Phospholipid compounds and uses thereof

Abstract

Disclosed are compounds and methods of using the compounds alone or in combination with additional agents, as well as pharmaceutical compositions 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 / 093,037, filed October 16, 2020, and 63 / 151,456, filed February 19, 2021, each of which is incorporated herein in its entirety for all purposes. [Background technology]

[0002] There is a need for compounds and methods for treating viral infections, such as Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae infections. The present disclosure addresses these and other needs. Summary of the Invention [Means for solving the problem]

[0003] In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein Z 1 is a bond, -CH2-, -CH2-CH2-, -CR ZA R ZB - or -CR ZA R ZB -C RZC R ZD - and Z 2 is a bond, -CH2-, -CH2-CH2-, -CR ZE R ZF - or -CR ZE R ZF -C RZG R ZH and R ZA , R ZC , R ZD , R ZE, R ZG , and R ZH are each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; R ZB and R ZF are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; X is a bond, -O-, -OCO-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - OCR 12A R 12B -(CR 13 =CR 14 )-, -(CR 12A R 12B ) q -O-(CR 12A R 12B ) q -, -S-, (CR 12A R 12B ) p -NR 12C -(CR 12A R 12B ) p - or (CR 12A R 12B ) p -NR 12C CO-(CR 12A R 12B ) p - in which Each R 12A are independently H, C1-C6 alkyl, or phenyl; R 2 and R 12A are joined to form a 4- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S; Each R 12B are independently H or C1-C6 alkyl, or R on the same carbon 12A and R 12B are bonded together to form a C3-C6 cycloalkylene, R12C is H, C1-C3 alkyl, -COR 12D , or -SO2R 12E or R 12C and R 1 are joined together to have 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally 1 to 4 R 12F forming a 5- to 6-membered heterocyclyl substituted with a group, Each R 12F are independently oxo or halo, or two R on adjacent carbons 12F are joined to form a fused phenyl optionally substituted with 1 or 2 substituents independently selected from F and Cl; R 12D is C1-C3 alkyl, C6-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 12D optionally 1, 2, or 3 R 12G is substituted with a group, Each R 12G are independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, C1-C3 haloalkyl, or -COOR 12H and R 12H is H or C1-C3 alkyl, R 12E is H or C1-C3 alkyl, R 13 is H, C1-C6 alkyl, or phenyl, R 14 is H, C1-C6 alkyl, or phenyl, each q is independently 1 or 2; each p is independently 0, 1, or 2; X 1 is a bond, -O-, NR X , or -CONR X - or -S-, R Xis H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)R XA and R XA is a C1-C3 alkyl, X 2 is -O- or -S-, X 3 is -O- or -S-, X 4 is =O or =S, R 1 H, C1~C 20 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, S, and O, or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 If is not H, then R 1 The group optionally contains one, two, or three R 1A is substituted with a group, Each R 1A are independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R 1B , -COOR 1B or C1-C3 haloalkyl, or two R on the same or adjacent carbons 1A are joined together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1B is H or C1-C3 alkyl, R 2 is H or C1-C3 alkyl, Y is a bond, phenylene, or C3-C6 cycloalkylene; R 3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; Each R 4are independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or two R on adjacent carbon atoms 4 groups, together with the carbon to which they are attached, form a carbon-carbon double bond, Each R 5 are independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; R on adjacent carbon atoms 4 Groups and R 5 groups, together with the carbon to which they are attached, form a carbon-carbon triple bond; R 6 is H or —C(O)C1-C6 alkyl, R 7 is H or —C(O)C1-C6 alkyl, m is an integer from 7 to 21; X is a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )-, (a)Z 1 is a bond, -CR ZA R ZB - or -CR ZA R ZB -C RZC R ZD -or (b)Z 2 is a bond, -CR ZE R ZF - or -CR ZE R ZF -C RZG R ZH -or (c)R 2 and R 12Aare joined to form a 4- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S; (d)X 1 is a bond, NR X , or -CONR X - or -S-, (e)X 2 is -S- or (f)X 3 is -S- or (g)X 4 is =S or (h)R 1 is C1~C 20 Alkyl, C3-C 10 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, C-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 The group is composed of three R 1A or substituted with a group, (i) R on the adjacent carbon atom 4 Groups and R 5 groups, together with the carbon to which they are attached, form a carbon-carbon triple bond, or (j) at least one R 1A is -SO2R 1B , -COOR 1B or (k) m is 7, 8, or 9.

[0004] In another aspect, the disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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

[0006] In another aspect, the present disclosure provides a method for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is used.

[0007] In another aspect, the disclosure provides the use of a compound of formula I, 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

[0008] I. Overview The present invention relates generally to methods and compounds for the treatment or prevention of viral infections, such as Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxoviridae, and Coronaviridae infections. II. Definition

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

[0010] As used herein, "a compound of the disclosure" or "a compound of Formula I" means a compound of Formula I or a pharmaceutically acceptable salt thereof. Similarly, the phrase "a compound of Formula (number)" means a compound of that formula and its pharmaceutically acceptable salts.

[0011] "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 methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -C H(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl 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( These include, but are not limited to, 4-methyl-2-pentyl (-CH(CH)CHCH(CH)), 3-methyl-3-pentyl (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), and 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), 3,3-dimethyl-2-butyl (-CH(CH)C(CH)).

[0012] "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 12 The 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), t-butoxy (-OC(CH3)3 or -OtBu), and the like.

[0013] 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 can have 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 -CF3, -CHF2, -CFH2, -CH2CF3, and the like.

[0014] "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 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

[0015] "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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0016] The term "halo," as used herein, refers to -F, -Cl, -Br, or -I. In some embodiments, a halo group is -F or -Cl. In some embodiments, a halo group is -F.

[0017] "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 may be monocyclic or polycyclic, and polycyclic rings may 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. The terms heterocycle or heterocyclyl do not encompass or overlap with heteroaryl, as defined below.

[0018] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S). As used herein, heteroaryl contains 5 to 20 ring atoms, 5 to 12 ring atoms, 5 to 8 ring atoms, or 5 to 6 ring atoms, and includes 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass and does not overlap with aryl, as defined above.

[0019] The term "optionally substituted" with respect to a particular moiety in a compound of Formula I (e.g., an optionally substituted aryl group) means that all of the substituents are hydrogen, or one or more of the hydrogens on the moiety can be replaced with a substituent as listed.

[0020] Unless otherwise specified, the carbon atoms of the compounds of Formula I 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.

[0021] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment" refers to the act of treating, as "treating" is defined immediately above.

[0022] As used herein, the term "therapeutically effective amount" refers to the amount of a compound of Formula I used herein required to provide a desired level of drug in the secretions and airway and lung tissues of a subject, or alternatively, in the bloodstream of a treated subject, that will produce an expected physiological response or desired biological effect when such a composition is administered by a selected route of administration. The exact amount will depend on numerous factors, such as the particular compound of Formula I, the specific activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and patient considerations such as the severity of the disease state and patient interaction, and can be readily determined by one of ordinary skill in the art based on the information provided herein.

[0023] 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 formula, C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, C4 and C5 are adjacent carbons, C5 and C6 are adjacent carbons, and C6 and C1 are adjacent carbons.

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

[0025] Provided herein are compounds of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein: Z 1 is a bond, -CH2-, -CH2-CH2-, -CR ZA R ZB - or -CR ZA R ZB -C RZC R ZD - and Z 2 is a bond, -CH2-, -CH2-CH2-, -CR ZE R ZF - or -CR ZE R ZF -C RZG R ZH and R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH are each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; R ZB and R ZF are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; X is a bond, -O-, -OCO-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - OCR 12A R 12B -(CR 13 =CR 14 )-, -(CR 12A R 12B ) q -O-(CR 12A R 12B ) q -, -S-, (CR 12A R 12B ) p -NR 12C -(CR 12A R 12B ) p- or (CR 12A R 12B ) p -NR 12C CO-(CR 12A R 12B ) p - in which Each R 12A are independently H, C1-C6 alkyl, or phenyl, or R 2 and R 12A are joined to form a 4-6 membered cycloalkyl or heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S; Each R 12B are independently H or C1-C6 alkyl, or R on the same carbon 12A and R 12B are bonded together to form a C3-C6 cycloalkylene, R 12C is H, C1-C3 alkyl, -COR 12D , or -SO2R 12E or R 12C and R 1 are joined together to have 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally 1 to 4 R 12F forming a 5- to 6-membered heterocyclyl substituted with a group, Each R 12F are independently oxo or halo, or two R on adjacent carbons 12F are joined to form a fused phenyl optionally substituted with 1 or 2 substituents independently selected from F and Cl; R 12D is C1-C3 alkyl, C6-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 12D optionally 1, 2, or 3 R 12G is substituted with a group, Each R 12Gare independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, C1-C3 haloalkyl, or -COOR 12H and R 12H is H or C1-C3 alkyl, R 12E is H or C1-C3 alkyl, R 13 is H, C1-C6 alkyl, or phenyl, R 14 is H, C1-C6 alkyl, or phenyl, each q is independently 1 or 2; each p is independently 0, 1, or 2; X 1 is a bond, -O-, NR X , or -CONR X - or -S-, R X is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)R XA and R XA is a C1-C3 alkyl, X 2 is -O- or -S-, X 3 is -O- or -S-, X 4 is =O or =S, R 1 H, C1~C 20 Alkyl, C3-C 10 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, C-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 If is not H, then R 1 The group optionally contains one, two, or three R 1A is substituted with a group, Each R 1Aare independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R 1B , -COOR 1B or C1-C3 haloalkyl, or two R on the same or adjacent carbons 1A are joined together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1B is H or C 1~3 is alkyl, R 2 is H or C1-C3 alkyl, Y is a bond, phenylene, or C3-C6 cycloalkylene; R 3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; Each R 4 are independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or two R on adjacent carbon atoms 4 groups, together with the carbon to which they are attached, form a carbon-carbon double bond, Each R 5 are independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; R on adjacent carbon atoms 4 Groups and R 5 groups, together with the carbon to which they are attached, form a carbon-carbon triple bond; R 6 is H or —C(O)C1-C6 alkyl, R 7 is H or —C(O)C1-C6 alkyl, m is an integer from 7 to 21; X is a bond, -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B )q - or - OCR 12A R 12B -(CR 13 =CR 14 )-, (a)Z 1 is a bond, -CR ZA R ZB - or -CR ZA R ZB -C RZC R ZD -or (b)Z 2 is a bond, -CR ZE R ZF - or -CR ZE R ZF -C RZG R ZH Or (c)R 2 and R 12A are joined to form a 4-6 membered cycloalkyl or heterocyclic ring having 1, 2, or 3 heteroatoms selected from N, O, and S; (d)X 1 is a bond, NR X , or -CONR X - or -S-, (e)X 2 is -S- or (f)X 3 is -S- or (g)X 4 is S or (h)R 1 is C1~C 20 Alkyl, C3-C 10 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, C-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 The group is composed of three R 1A or substituted with a group, (i) R on the adjacent carbon atom 4 Groups and R 5groups, together with the carbon to which they are attached, form a carbon-carbon triple bond, or (j) at least one R 1A is -SO2R 1B , -COOR 1B or (k) m is 7, 8, or 9.

[0026] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )- and Z 1 is a bond, -CR ZA R ZB - or -CR ZA R ZB -C RZC R ZD -It is.

[0027] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )- and Z 2 is a bond, -CR ZE R ZF - or -CR ZE R ZF -C RZG R ZH is.

[0028] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12AR 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )- and R 2 and R 12A are linked to form a 4- to 6-membered cycloalkyl or 4- to 6-membered heterocycle having 1, 2, or 3 heteroatoms selected from N, O, and S.

[0029] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )- and X 1 is a bond, NR X , or -CONR X - or -S-.

[0030] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )- and X 2 is -S-.

[0031] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14)- and X 3 is -S-.

[0032] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )- and X 4 is S.

[0033] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )- and R 1 is C1~C 20 Alkyl, C3-C 10 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, C-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 The group is composed of three R 1A is substituted with a group.

[0034] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14)- and R 4 Groups and R 5 The groups, together with the carbon to which they are attached, form a carbon-carbon triple bond.

[0035] In some embodiments, for compounds of formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )-, and m is 7, 8, or 9.

[0036] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z 1 is a bond, -CH2-, -CH2-CH2-, -CR ZA R ZB - or -CR ZA R ZB -C RZC R ZD - and Z 2 is a bond, -CH2-, -CH2-CH2-, -CR ZE R ZF - or -CR ZE R ZF -C RZG R ZH and R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH are each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; R ZB and R ZF are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; X is -OCO-, -(CR 12A R 12B ) q -O-(CR12A R 12B ) q -, -S-, (CR 12A R 12B ) p -NR 12C -(CR 12A R 12B ) p - or (CR 12A R 12B ) p -NR 12C CO-(CR 12A R 12B ) p - in which Each R 12A are independently H, C1-C6 alkyl, or phenyl, or R 2 and R 12A are joined to form a 4-6 membered cycloalkyl or heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S; Each R 12B are independently H or C1-C6 alkyl, or R on the same carbon 12A and R 12B are bonded together to form a C3-C6 cycloalkylene, R 12C is H, C1-C3 alkyl, -COR 12D , or -SO2R 12E or R 12C and R 1 are joined together to have 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally 1 to 4 R 12F forming a 5- to 6-membered heterocyclyl substituted with a group, Each R 12F are independently oxo or halo, or two R on adjacent carbons 12F are joined to form a fused phenyl optionally substituted with 1 or 2 substituents independently selected from F and Cl; R 12D is C1-C3 alkyl, C6-C 10aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 12D optionally 1, 2, or 3 R 12G is substituted with a group, Each R 12G are independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, C1-C3 haloalkyl, or -COOR 12H and R 12H is H or C1-C3 alkyl, R 12E is H or C1-C3 alkyl, each q is independently 1 or 2; each p is independently 0, 1, or 2; X 1 is a bond, -O-, NR X , or -CONR X - or -S-, R X is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)R XA and R XA is a C1-C3 alkyl, X 2 is -O- or -S-, X 3 is -O- or -S-, X 4 is =O or =S, R 1 H, C1~C 20 Alkyl, C3-C 10 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, C-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 If is not H, then R 1 The group optionally contains one, two, or three R 1A is substituted with a group, Each R1A are independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R 1B , -COOR 1B or C1-C3 haloalkyl, or two R on the same or adjacent carbons 1A are joined together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1B is H or C 1~3 is alkyl, R 2 is H or C1-C3 alkyl, Y is a bond, phenylene, or C3-C6 cycloalkylene; R 3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; Each R 4 are independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or two R on adjacent carbon atoms 4 groups, together with the carbon to which they are attached, form a carbon-carbon double bond, Each R 5 are independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; R on adjacent carbon atoms 4 Groups and R 5 groups, together with the carbon to which they are attached, form a carbon-carbon triple bond; R 6 is H or —C(O)C1-C6 alkyl, R 7 is H or —C(O)C1-C6 alkyl, m is an integer from 7 to 21.

[0037] In some embodiments of the compound of Formula I, Z 1 is -CH2- and Z 2is -CH2-. In some embodiments, Z 1 and Z 2 In some embodiments, one of Z 1 and Z 2 and are both -CH-CH-. In some embodiments, Z 1 is -CH-CH- and Z is -CH-. In some embodiments, Z 1 is -CH2- and Z2 is -CH2-CH2-.

[0038] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, Z 1 is a bond, -CH2-, -CH2-CH2-, -CR ZA R ZB - or -CR ZA R ZB -C RZC R ZD - and Z 2 is a bond, -CH2-, -CH2-CH2-, -CR ZE R ZF - or -CR ZE R ZF -C RZG R ZH and R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH are each independently H or C1-C3 alkyl, and R ZB and R ZF are each independently C1 to C3 alkyl.

[0039] In some embodiments of the compound of Formula I, Z 1 is a bond, -CH2-, -CH2-CH2-, -CR ZA R ZB - or -CR ZA R ZB -C RZC R ZD - and Z 2 is a bond, -CH2-, -CH2-CH2-, -CR ZE R ZF- or -CR ZE R ZF -C RZG R ZH and R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH are each independently H or methyl, and R ZB and R ZF are both methyl.

[0040] In some embodiments of the compound of Formula I, Z 1 is a bond, -CH2-, -CH2-CH2-, or -CH(CH3)-, and Z 2 is a bond, —CH—, —CH—CH—, or —CH(CH)—. In some embodiments, Z 1 is -CH2- and Z 2 is -CH2-. In some embodiments, Z 1 is -C(CH3)H-, and Z 2 is -CH2-. In some embodiments, Z 1 is -CH2- and Z2 is -C(CH3)H-. In some embodiments, Z 1 is -CH2- and Z2 is a bond. In some embodiments, Z 1 is a bond, and Z 2 is -CH2-.

[0041] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X 1 is a bond, -O-, -NR x , or S and R X is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)R XA and R XA is C1-C3 alkyl. In some embodiments, X 1 is a bond, -O-, -NR x , or S and R X is H, C1-C3 alkyl, or C1-C3 haloalkyl. 1is a bond, —O—, —NH—, —NCH3—, or S. In some embodiments, X 1 is a bond, —O—, or S. In some embodiments, X 1 is a bond or —O—. In some embodiments, X 1 is a bond. In some embodiments, X 1 is —O—. In some embodiments, X 1 is -S-. In some embodiments, X 1 is -NH-.

[0042] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X 1 is NR x -or-CONR X - and R x is C1-C3 alkyl or -C(O)R XA In some embodiments, X 1 is -NR x -or-CONR x - and R X is C1-C3 alkyl. In some embodiments, X 1 is -NR x -or-CONR x - and R x is methyl. In some embodiments, X 1 is -NR x -or-CONR x - and R x HA-C(O)R XA and R XA is methyl.

[0043] In some embodiments, the compound of formula I has formula Ia [ka] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, X2 , X 3 , X 4 , and m are as defined herein for Formula I.

[0044] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof, X 2 is S. In some embodiments, X 2 is O.

[0045] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof, X 3 is S. In some embodiments, X 3 is O.

[0046] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof, X 4 is S. In some embodiments, X 4 is O.

[0047] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof, R 2 is H. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0048] In some embodiments of the compound of Formula I, X is —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )- and q is 1 or 2. In some embodiments, X is a bond, —O—, —(CR 12A R 12B )-, -O(CR 12A R 12B )- or -OCR 12A R12B -(CR 13 =CR 14 In some embodiments, X is a bond, —O—, —(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, or -OCR 12A R 12B -(CR 13 =CR 14 In some embodiments, X is -O-, -O(CR 12A R 12B ) q - or - OCR 12A R 12B -(CR 13 =CR 14 )-, and q is 1 or 2. In some embodiments, X is -O-, -O(CR 12A R 12B )- or -OCR 12A R 12B -(CR 13 =CR 14 In some embodiments, X is -O-, -O(CR 12A R 12B 2- or -OCR 12A R 12B -(CR 13 =CR 14 In some embodiments, X is a bond, —O—, —(CR 12A R 12B ) q -, -0(CR 12A R 12B ) q - and q is 1 or 2. In some embodiments, X is a bond, -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-. In some embodiments, X is a bond, —O—, —(CR 12A R 12B )-, -O(CR 12A R 12B )-. In some embodiments, X is O. In some embodiments, X is -(CR 12A R 12B) q - and q is 1 or 2. In some embodiments, X is -(CR 12A R 12B In some embodiments, X is -(CR 12A R 12B )2-. In some embodiments, X is -O(CR 12A R 12B ) q and q is 1 or 2. In some embodiments, X is —O(CR 12A R 12B In some embodiments, X is —O(CR 12A R 12B )2-.

[0049] In some embodiments of the compound of Formula I, each R 12A are independently H, C1-C6 alkyl, or phenyl, and each R 12B are independently H or C1-C6 alkyl, and R 13 is H, C1-C6 alkyl, or phenyl, and R 14 is H, C1-C6 alkyl, or phenyl. In some embodiments, each R 12A are independently H or C1-C6 alkyl, and each R 12B are independently H or C1-C6 alkyl, and R 13 is H or C1-C6 alkyl, and R 14 is H or C1-C6 alkyl. In some embodiments, each R 12A are independently H or C1-C3 alkyl, and each R 12B are independently H or C1-C3 alkyl, and R 13 is H or C1-C3 alkyl, and R 14 is H or C1-C3 alkyl. In some embodiments, each R 12A is H, and each R 12B is H and R 13 is H and R 14 is H.

