. 1H NMR(400MHz,chloroform-d)δ 8.60(dd,J=19.4,2.0Hz,1H),7.91(d,J=7.6Hz,1H),7.83(ddd,J=14.0,8.0,2.1Hz,1H),7.58(t,J=8.4Hz,1H),7.47-7.31(m,2H) ),7.22-7.00(m,2H),6.71(dd,J=4.5,3.2Hz,1H),6.60(dd,J=11.2,4.5Hz,1H),5.80(s,2H),5.66(t,J=2.3Hz,1H),5.34-5.24( m,1H),5.12(dd,J=20.0,6.6Hz,1H),4.86-4.65(m,2H),4.62-4.18(m,4H),3.94-3.77(m,1H),3.53(dd,J=16.2,5.2Hz,2H),3.4 1(qd,J=6.8,2.0Hz,2H),1.79(d,J=3.5Hz,3H),1.61-1.48(m,2H),1.39(s,3H),1.27(d,J=2.1Hz,32H),0.90(t,J=6.7Hz,3H).MS m / z[M+1]=964.8. Intermediate I-35: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((6-cyanopyridin-3-yl)methoxy)-3-(octadecyloxy)propyl)hydrogenphosphate [ka]

[0441] Intermediate I-34 (0.068 mmol) was dissolved in 2:1 THF:ACN (2:1 mL). A solution of cesium fluoride (0.342 mmol) in water (0.092 mL) was added to the solution, followed by 4-(dimethylamino)pyridine (0.342 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature and adjusted to pH 3–4 by adding 10% aqueous citric acid (8.5 mL) followed by 2 M NaOH. Extraction with MeTHF / EtOAc (3:2, 50 mL × 2) was performed, and LCMS confirmed the absence of the desired product in the aqueous layer. The combined organic layers were washed once with brine, dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0–50% MeOH in DCM) to give intermediate I-35. 1 H NMR (400 MHz, chloroform-d) δ 7.85 (d, J = 6.6 Hz, 1H), 7.73 (q, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 14.6, 8.6 Hz, 1H), 6.83 (dt, J = 12.9, 5.0 Hz, 2H), 5.67-5.55 (m, 1H), 5.44 (t, J = 5.1 Hz, 1H), 5.27 (td, J = 8.1, 7.5, 3.8 Hz, 1H), 5.16(t,J=5.4Hz,1H),4.67-4.32(m,2H),4.24-3.99(m,3H),3.76-3.53(m,2H),3.50-3.35(m,3H),1. 69(s,3H),1.52-1.42(m,2H),1.38(d,J=2.9Hz,3H),1.26(d,J=17.7Hz,30H),0.90(t,J=6.6Hz,3H).MS m / z[M+1]=854.3. Intermediate I-36: (R)-1-(trityloxy)nonadecan-2-ol [ka]

[0442] A solution of (R)-2-((trityloxy)methyl)oxirane (6.32 mmol, 1 equiv.) and copper(I) iodide (1.81 mmol, 0.286 equiv.) in THF (20 mL) was cooled in an ice bath. Hexadecylmagnesium bromide (24 mL, 0.4 M, 1.52 equiv.) was added slowly over 35 min. The solution was stirred in the ice bath for 4 h while gradually warming to room temperature. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The organic fraction was dried over NaSO, filtered, concentrated in vacuo, and then purified twice by silica gel chromatography (0% to 15% EtOAc in hexanes) to give intermediate I-36. 1 H NMR (400 MHz, chloroform-d) δ 7.50-7.20 (m, 15H), 3.80-3.71 (m, 1H), 3.21-3.13 (m, 1H), 3.06-2.98 (m, 1H), 2.29 (d, J = 3.4 Hz, 1H), 1.46-1.16 (m, 32H), 0.92-0.84 (m, 3H). Intermediate I-37: (R)-3-fluoro-5-(((1-(trityloxy)nonadecan-2-yl)oxy)methyl)benzonitrile [ka]

[0443] To a solution of intermediate I-36 (2.08 mmol, 1 equiv.) in THF (10 mL) was added sodium tert-butoxide (2.08 mL, 2.0 M in THF, 2 equiv.). The solution was stirred at room temperature for 20 minutes, after which 3-(bromomethyl)-5-fluorobenzonitrile (4.05 mmol, 1.94 equiv.) was added. The solution was stirred at room temperature for 7 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic fractions were combined, washed with brine (50 mL), dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to give intermediate I-37. 1H NMR(400MHz,chloroform-d)δ 7.48-7.20(m,18H),4.71(d,J=12.8Hz,1H),4.55(d,J=12.8Hz,1H),3.56-3.47(m, 1H),3.23-3.17(m,2H),1.57-1.47(m,2H),1.34-1.18(m,30H),0.92-0.83(m,3H). 19 F NMR (376 MHz, chloroform-d) δ-110.57--110.69 (m). Intermediate I-38: (R)-3-Fluoro-5-(((1-hydroxynonadecan-2-yl)oxy)methyl)benzonitrile [ka]

[0444] To a solution of intermediate I-37 (1.66 mmol, 1 equiv) in 1:1:1 THF:iPrOH:MeOH (21 mL total) was added concentrated HCl (0.53 mL, 6.37 mmol, 3.85 equiv). The reaction mixture was heated to 65 °C and stirred for 1 h 30 min. The solution was quenched with saturated sodium bicarbonate (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The organic extracts were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 100% EtOAc in hexanes) to give intermediate I-38. 1 H NMR (400 MHz, chloroform-d) δ 7.46-7.43 (m, 1H), 7.36-7.31 (m, 1H), 7.30-7.24 (m, 1H), 4.64-4.62 (m, 2H), 3.80-3.70 (m, 1H), 3.66-3.48 (m, 2H), 1.79-1.71 (m, 1H), 1.68-1.45 (m, 2H), 1.40-1.16 (m, 30H), 0.91-0.84 (m, 3H). 19 F NMR (376 MHz, chloroform-d) δ-110.27--110.40 (m). Intermediate I-39: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-5-fluorobenzyl)oxy)-nonadecyl)phosphate [ka]

[0445] An oven-dried round-bottom flask was charged with 1H-1,2,4-triazole (0.744 mmol, 2.15 equiv.). The triazole was dissolved in ACN (5.0 mL) and pyridine (5.0 mL). Triethylamine (0.104 mL, 0.744 mmol, 2.15 equiv.) was added to the solution, followed by 2-chlorophenylphosphorodichloridate (0.06 mL, 0.346 mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 24 minutes, after which Intermediate I-3a (0.346 mmol, 1 equiv.) was added in one portion, followed by 1-methylimidazole (0.06 mL, 0.698 mmol, 2.02 equiv.). The solution was stirred for 1 hour. Intermediate I-38 (0.380 mmol, 1.1 equiv.) was added, and the reaction mixture was stirred for an additional 2 hours and 30 minutes. The reaction was quenched with a buffer solution of 4:1 citric acid (20% in water): 1 M NaOH (19 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The organic fractions were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 20% MeOH in DCM) to give intermediate I-39. MS m / z [M+1] = 937.27. Intermediate I-40: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3-cyano-5-fluorobenzyl)oxy)nonadecyl)hydrogenphosphate [ka]

[0446] Intermediate I-39 (0.244 mmol, 1 equiv) was dissolved in 2:1 THF:ACN (4.5 mL total). Cesium fluoride (2.12 mmol, 8.68 equiv) dissolved in water (0.30 mL) was added to the solution, followed by 4-(dimethylamino)pyridine (0.900 mmol, 3.69 equiv). The reaction mixture was heated to 80 °C and stirred for 5 h 30 min. The reaction was quenched with a buffer solution containing citric acid (2.86 mmol, 11.7 equiv) and NaOH (0.29 mL, 2 M, 2.34 equiv) in 20 mL of water. The aqueous layer was extracted with EtOAc (2 × 50 mL). The organic fractions were combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 50% MeOH in DCM) to afford intermediate I-40. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),7.51-7.47(m,1H),7.43-7.34(m,2H),6.86-6.77(m,2H),5 .63(d,J=3.6Hz,1H),5.29-5.23(m,1H),5.13(d,J=6.6Hz,1H),4.73(d, J=13.1Hz,1H),4.54-4.46(m,1H),4.16-4.07(m,2H),3.94-3.82(m,2H) ,3.60-3.49(m,1H),1.69(s,3H),1.47-1.20(m,35H),0.93-0.86(m,3H). 19 F NMR (376 MHz, methanol-d4) δ -112.67--113.35 (m). 31 P NMR (162 MHz, methanol-d4) δ -0.12--0.64 (m). MS m / z [M+1] = 827.24. Intermediate I-41: (R)-2-Methoxy-4-(((1-(trityloxy)henicosan-2-yl)oxy)methyl)benzonitrile [ka]