[0050] In some embodiments of the compound of Formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, q is 1 or 2, and each R 12A are independently H, C1-C6 alkyl, or phenyl, and each R 12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, q is 1 or 2, and each R 12A are independently H or C1-C6 alkyl, and each R 12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, q is 1 or 2, and each R 12A are independently H or C1-C3 alkyl, and each R 12B is independently H or C1-C3 alkyl. In some embodiments of the compound of Formula I, X is a bond, —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, q is 1 or 2, and each R 12A is H, and each R 12B is H. In some embodiments of the compound of Formula I, X is a bond, -O-, -CH2-, -CH2CH2-, -OCH2-, or -O(CH2)2-. In some embodiments of the compound of Formula I, X is a bond, -O-, -OCH2, or -CH2CH2.

[0051] In some embodiments of the compound of Formula I, X is —O—, —(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, q is 1 or 2, and each R 12A are independently H, C1-C6 alkyl, or phenyl, and each R 12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, q is 1 or 2, and each R 12A are independently H or C1-C6 alkyl, and each R 12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, q is 1 or 2, and each R 12A are independently H or C1-C3 alkyl, and each R 12B is independently H or C1-C3 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -, q is 1 or 2, and each R 12A is H, and each R 12B is H.

[0052] In some embodiments of the compound of Formula I, X is —O—, —(CR 12A R 12B )-, -O(CR 12A R 12B )- and R 12A is H or C1-C6 alkyl, and R 12Bis H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B )-, -O(CR 12A R 12B )- and R 12A is H or C1-C6 alkyl, and R 12B is H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B )-, -O(CR 12A R 12B )- and R 12A is H or C1-C3 alkyl, and R 12B is H or C1-C3 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B )-, -O(CR 12A R 12B )- and R 12A is H and R 12B is H.

[0053] In some embodiments of the compound of Formula I, X is —O—, —(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, and each R 12A are independently H, C1-C6 alkyl, or phenyl, and each R 12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, and each R 12A are independently H or C1-C6 alkyl, and each R 12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, and each R 12Aare independently H or C1-C3 alkyl, and each R 12B is independently H or C1-C3 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR 12A R 12B )2-, -O(CR 12A R 12B )2-, and each R 12A is H, and each R 12B is H.

[0054] In some embodiments of the compound of Formula I, X is -O-, -OCH2-, -OCH2-CH2-, -CH2-, -CH2-CH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -O-, -OCH2-, -CH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -O-. In some embodiments, X is -CH2- or -CH2-CH2-. In some embodiments, X is -CH2-CH2-. In some embodiments, X is -CH2-.

[0055] In some embodiments of the compound of Formula I, X is -O-, -OCH2-, -OCH2-CH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -O-, -OCH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -O-. In some embodiments, X is -OCH2-. In some embodiments, X is -OCH2-. In some embodiments, X is -OCH2-CH2-. In some embodiments, X is -OCH2-(CH=CH)-.

[0056] In some embodiments of the compound of Formula I, X is (CR 12A R 12B ) p -NR 12C -(CR 12A R 12B ) p -or (CR 12A R 12B ) p -NR 12C CO-(CR 12A R 12B )p - and p is 0, 1, or 2. In some embodiments, X is (CR 12A R 12B ) p -NR 12C -(CR 12A R 12B ) p -or (CR 12A R 12B ) p -NR 12C CO-(CR 12A R 12B ) p - and p is 0 or 1. In some embodiments, X is -NR 12C -or-NR 12C It is CO-.

[0057] In some embodiments of the compound of Formula I, X is —NR 12C -or-NR 12C CO- and R 12C H, C1~C 3 Alkyl, or -COR 12D and R 12D is C1-C3 methyl. In some embodiments, X is NR 12C -or-NR 12C CO- and R 12C is H, methyl, or -COCH3.

[0058] In some embodiments of the compound of Formula I, X is -(CR 12A R 12B ) p -NR 12C CO-(CR 12A R 12B ) p - and p is 0, 1, or 2. In some embodiments, X is -(CR 12A R 12B ) p -NR 12C CO-(CR 12A R 12B ) p - and p is 0 or 1. In some embodiments, X is -NR 12C In some embodiments, X is -NR12C CO- and R 12C is H, C1-C3 alkyl, or -COR 12D and R 12D is C1-C3 methyl. In some embodiments, X is -NR 12C CO- and R 12C is H, methyl, or —COCH. In some embodiments, X is —NR 12C CO- and R 12C is H or methyl. In some embodiments, X is —NR 12C CO- and R 12C is H. In some embodiments, X is —NR 12C CO- and R 12C is methyl.

[0059] In some embodiments of the compound of Formula I, X is -(CR 12A R 12B ) p -NR 12C -(CR 12A R 12B ) p - and p is 0, 1, or 2. In some embodiments, X is -(CR 12A R 12B ) p -NR 12C -(CR 12A R 12B ) p - and p is 0 or 1. In some embodiments, X is -NR 12C In some embodiments, X is -NR 12C - and R 12C is H, C1-C3 alkyl, or -COR 12D and R 12D is C1-C3 methyl. In some embodiments, X is —NR 12C - and R 12C is H, methyl, or —COCH. In some embodiments, X is —NR 12C - and R 12C is H or methyl. In some embodiments, X is —NR 12C - and R 12Cis H. In some embodiments, X is —NR 12C - and R 12C is methyl. In some embodiments, X is —NR 12C - and R 12C is -COCH3.

[0060] In some embodiments of the compound of Formula I, X is NR 12C - and R 12C and R 1 are joined together to have 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally 1 to 4 R 12F Form a 5- to 6-membered heterocyclyl substituted with a group, and each R 12F are independently oxo or halo, or two R on adjacent carbons 12F are joined to form a fused phenyl optionally substituted with 1 or 2 substituents independently selected from F and Cl. In some embodiments, X is -NR 12C - and R 12C and R 1 are bonded together to contain one N atom, and optionally 1 to 4 R 12F forming a 5-membered heterocyclyl substituted with a group, 12F are independently oxo or halo, or two R on adjacent carbons 12F are joined to form a fused phenyl optionally substituted with 1 or 2 substituents independently selected from F and Cl. In some embodiments, X is -NR 12C - and R 12C and R 1 are joined together, [ka] Form.

[0061] In some embodiments of a compound of Formula I, X is a bond, —O—, —S—, —CHO—, —NH—, —N(C(O)CH)—, —NCH—, or —N(CH)CO—. In some embodiments, X is a bond, —O—, —S—, —CHO—, —NH—, —N(C(O)CH)—, —NCH—, or —N(CH)CO—. In some embodiments, X is —O—, —S—, or —CHO—. In some embodiments, X is —O—. In some embodiments, X is —S—. In some embodiments, X is —CHO—. In some embodiments, X is —NH—, —N(C(O)CH)—, —NCH—, or —N(CH)CO—. In some embodiments, X is —NH—, —N(C(O)CH)—, or —NCH—.

[0062] In some embodiments of the compound of Formula I, X is a bond.

[0063] In some embodiments of the compound of Formula I, Y is phenylene or C3-C6 cycloalkylene. [ka] In some embodiments, Y is phenylene. In some embodiments, Y is [ka] In some embodiments, Y is C3-C6 cycloalkylene. In some embodiments, Y is cycloalkylene. In some embodiments, Y is [ka] In some embodiments, Y is a bond. In some embodiments, Y is a bond or phenylene. In some embodiments, Y is a bond or C3-C6 cycloalkylene.

[0064] In some embodiments of the compound of Formula I or Formula Ia, R1 is C1~C 20 Alkyl, C3-C 10 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, C-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 The group optionally contains one, two or three R 1A Some embodiments are substituted with R 1 is H, C1-C6 alkyl, C3-C 10 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, C-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 If is not H, then R 1 The group may optionally contain one or two R 1A In some embodiments, R 1 is C1~C 20 Alkyl, C3-C 10 cycloalkyl or a 5- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 The group optionally contains one, two, or three R 1A In some embodiments, R 1 is C1-C6 alkyl, C3-C 10 cycloalkyl or a 5- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 The group optionally contains one, two, or three R 1A In some embodiments, R 1 is C1~C 20 Alkyl, C3-C 10 Cycloalkyl, C6-C 10aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 The group optionally contains one, two, or three R 1A In some embodiments, R 1 is C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R 1 The group optionally contains one, two, or three R 1A In some embodiments, R 1 is C1~C 20 Alkyl, C3-C 10 Cycloalkyl or C6-C 10 aryl, and R 1 The group optionally contains one, two, or three R 1A In some embodiments, R 1 is C1-C6 alkyl, C3-C 10 Cycloalkyl or C6-C 10 aryl, and R 1 The group optionally contains one, two, or three R 1A In some embodiments, R 1 is C1~C 20 Alkyl or C6-C 10 aryl, and R 1 The group optionally contains one, two, or three R 1A In some embodiments, R 1 is C1 to C6 alkyl or C6 to C 10 aryl, and R 1 The group optionally contains one, two or three R 1A In some embodiments, R 1 optionally 1, 2, or 3 R 1A C1-C substituted with groups 20 In some embodiments, R1 optionally 1, 2, or 3 R 1A It is a C1-C6 alkyl substituted with a group.

[0065] In some embodiments of the compound of Formula I or Formula Ia, R 1 optionally 1, 2, or 3 R 1A C6-C substituted with a group 10 In some embodiments, R 1 is phenyl, naphthyl, thiophenyl, cyclohexyl, methyl, ethyl, or propyl.

[0066] In some embodiments of the compound of Formula I or Formula Ia, R 1 is unsubstituted. In some embodiments, R 1 is one R 1A In some embodiments, R 1 is two R 1A In some embodiments, R 1 The group is composed of three R 1A In some embodiments, each R 1A are independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R 1B , -COOR 1B or C1-C3 haloalkyl. In some embodiments, R 1A are independently methyl, phenyl, chloro, fluoro, methoxy, cyano, or CF. In some embodiments, two R 1A are joined together to form a 3- to 6-membered cycloalkyl ring or a 4- to 6-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, S, and O. In some embodiments, two R 1A are joined together to form a 3- to 6-membered cycloalkyl. In some embodiments, two R 1A are joined together to form a 5-membered cycloalkyl. In some embodiments, two R 1Aare joined together to form a 4-6 membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, S, and O.

[0067] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof, R 1 H, [ka] is selected from the group consisting of:

[0068] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof, R 1 H, [ka] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0069] In some embodiments of a compound of Formula I or Formula Ia, m is 10-20, and in some embodiments, m is 14-20. In some embodiments, m is 16, 17, 18, 19, or 20. In some embodiments, m is 17, 18, or 19. In some embodiments, m is 17. In some embodiments, m is 18. In some embodiments, m is 19. In some embodiments, m is 20.

[0070] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof, X 2 is O, X 3 is O, X 4 is O, R 2 is H, R1 optionally 1, 2, or 3 R 1A C6-C substituted with a group 10 It is aryl.

[0071] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof, X 2 is O, X 3 is O, X 4 is O, R 2 But H; R 6 is H, R 7 is H, R 1 is a C-C optionally substituted with 1, 2, or 3 R groups; 10 It is aryl.

[0072] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X 2 is O, X 3 is O, X 4 is O, R 2 But H; R 1 optionally 1, 2, or 3 R 1A C6-C substituted with a group 10 is aryl, R 6 is H, R 7 is H, R 3 is H or C1-C3 alkyl, Each R 4 are independently H or C1-C3 alkyl, Each R 5 are independently H or C1-C3 alkyl, or R on adjacent carbon atoms 4Groups and R 5 groups, together with the carbons to which they are attached, form a carbon-carbon triple bond; m is an integer of 8 to 20.

[0073] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X 2 is O, X 3 is O, X 4 is O, R 2 But H; R 1 is a C-C optionally substituted with 1, 2, or 3 R groups; 10 is aryl, R 6 is H, R 7 is H, R 3 is H, Each R 4 is H or Each R 5 is H, or R on adjacent carbon atoms 4 Groups and R 5 groups, together with the carbons to which they are attached, form a carbon-carbon triple bond; m is an integer of 10 to 20.

[0074] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X 2 is O, X 3 is O, X 4 is O, R 2 But H; R 1 is a C-C optionally substituted with 1, 2, or 3 R groups; 10 is aryl, R 6 is H, R7 is H, R 3 is H, Each R 4 is H, Each R 5 is H, m is an integer from 14 to 20.

[0075] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X 2 is O, X 3 is O, X 4 is O, R 2 But H; R 1 optionally 1, 2, or 3 R 1A C6-C substituted with a group 10 is aryl, R 6 is H, R 7 is H, R 3 is H, Each R 4 is H, Each R 5 is H, m is 17, 18, or 19.

[0076] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X 2 is O, X 3 is O, X 4 is O, R 2 But H; R 1 optionally 1, 2, or 3 R 1A C6-C substituted with a group 10 is aryl, R 6 is H, R7 is H, R 3 is H, Each R 4 is H, Each R 5 is H, m is 18 or 19.

[0077] In some embodiments, the compound of formula I is [ka] [ka] [ka] is selected from the group consisting of:

[0078] In some embodiments, the compound of Formula I or Formula Ia is [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compound of Formula I or Formula Ia is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the compound of Formula I or Formula Ia is [ka] or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the compound of Formula I or Formula Ia is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound of Formula I or Formula Ia is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound of Formula I or Formula Ia is [ka] or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the compound of Formula I or Formula Ia is [ka] or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the compound of Formula I or Formula Ia is [ka] or a pharmaceutically acceptable salt thereof.

[0086] formula: [ka] or a pharmaceutically acceptable salt thereof.

[0087] formula: [ka] or a pharmaceutically acceptable salt thereof.

[0088] formula: [ka] or a pharmaceutically acceptable salt thereof.

[0089] formula: [ka] or a pharmaceutically acceptable salt thereof.

[0090] formula: [ka] or a pharmaceutically acceptable salt thereof.

[0091] formula: [ka] or a pharmaceutically acceptable salt thereof.

[0092] formula: [ka] or a pharmaceutically acceptable salt thereof.

[0093] Any reference to a compound of the invention described herein also includes a reference to a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of the compounds of the invention include alkali metal or alkaline earth salts (e.g., Na + , Li + , K. + , Ca +2 , and Mg +2 ), ammonium and NR4 + (wherein R is as defined herein) Pharmaceutically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; (b) acid addition salts formed with acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like; (c) salts formed with organic acids such as benzoic acid, benzosulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, and leucine; and (c) salts formed with elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of compounds with hydroxy groups include Na + and NR4 + Examples of suitable cations include the anions of the above compounds in combination with suitable cations such as:

[0094] The compounds disclosed herein (e.g., compounds of Formula I) and pharmaceutically acceptable salts thereof may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism refers to the ability of a crystalline compound to exist in different crystal structures. Crystalline polymorphism can result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism refers to the ability of hydrates or solvates of a compound to exist in different crystal structures. Pseudopolymorphs of the present invention may exist due to differences in crystal packing (packing pseudopolymorphism) or differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of the compounds of Formula I and their pharmaceutically acceptable salts.

[0095] The compounds disclosed herein (e.g., compounds of Formula I) and their pharmaceutically acceptable salts can also exist as amorphous solids. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of atoms in the solid. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to create the amorphous forms of the present invention. The present invention includes all amorphous forms of the compounds of Formula I and their pharmaceutically acceptable salts.

[0096] For therapeutic use, salts of the active ingredients of the compounds of the present invention are pharmaceutically acceptable. That is, they are salts derived from pharmaceutically acceptable acids or bases. However, salts of non-pharmaceutically acceptable acids or bases may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether derived from pharmaceutically acceptable acids or bases, are within the scope of the present invention.

[0097] It should also be understood that the compositions herein include compounds of the present invention in their non-ionized as well as zwitterionic forms, as well as combinations with a stoichiometric amount of water in hydrates.

[0098] It should be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs, and pharmaceutically acceptable salts thereof of compounds within the scope of Formula I are encompassed by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

[0099] The compounds of the present invention, as exemplified by Formula I, may have chiral centers, such as chiral carbon or phosphorus atoms. Accordingly, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Additionally, the compounds of the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, chiral centers apparent from the depiction are provided as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as individual isolated or synthesized optical isomers substantially free of their enantiomeric or diastereomeric partners, are within the scope of the present invention. Racemic mixtures can be separated into their individual, substantially optically pure isomers by suitable techniques, such as, for example, separation of diastereomeric salts formed with optically active auxiliaries, e.g., acids or bases, followed by conversion back to optically active materials. In most cases, the desired optical isomer is synthesized by stereospecific reactions beginning with the appropriate stereoisomer of the desired starting material.

[0100] Stereochemical definitions and rules used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the indication of rotation of plane-polarized light by the compound; S, (-), or 1 means that the compound is levorotatory, while compounds with the prefix R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0101] The compounds of the present invention may also exist as tautomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the present invention. For example, ene-amine tautomers may exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all of their possible tautomers are within the scope of the present invention.

[0102] Any formula or structure given herein, including compounds of Formula I, is also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Isotopically labeled compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. 3 H, 13 C and 14 and those into which a radioactive isotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in the radiotherapy of patients.

[0103] The present disclosure also includes compounds of Formula I in which one to x hydrogens bonded to a carbon atom have been replaced by deuterium, where x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). In light of the present disclosure, such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0104] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0105] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0106] Whenever a compound described herein is substituted with more than one of the same group, e.g., designated "R" or "R", it will be understood that the groups can be the same or different, i.e., each group is independently selected.

[0107] Wavy Lines [ka] indicates the site of covalent attachment to an adjacent substructure, group, moiety, or atom. IV. Pharmaceutical Preparations

[0108] The compounds disclosed herein (e.g., compounds of Formula I) can be formulated with conventional carriers and excipients. For example, tablets contain excipients, lubricants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and, if intended for delivery by routes other than oral administration, are generally isotonic. All formulations may optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, and carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. The pH of the formulations ranges from about 3 to about 11, although in certain embodiments, it is about 7 to 10. In some embodiments, the pH of the formulations ranges from about 2 to about 5. In some embodiments, the pH of the formulations ranges from about 3 to about 4.

[0109] While it is possible for the compounds of the present disclosure ("active ingredients") to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefor and, optionally, other additional therapeutic ingredients, particularly the additional therapeutically active ingredients discussed herein. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically non-toxic to the recipient thereof.

[0110] Formulations include those suitable for the aforementioned routes of administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any suitable method known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0111] In some embodiments, the disclosed compounds have pharmacokinetic properties (e.g., good oral bioavailability) that are suitable for oral administration of the compounds. In some embodiments, formulations of the present invention suitable for oral administration can be presented 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 liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary, or paste.

[0112] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with one or more pharmaceutically acceptable excipients, such as binders, lubricants, inert diluents, preservatives, surface active agents, or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets can optionally be coated or scored, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom.

[0113] The oily phase of the emulsion of the present invention can be composed of known ingredients in a known manner. The phase can simply contain an emulsifier (otherwise known as an emulsion), but desirably contains a mixture of at least one emulsifier with a fat or oil, or a mixture of both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, which, together with the oil and fat, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0114] Emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Additional emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 80.

[0115] The selection of suitable oils or fats for the formulation is based on achieving the desired aesthetic properties. Creams should preferably be non-greasy, non-staining, and washable products with a suitable consistency to avoid leakage from tubes or other containers. 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, or a blend of branched esters known as Crodamol CAP, may also be used, the last three being preferred esters. These may be used alone or in combination, depending on the desired properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0116] Pharmaceutical formulations according to the present invention comprise a compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral administration, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium 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 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 may be used alone or with a wax.

[0117] 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.

[0118] Aqueous suspensions of the present invention contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients 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 stearates), 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 colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins. In some embodiments, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol®.

[0119] Oil suspensions can be prepared by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin.Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0120] Dispersible powders and granules of the present invention suitable for preparation of an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0121] The pharmaceutical composition of the present invention can also 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 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 formulations can also contain demulcents, preservatives, flavorings, or coloring agents.

[0122] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed 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. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0123] The amount of active ingredient that may be combined with a carrier material 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 to 1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 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.

[0124] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w.

[0125] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0126] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0127] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for pulmonary or nasal administration have particle sizes ranging from, for example, 0.1 to 500 micrometers, e.g., 0.5, 1, 30, 35, etc., and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveoli. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and may be delivered with other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as dry powders. In some embodiments, the compounds used herein are formulated and administered as spray formulations. In some embodiments, the compounds used herein are formulated for delivery via a face mask. In some embodiments, the compounds used herein are formulated for delivery via a face tent.

[0128] 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.

[0129] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions and suspensions 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.

[0130] 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.

[0131] It will be understood that in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0132] The present invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

[0133] A veterinary carrier is a substance useful for the purpose of administering the composition 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 compositions may be administered orally, parenterally, or by any other desired route.

[0134] The compounds of the present invention are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more compounds of the present invention as the active ingredient, in which release of the active ingredient is controlled and regulated to allow less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient. V. Kit

[0135] Also provided are kits comprising a compound disclosed herein (e.g., a compound of Formula I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a tautomer thereof. In some embodiments, the kits described herein may include a label and / or instructions for use of 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.

[0136] 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 compound of Formula I in the treatment of a disease or condition in a subject (e.g., a human) in need thereof.

[0137] In some embodiments, the kits provided herein contain individual unit doses of a compound described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. Examples of individual dosage units 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. In some embodiments, the kits 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.

[0138] Also provided is an article of manufacture comprising a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and a container. In some embodiments, the article of manufacture container can be a vial, bottle, ampoule, pre-filled syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or nebulizer. VI. Administration

[0139] One or more compounds of the present invention are administered by any route appropriate to 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 preferred route may vary depending, for example, on the condition of the recipient.

[0140] In the method of the present invention for treating viral infection, the compound of the present invention can be administered at any time to a person who may have come into contact with the virus or who is already suffering from the viral infection. In some embodiments, the compound of the present invention can be administered prophylactically to a person who comes into contact with a person suffering from a viral infection or who is at risk of coming into contact with a person suffering from a viral infection, such as a healthcare provider. In some embodiments, the compound of the present invention can be administered to a person who has tested positive for a viral infection but has not yet shown symptoms of the viral infection. In some embodiments, the compound of the present invention can be administered to a person at the onset of symptoms of the viral infection.

[0141] In some embodiments, the methods disclosed herein involve event-driven administration of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject.

[0142] As used herein, the term "event-driven" or "event-driven administration" refers to administering a compound of Formula I, 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 individual to the virus (or otherwise increases the individual's risk of being infected with the virus), and / or (2) during an event (or two or more recurring events) that exposes the individual to the virus (or otherwise increases the individual'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 individual to the virus (or otherwise increases the individual'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.

[0143] In certain embodiments, the methods disclosed herein involve administration before and / or after an event that exposes an individual to the virus or that otherwise increases the individual'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 involve pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein involve post-exposure prophylaxis (PEP).

[0144] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered prior to the subject's exposure to the virus.

[0145] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered before and after the subject's exposure to the virus.

[0146] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered after the subject's exposure to the virus.

[0147] An example of an event-driven dosing regimen includes administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 hours to 2 hours prior to the virus, followed by administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, every 24 hours for the duration of exposure, followed by another administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the final exposure, and finally another administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0148] A further example of an event-driven dosing regimen includes administering a compound of formula I, 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) about 24 hours after the last exposure.

[0149] The effective dose of active ingredient will depend, at least, on the nature of the condition being treated, its 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. This can be expected to be about 0.0001 to about 100 mg / kg body weight per day, typically about 0.01 to about 10 mg / kg body weight per day, more typically about 0.01 to about 5 mg / kg body weight per day, and most typically about 0.05 to about 0.5 mg / kg body weight per day. For example, the daily candidate dose for an adult weighing approximately 70 kg will range from 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can take the form of single or multiple doses.

[0150] Any suitable period for administering the compounds of the present invention 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 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer administration periods are also contemplated.

[0151] In some embodiments, the compounds disclosed herein are administered once 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.

[0152] 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.

[0153] In some embodiments, one or more compounds disclosed herein are administered once daily for about 6-12 days, e.g., about 8-10 days. In some embodiments, one or more compounds are administered once daily for about 9 days. In some embodiments, one or more compounds are administered once daily for about 10 days. In some embodiments, about 50-150 mg of one or more compounds disclosed herein are administered once daily for about 5-12 days, e.g., about 10 days. In some embodiments, about 100 mg of one or more compounds disclosed herein are administered once daily for about 5-12 days, e.g., about 10 days. VII.How to use

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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, whereby the viral polymerase is inhibited.

[0160] Also provided are methods of using the compounds disclosed herein for use in treating or preventing a viral infection in a subject in need thereof. For example, provided herein are methods of using the compounds disclosed herein for use in treating a viral infection in a subject in need thereof.

[0161] 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. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles, mumps, and parainfluenza viruses. In some embodiments, the Paramyxoviridae virus is Sosuga virus.

[0162] In some embodiments, the viral infection is a Pneumoviridae virus infection. Accordingly, 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 a compound provided herein to the human. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0163] In some embodiments, the present disclosure provides a compound disclosed herein for use in treating a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0164] In some embodiments, the present disclosure provides a method for treating a respiratory syncytial virus (RSV) infection in a human in need thereof, the method comprising administering a compound provided herein to the human. In some embodiments, the human is suffering from a chronic respiratory syncytial virus infection. In some embodiments, the human is acutely infected with RSV.

[0165] In some embodiments, a method of inhibiting RSV replication is provided, comprising administering to a human in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0166] 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.

[0167] 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 a compound of the disclosure to the human. 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 pleuritis (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 a Coxsackie A virus infection, a Coxsackie A virus infection, an Enterovirus D68 infection, an Enterovirus B69 infection, an Enterovirus D70 infection, an Enterovirus A71 infection, and a Poliovirus infection.

[0168] In some embodiments, the present disclosure provides a compound for use in treating a Picornaviridae virus infection in a human in need thereof, hi some embodiments, the Picornaviridae virus infection is a human rhinovirus infection.

[0169] In some embodiments, the viral infection is a Flaviviridae virus infection. Accordingly, 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 the human a compound described herein. Representative Flaviviridae viruses include, but are not limited to, Dengue fever, Yellow fever, West Nile, Zika, Japanese encephalitis virus, 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 Hepatitis C virus infection.

[0170] In some embodiments, the disclosure provides use of a compound of the disclosure for the treatment of 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.

[0171] In some embodiments, the viral infection is a Filoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (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.

[0172] In some embodiments, the present disclosure provides a compound for use in treating a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0173] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, provided herein are methods of treating a coronavirus infection in a human in need thereof, the method comprising administering a compound provided herein to the human. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or a zoonotic coronavirus (PEDV or HKUCoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection. In some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase, and SARS-CoV-2.

[0174] In some embodiments, the disclosure provides compounds for use in treating a coronavirus infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or a zoonotic coronavirus (PEDV or HKUCoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0175] In some embodiments, the viral infection is an Arenaviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating an Arenaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0176] In some embodiments, the present disclosure provides a compound for use in treating an Arenaviridae virus infection in a human in need thereof, hi some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0177] In some embodiments, the viral infection is an orthomyxovirus infection, such as an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0178] In some embodiments, the viral infection is a nairovirus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a nairovirus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the nairovirus infection is a Crimean-Congo hemorrhagic fever virus infection. In some embodiments, the nairovirus infection is a Hazara virus infection.

[0179] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a viral infection along with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected individual simultaneously with the compounds of the present disclosure, or before or after administration of the compounds of the present disclosure. VIII. Combination Therapy

[0180] 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, the methods 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 one or more additional therapeutic agents include one or more additional therapeutic agents from the same class or group (non-limiting examples include one or more antiviral agents, one or more vaccines, one or more antibodies) and / or one or more additional therapeutic agents from a different class or group.

[0181] 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 cytochrome P450 3A4 inhibitor, a peptidyl-prolyl cis-trans isomerase A inhibitor, 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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 immune globulin [VariZIG], varicella zoster immune globulin [VZIG], and combinations thereof.

[0190] 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.

[0191] 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.

[0192] 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 NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside 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 AT-527, daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0193] 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.

[0194] 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 alfacon1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon1, pegylated interferon alfa lb, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, interferon alfa lb, 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 alfacon1, 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. In some examples, the additional therapeutic agent is interferon beta. For example, the additional therapeutic agent is interferon beta-1a, such as SNG-001. In some embodiments, the additional therapeutic agent is an interferon inducer, such as tilorone hydrochloride. In some embodiments, the additional therapeutic agent is an IL-17 antagonist, such as ixekizumab, secukinumab, MU-838, and vidofludimus.

[0195] 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, azoximer bromide, IMM-101, and combinations thereof.

[0196] 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.

[0197] 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.

[0198] In some embodiments, the antiviral agent is DFV890. In some embodiments, the antiviral agent is MAS825. In some embodiments, the antiviral agent is emetine. In some embodiments, the antiviral agent is virafin. In some embodiments, the antiviral agent is berdazimer sodium. In some embodiments, the antiviral agent is KT-07. In some embodiments, the antiviral agent is iota-carrageenan. In some embodiments, the antiviral agent is polyoxidonium. In some embodiments, the antiviral agent is vitespiramycin. In some embodiments, the antiviral agent is an anti-adrenomedullin antibody such as enibarcimab. In some embodiments, the antiviral agent is an annexin A5 stimulator such as SY-005.spyke. In some embodiments, the antiviral agent is a COVID19 replicase polyprotein 1ab inhibitor such as DC-402234. In some embodiments, the antiviral agent is a host cell factor modulator such as GBV-006. In some embodiments, the antiviral agent is protoporphyrin IX, stannous, SnPP protoporphyrin, and verteporfin. In some embodiments, the antiviral agent is RBT-9. In some embodiments, the antiviral agent is thymosin. In some embodiments, the additional therapeutic agent is ivermectin.

[0199] 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.

[0200] In some embodiments, the additional therapeutic agent is a drug for the treatment of malaria. For example, the additional therapeutic agent is Pyramax, a dihydroartomisinin-piperaquine. In some embodiments, the additional therapeutic agent is chloroquine.

[0201] 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.

[0202] In some embodiments, the additional therapeutic agent is an agent for the treatment of coronavirus, hi 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, and combinations thereof.

[0203] 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 selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma, and 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 ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0204] 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, AT-527, GS-6620, PSI-938, ribavirin, tegobuvir, ladalbuvir, 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.

[0205] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0206] 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 AIC-649, α-hydroxytropolone, amdoxovir, antroquinonol, β-hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, CV-431, 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, and U.S. Patent Application Publication No. 20150210682 (Roche), U.S. Patent Application Publication No. 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 additional therapeutic agents include, but are not limited to, compounds disclosed in U.S. Patent Application Publication Nos. 16128335(A1) (Roche), 16120186(A1) (Roche), U.S. Patent Application Publication Nos. 2016237090(A) (Roche), WO 16107833(A1) (Roche), 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, such as HBV cyclosporine, ...

[0207] 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.

[0208] In some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an immune modulator, an immunotherapeutic agent, an antibody-drug conjugate, a gene modulating agent, a gene editing agent (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), and a cell therapy (e.g., chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, autologous stem cell therapy). In some embodiments, the additional therapeutic agent is an immunotherapeutic peptide such as tertomotide. In some embodiments, the additional therapeutic agent is a CCL26 gene inhibitor such as mocedipimod. In some embodiments, the additional therapeutic agent is FT-516.

[0209] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination drugs, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0210] 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 araf include, but are not limited to, elazofenamide, 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;

[0211] 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.

[0212] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, elvitegravir, curcumin, 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.

[0213] 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, balixafortide, motixafortide, and vMIP (Haimipu).

[0214] 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.

[0215] 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.

[0216] 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.

[0217] In some instances, the additional therapeutic agent is an HIV vaccine, such as DermaVir.

[0218] 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.

[0219] 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.

[0220] In some embodiments, the additional therapeutic agent is a CD73 antagonist such as FP-1201. In some embodiments, the additional therapeutic agent is a CGRP receptor antagonist such as BHV-3500. In some embodiments, the additional therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidyl-prolyl cis-trans isomerase A inhibitor such as alisporivir. In some embodiments, the additional therapeutic agent is a progesterone receptor agonist such as progesterone-IBSA. In some embodiments, the additional therapeutic agent is a GAB A receptor modulator such as brexanolone.

[0221] In some embodiments, the additional therapeutic agent is 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). In some embodiments, the additional therapeutic agent is a TEK receptor tyrosine kinase inhibitor.

[0222] In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor such as masitinib. In some embodiments, the additional therapeutic agent is a sphingosine kinase-2 (sk2) inhibitor such as opaganib. In some embodiments, the additional therapeutic agent is a Syk tyrosine kinase inhibitor such as fostamasitinib sodium hydrate. In some embodiments, the additional therapeutic agent is a cholesterol ester transfer protein inhibitor such as dalcetrapib. In some embodiments, the additional therapeutic agent is a kinase inhibitor such as pacritinib. In some embodiments, the additional therapeutic agent is an Axl tyrosine kinase receptor inhibitor such as bemcentinib. In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor. In some embodiments, the additional therapeutic agent is a checkpoint kinase inhibitor such as prexasertib. In some embodiments, the additional therapeutic agent is a MAP kinase inhibitor such as KTH-222 or ATI-450. In some embodiments, the additional therapeutic agent is a casein kinase II inhibitor such as silmitasertib. In some embodiments, the additional therapeutic agent is a Bcr-Abl tyrosine kinase inhibitor, such as radotinib. In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as ethyl icosapentate. In some embodiments, the additional therapeutic agent is an mTOR inhibitor, such as sirolimus. In some embodiments, the additional therapeutic agent is a pi3k / mTOR inhibitor, such as dactolisib. In some embodiments, the additional therapeutic agent is an Hsp90 inhibitor, such as ganetespib or ADX-1612. In some embodiments, the additional therapeutic agent is a MEK inhibitor, such as ATR-002. In some embodiments, the additional therapeutic agent is a topoisomerase II inhibitor, such as etoposide. In some embodiments, the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor or veldinexor. In some embodiments, the additional therapeutic agent is a dual inhibitor of PARP1 / 2 and tankyrase1 / 2, such as stenoparib (2X-121).In some embodiments, the additional therapeutic agent is a cyclin-dependent kinase inhibitor, such as CYC-065, CYC-202, fadracilib, or seliciclib. In some embodiments, the additional therapeutic agent is a cytosine DNA methyltransferase inhibitor, such as decitabine, azacitidine, or DUR-928. In some embodiments, the additional therapeutic agent is a DHFR inhibitor, such as methotrexate. In some embodiments, the additional therapeutic agent is a deoxyribonuclease stimulator, such as Descartes-30. In some embodiments, the additional therapeutic agent is a ribonuclease stimulator, such as ranpirnase. In some embodiments, the additional therapeutic agent is a eukaryotic initiation factor 4A1 (eIF4A1) inhibitor, such as zotatifin. In some embodiments, the additional therapeutic agent is a small ubiquitin-related modifier inhibitor, such as TAK-981. In some embodiments, the additional therapeutic agent is a ubiquitin ligase modulator, such as KPG-818. In some embodiments, the additional therapeutic agent is an integrin agonist, such as 7HP-349. In some embodiments, the additional therapeutic agent is a BET inhibitor such as apabetalone. In some embodiments, the additional therapeutic agent is a BRD4 inhibitor such as CPI-0610, ABBV-744, etc. In some embodiments, the additional therapeutic agent is an ER1 inhibitor such as tolmifen.

[0223] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of MRTX-849(G12C) and K-Ras(G12D) selective inhibitory peptides, including AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602 (Ras GTP), RT11, KRpep-2(Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0224] 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, disulfiram plus copper gluconate, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib.

[0225] 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, an inactivated vaccine (i.e., an inactivated SARS-CoV-2 vaccine), a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, a viral vector vaccine, a cellular vaccine, a dendritic cell vaccine (i.e., LV-SMENP-DCs, LV-SMENP-DCs, or AV-COVID-19), or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273, mRNA-1273.211, mRNA-1273.351, mRNA-1283, CVnCoV, DS-5670, SP-0254, ARCoV, or Nanocovax. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the therapeutic agent is a DNA vaccine such as AG301-COVID19, bacTRL-spike, GX-19, AG-0301-COVID19, ZyCoC-D, GLS-5310, or CORVax. In some embodiments, the additional therapeutic agent is a live-attenuated RSV vaccine MEDI-559, human monoclonal antibody REGN2222 against RSV, palivizumab, respiratory syncytial virus immune globulin intravenously [RSV-IGIV], or 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.For example, (i) influenza A monovalent vaccines (e.g., influenza A [H5N1] virus monovalent vaccine and influenza A [H1N1] 2009 virus monovalent vaccine), (ii) trivalent vaccines for influenza A and B viruses (e.g., Afluria, Agriflu, Flude, Fluarix, Flublox, Flucervax, Flulaval, Fluvirin, and Fluzone), and (iii) quadrivalent vaccines 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 MERS vaccine (e.g., MVA-MERS-S, VTP-500). In some embodiments, the additional therapeutic agent is a BCG vaccine. In some embodiments, the additional therapeutic agent is a recombinant protein subunit vaccine (e.g., ZF-2001), EuCorVAc-19, GBP-510, Sinopharma vaccine, SpyCatcher vaccine, SP-0253, VBI-2902, UB-612, MVC-COV1901. In some embodiments, the additional therapeutic agent is an attenuated bacterial vaccine (e.g., MV-130). In some aspects, the additional therapeutic agent is a recombinant non-replicating vaccine (e.g., JNJ784326735 (Ad26 SARS-CoV-2)). In some embodiments, the additional therapeutic agent is a poly-TLR agonist polyantigenic vaccine (e.g., Mycobacterium w). In some embodiments, the additional therapeutic agent is a QAZCOVID-IN vaccine. In some embodiments, the additional therapeutic agent is a GRAd-COV2 vaccine. In some embodiments, the additional therapeutic agent is an EpiVacCorona vaccine. In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine. In some embodiments, the additional agent is Gam-COVID-Vac (Ad26), Gam-COVID-Vac (Ad5), Gam-COVID-Vac (Ad26 prime-boost), Sputnik-Light vectored vaccine (rAd26), Covex-19, NasoVAX, NDV-HXP-S vaccine, AdCOVID, or a VSV vector-based vaccine. In some embodiments, the additional therapeutic agent is a TiterQuil-1055 adjuvanted vaccine. In some embodiments, the additional therapeutic agent is LUNAR-COV19 (ARCT-021). In some embodiments, the additional agent is TerraCoV2. In some embodiments, the additional agent is COVID-19 S-Trimer. In some embodiments, the additional agent is TNX-1810, and / or TNX-1820, and / or TNX-1830.In some embodiments, the additional agent is VaxiPatch COVID-19 vaccine. In some embodiments, the additional agent is VBI-2901. In some embodiments, the additional agent is VLA-2001. In some embodiments, the additional agent is exoVACC-SARS-CoV2. In some embodiments, the additional agent is SCB-2019. In some embodiments, the additional agent is MV-SARS-CoV-2. In some embodiments, the additional agent is NVX-CoV2373, Matrix-M, and NVX-CoV2373. In some embodiments, the additional agent is selected from the group consisting of BBV152A, B, C, PicoVac, KBP-COVID-19, MF59 adjuvant SARS-CoV-2 Sclamp, MVC-COV1901, SCB-2019 (COVID-19 S-trimer + CpG1018 + AS03), TMV-083, V-591, VPM1002, V-SARS, AdCLD-Cov19, AKS-452, BVRS-GamVac, BVRS-GamVac-Combi, CIGB-2020, COVAC-2, FINLAY-FR-1, KD-414, S-268019, T-COVID, CDX-005, COH-04S1, ABNCoV2, ERUCOV-19, fakhravac, Kocak-19 inaktif adjuvanliCOVID-19 vaccine, NBP-2001, CoVepiT, VXA-CoV2-1, CoVac-1, AT-301, LNP-nCoVsaRNA, AdimrSC-2f, BBV-154, COVID-19 XWG-03, FINLAY-FR-2, MV-014-212, MVA-SARS-2-S, RAZI Cov Pars, SPFN_1B-06-PL, V-590, Ad5-Covid-S / N, CORAL.

[0226] 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 2019-nCov 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 a PD-1 antibody. In some embodiments, the additional therapeutic agent is REGN-COV2. In some embodiments, the additional therapeutic agent is LY-CoV555. In some embodiments, the additional therapeutic agent is an anti-IL-6R mAb. For example, the additional therapeutic agent is TZLS-501 or siltuximab. In some embodiments, the additional therapeutic agent is an antibody that targets a specific site on ACE2. In some embodiments, the additional therapeutic agent is a polypeptide that targets the SARS-CoV-2 spike protein (S-protein). In some embodiments, the additional therapeutic agent is a viral suppressor factor (VSF, HzVSFv13).