[0447] A solution of intermediate I-112 (1.88 mmol, 1.0 equiv.) in THF (6.0 mL) was cooled in an ice bath, and sodium tert-butoxide (2.0 mL, 2.0 M in THF, 2.12 equiv.) was added. 4-(Bromomethyl)-2-methoxybenzonitrile (2.57 mmol, 1.36 equiv.) was added in one portion. The solution was stirred overnight at room temperature. The reaction mixture was heated to 60° C. and stirred for 5 hours 30 minutes, then overnight at room temperature. The solution was cooled in an ice bath, and sodium tert-butoxide (1.00 mL, 2.0 M in THF, 1.06 equiv.) was added, followed by additional 4-(bromomethyl)-2-methoxybenzonitrile (0.792 mmol, 0.420 equiv.). After stirring for 7 hours and 30 minutes, additional 4-(bromomethyl)-2-methoxybenzonitrile (1.08 mmol, 0.575 equiv.) was added, and the solution was again stirred at room temperature overnight. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic fractions were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified twice by silica gel chromatography (0% to 75% EtOAc in hexanes, then 0% to 15% EtOAc in hexanes) to give compound I-41. 1 H NMR(400MHz,chloroform-d)δ 7.49(d,1H),7.47-7.41(m,6H),7.35-7.20(m,9H),7.02-6.99(m,1H),6.96-6.92(m,1H),4.72(d,J=13.0Hz,1H),4.59(d,J =13.0Hz,1H),3.84(s,3H),3.57-3.48(m,1H),3.24-3.14(m,2H),1.58-1.48(m,2H),1.37-1.15(m,34H),0.91-0.84(m,3H). Intermediate I-42: (R)-4-(((1-hydroxyhenicosan-2-yl)oxy)methyl)-2-methoxybenzonitrile [ka]

[0448] To a solution of intermediate I-41 (1.02 mmol, 1 equiv) in 1:1:1 THF:iPrOH:MeOH (18.0 mL total) was added concentrated HCl (0.33 mL, 3.91 mmol, 3.85 equiv). The reaction mixture was heated to 65 °C and stirred for 4 h 30 min. The solution was quenched with saturated sodium bicarbonate (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The organic extracts were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 20% EtOAc in hexanes, then 0% to 100% EtOAc in hexanes) to give intermediate I-42. 1 H NMR (400 MHz, chloroform-d) δ 7.55-7.50 (m, 1H), 7.02-6.99 (m, 1H), 6.99-6.94 (m, 1H), 4.69-4.59 (m, 2H), 3.96-3.93 (m, 3H), 3.78-3.70 (m, 1H), 3.64-3.47 (m, 2H), 1.85-1.74 (m, 1H), 1.69-1.17 (m, 36H), 0.92-0.84 (m, 3H). Intermediate I-43: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((4-cyano-3-methoxybenzyl)oxy)henicosyl)phosphate [ka]

[0449] To a solution of intermediate I-42 (0.192 mmol, 1 equiv.), intermediate I-27 (0.192 mmol, 1 equiv.), triethylamine (0.04 mL, 0.287 mmol, 1.5 equiv.), and 1-methylimidazole (0.04 mL, 0.502 mmol, 2.62 equiv.) in DCM (2.0 mL) was added BOP-Cl (0.617 mmol, 3.22 equiv.), and the solution was stirred at room temperature for 4 h. An additional 5 mg of ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)hydrogenphosphate (0.00958 mmol, 0.05 equiv.) was added, and the solution was stirred at room temperature for 6 days. The reaction mixture was diluted with 2:1 EtO:EtOAc (60 mL) and quenched with 4:1 water:saturated NaHCO (50 mL). The layers were separated, and the aqueous layer was extracted with 2:1 EtO:EtOAc (60 mL) and once more with EtOAc (50 mL). The organic extracts were combined, dried over NaSO, filtered, concentrated in vacuo, and then purified on silica gel (0% to 10% MeOH in DCM) to give intermediate I-43. MS m / z[M+1]=977.4. Intermediate I-44: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((4-cyano-3-methoxybenzyl)oxy)henicosyl)hydrogenphosphate [ka]

[0450] Intermediate I-43 (0.102 mmol, 1.0 equiv) was dissolved in 2:1 THF:ACN (4.5 mL total). Cesium fluoride (1.45 mmol, 14.2 equiv) dissolved in water (0.70 mL) was added to the solution, followed by 4-(dimethylamino)pyridine (0.409 mmol, 4 equiv). The reaction mixture was heated to 80 °C and stirred for 5 h 30 min. The reaction was quenched with a buffer solution containing citric acid (4.65 mL, 0.22 M, 10 equiv) and NaOH (0.10 mL, 2 M, 2 equiv). The aqueous layer was extracted (2x) with EtOAc. The organic fractions were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 50% MeOH in DCM) to give intermediate I-44. MS m / z[M+1]=867.4. Intermediate I-45: (S)-Icosane-1,2-diol [ka]

[0451] To a solution of tBuOH (50 mL) and water (50 mL) was added AD-mix-α (1.32 g per mmol of olefin). The mixture was stirred vigorously for 5 minutes and then cooled in an ice bath over 10 minutes. Eicosene (8.77 mol, 1 equiv.) was added in one portion, and the reaction mixture was stirred at room temperature overnight. Sodium sulfite (15.0 g, 0.119 mol, 13.6 equiv.) was added, and the solution was stirred at room temperature for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to remove tBuOH. The concentrated filtrate was diluted with water (25 mL) and extracted with EtOAc (3 × 75 mL). The organic extract was washed with brine, dried over NaSO, filtered, and concentrated in vacuo before being purified by silica gel (0% to 100% EtOAc in hexanes) followed by further elution of the product using 0% to 40% MeOH in DCM to give intermediate I-45. 1 H NMR (400 MHz, chloroform-d) δ 3.78-3.62 (m, 2H), 3.50-3.40 (m, 1H), 2.04-1.19 (m, 36H), 0.92-0.85 (m, 3H). Intermediate I-46: (S)-1-(trityloxy)icosan-2-ol [ka]

[0452] To a solution of intermediate I-45 (1.08 mmol, 1 equiv.) and 4-(dimethylamino)pyridine (0.426 mmol, 0.394 equiv.) in DCM (10 mL) was added triethylamine (0.17 mL, 1.24 mmol, 1.15 equiv.). This was followed by the addition of trityl chloride (1.10 mmol, 1.02 equiv.). The reaction mixture was stirred overnight at room temperature. An additional 25 mg of trityl chloride (0.090 mmol, 0.083 equiv.) was added, and the solution was stirred at room temperature for an additional 6 h. The reaction mixture was diluted with DCM (50 mL) and poured into ice-water (50 mL). The layers were separated, and the aqueous layer was extracted with an additional 50 mL of DCM. The organic extracts were combined, washed with brine (50 mL), dried over Na2SO4, filtered, concentrated in vacuo, and then purified on silica gel (0% to 90% DCM in hexanes) to give intermediate I-46. H NMR (400 MHz, chloroform-d) δ 7.46-7.20 (m, 15H), 3.80-3.71 (m, 1H), 3.18 (dd, J = 9.3, 3.3 Hz, 1H), 3.02 (dd, J = 9.4, 7.6 Hz, 1H), 2.29 (s, 1H), 1.47-1.15 (m, 34H), 0.91-0.84 (m, 3H). Intermediate I-47: (S)-3-Fluoro-5-(((1-(trityloxy)icosan-2-yl)oxy)methyl)benzonitrile [ka]

[0453] To a solution of intermediate I-46 (0.294 mmol, 1 equiv.) in THF (3.0 mL) was added sodium tert-butoxide (0.29 mL, 2.0 M in THF, 2 equiv.). The solution was stirred at room temperature for 5 minutes, and then 3-(bromomethyl)-5-fluorobenzonitrile (0.784 mmol, 2.67 equiv.) was added. The solution was stirred at room temperature overnight. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 × 25 mL). The organic fractions were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to give intermediate I-47. 1 H NMR(400MHz,chloroform-d)δ 7.52-7.21(m,18H),4.71(d,J=12.8Hz,1H),4.55(d,J=12.8Hz,1H),3.55-3.48(m, 1H),3.23-3.18(m,2H),1.64-1.44(m,2H),1.34-1.20(m,32H),0.91-0.85(m,3H). 19 F NMR (376 MHz, chloroform-d) δ-110.57--110.72 (m). Intermediate I-48: (S)-3-Fluoro-5-(((1-hydroxyicosan-2-yl)oxy)methyl)benzonitrile [ka]

[0454] To a solution of intermediate I-47 (0.286 mmol, 1 equiv) in 1:1:1 THF:iPrOH:MeOH (6 mL total) was added concentrated HCl (0.10 mL, 1.20 mmol, 4.19 equiv). The reaction mixture was heated to 65 °C and stirred for 1 h 30 min. The solution was quenched with saturated sodium bicarbonate (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL). The organic extracts were combined, dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 100% EtOAc in hexanes) to give intermediate I-48. 1H NMR (400 MHz, chloroform-d) δ 7.45 (s, 1H), 7.37-7.31 (m, 1H), 7.29-7.24 (m, 1H), 4.65-4.61 (m, 2H), 3.78-3.70 (m, 1H), 3.65-3.56 (m, 1H), 3.56-3.48 (m, 1H), 1.88-1.45 (m, 3H), 1.41-1.19 (m, 32H), 0.88 (t, J = 6.7 Hz, 3H). 10 F NMR (376 MHz, chloroform-d) δ-110.26--110.38 (m). Intermediate I-49: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((S)-2-((3-cyano-5-fluorobenzyl)oxy)icosyl)phosphate [ka]