[0227] 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 2019-nCov 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. In some embodiments, the additional therapeutic agent is an anti-IL-6R mAb. For example, the additional therapeutic agent is TZLS-501 or siltuximab. In some embodiments, the additional therapeutic agent is an antibody targeting a specific site on ACE2. In some embodiments, the additional therapeutic agent is a polypeptide targeting the SARS-CoV-2 spike protein (S-protein). In some embodiments, the additional therapeutic agent is a viral suppressor factor (VSF, HzVSFv13).

[0228] In some embodiments, the additional therapeutic agent is an anti-CD147 antibody. For example, the additional therapeutic agent is meplasmab. In some embodiments, the additional therapeutic agent is a phosphodiesterase type 4 (PDE4) or phosphodiesterase type 5 (PDE5) inhibitor. In some embodiments, the additional therapeutic agent is a PDE5 inhibitor, for example, the additional therapeutic agent is sildenafil. In some embodiments, the additional therapeutic agent is a PDE3 / PDE4 inhibitor, for example, the additional therapeutic agent is brilacidin and ensifentrine.

[0229] In some embodiments, the additional therapeutic agent is an agent that targets NKGA2. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor. In some embodiments, the additional therapeutic agent is an NKG2 AB-activating NK receptor antagonist, such as monalizumab. In some examples, the additional therapeutic agent is a CTLA-4 checkpoint inhibitor, such as BPI-002. In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as CPI-006 or AK-119.

[0230] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection, hi some embodiments, the additional therapeutic agent is an amnion-derived cell cytokine solution, such as ST-266.

[0231] 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 AT-527, ribavirin, favipiravir, lamivudine, galidesivir, pimodivir, and combinations thereof.

[0232] 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.

[0233] In some embodiments, the additional therapeutic agent is a β-catenin inhibitor, e.g., the additional therapeutic agent is tetradrine. In some embodiments, the additional therapeutic agent is a trypsin inhibitor, e.g., the additional therapeutic agent is urinastatin (TAK-671).

[0234] In some embodiments, the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZ1, CPI-0610, sapanisertib, rapamycin, zotatifin, veldinexor, chloroquine, dabrafenib, WDB002, sanglifehrin A, FK-506, pevonedistat, ternatin 4, 4E2RCat, tomivosertib, PS3061, IHVR-19029, captopril, lisinopril, camostat, nafamostat, chloramphenicol, tigecycline, linezolid, and combinations thereof.

[0235] In some embodiments, the additional therapeutic agent is JQ-1, RVX-208, silmitasertib, TMCB, apicidin, valproic acid, bafilomycin A1, E-52862, PD-144418, RS-PPCC, PD28, haloperidol, entacapone, indomethacin, LTX-109, MAS-825, metformin, metformin glucoside, MRG-001, Medregen, MRx-0004, thimerosal ruxolitinib, ponatinib, H-89, merimepodib, migalastat, mycophenolic acid, ribavirin, XL413, CCT365623, midostaurin, ruxolitinib, ZINC1775962367, ZINC4326719, ZINC4511851, ZINC95559591, AC-55541, AZ8838, daunorubicin, GB110, S-verapamil, AZ3451, and combinations thereof.

[0236] In some embodiments, the additional therapeutic agent is selected from the group consisting of tilorone, cyclosporine, loperamide, mefloquine, amodiaquine, proscillaridin, digitoxin, digoxin, hexachlorophene, hydroxyprogesterone caproate, salinomycin, ouabain, cepharanthine, ciclesonide, oxyclozanide, anidulafungin, gilteritinib, berbamine, tetrandrine, abemaciclib, ivacaftor, bazedoxifene, niclosamide, eltrombopag, and combinations thereof.

[0237] In some embodiments, the additional therapeutic agent is a drug that targets coronavirus main protease 3CL (e.g., lopinavir). In some embodiments, the additional therapeutic agent is a drug that targets papain-like protease PL (e.g., lopinavir). In some examples, the additional therapeutic agent is a drug that functions as a virus-host cell fusion inhibitor to prevent viral entry into host cells (e.g., arbidol). In some embodiments, the additional therapeutic agent is a TMPRSS2 inhibitor (e.g., camostat mesylate).

[0238] In some embodiments, the additional therapeutic agent is a serine protease inhibitor such as LB1148, upamostat, RHB-107, or alpha-1 antitrypsin, tranexamic acid, etc. In some embodiments, the additional therapeutic agent is a replicase polyprotein 1a inhibitor / replicase polyprotein 1 ab inhibitor / protease inhibitor / coronavirus 3C protease-like inhibitor, e.g., PF-07304814.

[0239] In some embodiments, the additional therapeutic agent is a SARS-coronavirus 3C protease-like inhibitor, such as PF-07321332. In some embodiments, the additional therapeutic agent is a MAP kinase inhibitor, such as DS-2319 or repurposed nafamostat mesylate. In some embodiments, the additional therapeutic agent is a serine protease inhibitor / transmembrane serine protease 2 inhibitor, such as nafamostat. In some embodiments, the additional therapeutic agent is a cysteine ​​protease inhibitor, such as SLV-213. In some embodiments, the additional therapeutic agent is a serine threonine protein kinase inhibitor, such as berzosertib. In some embodiments, the additional therapeutic agent is an inhibitor of neutrophil elastase, such as lonoderestat. In some embodiments, the additional therapeutic agent is an alpha-ketoamide.

[0240] In some examples, the additional therapeutic agent is a poly ADP-ribose polymerase 1 (PARP1) inhibitor, for example, the additional therapeutic agent is CVL218.

[0241] In some embodiments, the additional therapeutic agent is a 6'-fluorinated aristemicin analog, acyclovir fleximer analog, disulfiram, a thiopurine analog, ASC09F, CNM-AgZn-17, genistein, JAN-101, nitric oxide (inhaled), nitric oxide-based antiviral formulations (oral), RTD-1, PrEP-001, QBKPN, RUTI, GC376, GC813, phenylisoserine derivatives, neuroimidase inhibitor analogs, pyrithiobac derivatives, vananine and 5-hydroxychromone derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinones E-64-C and E-64-D, OC43-H R2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, S-1226, 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.

[0242] In some embodiments, the additional therapeutic agent is an anti-CD147 antibody, e.g., the additional therapeutic agent is meplasmab.

[0243] 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 viral antibody of 2019-nCoV.

[0244] In some embodiments, the antibody is ABBV-47D11. In some embodiments, the antibody is COVI-GUARD. In some embodiments, the antibody is C144-LS or C135-LS. In some embodiments, the antibody is DXP-604. In some embodiments, the antibody is JMB-2002. In some embodiments, the antibody is LY-CovMab. In some embodiments, the antibody is LY-CoV555. In some embodiments, the antibody is S309. In some embodiments, the antibody is SAB-185. In some embodiments, the antibody is SI-F019. In some embodiments, the antibody is CB6. In some embodiments, the antibody is COR-101. In some embodiments, the antibody is STI-1499. In some embodiments, the antibody is JS016. In some embodiments, the antibody is VNAR. In some embodiments, the antigen is VIR-7832 and / or VIR-7831. In some embodiments, the antibody is REGN-COV2 (casirivimab + imdevimab REGN10933 + RGN10987). In some embodiments, the antibody is BAT2020, BAT2019. In some embodiments, the antibody is 47D11. In some embodiments, the antibody cocktail is COVI-SHIELD. In some embodiments, the antibody is BRII-196, BRII-198 antibody. In some embodiments, the antibody is ADG-20. In some embodiments, the antibody is ABP-300. In some embodiments, the antibody is BI-767551. In some embodiments, the antibody is GSK-4182136. In some embodiments, the antibody is AZD-7442. In some embodiments, the antibody is regdanvimab. In some embodiments, the antibody is etesevimab. In some embodiments, the antibody is SAB-301. In some embodiments, the antibody is AOD-01. In some embodiments, the antibody is COVI-AMG. In some embodiments, the antibody is MW-33. In some embodiments, the antibody is DXP-593.In some embodiments, the antibody is BSVEQAb. In some embodiments, the coronavirus is anti-SARS-CoV-2 IgY. In some embodiments, the antibody is COVID-EIG. In some embodiments, the antibody is CSL-760. In some embodiments, the antibody is REGN-3048-3051. In some embodiments, the antibody is ADM-03820. In some embodiments, the antibody is HFB-30132A. In some embodiments, the additional therapeutic agent is an anti-hemolysin alpha antibody, such as tosatoxumab. In some embodiments, the additional therapeutic agent is the anti-LPS antibody IMM-124-E. In some embodiments, the antibody is INM-005, SCTA01, TY-027, XAV-19.

[0245] In some embodiments, the additional therapeutic agent is a steroid, e.g., a corticosteroid, hi some embodiments, the additional therapeutic agent is dexamethasone.

[0246] The compositions of the invention may also be used in combination with other active ingredients. For the treatment of 2019-nCoV virus infection, preferably, the other active therapeutic agent is active against coronavirus infection, e.g., 2019-nCoV virus infection. The compounds and compositions of the invention may also be used in combination with parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (such as metronidazole, amphotericin B, amoxicillin / clavulanate, trimethoprim / sulfamethoxazole, and cephalosporin antibiotics, e.g., 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., interferon), and the like. The additional therapeutic agent is intended for use in conjunction with general care provided to patients with 2019-nCoV virus infection, including other small molecule or biological antivirals targeting 2019-nCoV (such as, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, analgesics, and drugs for other common illnesses in the patient population, such as antimalarials (including artemether and artemether-lumefantrine combination therapy), typhoid fever (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is molnupiravir. In some embodiments, the additional therapeutic agent is AT-527. In some embodiments, the additional therapeutic agent is PF-07321332. In some examples, the additional therapeutic agent is a corticosteroid, for example, the additional therapeutic agent is ciclesonide.

[0247] In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as Panaphix (PAX-1), which inhibit the production of pro-inflammatory cytokines. In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as NCP-112, which inhibit excessive immune responses, such as cytokine storm.

[0248] In some embodiments, the additional therapeutic agent is an antifungal agent, such as itraconazole or 17-OH-itraconazole.

[0249] In some embodiments, the additional therapeutic agent is an immune modulator. Examples of immune system therapeutic agents include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators (i.e., nivolumab); programmed death-ligand 1 (Pd-L1) modulators (i.e., camrelizumab, penicillin-1, cerebrospinal fluid (PEF)-1, cerebrospinal fluid (CFU ... brolizumab); IL-15 modulators, DermaVir; interleukin-7 modulators (i.e., efentakine alfa, plaquenil (efmarodocoxin), (CYT-107); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivatives; mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (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, pegylated interferon lambda-1a, 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. In some embodiments, the additional therapeutic agent is CD24Fc.In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anakinra, astegolimab (MSTT1041A, RG-6149), or UTTR1147A.

[0250] In some embodiments, the additional therapeutic agent is Ampligen. In some embodiments, the additional therapeutic agent is lefitolimod. In some embodiments, the additional therapeutic agent is Gamnex. In some embodiments, the additional therapeutic agent is a CD3 antagonist such as foralaumab. In some embodiments, the additional therapeutic agent is a KEAP1 modulator such as SFX-01. In some embodiments, the additional therapeutic agent is a PARP inhibitor such as BGP-15. In some embodiments, the additional therapeutic agent is octagam. In some embodiments, the additional therapeutic agent is RPH-104. In some embodiments, the additional therapeutic agent is canakinumab. In some embodiments, the additional therapeutic agent is a leukocyte Ig-like receptor A4 modulator such as daxudilimab. In some embodiments, the additional therapeutic agent is a melanocortin MC1 receptor agonist such as PL-8177. In some embodiments, the additional therapeutic agent is an IL-33 ligand inhibitor such as MEDI3506. In some embodiments, the additional therapeutic agent is an IL-5 receptor antagonist such as mepolizumab. In some embodiments, the additional therapeutic agent is an IL-12 / IL23 inhibitor, such as apilimod or apilimod dimesylate. In some embodiments, the additional therapeutic agent is an IL-15 receptor agonist, such as N-803. In some embodiments, the additional therapeutic agent is an IL-18 ligand inhibitor, such as tadekinig alfa. In some embodiments, the additional therapeutic agent is an IL-22 agonist, such as efmarodocoquin alfa or F-652. In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab.

[0251] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, olokizumab, sirumab, clazakizumab, revilimab, or a combination thereof. In some embodiments, the additional therapeutic agent is a tocilizumab biosimilar (e.g., CMAB-806).

[0252] In some embodiments, the additional therapeutic agent is an apolipoprotein B modulator / IL-6 receptor antagonist / serum amyloid A protein modulator / transthyretin modulator. For example, the additional therapeutic agent is amylo-5MER.

[0253] In some embodiments, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, e.g., the additional therapeutic agent is AP-1189.

[0254] In some embodiments, the additional therapeutic agent is an NLRP3 inflammasome inhibitor, hi some embodiments, the additional therapeutic agent is dapanstril, DFV-890.

[0255] In some embodiments, the additional therapeutic agent is a nicotinamide phosphoribosyltransferase inhibitor, e.g., the additional therapeutic agent is enamptcumab.

[0256] In some embodiments, the additional therapeutic agent is a dipeptidase 1 (DPEP-1) inhibitor. For example, the additional therapeutic agent is Metablok (LSALT peptide).

[0257] 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.

[0258] In some embodiments, the additional therapeutic agent is a JAK inhibitor, e.g., the additional therapeutic agent is baricitinib, filgotinib, Olumiant, TD-0903, or a combination thereof. In some examples, the additional therapeutic agent is jactinib.

[0259] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, such as pirfenidone or LYT-100.

[0260] In some embodiments, the additional therapeutic agent is an anti-inflammatory agent such as dosiparstat sodium, eicosapentaenoic acid, didodecyl methotrexate, raveximode, or EG-009.

[0261] In some embodiments, the additional agent is a TREM receptor 1 antagonist used in the treatment of septic shock, such as nangibotide.

[0262] In some embodiments, the additional therapeutic agent is a CCR1 antagonist, such as MLN-3897. In some embodiments, the additional therapeutic agent is a complement C3 inhibitor, such as NGM-621 or AMY-101. In some embodiments, the additional therapeutic agent is a complement C1s subcomponent inhibitor, such as RLS-0071. In some embodiments, the additional therapeutic agent is a complement factor C2 modulator, such as ARGX-117. In some embodiments, the additional therapeutic agent is a galectin-3 inhibitor, such as belapectin. In some embodiments, the additional therapeutic agent is a heparanase inhibitor, such as tridecasodium pixatimod sodium. In some embodiments, the additional therapeutic agent is an anti-MASP2 antibody, such as narsoplimab. In some embodiments, the additional therapeutic agent is a calcium channel modulator, such as dantrolene sodium. In some embodiments, the additional therapeutic agent is a calcium channel stimulator, such as solnatide. In some embodiments, the additional therapeutic agent is an alkaline phosphatase stimulator, such as bovine alkaline phosphatase. In some embodiments, the additional therapeutic agent is a complement factor D inhibitor, such as ACH-0144471. In some embodiments, the additional therapeutic agent is an NK1 antagonist, such as LY-686017. In some embodiments, the additional therapeutic agent is a zonulin inhibitor, such as larazotide acetate. In some embodiments, the additional therapeutic agent is an aryl hydrocarbon receptor agonist / stem cell antigen-1 inhibitor, such as amphotericin. In some embodiments, the additional therapeutic agent is a dual complement factor C5 / leukotriene BLT receptor antagonist, such as nomacopan. In some embodiments, the additional therapeutic agent is a superoxide dismutase stimulator, such as avasopasem manganese. In some embodiments, the additional therapeutic agent is an opioid receptor antagonist, such as naltrexone. In some embodiments, the additional therapeutic agent is an opioid receptor agonist, such as metenkefalin. In some embodiments, the additional therapeutic agent is a BMP10 / BMP15 gene inhibitor, such as lucinactant.In some embodiments, the additional therapeutic agent is an actin antagonist such as gelsolin. In some embodiments, the additional therapeutic agent is a CD95 antagonist such as asnercept. In some embodiments, the additional therapeutic agent is a fractalkine ligand (CX3CL1) inhibitor such as quetomoliimab. In some embodiments, the additional therapeutic agent is a platelet glycoprotein VI (GPVI)I inhibitor such as glenzocimab. In some embodiments, the additional therapeutic agent targets IKKβ and NFκβ, such as OP-101. In some embodiments, the additional therapeutic agent is a glucocorticoid receptor agonist such as hydrocortisone, dexamethasone, or dexamethasone phosphate. In some embodiments, the additional therapeutic agent is a PDGF receptor antagonist / TGFβ receptor antagonist / p38 MAP kinase inhibitor such as dupirfenidone. In some embodiments, the additional therapeutic agent is a PGD2 antagonist such as asapiprant. In some embodiments, the additional therapeutic agent is a prostaglandin E synthase-1 inhibitor, such as sonlichromanol hydrochloride. In some embodiments, the additional therapeutic agent is a superoxide dismutase modulator, such as tempol. In some embodiments, the additional therapeutic agent is a TLR-4 antagonist, such as REVTx-99. In some embodiments, the additional therapeutic agent is a TLR-2 / TLR-4 antagonist, such as VB-201. In some embodiments, the additional therapeutic agent is a TLR-7 / TLR-8 antagonist, such as M-5049. In some embodiments, the additional therapeutic agent is an immunosuppressant, such as tacrolimus, BXT-10, ibudilast, FP-025, apremilast, abatacept, crizanlizumab, itolizumab, bardoxolone methyl, or M-5049. In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor, such as DNL-758. In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist, such as BMS-986253 (HuMax-IL8), DF-1681 (reparixin), etc. In some embodiments, the additional therapeutic agent is a CD14 inhibitor, such as IC-14, atibuclimab, etc.

[0263] In some embodiments, the additional therapeutic agent is a cyclophilin A inhibitor, such as CRV-431. In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase (DHODH) inhibitor, such as brequinar, PCT-299, or ASLAN-003. In some embodiments, the additional therapeutic agent is a G protein-coupled bile acid receptor 1 agonist (GPCR19) agonist, such as HY-209. In some embodiments, the additional therapeutic agent is a Grp78 calcium-binding protein inhibitor / Jun N-terminal kinase inhibitor / transferrin modulator / p38 MAP kinase modulator, such as IT-139. In some embodiments, the additional therapeutic agent is a histone deacetylase-6 (HDAC-6) inhibitor, such as CKD-506. In some embodiments, the additional therapeutic agent is a Lyn tyrosine kinase stimulator, such as trimidone. In some embodiments, the additional therapeutic agent is a Tek tyrosine kinase receptor stimulator, such as AV-001. In some embodiments, the additional therapeutic agent is an integrin α-V / β-1 and α-V / β-6 antagonist, such as PLN-74809. In some embodiments, the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, such as PF-06650833.

[0264] In some embodiments, the additional therapeutic agent is a kallikrein inhibitor / KLKB1 gene inhibitor, such as IONIS-PKK-LRx. In some embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor, such as alverestat or lonoderestat acetate. In some embodiments, the additional therapeutic agent is a Maxi-K potassium channel inhibitor, such as ENA-001. In some embodiments, the additional therapeutic agent is a nuclear factor κB inhibitor / p38 MAP kinase inhibitor, such as GLS-1027. In some embodiments, the additional therapeutic agent is a nuclear factor κB inhibitor, such as timbetasin or liposomal curcumin. In some embodiments, the additional therapeutic agent is an antifibrotic agent, such as RT-1840, nintedanib, GB-0139, nintedanib, or pamrevlumab. In some embodiments, the additional therapeutic agent is a hepatocyte growth factor (HGF) mimetic, such as SNV-003 (ANG-3777). In some embodiments, the additional therapeutic agent is an A3 adenosine receptor (A3AR) antagonist, for example, the additional therapeutic agent is piclidenoson.

[0265] 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., azilomycin, clarithromycin, and mycoplasma pneumoniae), a fluoroquinolone (e.g., ciprofloxacin, besifloxacin, and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof. In some embodiments, the antibiotic is XEL 1004. In some embodiments, the antibiotic is eravacycline.

[0266] In some embodiments, the additional therapeutic agent is a bactericidal permeability protein inhibitor / outer membrane protein inhibitor, such as RECCE-327.

[0267] 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 individual. 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.