[0455] To a solution of intermediate I-48 (0.148 mmol, 1 equiv.), intermediate I-27 (0.134 mmol, 1 equiv.), triethylamine (0.07 mL, 0.537 mmol, 4 equiv.), and 1-methylimidazole (0.02 mL, 0.268 mmol, 2 equiv.) in DCM (5.0 mL) was added BOPCl (0.537 mmol, 4 equiv.). The solution was stirred at room temperature overnight. An additional 140 mg of BOP-Cl (0.550 mmol, 4.1 equiv.) and 0.05 mL of 1-methylimidazole (0.627 mmol, 4.68 equiv.) were added, and the solution was stirred at room temperature for 3 h. An additional 54 mg of BOP-Cl (0.212 mmol, 1.58 equiv.) was added, and the reaction mixture was stirred for 1 h. The solution was diluted with EtOAc (20 mL) and quenched with 4:1 water:saturated NaHCO (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The organic extracts were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified on silica gel (0%-10% MeOH in DCM) to give Intermediate-49. MS m / z [M+1] = 951.33. Intermediate I-50: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((S)-2-((3-cyano-5-fluorobenzyl)oxy)icosyl)hydrogenphosphate [ka]

[0456] Intermediate I-49 (0.0851 mmol, 1.0 equiv) was dissolved in 2:1 THF:ACN (4.5 mL total). Cesium fluoride (0.829 mmol, 9.74 equiv) dissolved in water (0.50 mL) was added to the solution, followed by 4-dimethylaminopyridine (0.341 mmol, 4.0 equiv). The reaction mixture was heated to 80 °C and stirred for 2 h, then for an additional 40 min. The reaction was quenched with a buffered solution of citric acid (20 mL, 0.22 M, 51.7 equiv) and NaOH (0.44 mL, 2 M, 10.3 equiv). The aqueous layer was extracted with EtOAc (3 × 30 mL). The organic fractions were combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 40% MeOH in DCM) to afford intermediate I-50. 1 H NMR(400MHz, methanol-d4)δ 7.87-7.80(m,1H),7.52-7.31(m,3H),6.89-6.76(m,2H),5.67-5.59(m,1H),5.30-5.22(m,1H),5.17-5.08(m,1H),4.77-4.69(m,1H),4 MS m / z[M+1]=841.34. Intermediate I-51a: (S)-2-((5-bromopyridin-3-yl)methoxy)-3-(octadecyloxy)propan-1-ol [ka]

[0457] Intermediate I-51a was prepared in a similar manner to intermediate I-23, using 3-bromo-5-(bromomethyl)pyridine in place of intermediate 3-(bromomethyl)-5-fluorobenzonitrile. 1H NMR(400MHz,chloroform-d)δ 8.66(d,J=2.1Hz,1H),8.62-8.50(m,1H),8.13-7.97(m,1H),4.88-4.70(m,2H),3.84-3.77(m,1H),3.77-3.69(m, 2H),3.64-3.55(m,2H),3.47(td,J=6.7,1.6Hz,2H),1.66-1.52(m,2H),1.40-1.20(m,30H),0.98-0.84(m,3H).MS m / z[M+1]=514.3. Intermediate I-51: (S)-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)nicotinonitrile [ka]

[0458] Tetrakis(triphenylphosphine)palladium(0) (15.3 μmol) was added to a vigorously stirred mixture of intermediate I-51a (146 μmol), zinc(II) cyanide (35.9 mg, 309 μmol), and N,N-dimethylformamide (2.0 mL) at room temperature, and the resulting mixture was heated to 100 °C. After 3 h, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL), ethyl acetate (20 mL), saturated sodium bicarbonate solution (10 mL), and saturated aqueous sodium carbonate (5 mL) were added sequentially. The organic layer was washed with water (2 × 80 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0–50% ethyl acetate in hexanes) to give intermediate I-51. MS m / z [M+1] = 461.4 Intermediate I-52: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((5-cyanopyridin-3-yl)methoxy)-3-(octadecyloxy)propyl)phosphate [ka]

[0459] To a solution of intermediate I-51 (0.0918 mmol, 1 equiv.), intermediate I-27 (0.0918 mmol, 1 equiv.), triethylamine (0.02 mL, 0.143 mmol, 1.56 equiv.), and 1-methylimidazole (0.02 mL, 0.251 mmol, 2.73 equiv.) in DCM (2.0 mL) was added BOP-Cl (0.255 mmol, 2.78 equiv.). The solution was stirred at room temperature overnight. The solution was allowed to stand at room temperature for 2 days. An additional 70 mg of BOP-Cl (0.275 mmol, 2.99 equiv.) and 0.03 mL of 1-methylimidazole (0.376 mmol, 4.1 equiv.) were added, and the solution was stirred at room temperature overnight. The solution was diluted with EtOAc (20 mL) and quenched with 4:1 water:saturated NaHCO (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and then purified on silica gel (0% to 10% MeOH in DCM) to give intermediate I-52. MS m / z [M+1] = 964.33. Intermediate I-53: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((5-cyanopyridin-3-yl)methoxy)-3-(octadecyloxy)propyl)hydrogenphosphate [ka]

[0460] Intermediate I-52 (0.0649 mmol, 1 equiv) was dissolved in 2:1 THF:ACN (4.5 mL total). Cesium fluoride (0.876 mmol, 13.5 equiv) dissolved in water (0.50 mL) was added to the solution, followed by 4-(dimethylamino)pyridine (0.260 mmol, 4 equiv). The reaction mixture was heated to 80 °C and stirred for 2 h 30 min. The reaction was quenched with a buffer solution of citric acid (20 mL, 0.22 M, 67.8 equiv) and NaOH (0.44 mL, 2 M, 13.6 equiv). The aqueous layer was extracted with EtOAc (3 × 30 mL). The organic fractions were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (0% to 40% MeOH in DCM) to give intermediate I-53. 1 H NMR (400 MHz, methanol-d4) δ 8.75-8.71(m,2H),8.19-8.16(m,1H),7.84(s,1H),6.84-6.78(m,2H),5.63(d ,J=3.6Hz,1H),5.26(dd,J=6.6,3.6Hz,1H),5.14(d,J=6.6Hz,1H),4.81-4.64( m,2H),4.16-4.08(m,2H),3.99-3.90(m,2H),3.79-3.71(m,1H),3.53-3.36(m, 4H),1.69(s,3H),1.59-1.48(m,2H),1.41-1.21(m,33H),0.92-0.87(m,3H).MS m / z[M+1]=854.28. Intermediate I-54: (R)-3-fluoro-5-(((1-(trityloxy)henicosan-2-yl)oxy)methyl)benzonitrile [ka]

[0461] A solution of intermediate I-112 (2.24 mmol, 1.0 equiv) in THF (10.0 mL) was cooled in an ice bath, to which NaH (60% dispersion in mineral oil) (9.79 mmol, 4.37 equiv) was slowly added. The solution was vigorously stirred for 5 minutes. 3-(Bromomethyl)-5-fluorobenzonitrile (3.00 mmol, 1.34 equiv) was added in one portion. The reaction mixture was heated to 80° C. and stirred under nitrogen for 2 hours, then for an additional 15 minutes. The solution was stirred at 60° C. overnight. The reaction mixture was quenched with saturated ammonium chloride until gas evolution ceased. The solution was diluted with water (100 mL), and the aqueous layer was extracted with EtOAc (3×100 mL). The organic fractions were combined, washed with brine (100 mL), dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to provide intermediate I-54. 1 H NMR(400MHz,chloroform-d)δ 7.47-7.21(m,18H),4.71(d,J=12.9Hz,1H),4.55(d,J=12.8Hz,1H),3.55-3.47(m, 1H),3.23-3.17(m,2H),1.58-1.46(m,2H),1.35-1.18(m,34H),0.92-0.84(m,3H). 19 F NMR (376 MHz, chloroform-d) δ-110.60--110.67 (m). Intermediate I-55: (R)-3-fluoro-5-(((1-hydroxyhenicosan-2-yl)oxy)methyl)benzonitrile [ka]

[0462] To a solution of intermediate I-54 (1.27 mmol, 1 equiv) in 1:1:1 THF:iPrOH:MeOH (21 mL total) was added concentrated HCl (0.41 mL, 12.0 M, 3.85 equiv). The reaction mixture was heated to 65 °C and stirred for 2 h. The solution was quenched with saturated sodium bicarbonate and water (50 mL) until gas evolution ceased. The pH of the aqueous layer was adjusted to 7 using saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc (2 × 75 mL). The organic extracts were combined, washed with brine (50 mL), dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 100% EtOAc in hexanes) to give intermediate I-55. 1 H NMR (400 MHz, chloroform-d) δ 7.46-7.43 (m, 1H), 7.37-7.31 (m, 1H), 7.30-7.24 (m, 1H), 4.65-4.61 (m, 2H), 3.79-3.70 (m, 1H), 3.65-3.48 (m, 2H), 1.76 (s, 1H), 1.68-1.47 (m, 2H), 1.45-1.17 (m, 3H), 0.93-0.83 (m, 3H). 19 F NMR (376 MHz, chloroform-d) δ-110.27--110.37 (m). Intermediate I-56: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-5-fluorobenzyl)oxy)henicosyl)phosphate [ka]