[0268] In some embodiments, a compound disclosed herein is used in combination with immune globulin derived from a cured COVID-19 patient. In some embodiments, a compound disclosed herein is used in combination with plasma transfusion. In some embodiments, a compound disclosed herein is used in combination with stem cells. In some embodiments, a compound disclosed herein is used in combination with plasma-derived anti-SARS-CoV-2 IgG. In some embodiments, a compound disclosed herein is used in combination with TAK-888, NP-028 (anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG)), or GC-5131A. In some embodiments, a compound disclosed herein is used in combination with COVID-19 convalescent plasma or immune globulin. In some embodiments, a compound disclosed herein is used in combination with stem cells. For example, in some embodiments, the compounds disclosed herein are used in combination with AdMSCs, ADR-001, allo-hMSCs, CAP-1002, hCT-MSCs, HB-adMSCs, itMSCs, MultiStem, Pluristem, Remestemcel-L (mesenchymal stem cells), NurOwn®, Rexlemestrocel-L, UCMSCs, or ACT-20.

[0269] 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, MT-2766, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, and RO-7020531. In some embodiments, the additional therapeutic agent is PUL-042.

[0270] In some embodiments, the additional therapeutic agent is selected from the group consisting of AVM-0703, bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, crividipine, atorvastatin, trimodulin, rosuvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.

[0271] 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).

[0272] In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2), e.g., alumasedase alfa (APN-01), HLX-71. In some embodiments, the additional therapeutic agent is an angiotensin II receptor agonist. In some examples, the additional therapeutic agent is an AT2 partial agonist or an AT1 partial antagonist. In some embodiments, the additional therapeutic agent is L-163491. In some embodiments, the additional therapeutic agent is valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan. In some embodiments, the additional therapeutic agent is VP-01, TXA-127. In some embodiments, the additional therapeutic agent is telmisartan.

[0273] In some embodiments, the additional therapeutic agent is an ACE inhibitor such as ramipril, captopril, enalapril, lisopril, etc. In some embodiments, the additional therapeutic agent is an angiotensin II AT-1 receptor antagonist / β-arrestin stimulator such as TRV-027.

[0274] In some embodiments, the additional therapeutic agent is an ACE2 inhibitor / COVID19 spike glycoprotein inhibitor such as MP-0420. In some embodiments, the additional therapeutic agent is a caspase inhibitor such as emricasan. In some embodiments, the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor such as ADX-629. In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor such as RP-7214.

[0275] In some embodiments, the additional therapeutic agent is a protein tyrosine kinase inhibitor, such as a dihydroorotate dehydrogenase inhibitor or repurposed leflunomide. In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as AT-001. In some embodiments, the additional therapeutic agent is a platelet inhibitor. For example, the additional therapeutic agent is dipyridamole. In some embodiments, the additional therapeutic agent is an anticoagulant, such as heparin (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparinux. In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201. In some embodiments, the additional therapeutic agent is a factor XIIa antagonist, such as galadacumab. In some embodiments, the additional therapeutic agent is a factor XIa antagonist, such as EP-7041. In some embodiments, the additional therapeutic agent is a VE-PTP inhibitor, such as razuprotafib. In some embodiments, the additional therapeutic agent is a VIP2 receptor agonist, such as PB-1046. In some embodiments, the additional therapeutic agent is an antithrombotic agent, such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, tranexamic acid, or tenecteplase. In some embodiments, the additional therapeutic agent is a vasodilator, such as iloprost, bentaprost, bazegepant, angiotensin I-7, ambrisentan, NORS, pentoxifylline, propranolol, RESP301, sodium nitrite, or TRV-027. In some embodiments, the additional therapeutic agent is a coagulation modulator, such as lanadelumab.

[0276] In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone. In some embodiments, the additional therapeutic agent is an antihypoxic agent, such as trans-sodium crocetinate. In some embodiments, the additional therapeutic agent is MK-5475. In some embodiments, the additional therapeutic agent is a hypoxia-inducible factor (HF) prolyl hydroxylase-2 (PHD-2) inhibitor, such as desidustat or vadadustat. In some embodiments, the additional therapeutic agent is a renin inhibitor, such as aliskiren. In some embodiments, the additional therapeutic agent is a calcium channel inhibitor, such as nifedipine. In some embodiments, the additional therapeutic agent is a chelating agent, such as desferal, deferiprone, or deferoxamine. In some embodiments, the additional therapeutic agent is a retinoic acid receptor agonist, such as isotretinoin or fenrenide. In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurosin (Nanomedivir). In some embodiments, the additional therapeutic agent is a human antimicrobial peptide, such as LL-37i. In some embodiments, the additional therapeutic agent is a microbiome modulator, such as EDP-1815 or KB-109. In some embodiments, the additional therapeutic agent is an estrogen receptor antagonist, such as tamoxifen. In some embodiments, the additional therapeutic agent is an estrogen receptor modulator, such as estetrol. In some embodiments, the additional therapeutic agent is an androgen receptor antagonist, such as bicalutamide, enzalutamide, or proxalamide. In some embodiments, the additional therapeutic agent is a GNRH receptor antagonist, such as degarelix. In some embodiments, the additional therapeutic agent is a sex hormone modulator, such as dutasteride. In some embodiments, the additional therapeutic agent is a thyroid hormone modulator, such as sobetirome. In some embodiments, the additional therapeutic agent is a carpene inhibitor, such as BLD-2660.In some embodiments, the additional therapeutic agent is a GM-CSF ligand inhibitor, such as gimsilumab, lenzilumab, namilumab, TJM2, otilimab, or plonmarlimab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor antagonist, such as mavrilimumab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim. In some embodiments, the additional therapeutic agent is an alpha 1 adrenergic receptor antagonist, such as prazosin. In some embodiments, the additional therapeutic agent is a neuropilin 2 inhibitor, such as ATYR-1923.

[0277] In some embodiments, the additional therapeutic agent is a calcium activated calcium channel (CRAC) channel inhibitor, such as CM-4620. In some embodiments, the additional therapeutic agent is a calcium activated chloride channel (CACC) inhibitor, such as crofelemer. In some embodiments, the additional therapeutic agent is a proto-oncogene Mas agonist, such as BIO101. In some embodiments, the additional therapeutic agent is a DPP4 inhibitor, such as saxagliptin, sitagliptin, alogliptin, or linagliptin. In some embodiments, the additional therapeutic agent is a glucose cotransporter type 2 (SGLT-2) inhibitor, such as dapagliflozin propanediol. In some embodiments, the additional therapeutic agent is a fractalkine receptor inhibitor, such as KAND-567. In some embodiments, the additional therapeutic agent is an alpha-2 receptor agonist. For example, the additional therapeutic agent is dexmedetomidine. In some embodiments, the additional therapeutic agent is an mCBM40 (multivalent carbohydrate binding module family 40 domain) product, for example, the additional therapeutic agent is pneumifil. In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine or tranilast. In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine. In some embodiments, the additional therapeutic agent is an antihistamine, such as chloroperastine or clemastine. In some embodiments, the additional therapeutic agent is a vasoactive intestinal peptide receptor 1 agonist, such as aviptadil. In some embodiments, the additional therapeutic agent is a drug to treat respiratory distress syndrome (ARDS), such as FX-06. In some embodiments, the additional therapeutic agent is BIO-11006.

[0278] In some embodiments, the additional therapeutic agent is sodium pyruvate. In some embodiments, the additional therapeutic agent is LEAF-4L6715, LEAF-4L7520. In some embodiments, the additional therapeutic agent is a respiratory stimulant, such as almitrine. In some embodiments, the additional therapeutic agent is a bronchodilator, such as brensocatib or formoterol. In some embodiments, the additional therapeutic agent is a beta-2 adrenergic receptor agonist, such as salmeterol. In some embodiments, the additional therapeutic agent is a hyaluronidase inhibitor, such as astodrimer. In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as CERC-002. In some embodiments, the additional therapeutic agent is a CRAC (calcium release-activated calcium) channel inhibitor, such as CM-4620-IE. In some embodiments, the additional therapeutic agent is a TLR4 inhibitor, such as EB-05, NI-0101, or E-5564. In some embodiments, the additional therapeutic agent is a desoxyribonuclease I stimulator, such as GNR-039. In some embodiments, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine. In some embodiments, the compounds described herein are used in combination with respiratory-specific small interfering RNA therapy. In some embodiments, these therapies are delivered by nebulizer. In some embodiments, the additional therapeutic agent is a vimentin modulator. For example, the additional therapeutic agent is pritumumab, hzVSF-v13. In some embodiments, the additional therapeutic agent is a modulator of Nsp15 (nonstructural protein 15), such as benzopurpurin B, C-467929, C-473872, AB001, NSC-306711, and N-65828.

[0279] In some embodiments, the additional therapeutic agent is a xanthine dehydrogenase inhibitor, such as oxypyrinol (XRx-101). In some embodiments, the additional therapeutic agent is a xanthine oxidase inhibitor, such as bucillamine or Xrx-101. In some embodiments, the additional therapeutic agent is a cathepsin inhibitor, such as VBY-825 or ONO-5334. In some embodiments, the additional therapeutic agent is a transforming growth factor beta (TGF-β) inhibitor. For example, the additional therapeutic agent is OT-101. In some embodiments, the additional therapeutic agent is an N-methyl-D-aspartate (NMDA) receptor antagonist. For example, the additional therapeutic agent is ifenprodil or trans-crocetin. In some embodiments, the additional therapeutic agent is a glycogenolysis inhibitor. For example, the additional therapeutic agent is WP-1122. In some embodiments, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast. In some embodiments, the additional therapeutic agent is a leukotriene BLT receptor antagonist, such as ebselen. In some embodiments, the additional therapeutic agent is a tubulin inhibitor, such as VERU-111 or colchicine. In some embodiments, the additional therapeutic agent is a glucosylceramide synthase inhibitor, such as miglustat. In some embodiments, the additional therapeutic agent is an Nrf2 activator, such as PB125. In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as ABX464. In some embodiments, the additional therapeutic agent is a nuclear import inhibitor, such as iCP-NI (CV-15). In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as PPP003. In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as LSALT peptide. In some embodiments, the additional therapeutic agent is a cyclooxygenase inhibitor, such as celecoxib, naproxen, or aspirin / dipyridamole. In some embodiments, the additional therapeutic agent is an antitoxin, such as CAL02. In some embodiments, the additional therapeutic agent is a nitric oxide stimulator, such as GLS-1200.

[0280] In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064. In some embodiments, the additional therapeutic agent is a complement inhibitor, such as ravulizumab. In some embodiments, the additional therapeutic agent is a colony-stimulating factor 1 receptor (CSF1R) inhibitor, such as abduralimab or axatilimab. In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab or zilucoplan, or a complement C5a factor inhibitor, such as BDB-001, IFX-1, or advallimab. In some embodiments, the additional therapeutic agent is a complement C1s inhibitor, such as conestat. In some embodiments, the additional therapeutic agent is a C3 inhibitor, such as APL-9 or AMY-101. In some embodiments, the additional therapeutic agent is an anti-C5aR antibody, such as advolalimab or vilobelimab. In some embodiments, the additional therapeutic agent is an anti-elongation factor 1 alpha 2 inhibitor, such as plitidepsin. In some embodiments, the additional therapeutic agent is an angiopoietin ligand-2 inhibitor, such as LY-3127804. In some embodiments, the additional therapeutic agent is a lysine-specific histone demethylase 1 inhibitor, such as vafidemstat. In some embodiments, the additional therapeutic agent is a histone inhibitor, such as STC-3141. In some embodiments, the additional therapeutic agent is a hyaluronic acid inhibitor. In some embodiments, the additional therapeutic agent is a dopamine D2 receptor antagonist, such as chlorpromazine. In some embodiments, the additional therapeutic agent is a proton pump inhibitor, such as omeprazole. In some embodiments, the additional therapeutic agent is a PGI2 antagonist, such as epoprostenol. In some embodiments, the additional therapeutic agent is a plasminogen activator 1 inhibitor, such as TM-5614. In some embodiments, the additional therapeutic agent is a ubiquinol cytochrome C reductase 14 kDa inhibitor, such as telacevec.

[0281] 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 2004 / 112687, WO 2006 / 135978, WO 2018 / 145148, and WO 2009 / 018609.

[0282] In some embodiments, the additional therapeutic agent is a cell therapy such as allogeneic natural killer cells, antigen-presenting cells (APCs), invariant natural killer T (iNKT) cells, induced pluripotent stem cells (iPSCs), allogeneic T cells, autologous adipose-derived mesenchymal stem cells, allogeneic bone marrow-derived mesenchymal stem cells, allogeneic mesenchymal hemangioblast-derived mesenchymal stem cells, regulatory T cells (Tregs), dendritic cells, etc. In some embodiments, the additional therapeutic agent is a SARS-CoV-2-specific cytotoxic T lymphocyte. In some embodiments, the additional therapeutic agent is agenT-797, Allocetra, ALVR-109, BM-Allo.MSC, BM-Allo-MSC, CAStem, Cellgram-AKI, CK-0802, CL-2020, IL-15-NK cells, NKG2DCAR-NK cells, ACE2 CAR-NK cells, DWP-710, partially HLA-matched virus-specific T cells (VST), FT-516, RAPA-501, SARS-CoV-2-specific T cells, HLCM-051, ExoFlo, HCR-040, it-hMSC, KI-MSC-PL-205, ORBCEL-C, pathogen-specific aAPC, ProTrans, SBI-101, StemVacs, STI-8282, taniraleucel, UMSC-01.

[0283] In some embodiments, the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZ1, CPI-0610, sapanisertib, rapamycin, zotatifin, veldinexor, chloroquine, dabrafenib, WDB002, sanglifehrin A, FK-506, pevonedistat, ternatin 4, 4E2RCat, tomivosertib, PS3061, IHVR-19029, XC-7, long-acting injectable ivermectin, captopril, lisinopril, camostat, chloramphenicol, tigecycline, linezolid, and combinations thereof.

[0284] In some embodiments, the additional therapeutic agent is selected from the group consisting of tilorone, cannabidiol, cyclosporine, loperamide, mefloquine, amodiaquine, proscillaridin, digitoxin, digoxin, hexachlorophene, hydroxyprogesterone caproate, salinomycin, ouabain, cepharanthine, ciclesonide, oxyclozanide, anidulafungin, gilteritinib, berbamine, tetrandrine, abemaciclib, ivacaftor, bazedoxifene, niclosamide, eltrombopag, and combinations thereof.

[0285] 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, ISPM-19, cypargamine, artemisone, and combinations thereof.

[0286] 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 patient. 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.

[0287] 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 patient's body.

[0288] 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., administration of a compound of the present disclosure within seconds, minutes, or hours of administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the present disclosure can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a compound of the present disclosure. In some cases, it 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.

[0289] 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, an effective dosage of each active ingredient is 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. 1. Combination therapy for the treatment of pneumoviridae

[0290] The compounds provided herein may also be used in combination with other active therapeutic agents. In the case of treating Pneumoviridae virus infections, preferably, the other active therapeutic agent is active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. Non-limiting examples of these other active therapeutic agents against RSV include ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and presatovir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAb; and viral replication inhibitors such as nitazoxanide.

[0291] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of RSV, including, but not limited to, MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI δM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccines.

[0292] 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.

[0293] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines. 2. Combination therapy for the treatment of Picornaviridae

[0294] The compounds provided herein can also be used in combination with other active therapeutic agents.When treating Picornaviridae virus infections, preferably, the other active therapeutic agents are active against Picornaviridae virus infections, particularly enterovirus infections.Non-limiting examples of these other active therapeutic agents include capsid binding inhibitors, such as pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (U.S. Patent No. 7,078,403) and Watson (U.S. Patent No. 7,166,604); fusion sialidase proteins such as DAS-181; capsid protein VP1 inhibitors such as VVX-003 and AZN-001; viral protease inhibitors such as CW-33; phosphatidylinositol 4 kinase β inhibitors such as GSK-480 and GSK-533; anti-EV71 antibodies.

[0295] 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. 3. Combination therapy for respiratory infections

[0296] Most infections caused by Pneumoviridae and Picornaviridae viruses are respiratory infections.Therefore, additional active therapeutic agents used to treat respiratory symptoms and sequelae of infections can be used in combination with the compounds provided herein.The additional agents are preferably administered orally or by direct inhalation.For example, other preferred additional therapeutic agents that can be combined with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids. Glucocorticoids

[0297] 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 treatment (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 may 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

[0298] 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, signaling pathways that are key points for anti-inflammatory therapeutic intervention (see review by PJBarnes, 2006).These additional therapeutic agents include, but are not limited to, 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)-cyclohexanecarboxylic acid 2-diethyl 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

[0299] 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.

[0300] Combinations of inhaled β2-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 β2-adrenergic receptor agonists with the compounds provided herein are also suitable, but not limited to, combinations useful for treating respiratory viral infections.

[0301] Other examples of β2 adrenergic receptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abesiterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471. Anticholinergic drugs

[0302] Anticholinergic agents may be useful for the treatment or prevention of pulmonary bronchoconstriction and, therefore, are 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); 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); );2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (revatropate);2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (darifenacin);4-azepan-1-yl-2,2-diphenyl-butyramide (buzepide);7-[3-( 2-Diethylamino-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] 3-[2-(2-diethylamino-acetoxy)-2,2-dithiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (acridinium-N,N-diethylglycinate); or (2-diethylamino-acetoxy)-dithiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; rebefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, bencycloquidium bromide, but are not limited to these. mucolytics

[0303] 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.

[0304] Nebulized hypertonic saline is used to improve the immediate and long-term clearance of small airways in patients 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, about 3% hypertonic saline is used. 4. Combination Therapy for the Treatment of Flaviviridae Virus Infections

[0305] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In the case of treating Flaviviridae infections, preferably the other active therapeutic agent is active against Flaviviridae infections.

[0306] For the treatment of dengue virus infection, non-limiting examples of other active therapeutic agents are host cell factor modulators such as GBV-006; fenretinide ABX-220, BRM-211; α-glucosidase 1 inhibitors such as celgosivir; platelet activating factor receptor (PAFR) antagonists such as modipafant; cadherin-5 / factor Ia modulators such as FX-06; NS4B inhibitors such as JNJ-8359; viral RNA splicing modulators such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0307] 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, rDEN2δ30-7169; and DENV-1 PIV. 5. Combination Therapy for the Treatment of Flaviviridae Virus Infections

[0308] The compounds provided herein may also be used in combination with other active therapeutic agents. In the case of treatment of Filoviridae infections, preferably the other active therapeutic agent is active against Filoviridae infections, particularly Marburg virus infection, Ebola virus infection, and Cueva virus infection. Non-limiting examples of these other active therapeutic agents include ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma, and 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), TKM-Ebola, 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), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cell factor modulators such as GMV-006; cadherin-5 / factor Ia modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0309] Other non-limiting active therapeutic agents active against Ebola include 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).

[0310] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, including, but 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.

[0311] 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.

[0312] The compounds provided herein are also intended for use in combination with the general care provided to patients 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 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 medications for other common illnesses in the patient population, such as shigellosis. IX. Compound Preparation

[0313] In some embodiments, the present disclosure provides processes and intermediates useful for preparing the compounds provided herein, or pharmaceutically acceptable salts thereof.

[0314] The compounds described herein can be purified by any of the techniques known in the art, including chromatographic techniques such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0315] 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," 4th 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.

[0316] Exemplary chemicals useful in the methods of the embodiments will now be described 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.

[0317] Although the methods of the present disclosure generally provide a particular 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.

[0318] Representative syntheses of compounds of the present disclosure are described in the following schemes and specific examples below. [Example]

[0319] Intermediate 1-1: tert-butyl (R)-2,2-dimethyl-4-((octadecyloxy)methyl)oxazolidine-3-carboxylate: [ka] Sodium hydride (60 wt% dispersion in mineral oil, 1.58 g, 40 mmol) was added to a vigorously stirred solution of tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (3.05 g, 13.2 mmol) in N,N-dimethylformamide (25 mL) at 0 °C. After 40 min, a solution of 1-bromooctadecane (11.0 g, 33.0 mmol) in tetrahydrofuran (10 mL) was added via syringe, and the resulting mixture was allowed to warm to room temperature. After 58 h, saturated aqueous ammonium chloride (25 mL) and diethyl ether (450 mL) were added sequentially. The organic layer was washed with water (2 × 400 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 15% ethyl acetate in hexanes) to give Intermediate 1-1. LCMS: 478.4 [M+Na] + . Intermediate 1-2: (S)-2-amino-3-(octadecyloxy)propan-1-ol: [ka]

[0320] A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 9.15 mL, 37 mmol) was added via syringe to a stirred solution of intermediate 1-1 (4.80 g, 9.92 mmol) in 1,4-dioxane (21.6 mL) and water (0.62 mL) at 0 °C. After 1 min, the resulting mixture was warmed to room temperature. After 4 h, saturated aqueous sodium carbonate (30 mL), diethyl ether (300 mL), and tetrahydrofuran (300 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 2 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 1-2. LCMS: 344.3. Intermediate 1-3: (S)-2-(isoindolin-2-yl)-3-(octadecyloxy)propan-1-ol: [ka]

[0321] Phthalaldehyde (36.1 mg, 269 μmol) was added to a vigorously stirred solution of Intermediate 1-2 (84.0 mg, 244 μmol) in dichloromethane (3.5 mL) at room temperature. After 2 minutes, sodium triacetoxyborohydride (259 mg, 1.22 mmol) was added, and the resulting mixture was heated to 60°C. After 80 minutes, the resulting mixture was cooled to room temperature, and saturated aqueous sodium carbonate (6 mL) and water (15 mL) were added sequentially. The aqueous layer was extracted with dichloromethane (2 × 25 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), and the resulting mixture was stirred and cooled to 0°C. Lithium aluminum hydride solution (2.0 M in tetrahydrofuran, 700 μL, 1.4 mmol) was added via syringe over 1 minute, and the resulting mixture was allowed to warm to room temperature over 4 minutes. The resulting mixture was heated to 60°C. After 15 hours, the resulting mixture was heated to 70°C. After 3.5 hours, the resulting mixture was cooled to 0°C, and water (55 μL), aqueous sodium hydroxide (2.0 M, 110 μL), and water (110 μL) were added sequentially. The resulting suspension was filtered through Celite, and the filter cake was extracted sequentially with ethyl acetate (20 mL) and dichloromethane (20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (0-10% methanol in dichloromethane) to give Intermediate 1-3. LCMS: 446.3. Intermediate 1-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-(isoindolin-2-yl)-3-(octadecyloxy)propyl)phosphate: [ka]

[0322] 2-Chlorophenyl phosphorodichloridate (19.6 μL, 121 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (16.8 mg, 244 μmol), triethylamine (34.0 μL, 244 μmol), and tetrahydrofuran (0.3 mL) at room temperature. After 35 min, intermediate 1-4 (34.8 mg, 105 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (9.7 μL, 121 μmol) were added sequentially. After 60 min, a solution of intermediate 1-3 (40.7 mg, 91.3 μmol) in tetrahydrofuran (1.0 mL) was added via syringe. After 223 min, 1-(mesitylsulfonyl)-3-nitro-1H-1,2,4-triazole (27.1 mg, 91.3 μmol) and triethylamine (40.0 μL, 287 μL) were added sequentially. After 13 h, saturated aqueous sodium bicarbonate (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% methanol in dichloromethane) to give intermediate 1-5. LCMS: 949.5. Example 1: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(isoindolin-2-yl)-3-(octadecyloxy)propyl)hydrogenphosphate (1): [ka]

[0323] Potassium trimethylsilanolate (38.0 mg, 296 μmol) was added to a vigorously stirred solution of intermediate 1-5 (47.6 mg, 50.1 μmol) in tetrahydrofuran (0.7 mL) at room temperature. After 48 min, concentrated hydrochloric acid (300 μL, 3.6 mmol) was added via syringe. After 60 min, the resulting mixture was purified by reverse-phase preparative HPLC (acetonitrile / water with 0.1% trifluoroacetic acid) to give compound 1. 1 H NMR (400MHz, methanol-d4) δ7.95(s,1H),7.40(s,4H),7.06(d,J=4.6Hz,1H),7.00(d,J=4.7Hz,1H),4.97-4.73(m,5H),4.42-4.34 (m,1H),4.24-4.05(m,5H),3.90-3.71(m,3H),3.50-3.40(m,2H),1.67-1.47(m,2H),1.38-1.21(m,30H),0.92(t,J=6.8Hz,3H). LCMS:799.3. Intermediate 2-1: (S)-2-(methylamino)-3-(octadecyloxy)propan-1-ol: [ka]

[0324] A vigorously stirred mixture of Intermediate 1-2 (520 mg, 1.51 mmol) and ethyl formate (20 mL) was heated to 72 °C. After 43 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was azeotropically dried by concentrating from toluene (2 × 5 mL) under reduced pressure. The residue was dissolved in tetrahydrofuran, and the resulting mixture was cooled to 0 °C and stirred. Lithium aluminum hydride solution (2.0 M in tetrahydrofuran, 3.80 mL, 7.6 mmol) was added via syringe over 2 min. After 2 min, the resulting mixture was heated to 61 °C. After 16.5 h, the resulting mixture was cooled to 0 °C, and water (302 μL), aqueous sodium hydroxide solution (2.0 M, 604 μL), and water (604 μL) were added sequentially. Water (50 mL) and brine (50 mL) were added sequentially, and the aqueous layer was extracted with dichloromethane (2 × 125 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-33% methanol in dichloromethane) to give intermediate 2-1. LCMS: 358.4. Intermediate 2-2: (S)-2-(benzyl(methyl)amino)-3-(octadecyloxy)propan-1-ol: [ka]

[0325] Benzaldehyde (25.6 μL, 252 μmol) was added via syringe to a vigorously stirred solution of intermediate 2-1 (60.0 mg, 168 μmol) in dichloromethane (3.0 mL) at room temperature. After 2 minutes, sodium triacetoxyborohydride (178 mg, 839 μmol) was added, and the resulting mixture was heated to 50°C. After 14 hours, the resulting mixture was cooled to room temperature, and saturated aqueous sodium carbonate (5 mL) and water (15 mL) were added sequentially. The aqueous layer was extracted with dichloromethane (2 × 125 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0–8% methanol in dichloromethane) to give intermediate 2-2. LCMS: 448.4. Example 2: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzyl(methyl)amino)-3-(octadecyloxy)propyl)hydrogenphosphate (2): [ka]

[0326] Compound 2 was synthesized in the same manner as compound 1, using intermediate 2-2 instead of intermediate 1-3. 1 H NMR (400MHz, methanol-d4) δ7.97(s,1H),7.60-7.33(m,5H),7.14-7.02(m,2H),5.00-4.71(m,3H),4.46-4.34(m,1H) ,4.31-3.99(m,5H),3.81-3.66(m,3H),3.56-3.44(m,2H),2.67(s,3H),1.72-1.07(m,32H),0.91(t,J=6.7Hz,3H). LCMS:801.3. Example 3: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-chloro-4-fluorobenzyl)(methyl)amino)-3-(octadecyloxy)propyl)hydrogenphosphate (3): [ka]

[0327] Compound 3 was synthesized in the same manner as compound 2, using 3-chloro-4-fluorobenzaldehyde instead of benzaldehyde. 1 H NMR (400 MHz, methanol-d4) δ 8.02 (s, 1H), 7.72 (dd, J = 6.9, 2.2 Hz, 1H), 7.60-7.49 (m, 1H), 7.36 (t, J = 8.8 Hz, 1H), 7.17 (d, J = 4.7 Hz, 1H), 7.11 (d, J = 4.7 Hz, 1H), 5.00-4.81 (m, 2H), 4.79 (d, J =5.3Hz,1H),4.53-4.34(m,1H),4.29-4.15(m,3H),4.15-4.01(m,2H),3.82-3.67(m,3H),3. 58-3.46(m,2H),2.88(s,3H),1.69-1.56(m,2H),1.43-1.22(m,30H),0.92(t,J=6.5Hz,3H). LCMS:851.4[MH] - . Intermediate 4-1: (S)-3-chloro-4-fluoro-N-(1-hydroxy-3-(octadecyloxy)propan-2-yl)-N-methylbenzamide: [ka]

[0328] 3-Chloro-4-fluorobenzoyl chloride (23.1 mg, 120 μmol) was added to a stirred mixture of intermediate 2-1 (42.8 mg, 120 μmol), triethylamine (33.4 μL, 239 μmol), and dichloromethane (2.0 mL) at room temperature. After 60 minutes, the resulting mixture was purified by flash column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give intermediate 4-1. LCMS: 514.3. Intermediate 4-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl bis(2-chlorophenyl)phosphate: [ka]

[0329] 2-Chlorophenyl phosphorodichloridate (84.5 μL, 524 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (72.6 mg, 1.05 μmol), triethylamine (147 μL, 1.05 μmol), and tetrahydrofuran (0.9 mL) over 2 min at room temperature. After 30 min, intermediate 1-4 (150 mg, 453 μmol), tetrahydrofuran (0.45 mL), and 1-methylimidazole (41.9 μL, 525 μmol) were added sequentially. After 60 min, 2-chlorophenol (235 μL, 2.26 mmol) and triethylamine (350 μL, 2.50 mmol) were added sequentially. After 16 h, the resulting mixture was purified by flash column chromatography on silica gel (0–3.75% methanol in dichloromethane) to give intermediate 4-2. LCMS:963.2. Example 4: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(3-chloro-4-fluoro-N-methylbenzamido)-3-(octadecyloxy)propyl)hydrogenphosphate (4). [ka]

[0330] A vigorously stirred mixture of Intermediate 4-2 (59.5 mg, 94.1 μmol), Intermediate 4-1 (48.4 mg, 94.1 μmol), magnesium chloride (44.8 mg, 471 μmol), and tetrahydrofuran (1.0 mL) was heated to 53°C. After 5 minutes, N,N-diisopropylethylamine (82.0 μL, 471 μmol) was added via syringe over 1 minute. After 44 minutes, the resulting mixture was heated to 90°C. After 16 minutes, the resulting mixture was cooled to room temperature over 6 minutes, and a solution of 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (1.0 M in tetrahydrofuran / toluene, 157 μL, 157 μmol) was added via syringe. After 6 minutes, the resulting mixture was heated to 50°C. After 40 min, the resulting mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (30 mL) were added sequentially. The organic layer was washed with water (2 × 20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.6 mL), and the resulting mixture was vigorously stirred at room temperature. Potassium tert-pentoxide solution (1.7 M in toluene, 111 μL, 188 μmol) was added via syringe over 1 min, and the resulting mixture was heated to 50 °C. After 25 min, the resulting mixture was cooled to room temperature, and concentrated hydrochloric acid (350 μL, 4.2 mmol) was added via syringe. After 2 h, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 4 as a 2:1 mixture of amide rotamers. 1H NMR (400 MHz, methanol-d₄) δ 8.02 (s, 1H), 7.76-7.04 (m, 5H), 5.03-4.51 (m, 1H), 4.49-3.45 (m, 11H), 2.93 (s, 1H), 2.91 (s, 2H), 1.69-1.50 (m, 2H), 1.46-1.20 (m, 30H), 0.96-0.87 (m, 3H). LCMS: 865.3 [MH] - . Intermediate 5-1: Methyl (2R,3S)-2-hydroxy-3-(octadecyloxy)butanoate: [ka]

[0331] 4-Toluenesulfonic acid monohydrate (28.4 mg, 149 μmol) was added to a vigorously stirred mixture of methyl (2R,3S)-2,3-dihydroxybutanoate (200 mg, 1.49 mmol) (Servi, SJ Org. Chem. 1985, 50, 5865), octadecanol (420 mg, 1.57 mmol), anhydrous magnesium sulfate (332 mg, 2.76 mmol), and dichloromethane (4.0 mL) at room temperature, and the resulting mixture was heated to 60 °C. After 2 h, the resulting mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate (5 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), and the resulting mixture was immersed in a dry ice / acetone bath at -78 °C. After 1 min, titanium tetrachloride (327 μL, 2.98 mmol) was added via syringe. After 5 min, triethylsilane (1.19 mL, 7.46 mmol) was added via syringe, and the resulting mixture was allowed to warm to room temperature over 19.5 h. Water (30 mL) was added. After 3 min, the aqueous layer was extracted with dichloromethane (2 × 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 15% ethyl acetate in hexanes) to give intermediate 5-1. LCMS: 409.3 [M+Na]+ . Intermediate 5-2: Methyl (2R,3S)-2-(benzyloxy)-3-(octadecyloxy)butanoate: [ka]

[0332] Trifluoromethanesulfonic acid (2.3 μL, 26 μmol) was added via syringe to a stirred mixture of intermediate 5-1 (100 mg, 259 μmol) and benzyl 2,2,2-trichloroacetimidate (120 μL, 647 μmol) in 1,4-dioxane (2.0 mL) at room temperature. After 2 h, 4-methylmorpholine (30 μL) was added via syringe, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 5% ethyl acetate in hexanes) to give intermediate 5-2. LCMS: 499.4 [M+Na] + . Intermediate 5-3: (2S,3S)-2-(benzyloxy)-3-(octadecyloxy)butan-1-ol: [ka]

[0333] Lithium aluminum hydride solution (1.0 M in tetrahydrofuran, 455 μL, 460 μmol) was added via syringe over 1 min to a stirred solution of intermediate 5-2 (72.3 mg, 152 μmol) in tetrahydrofuran (4.0 mL) at 0 °C. After 1 h, water (20 μL), aqueous sodium hydroxide (2.0 M, 40 μL), and water (20 μL) were added sequentially. The resulting suspension was filtered through Celite, and the filter cake was extracted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (0-25% ethyl acetate in hexanes) to give intermediate 5-3. LCMS: 471.4 [M+Na] + . Intermediate 5-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((2S,3S)-2-(benzyloxy)-3-(octadecyloxy)butyl)(2-chlorophenyl)phosphate: [ka]

[0334] 2-Chlorophenyl phosphorodichloridate (18.9 μL, 117 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (16.2 mg, 234 μmol), triethylamine (32.6 μL, 234 μmol), and tetrahydrofuran (0.2 mL) at room temperature. After 30 minutes, intermediate 1-4 (37.4 mg, 113 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (8.6 μL, 110 μmol) were added sequentially. After 60 minutes, a solution of intermediate 5-3 (36.2 mg, 80.7 μmol) in tetrahydrofuran (0.7 mL) was added via syringe. 1-Methylimidazole (20 μL, 250 μmol) was added via syringe. After 22 hours, saturated aqueous sodium bicarbonate (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-5% methanol in dichloromethane) to give intermediate 5-4. LCMS: 951.5. Example 5: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((2S,3S)-2-(benzyloxy)-3-(octadecyloxy)propyl)hydrogenphosphate (5): [ka]

[0335] Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 242 μL, 240 μmol) was added via syringe to a stirred mixture of intermediate 5-4 (76.8 mg, 80.6 μmol), 4-(dimethylamino)pyridine (29.5 mg, 242 μmol), tetrahydrofuran (0.1 mL), and water (72.6 μL, 4.03 mmol) at room temperature, and the resulting mixture was heated to 50 °C. After 1 h, the resulting mixture was cooled to room temperature, and chlorotrimethylsilane (30.7 μL, 242 μmol) and concentrated hydrochloric acid (300 μL, 3.6 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 5. 1 H NMR (400MHz, methanol-d4) δ8.03(s,1H),7.39-7.33(m,2H),7.33-7.20(m,4H),7.19(d,J=4.8Hz,1H),4.7 8(d,J=5.2Hz,1H),4.73(d,J=11.7Hz,1H),4.58(d,J=11.6Hz,1H),4.39-4.30(m,1H),4.27(t,J=5.5Hz ,1H),4.24-4.17(m,1H),4.17-4.04(m,2H),4.04-3.91(m,1H),3.67-3.54(m,2H),3.54-3.46(m,1H),3 .46-3.36(m,1H),1.57-1.46(m,2H),1.40-1.21(m,30H),1.11(d,J=5.9Hz,3H),0.92(t,J=6.7Hz,3H). LCMS:800.4[MH] - . Intermediate 6-1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-6-(prop-1-en-2-yl)-2-sulfidohexahydrobenzo[d][1,3,2]oxathiaphosphor-2-yl)oxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile: [ka]

[0336] 1,8-Diazabicyclo[5.4.0]undec-7-ene (609 μL, 4.07 mmol) was added via syringe to a vigorously stirred mixture of Intermediate 1-4 (1.00 g, 3.02 mmol), (2R,3aR,6S,7aR)-3a-methyl-2-((perfluorophenyl)thio)-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphol 2-sulfide (1.75 g, 3.92 mmol), and acetonitrile (24.0 mL) over 2 minutes at room temperature. After 10 minutes, saturated aqueous ammonium chloride (1.0 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with water (70 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% methanol in dichloromethane) to give intermediate 6-1. LCMS: 578.2. Intermediate 6-2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-2-oxido-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphor-2-yl)oxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile: [ka]

[0337] Selenium dioxide (316 mg, 2.84 mmol) was added to a vigorously stirred solution of Example 6-1 (1.57 g, 2.71 mmol) in acetonitrile (23.5 mL) and water (8.9 mL) at room temperature. After 60 minutes, ethyl acetate (250 mL) was added, and the resulting mixture was filtered through Celite. The organic layer of the filtrate was washed with a mixture of water and brine (1:1 v:v, 120 mL), and the aqueous layer was extracted with ethyl acetate (75 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% methanol in dichloromethane) to give Intermediate 6-2. LCMS: 562.2. Intermediate 6-3: (S)-3-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)(methyl)amino)methyl)benzonitrile: [ka]

[0338] Intermediate 6-3 was synthesized in a similar manner to intermediate 2-2, using 3-fluoro-5-formylbenzonitrile instead of benzaldehyde. LCMS: 491.4. Example 6: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-cyano-5-fluorobenzyl)(methyl)amino)-3-(octadecyloxy)propyl)hydrogenphosphate (6). [ka]

[0339] 1,8-Diazabicyclo[5.4.0]undec-7-ene (17.4 μL, 116 μmol) was added via syringe to a vigorously stirred mixture of intermediate 6-2 (21.8 mg, 38.8 μmol), intermediate 6-3 (19.0 mg, 38.8 μmol), and tetrahydrofuran (0.35 mL) at room temperature. After 55 min, concentrated hydrochloric acid (250 μL, 3.0 mmol) was added via syringe. After 2 h, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) followed by flash column chromatography on silica gel (0–70% methanol in dichloromethane) to give compound 6. 1 H NMR (400MHz, methanol-d4) δ7.86(s,1H),7.54(s,1H),7.46(d,J=9.5Hz,1H),7. 36(d,J=8.0Hz,1H),7.01(d,J=4.6Hz,1H),6.88(d,J=4.6Hz,1H),4.98-4.74 (m,1H),4.60(s,1H),4.40-4.34(m,1H),4.33-4.28(m,1H),4.24-3.37(m,8H ),2.24(s,3H),1.62-1.48(m,2H),1.42-1.21(m,30H),0.92(t,J=6.8Hz,3H). LCMS:844.2. Intermediate 7-1: (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-yl 4-methylbenzenesulfonic acid: [ka]

[0340] 4-Toluenesulfonyl chloride (929 mg, 4.87 mmol) was added to a stirred solution of (S)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (1.40 g, 3.04 mmol) (Xia, J.; Hui, Y.-Z. Tetrahedron: Asymmetry 1997, 8, 3131), N,N-diisopropylethylamine (848 μL, 4.87 mmol), 4-(dimethylamino)pyridine (37.2 mg, 304 μmol), and dichloromethane (7.0 mL) at 0° C. After 2 minutes, the resulting mixture was warmed to room temperature. After 170 minutes, 4-(dimethylamino)pyridine (67.0 mg, 548 mmol) was added. After 30 minutes, the resulting mixture was heated to 65° C. After 17 hours, the resulting mixture was cooled to room temperature, and diethyl ether (120 mL), ethyl acetate (20 mL), and aqueous hydrogen chloride (2.0 M, 5 mL) were added sequentially. The organic layer was washed sequentially with water (100 mL) and a mixture of water and saturated aqueous sodium bicarbonate (5:1 v:v, 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 50% dichloromethane in hexanes) to give intermediate 7-1. LCMS: 635.4 [M+Na] + . Intermediate 7-2: (R)-(2-(benzylthio)-3-(octadecyloxy)propoxy)(tert-butyl)dimethylsilane: [ka]

[0341] A solution of potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 367 μL, 370 μmol) was added to a vigorously stirred solution of benzyl mercaptan (43.1 μL, 367 μmol) in N,N-dimethylformamide (0.6 mL) via syringe at room temperature. After 4 minutes, intermediate 7-1 was added, and the resulting mixture was heated to 90 °C. After 30 minutes, the resulting mixture was cooled to room temperature. Saturated aqueous ammonium chloride (5 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 8% ethyl acetate in hexanes) to give intermediate 7-2. LCMS: 587.4 [M+Na] + . Intermediate 7-3: (S)-2-(benzylthio)-3-(octadecyloxy)propan-1-ol: [ka]