[0463] An oven-dried round-bottom flask was charged with 1H-1,2,4-triazole (2.60 mmol, 2.15 equiv.). The triazole was dissolved in ACN (10.0 mL) and pyridine (10.0 mL). Triethylamine (0.36 mL, 2.60 mmol, 2.15 equiv.) was added to the solution under argon, followed by 2-chlorophenylphosphorodichloridate (0.20 mL, 1.21 mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 27 minutes, after which Intermediate I-3a (1.21 mmol, 1 equiv.) was added in one portion, followed by 1-methylimidazole (0.16 mL, 2.02 mmol, 1.67 equiv.). The solution was stirred for approximately 1 hour. Intermediate I-55 (1.33 mmol, 1.1 equiv.) was added, and the reaction mixture was stirred under argon for an additional 2 hours. The reaction was quenched with a buffer solution of 4:1 citric acid (20% in water): 1 M NaOH (50 mL). The aqueous layer was extracted with EtOAc (4 x 50 mL). The organic fractions were combined, washed with brine (50 mL), dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0-20% MeOH in DCM) to give intermediate I-56. MS m / z [M+1] = 965.24. Intermediate I-57: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)oxy)henicosyl)hydrogenphosphate [ka]

[0464] Intermediate I-56 (1.22 mmol, 1.0 equiv) was dissolved in 2:1 THF:ACN (13.5 mL total). Cesium fluoride (3.65 mmol, 3 equiv) dissolved in water (1.5 mL) was added to the solution, followed by 4-dimethylaminopyridine (4.09 mmol, 3.37 equiv). The reaction mixture was heated to 80° C. and stirred for 1 hour 30 minutes, then for an additional 30 minutes. The reaction was quenched with a buffered solution of citric acid (12.2 mmol, 10 equiv) dissolved in water (60 mL) and NaOH (1.22 mL, 2 M, 2 equiv). The aqueous layer was extracted with EtOAc (3×100 mL). The organic fractions were combined, washed with 3:2 water:brine (50 mL), dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 50% MeOH in DCM) to give intermediate I-57. MS m / z [M+1] = 855.25. Intermediate I-58: ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(heptadecyloxy)propyl)phosphate [ka]

[0465] Intermediate I-4 (0.0724 mmol) was dissolved in THF-ACN (1:0.5 mL), and CsF (95.4 mg, 0.628 mmol) in water (0.1 mL) was added, followed by DMAP (0.267 mmol). The resulting mixture was heated at 80 °C for 3.5 h. After dilution with PBS buffer pH 7 (5 mL), the mixture was partitioned between brine (10 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layers were dried under sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 50% MeOH in DCM) to give intermediate I-58. MS m / z [M+1] = 857. Intermediate I-59: (S)-1-(trityloxy)henicosan-2-ol [ka]

[0466] (S)-2-((trityloxy)methyl)oxirane (7.11 mmol) was dissolved in 2-MeTHF (7.0 mL). To this was added copper(I) iodide (0.777 mmol). The white slurry was cooled in an ice bath. Octadecylmagnesium bromide (42 mL, 0.213 M) was added slowly over 45 minutes, maintaining the internal temperature below 11.4 °C. The solution was stirred in the ice bath for 3 hours and 15 minutes while gradually warming to room temperature. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and water (50 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 × 75 mL). The organic fraction was washed with 1:1 brine:water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was dry loaded onto silica and purified twice by silica gel chromatography (0-100% EtOAc in hexanes, then 0-20% EtOAc in hexanes) to afford intermediate I-59. 1 H NMR (400 MHz, chloroform-d) δ 7.47-7.41 (m, 6H), 7.34-7.22 (m, 9H), 3.81-3.72 (m, 1H), 3.18 (dd, J = 9.4, 3.3 Hz, 1H), 3.03 (dd, J = 9.3, 7.5 Hz, 1H), 2.31 (s, 1H), 1.50-1.16 (m, 36H), 0.89 (t, J = 6.7 Hz, 3H). Intermediate I-60: (S)-3-Fluoro-5-(((1-(trityloxy)henicosan-2-yl)oxy)methyl)benzonitrile [ka]

[0467] To a solution of intermediate I-59 (2.72 mmol) in THF (15 mL) was added sodium tert-butoxide (2.7 mL, 2.0 M in THF). The solution was stirred at room temperature for 5 minutes, and then 3-(bromomethyl)-5-fluorobenzonitrile (5.05 mmol) was added. The solution was stirred at room temperature overnight. The reaction mixture was diluted with water (75 mL) and extracted with EtOAc (3 × 50 mL). The organic fractions were combined, washed with brine, dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0–10% EtOAc in hexanes) to give intermediate I-60. 1 H NMR(400MHz,chloroform-d)δ 7.48-7.19(m,18H),4.71(d,J=12.8Hz,1H),4.55(d,J=12.9Hz,1H),3.55-3.47(m, 1H),3.23-3.18(m,2H),1.58-1.47(m,2H),1.34-1.18(m,34H),0.91-0.85(m,3H). 19 F NMR (376 MHz, chloroform-d) δ-110.59--110.68 (m). Intermediate I-61: (S)-3-Fluoro-5-(((1-hydroxyhenicosan-2-yl)oxy)methyl)benzonitrile [ka]

[0468] To a solution of intermediate I-60 (2.03 mmol) in 1:1:1 THF:MeOH:iPrOH (21.0 mL total) was added concentrated HCl (0.65 mL). The reaction mixture was gradually heated to 65 °C and stirred for 3 h 45 min. The solution was allowed to stand at room temperature overnight before being quenched with saturat...

Claims

1. A compound of formula I, 【Chemical 349】 or a pharmaceutically acceptable salt thereof, R １ But C ３ ~C １０ Cycloalkyl, C ６ ~C １０ aryl, or 5-10 membered heteroaryl containing 1, 2 or 3 N; R １ wherein the cycloalkyl, aryl, or heteroaryl is R １Ａ and -NR １３Ａ R １４Ａ optionally substituted with 1, 2, or 3 groups independently selected from Each R １Ａ But independently, halo, cyano, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ haloalkoxy, or a 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N and O; Each R １３Ａ are independently H or C １ ~C ３ is alkyl, Each R １４Ａ are independently H or C １ ~C ３ is alkyl, R ２ is H or C １ ~C ３ is alkyl, R ３ But C １ ~C ３ is alkyl, Each R ４ But independently, H, halo, C １ ~C ３ Alkyl, C １ ~C ３ haloalkyl, or C ３ ~C ６ is cycloalkyl, R ５ is H, Two or more adjacent (CR ４ R ５ ) groups are optionally connected via a double bond, R ６ is H or -C(O)C １ ~C ６ is alkyl, R ７ is H or -C(O)C １ ~C ６ is alkyl, m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21; L is -O-, -(CR １２Ａ R １２Ｂ ) ｎ -, -O(CR １２Ａ R １２Ｂ ) ｎ -, - (CR １２Ａ R １２Ｂ ) ｎ -O-, -(CR １２Ａ R １２Ｂ ) ｎ -O-(CR １２Ａ R １２Ｂ ) ｎ - and Each R １２Ａ are independently H or C １ ~C ６ is alkyl, Each R １２Ｂ are independently H or C １ ~C ６ is alkyl, n is 1 or 2; Q is a bond or phenylene; T is a bond or —O—; X is a bond or C １ ~C ３ is alkylene, Z is -O-, -O-(C １ ~C ６ )-alkylene or NR １５ -(C １ ~C ６ )-alkylene; R １５ is H or C １ ~C ３ is alkyl, However, the compound is 【Chemical 352】 isn't it, The compound or a pharmaceutically acceptable salt thereof.

2. A compound or a pharmaceutically acceptable salt thereof, wherein said compound has the following structure: 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8A】 【Chemistry 2-8B】 【Chemistry 2-9】 or a pharmaceutically acceptable salt thereof, selected from:

3. The compound is represented by formula III 【Hua 361】 is a compound of 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

4. The compound is of formula V 【Chemical 367】 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

5. below: 【Chemical 397】 【Chemical 398】 or a pharmaceutically acceptable salt thereof.

6. below: 【Chemical 399】 【Chemistry 400】 【Chemistry 401】 or a pharmaceutically acceptable salt thereof.

7. below: 【Chemistry 402】 or a pharmaceutically acceptable salt thereof.

8. below: 【Chemistry 403】 or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical formulation comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

10. 10. The pharmaceutical formulation according to claim 9 for treating or preventing a viral infection in a subject in need thereof.

11. The pharmaceutical preparation according to claim 10, wherein the viral infection is a Pneumoviridae virus infection.

12. The pharmaceutical preparation according to claim 11, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection or a human metapneumovirus infection.

13. The pharmaceutical preparation according to claim 10, wherein the viral infection is a Picornaviridae virus infection.

14. 14. The pharmaceutical preparation of claim 13, wherein the Picornaviridae virus infection is a human rhinovirus infection.

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