[0342] Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 194 μL, 190 μmol) was added via syringe to a stirred solution of intermediate 7-2 (46.3 mg, 81.9 μmol) in tetrahydrofuran (0.2 mL) at room temperature. After 40 minutes, saturated aqueous ammonium chloride solution (5 mL), diethyl ether (10 mL), and ethyl acetate (5 mL) were added sequentially. The organic layer was washed with water (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 9% ethyl acetate in hexanes) to give intermediate 7-3. LCMS: 473.4 [M+Na] + . Example 7: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(benzylthio)-3-(octadecyloxy)propyl)hydrogenphosphate: (7) [ka]

[0343] Compound 7 was synthesized in the same manner as compound 5, using intermediate 7-3 instead of intermediate 5-3. 1 H NMR (400MHz, methanol-d4) δ8.09(s,1H),7.40-7.18(m,7H),4.84-4.73(m,1H),4.44-3.39(m, 12H), 2.96-2.85 (m, 1H), 1.68-1.43 (m, 2H), 1.30 (d, J = 3.1Hz, 30H), 0.92 (t, J = 6.7Hz, 3H). LCMS:802.4[MH] - . Intermediate 8-1: Methyl (2R,3R)-2,3-dihydroxybutanoate: [ka]

[0344] A solution of sodium nitrite (3.13 g, 45.5 mmol) in water (4.76 mL) was added to a stirred mixture of D-allothreonine (5.00 g, 41.9 mmol) in concentrated sulfuric acid (1.26 mL, 2.21 mmol) and water (10.2 mL) using an addition funnel over 30 minutes at 0°C, and the resulting mixture was allowed to warm to room temperature. After 23 hours, the resulting mixture was concentrated under reduced pressure, and the residue was suspended in ethanol (95.2 mL). The resulting suspension was filtered, and the filtrate was concentrated to a volume of approximately 24 mL. Ethanol (47.6 mL) was added, and the resulting suspension was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was azeotropically dried by concentrating under reduced pressure from a mixture of methanol and toluene (1:1 v:v, 47.6 mL). The residue was dissolved in methanol (28.6 mL), and the resulting mixture was stirred at room temperature. A solution of hydrogen chloride (3.0 M in methanol, 50.0 mL, 150 mmol) was added via syringe. After 16 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 50% ethyl acetate in hexanes) to give intermediate 8-1.1 H NMR (400 MHz, chloroform-d) δ 4.25 (d, J = 3.7 Hz, 1H), 4.09 (qd, J = 6.5, 3.7 Hz, 1H), 3.85 (s, 3H), 1.22 (d, J = 6.5 Hz, 3H). Example 8: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((2S,3R)-2-(benzyloxy)-3-(octadecyloxy)propyl)hydrogenphosphate (8). [ka]

[0345] Compound 8 was synthesized in the same manner as compound 5, using intermediate 8-1 instead of methyl (2R,3R)-2,3-dihydroxybutanoate. 1 H NMR (400MHz, methanol-d4) δ8.00(s,1H),7.34(d,J=7.0Hz,2H),7.31-7.26(m,2H),7.26-7.20(m,2H),7.1 7(d,J=4.7Hz,1H),4.77(d,J=5.2Hz,1H),4.71(d,J=11.7Hz,1H),4.61(d,J=11.7Hz,1H),4.42-4.28(m, 1H),4.26(t,J=5.5Hz,1H),4.22-4.14(m,1H),4.13-3.97(m,2H),3.97-3.88(m,1H),3.65-3.59(m,1H), 3.59-3.36(m,3H),1.56-1.45(m,2H),1.41-1.24(m,30H),1.15(d,J=6.3Hz,3H),0.91(t,J=6.7Hz,3H). LCMS:800.4[MH] - . Intermediate 9-1: (S)-2-(5,6-dichloroisoindolin-2-yl)-3-(octadecyloxy)propan-1-ol: [ka]

[0346] Intermediate 1-2 (93.0 mg, 271 μmol), tetrahydrofuran (1.5 mL), and N,N-diisopropylethylamine (120 μL, 690 μmol) were added sequentially to 1,2-bis(bromomethyl)-4,5-dichlorobenzene (90.7 mg, 273 μmol) (Xu, F.; Peng, L.; Shinohara, K.; Morita, T.; Yoshida, S.; Hosoya, T.; Orita, A.; Otera, J. J. Org. Chem. 2014, 79, 11592) at room temperature, and the resulting mixture was vigorously stirred and heated to 65 °C. After 3 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0–9% methanol in dichloromethane) to give intermediate 9-1. LCMS: 514.3. Example 9: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(5,6-dichloroisoindolin-2-yl)-3-(octadecyloxy)propyl)hydrogenphosphate (9). [ka]

[0347] 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (22.2 μL, 76.6 μmol) was added via syringe to a vigorously stirred mixture of Intermediate 9-1 (21.2 mg, 35.6 μmol), Intermediate 6-2 (20.0 mg, 35.6 μmol), and tetrahydrofuran (0.35 mL) at 0° C. over 2 minutes. After 1 minute, the resulting mixture was warmed to room temperature. After 14 minutes, 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (20.7 μL, 71.3 μmol) was added via syringe over 1 minute. After 32 minutes, the resulting mixture was heated to 50° C. After 25 min, the resulting mixture was cooled to room temperature, and water (50 μL) and concentrated hydrochloric acid (300 μL, 3.6 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 9. 1 H NMR (400MHz, methanol-d4) δ8.01(s,1H),7.59(s,2H),7.13(d,J=4.9Hz,1H),7.10(d,J=4.6Hz,1H),4.95-4.73(m,5H),4.44-4.34 (m,1H),4.28-4.09(m,5H),3.96-3.73(m,3H),3.53-3.42(m,2H),1.64-1.50(m,2H),1.40-1.21(m,30H),0.92(t,J=6.7Hz,3H). LCMS:866.3[MH] - . Intermediate 10-1: (S)-2-((3-chloro-4-fluorobenzyl)amino)-3-(octadecyloxy)propan-1-ol: [ka]

[0348] 3-Chloro-4-fluorobenzaldehyde (55.7 mg, 351 μmol) was added to a vigorously stirred mixture of Intermediate 1-2 (80.4 mg, 234 μmol), anhydrous sodium sulfate (49.9 mg, 1.17 mmol), and tetrahydrofuran (1.0 mL) at room temperature, and the resulting mixture was heated to 60° C. After 180 min, the resulting mixture was cooled to room temperature. After 103 min, sodium borohydride (44.3 mg, 1.17 mmol) and methanol (2.0 mL) were added sequentially. After 360 min, ethyl acetate (60 mL), saturated aqueous sodium carbonate (10 mL), and brine (20 mL) were added sequentially. The organic layer was washed sequentially with water (20 mL) and a mixture of water and brine (1:1 v:v, 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-25% methanol in dichloromethane) to give intermediate 10-1. LCMS: 486.3. Intermediate 10-2: (S)-N-(3-chloro-4-fluorobenzyl)-N-(1-hydroxy-3-(octadecyloxy)propan-2-yl)acetamide: [ka]

[0349] Acetic anhydride (5.8 μL, 62 μmol) was added via syringe to a stirred mixture of intermediate 10-1 (30.0 mg, 61.7 μmol), triethylamine (25.8 μL, 185 μmol), and dichloromethane at room temperature. After 30 minutes, the resulting mixture was purified by flash column chromatography on silica gel (0-100% ethyl acetate in hexanes) to give intermediate 10-2. LCMS: 550.4 [M+Na] + . Example 10: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(N-(3-chloro-4-fluorobenzyl)(acetamido)-3-(octadecyloxy)propyl) hydrogen phosphate (10). [ka]

[0350] 1,8-Diazabicyclo[5.4.0]undec-7-ene (8.0 μL, 53 μmol) was added via syringe to a vigorously stirred mixture of Intermediate 6-2 (15.0 mg, 26.7 μmol), Intermediate 10-2 (14.1 mg, 26.7 μmol), and tetrahydrofuran (0.70 mL) over 1 min at room temperature. After 25 min, water (50 μL) and concentrated hydrochloric acid (250 μL, 3.0 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give Compound 10 as a 2.4:1 mixture of amide rotamers. 1 H NMR (400 MHz, methanol-d₄) δ 8.05 (s, 0.37H), 8.03 (s, 0.63H), 7.48-7.04 (m, 5H), 4.96-2.99 (m, 14H), 2.25 (s, 1.9H), 2.01 (s, 1.1H), 1.59-1.19 (m, 30H), 0.96-0.82 (m, 3H). LCMS: 879.4 [MH] - . Intermediate 11-1: (S)-2-(1-hydroxy-3-(octadecyloxy)propan-2-yl)isoindolin-1-one: [ka]

[0351] Phthalaldehyde (21.5 mg, 160 μmol) was added to a vigorously stirred solution of Intermediate 1-2 (50.0 mg, 146 μmol) in dichloromethane (2.5 mL) at room temperature. After 2 minutes, acetic acid (41.7, 728 μmol) was added via syringe, and the resulting mixture was heated to 50°C. After 45 minutes, the resulting mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate (6 mL) and ethyl acetate (60 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (3:1 v:v, 40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-8% methanol in dichloromethane) to give Intermediate 11-1. LCMS: 460.4. Example 11: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-3-(octadecyloxy)-2-(1-oxoisoindolin-2-yl)propyl)hydrogenphosphate (11): [ka]

[0352] Compound 11 was synthesized in the same manner as compound 10, using intermediate 11-1 instead of intermediate 10-2. 1 H NMR (400MHz, methanol-d4) δ8.08(d,J=2.6Hz,1H),7.75(d,J=7.9Hz,1H),7.62-7.53(m,2H),7.52-7.43(m,1H),7.33-7.27(m,1H),7.2 4-7.15(m,1H),4.95-4.48(m,3H),4.38-3.93(m,7H),3.81-3.64(m,2H),3.53-3.32(m,2H),1.59-1.06(m,32H),1.08-0.82(m,3H). LCMS:811.4[MH] - . Intermediate 12-1: (R)-2-(benzyloxy)-3-(octadecyloxy)propanal: [ka]

[0353] 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H-one) (787 mg, 1.86 mmol) was added to a stirred solution of (S)-2-(benzyloxy)-3-(octadecyloxy)propan-1-ol (403 mg, 928 μmol) at room temperature. After 70 minutes, diethyl ether (100 mL), ethyl acetate (25 mL), aqueous sodium thiosulfate (1.0 M, 5 mL), and saturated aqueous sodium bicarbonate (40 mL) were added sequentially. The organic layer was washed sequentially with water (60 mL), a mixture of water and saturated aqueous sodium bicarbonate (100 mL), and water (60 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 10% ethyl acetate in hexanes) to give intermediate 12-1. LCMS: 455.4 [M+Na] + . Intermediate 12-2: (3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-ol (faster eluting diastereomer on silica gel): Intermediate 13-1: (3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-ol (slow-eluting diastereomer on silica gel): [ka]

[0354] A solution of intermediate 12-1 (327 mg, 755 μmol) in tetrahydrofuran (8.0 mL) at −10° C. was added via cannula over 3 minutes to a solution of methylmagnesium bromide (3.2 M in 2-methyltetrahydrofuran, 1.20 mL, 3.8 mmol) at 0° C. After 120 minutes, saturated aqueous ammonium chloride (5 mL) and diethyl ether (100 mL) were added sequentially. The organic layer was washed with water (60 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 4.5% tetrahydrofuran in hexanes) to give intermediate 12-2 (faster-eluting diastereomer) and intermediate 13-1 (slower-eluting diastereomer). Intermediate 12-2: LCMS: 471.4 [M+Na] + Intermediate 13-1: LCMS: 471.4 [M+Na] + . Example 12: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-yl)hydrogenphosphate (12): [ka]

[0355] Compound 12 was synthesized in the same manner as compound 10, using intermediate 12-2 instead of intermediate 10-2. 1 H NMR (400MHz, methanol-d4) δ8.02(s,1H),7.36-7.20(m,6H),7.16(d,J=4.7Hz,1H),4.77(d,J=5.2Hz,1H),4.67(d,J=11.8Hz,1H),4.60(d, J=11.6Hz,1H),4.39-4.30(m,1H),4.29-4.02(m,3H),3.79-3.37(m,6H),1.63-1.47(m,2H),1.41-1.21(m,33H),0.92(t,J=6.7Hz,3H). LCMS:800.4[MH] - . Example 13: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-yl)hydrogenphosphate (13): [ka]

[0356] Compound 13 was synthesized in the same manner as compound 10, using intermediate 13-1 instead of intermediate 10-2. 1 H NMR (400MHz, methanol-d4) δ8.02(s,1H),7.36(d,J=7.3Hz,2H),7.30(t,J=7.4Hz,2H),7 .26-7.20(m,2H),7.16(d,J=4.7Hz,1H),4.78(d,J=5.2Hz,1H),4.72(s,1H),4.68(d,J =11.7Hz,1H),4.48-4.39(m,1H),4.39-4.31(m,1H),4.30-4.16(m,2H),4.16-4.05(m, 1H),3.80-3.39(m,5H),1.61-1.48(m,2H),1.43-1.21(m,33H),0.92(t,J=6.8Hz,3H). LCMS:800.4[MH] - . Intermediate 14-1: (S)-2-(1-hydroxy-3-(octadecyloxy)propan-2-yl)isoindoline-1,3-dione: [ka]

[0357] Ethyl 1,3-dioxoisoindoline-2-carboxylate (35.1 mg, 160 μmol) was added to a vigorously stirred solution of intermediate 1-2 (55.0 mg, 160 μmol) in tetrahydrofuran (1.0 mL) at room temperature. After 15.5 hours, the resulting mixture was heated to 65° C. After 75 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 12% ethyl acetate in dichloromethane) to give intermediate 14-1. LCMS: 496.4 [M+Na] + . Example 14: 2-(((2R)-1-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3-(octadecyloxy)propan-2-yl)carbamoyl)benzoic acid (14) Example 15: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(1,3-dioxoisoindolin-2-yl)-3-(octadecyloxy)propyl)hydrogenphosphate (15). [ka]

[0358] Compounds 14 and 15 were synthesized in the same manner as compound 10, using intermediate 14-1 instead of intermediate 10-2. Compound 14: 1H NMR (400 MHz, methanol-d4) δ 8.07 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.63-7.56 (m, 1H), 7.56-7.51 (m, 1H), 7.51-7.45 (m, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H), 4.81 (d, J = 5.1 Hz, 1H), 4.38-4.34 (m, 1H), 4.34 -4.25(m,2H),4.24-4.14(m,1H),4.14-4.04(m,1H),4.02-3.95(m,2H),3.62(dd,J=9.8,5.6Hz,1H),3.56 (dd,J=9.8,6.7Hz,1H),3.52-3.42(m,2H),1.62-1.50(m,2H),1.42-1.19(m,30H),0.92(t,J=6.7Hz,3H). LCMS:843.4[MH] - . Compound 15: 1 H NMR (400MHz, methanol-d4) δ8.06(s,1H),7.84-7.79(m,2H),7.79-7.73(m,2H),7.28-7.12(m,2H),4.8 0(d,J=5.2Hz,1H),4.42-3.91(m,7H),3.90-3.32(m,4H),1.78-1.03(m,32H),0.92(t,J=6.7Hz,3H). LCMS:825.4[MH] - . Intermediate 16-1: (S)-3-((1-hydroxy-3-(octadecyloxy)propan-2-yl)amino)benzonitrile: [ka]

[0359] A solution of sodium tert-butoxide (2.0 M in tetrahydrofuran, 177 μL, 350 μmol) was added via syringe over 1 min to a vigorously stirred solution of Intermediate 1-2 (105 mg, 305 μmol), 3-bromobenzonitrile (55.5 mg, 305 μmol), and [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-methylamino-1,1′-biphenyl)]palladium(II) methanesulfonate (15.9 mg, 17.3 μmol) in 1,4-dioxane (1.3 mL) at 50° C., and the resulting mixture was heated to 100° C. After 35 min, the resulting mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate (5 mL) and ethyl acetate (50 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 28% ethyl acetate in dichloromethane) to give intermediate 16-1. LCMS: 445.4. Example 16: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-cyanophenyl)amino)-3-(octadecyloxy)propyl)hydrogenphosphate (16). [ka]

[0360] Compound 16 was synthesized in the same manner as compound 10, using intermediate 16-1 instead of intermediate 10-2. 1H NMR (400 MHz, methanol-d4) δ 8.04 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.24-7.16 (m, 2H), 6.95-6.87 (m, 2H), 6.85 (dt, J = 7.5, 1.1 Hz, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.42-4.32 (m, 1H), 4.25 (t, J = 5.5 Hz, 1H) ),4.19(ddd,J=11.6,5.2,3.1Hz,1H),4.07(dt,J=11.8,4.8Hz,1H),3.93(t,J=5.8Hz,2H),3.77 -3.66(m,1H),3.55-3.42(m,4H),1.64-1.47(m,2H),1.41-1.23(m,30H),0.92(t,J=6.8Hz,3H). LCMS:796.4[MH] - . Intermediate 17-1: (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ylbenzoate: [ka]

[0361] Benzoyl chloride (38.0 μL, 327 μmol) was added via syringe to a stirred mixture of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (137 mg, 297 μmol), triethylamine (124 μL, 892 μmol), 4-(dimethylamino)pyridine (7.3 mg, 60 μmol), and dichloromethane (1.2 mL) at room temperature. After 40 minutes, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 8% ethyl acetate in hexanes) to give intermediate 17-1. LCMS: 585.4 [M+Na] + . Intermediate 17-2: (S)-1-hydroxy-3-(octadecyloxy)propan-2-yl benzoate: [ka]

[0362] Triethylamine trihydrofluoride (485 μL, 2.97 mmol) was added via syringe to a vigorously stirred solution of intermediate 17-2 (72.2 mg, 128 μmol) in tetrahydrofuran (2.0 mL) at room temperature. After 14 h, diethyl ether (40 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL) and a mixture of saturated aqueous sodium bicarbonate and brine (5:1 v:v, 40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 35% ethyl acetate in hexanes) to give intermediate 17-2. LCMS: 471.4 [M+Na] + . Example 17: (2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3-(octadecyloxy)propan-2-ylbenzoate (17): [ka]

[0363] Compound 17 was synthesized in the same manner as compound 5, using intermediate 17-2 instead of intermediate 5-3. 1 H NMR (400MHz, methanol-d4) δ8.09(s,1H),8.04-7.98(m,2H),7.62-7.55(m,1H),7.45(t, J=7.7Hz,2H),7.37(d,J=4.8Hz,1H),7.19(d,J=4.8Hz,1H),5.38-5.24(m,1H),4.72( d,J=5.2Hz,1H),4.41-4.32(m,1H),4.32-4.22(m,1H),4.23-4.08(m,4H),3.76-3.66 (m,2H),3.57-3.40(m,2H),1.58-1.46(m,2H),1.41-1.16(m,30H),0.99-0.80(m,3H). LCMS:800.4[MH] - . Intermediate 18-1: (R)-1-(octadecyloxy)-3-phenoxypropan-2-ol: [ka]

[0364] Triphenylphosphane (80.0 mg, 0.305 mmol) was added to a solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (109 mg, 0.237 mmol), phenol (41.0 mg, 0.436 mmol), and diisopropyl azodicarboxylate (0.0750 mL, 0.359 mmol) in tetrahydrofuran (2 mL) in THF cooled to 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 24 h, at which point the solvent was removed under reduced pressure and the crude product was absorbed onto silica gel and purified by flash column chromatography on silica gel (0–10% ethyl acetate in hexanes) to give (S)-tert-butyldimethyl(3-(octadecyloxy)-2-phenoxypropoxy)silane. 1 H NMR (400MHz, chloroform-d) δ7.33-7.22(m,2H),7.03-6.90(m,3H),4.43(q,J=5.1Hz,1H),3.89-3.79(m,2H),3.67(qd,J=1 0.4,4.9Hz,2H),3.49(td,J=6.5,1.9Hz,2H),1.63-1.53(m,2H),1.27(s,30H),0.90(s,9H),0.08(s,3H),0.06(s,3H).

[0365] A 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.500 mL, 0.500 mmol) was added to a solution of (S)-tert-butyldimethyl(3-(octadecyloxy)-2-phenoxypropoxy)silane (84.0 mg, 0.157 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred for 1 h, at which point the reaction mixture was diluted with ethyl acetate and washed sequentially with 3× water, followed by saturated aqueous sodium chloride solution. The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 20% ethyl acetate in hexanes) to give intermediate 18-1. 1 H NMR (400MHz, chloroform-d) δ7.41-7.17(m,2H),7.12-6.94(m,3H),4.50(dq,J=6.2,4.7Hz,1H),3.92(qd,J=11.8,4. 7Hz,2H),3.79-3.62(m,2H),3.49(td,J=6.6,1.3Hz,2H),1.59(q,J=6.9Hz,2H),1.28(s,30H),0.93-0.87(m,3H). Intermediate 18-2: (R)-bis(4-nitrophenyl)(1-(octadecyloxy)-3-phenoxypropan-2-yl)phosphate: [ka]

[0366] Triethylamine (25 μL, 18 μmol) was added via syringe to a stirred mixture of Intermediate 18-1 (31 mg, 73.7 μmol), 4-nitrophenyl phosphorodichloridate (46.8 mg, 18.3 μmol), and dichloromethane (2.0 mL) at 0 °C. After 60 min, the resulting mixture was warmed to room temperature. After 30 min, 4-nitrophenyl phosphorodichloridate (27.0 mg, 105 μmol) and triethylamine (20.0 μL, 143 μmol) were added sequentially. After 30 min, 4-nitrophenol (56 mg, 0.43 mmol) and triethylamine (50 μL, 0.36 mmol) were added sequentially. After 18 h, diethyl ether (60 mL) and aqueous citric acid (10 wt%, 10 mL) were added sequentially. The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 20% ethyl acetate in hexanes) to give intermediate 18-2. 1 H NMR(400MHz,chloroform-d)δ8.21(dd,J=9.0,1.4Hz,4H),7.36(dt,J=9.1,1.4Hz, 4H),7.32-7.22(m,2H),7.01(t,J=7.4Hz,1H),6.89-6.83(m,2H),4.71-4.54( m,3H),3.67(dd,J=10.2,4.0Hz,1H),3.59(dd,J=10.2,6.2Hz,1H),3.45(t,J= 6.6Hz, 2H), 1.55 (t, J = 6.9Hz, 2H), 1.27 (d, J = 2.9Hz, 30H), 0.97-0.85 (m, 3H). Intermediate 18-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(4-nitrophenyl)((R)-1-(octadecyloxy)-3-phenoxypropan-2-yl)phosphate: [ka]

[0367] A vigorously stirred mixture of intermediate 18-2 (23 mg, 31 μmol), intermediate 1-4 (11.3 mg, 34 μmol), magnesium chloride (17 mg, 0.18 mmol), and tetrahydrofuran (1 mL) was stirred at room temperature. After 30 min, N,N-diisopropylethylamine (30 μL, 0.17 mmol) was added. After 18 h, the resulting mixture was adsorbed onto silica gel under reduced pressure and purified by flash column chromatography on silica gel (0-4% methanol in dichloromethane) to give intermediate 18-3. 1 H NMR (400MHz, acetonitrile-d3) δ8.10-7.99(m,2H),7.89(s,1H),7.32-7.15(m,4H),7.04-6.84(m,4H),6.74( dd,J=14.7,4.6Hz,1H),5.38(dd,J=14.6,6.6Hz,1H),4.95(ddd,J=14.3,6.6,3.6Hz,1H),4.60(ddd,J=1 0.1,6.9,4.2Hz,2H),4.45-4.22(m,4H),3.56(dd,J=5.1,3.8Hz,2H),3.41(td,J=6.5,2.5Hz,2H),1.70( d,J=1.2Hz,3H),1.49(t,J=6.7Hz,2H),1.39(d,J=2.4Hz,3H),1.28(d,J=9.9Hz,30H),0.93-0.83(m,3H). Example 18: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-1-(octadecyloxy)-3-phenoxypropan-2-yl)hydrogenphosphate (18). [ka]

[0368] Aqueous sodium hydroxide (2.0 M, 60 μL, 120 μmol) was added via syringe to a vigorously stirred solution of intermediate 18-3 (11 mg, 11.8 μmol) in tetrahydrofuran (1 mL) at room temperature, and the resulting mixture was heated to 50 °C. After 4.5 h, the resulting mixture was cooled to room temperature. Concentrated aqueous hydrogen chloride (12 M) was added dropwise until the pH was 1. The solution was stirred at room temperature for 18 h, at which point the pH was raised to approximately 8 by the dropwise addition of triethylamine, and the reaction mixture was then partitioned between pH 3.5 phosphate buffer and 3:2 2-methyltetrahydrofuran:ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (methanol / water + 0.1% trifluoroacetic acid) to give compound 18. 1 H NMR (400MHz, methanol-d4) δ8.04(s,1H),7.29-7.13(m,5H),6.96(d,J=7.9Hz,2H),4.80(d,J=4.7Hz,1H),4.56(d,J=7.4Hz,1H),4.35(s,1H),4.27( d,J=6.0Hz,1H),4.05(dd,J=51.4,17.4Hz,4H),3.79-3.52(m,4H),3.52- 3.40(m,3H),1.53(s,2H),1.29(d,J=9.6Hz,35H),0.92(t,J=6.6Hz,4H). LCMS:774.1. Intermediate 19-1: 3-(hexadecylthio)propan-1-ol: [ka]

[0369] To a solution of 3-mercapto-1-propanol (829 mg, 9 mmol) and 1-bromohexadecane (916 mg, 3 mmol) in DMSO (3 mL) and THF (3 mL) was added powdered KOH (673 mg, 12 mol) at room temperature. The mixture was stirred at room temperature overnight. After cooling, the mixture was poured into ice water and extracted with DCM. The extract was concentrated, dried over Na2SO4, and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt / hexane, 1:2) to give the product as a solid. Intermediate 19-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(3-(hexadecylthio)propyl)phosphate: [ka]

[0370] To a solution of 1,2,4-triazole (43 mg, 0.62 mmol) and triethylamine (87 μL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). The mixture was stirred for 30 min and then filtered. To the filtrate, additional THF (1.2 mL), nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol) were added sequentially. After 1 h, 3-(hexadecylthio)propan-1-ol (75 mg, 0.235 mmol) was added to the mixture, which was stirred overnight at room temperature. The solvent was removed, and the residue was purified by flash chromatography on silica gel (0–15% MeOH in CHCl) to give the compound. Example 19: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(3-(hexadecylthio)propyl)hydrogenphosphate (19): [ka]

[0371] 1,1,3,3-Tetramethylguanidine (156 mg, 1.35 mmol) and syn-2-pyridinealdoxime (275 g, 2.25 mmol) in THF (2 mL) were added to a solution of 19-2 (185 mg, 0.225 mmol) in THF (4 mL) and stirred at room temperature overnight. The reaction was concentrated in vacuo, and the residue was purified by flash chromatography with 0 to 50% MeOH in DCM to give the intermediate.

[0372] The above intermediate was dissolved in THF (1.5 mL). The residue was cooled in an ice bath. Concentrated aqueous HCl (0.3 mL) was added. The cold bath was removed and the reaction was stirred vigorously for 3 h. The mixture was neutralized with Na2CO3, diluted with MeOH, and filtered. The solution was purified by silica gel column chromatography with 0-40% MeOH in DCM to give the product. 1 H NMR (400 MHz, methanol-d₄) δ 7.90 (s, 1H), 6.99 (d, J = 4.6 Hz, 1H), 6.94 (d, J = 4.6 Hz, 1H), 4.38 (m, 1H), 4.29 (m, 1H), 4.20-3.98 (m, 2H), 3.91-3.79 (m, 2H), 2.47 (m, 4H), 1.84-1.70 (m, 2H), 1.52 (m, 2H), 1.29 (d, J = 3.6 Hz, 28H), 0.98-0.83 (m, 3H). 31P NMR (162 MHz, methanol-d₄) δ -0.43. MS: 670.19 (M+1). Intermediate 20-1: 2-(hexadecyloxy)ethan-1-ol: [ka]

[0373] To a solution of ethylene glycol (838 mg, 13.5 mmol) in dry DMF (6 mL) was added NaH (172 mg, 4.5 mmol of a 60% oil dispersion) in portions at 0° C., and the mixture was stirred at room temperature for 10 min. 1-Bromohexadecane (916 mg, 3 mmol) and KI (498 mg, 3 mmol) were added, and the mixture was heated at 95° C. for 4 h. After cooling, the mixture was poured into ice water and extracted with DCM. The extracts were combined, dried over Na2SO4, and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt / hexane, 1:2) to give the product as a solid. 1H NMR (400 MHz, chloroform-d) δ 3.75 (dd, J = 5.2, 4.0 Hz, 2H), 3.62-3.53 (m, 2H), 3.49 (t, J = 6.7 Hz, 2H), 1.81 (s, 2H), 1.67-1.54 (m, 2H), 1.28 (s, 28H), 0.90 (t, J = 6.7 Hz, 3H). Intermediate 20-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(2-(hexadecyloxy)ethyl)phosphate: [ka]

[0374] Intermediate 20-2 was synthesized in a similar manner to intermediate 19-2 using intermediate 2-(hexadecyloxy)ethan-1-ol. Example 20: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-(hexadecyloxy)ethyl)hydrogenphosphate (20): [ka]

[0375] Compound 20 was synthesized in a similar manner to compound 19. 1 H NMR (400 MHz, methanol-d₄) δ 8.17 (s, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 4.75 (s, 1H), 4.49-4.00 (m, 6H), 3.64 (s, 2H), 3.49 (m, 2H), 1.57 (m, 2H), 1.47-1.15 (m, 26H), 0.91 (t, J = 6.6 Hz, 3H). 31 P NMR (162 MHz, methanol-d4) δ -0.93. MS: 640.25 (M+1). Intermediate 21-1: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(2-(hexadecyloxy)ethyl)phosphate: [ka]

[0376] Intermediate 21-1 was synthesized in a similar manner to 19-2 using intermediate 2-(octadecyloxy)ethan-1-ol. Example 21: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-(octadecyloxy)ethyl)hydrogenphosphate (21): [ka]

[0377] Compound 21 was synthesized in a similar manner to compound 19. 1H NMR (400MHz, methanol-d4) δ8.12(s,1H),7.41(d,J=4.8Hz,1H),7.21(d,J=4.8Hz,1H),4.77(m,1H),4.38(t,J=4.6Hz,1H) ,4.33-4.14(m,3H),4.09-3.99(m,2H),3.61(m,2H),3.48(m,2H),1.55(m,2H),1.40-1.18(m,30H),0.98-0.84(m,3H). 31 P NMR (162 MHz, methanol-d4) δ -0.24. MS: 668.25 (M+1). Intermediate 22-1: (R)-1-(benzyloxy)-3-((tert-butyldiphenylsilyl)oxy)propan-2-ol: [ka]

[0378] A solution of tert-butyldiphenylsilyl chloride (3.59 g, 13.1 mmol) in anhydrous DMF (7 mL) was added to a stirred mixture of imidazole (897 mg, 13.2 mmol) and 1-O-benzylglycerol 1 (2 g, 11 mmol) in dry DMF (10 mL). The mixture was then stirred overnight at room temperature. Water was added to the mixture, which was then extracted with EtOAc. The organic phases were combined, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-50 EtOAc in hexanes) to give the product as a colorless oil. Intermediate 22-2: (R)-(3-(benzyloxy)-2-(octadecyloxy)propoxy)(tert-butyl)diphenylsilane: [ka]

[0379] NaH (60% oil dispersion, 88 mg, 2.29 mmol) was suspended in THF (6 mL) and cooled to 0 °C. A solution of 1-O-octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol (275 mg, 0.654 mmol) in THF (2.5 mL) was added over 30 seconds. After 30 minutes, a solution of 1-bromooctadecane (872 mg, 2.62 mmol) in THF (2.5 mL) was added at 0 °C. The mixture was heated to reflux for 12 hours. The reaction was then quenched with water (15 mL). The mixture was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0–60% EtOAc in hexanes) to give the product. Intermediate 22-3: (S)-3-(benzyloxy)-2-(octadecyloxy)propan-1-ol: [ka]

[0380] Intermediate 22-2 (96 mg, 0.143 mmol) obtained in the previous step was dissolved in 1 mL of THF, and a 1N TBAF solution in THF (1N, 0.214 mL, 0.214 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. Water (2.5 mL) was then added, and the resulting mixture was extracted with EtOAc (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0–60% EtOAc in hexane) to give the product. Intermediate 22-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-3-(benzyloxy)-2-(octadecyloxy)propyl)(2-chlorophenyl)phosphate: [ka]

[0381] Intermediate 22-4 was synthesized in a similar manner to 19-2 using intermediate 22-3. Example 22: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-3-(benzyloxy)-2-(octadecyloxy)propyl)hydrogenphosphate (22): [ka]

[0382] Intermediate 22-4 (111 mg, 0.118 mmol) was dissolved in THF (2.5 mL), and then 0.5 N NaOH (0.9 mL) was added at 0 °C. The mixture was stirred at 50 °C for 2.5 h. The mixture was neutralized with 2 N HCl at 0 °C. The mixture was diluted with methanol, and Na SO was added. The mixture was filtered, and the filtrate was evaporated to give a residue.

[0383] The residue was dissolved in THF (0.5 mL). The residue was cooled in an ice bath. Concentrated aqueous HCl (0.1 mL) was added. The cold bath was removed and the reaction was stirred vigorously for 3 h. The mixture was neutralized with Na2CO3, diluted with MeOH, and filtered. The filtrate was evaporated to give a residue which was purified by silica gel column chromatography (0-40% MeOH in DCM) to give the product. 1 H NMR (400MHz, methanol-d4) δ7.88(s,1H),7.36-7.20(m,5H),6.98(d,J=4.6Hz,1H),6.92(d,J=4.7Hz,1H),4.50(s,2H),4.3 6(m,1H),4.25(m,1H),4.11(m,2H),3.95-3.81(m,2H),3.68-3.43(m,4H),1.50(m,2H),1.28(d,30H),0.98-0.85(m,3H). 31 P NMR (162 MHz, methanol-d4) δ -0.49. Intermediate 23-1: (R)-(3-(benzyloxy)-2-(hexadecyloxy)propoxy)(tert-butyl)diphenylsilane: [ka]

[0384] Intermediate 23-1 was synthesized in a similar manner to intermediate 22-2 using 1-bromohexadecane as the alkylating reagent. Intermediate 23-2: (S)-3-(benzyloxy)-2-(hexadecyloxy)propan-1-ol: [ka]

[0385] Intermediate 23-2 was synthesized in a similar manner to 22-3 using intermediate 23-1. Intermediate 23-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-3-(benzyloxy)-2-(hexadecyloxy)propyl)(2-chlorophenyl)phosphate: [ka]

[0386] Intermediate 23-3 was synthesized in the same manner as intermediate 19-2 using intermediate 23-2. Example 23: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-3-(benzyloxy)-2-(hexadecyloxy)propyl)hydrogenphosphate (23). [ka]

[0387] Compound 23 was synthesized in the same manner as compound 22. 1 H NMR (400MHz, methanol-d4) δ8.11(d,J=10.2Hz,1H),7.41(m,1H),7.36-7.09(m,6H),4.74(m,1H),4.53(m,1H),4.38(s,1 H),4.19(m,2H),4.12-3.86(m,1H),3.76-3.48(m,2H),1.68-1.47(m,2H),1.45-1.19(m,26H),0.92(t,J=6.7Hz,3H). 31 P NMR (162 MHz, methanol-d4) δ -0.35. Intermediate 24-1: (R)-(3-(benzyloxy)-2-(tetradecyloxy)propoxy)(tert-butyl)diphenylsilane: [ka]

[0388] Intermediate 24-1 was synthesized in a similar manner to 22-2 using 1-bromotetradecane as the alkylating reagent. Intermediate 24-2: (S)-3-(benzyloxy)-2-(hexadecyloxy)propan-1-ol: [ka]

[0389] Intermediate 24-2 was synthesized in a similar manner to 19-2 using intermediate 24-1. Intermediate 24-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-3-(benzyloxy)-2-(tetradecyloxy)propyl)(2-chlorophenyl)phosphate: [ka] Intermediate 24-3 was synthesized in a similar manner to 19-2 using intermediate 24-2. Example 24: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-3-(benzyloxy)-2-(tetradecyloxy)propyl)hydrogenphosphate (24). [ka]

[0390] Compound 24 was synthesized in a similar manner to compound 22. 1 H NMR (400 MHz, methanol-d₄) δ 7.92 (s, 1H), 7.37-7.17 (m, 5H), 7.03 (t, J = 4.2 Hz, 1H), 7.00-6.94 (m, 1H), 4.50 (s, 2H), 4.36 (m, 1H), 4.25 (m, 1H), 4.12 (m, 2H), 3.89 (m, 1H), 3.72-3.45 (m, 3H), 1.50 (m, 2H), 1.28 (d, 22H), 0.91 (t, J = 6.2 Hz, 3H). 31P NMR (162 MHz, methanol-d₄) δ -0.38. Intermediate 25-1: Preparation of 3-nonoxypropan-1-ol: [ka]

[0391] To a solution of 1,3-propanediol (1.03 g, 13.5 mmol) in dry DMF (6 mL) was added NaH (60% oil dispersion; 172 mg, 4.5 mmol) in portions at 0 °C, and the mixture was stirred at room temperature for 10 min. 1-Bromonan (621 mg, 3 mmol) and KI (498 mg, 3 mmol) were added, and the mixture was heated at 95 °C for 4 h. After cooling, the mixture was poured into ice water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt / hexane, 1:2) to give the product. 1H NMR (400MHz, DMSO-d6) δ4.36(t,J=5.2Hz,1H),3.51-3.36(m,5H),1.63(m,2H),1.47(m,2H),1.26(d,14H),0.91-0.79(m,3H). Intermediate 25-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(3-(nonyloxy)propyl)phosphate: [ka]

[0392] Intermediate 25-2 was synthesized in a similar manner to 19-2 using intermediate 3-(nonyloxy)propan-1-ol. Example 25: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(3-(nonyloxy)propyl)hydrogenphosphate (25): [ka]

[0393] Compound 25 was synthesized in a similar manner to compound 19. 1 H NMR (400MHz, methanol-d4) δ8.07(s,1H),7.32(d,J=4.7Hz,1H),7.18(d,J=4.8Hz,1H),4.78(d,J=5.2Hz,1H),4.38(m,1H),4.31-4.19(m ,2H),4.18-4.06(m,1H),3.98(m,2H),3.51(m,2H),3.41(m,2H),1.87(m,2H),1.53(m,2H),1.42-1.17(m,12H),0.91(t,J=6.7Hz,3H). 31 P NMR (162 MHz, methanol-d4) δ 0.22. MS: 556.11 (M+1). Intermediate 26-1: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(2-(octyloxy)ethyl)phosphate: [ka]

[0394] Intermediate 26-1 was synthesized in a similar manner to 19-2 using intermediate 2-(octyloxy)ethan-1-ol. MS: 568.17 (M+1). Example 26: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-(octyloxy)ethyl)hydrogenphosphate (26): [ka]

[0395] Compound 26 was synthesized in a similar manner to compound 19. 1 H NMR (400MHz, methanol-d4) δ8.08(s,1H),7.34(d,J=4.8Hz,1H),7.17(d,J=4.8Hz,1H),4.78(d,J=5.3Hz,1H),4.43-4.31(m,1H),4.25(mz, 2H),4.15(m,1H),4.05-3.95(m,2H),3.65-3.56(m,2H),3.47(m,2H),3.33(m,2H),1.62-1.48(m,2H),1.29(d,10H),0.94-0.81(m,3H). 31 P NMR (162 MHz, methanol-d4) δ 0.13. MS: 528.07 (M+1). Intermediate 27-1: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)(2-(undecyloxy)ethyl)phosphate: [ka]

[0396] Intermediate 27-1 was synthesized in a similar manner to 19-2 using intermediate 2-(undecyloxy)ethan-1-ol. Example 27: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-(undecyloxy)ethyl)hydrogenphosphate (27): [ka]

[0397] Compound 27 was synthesized in a similar manner to compound 19. 1 H NMR (400MHz, methanol-d4) δ8.07(s,1H),7.32(d,J=4.8Hz,1H),7.18(d,J=4.8Hz,1H),4.79(d,J=5.2Hz,1H),4.37(m,1H),4.30-4. 20(m,2H),4.13(m,1H),3.99(m,2H),3.63-3.55(m,2H),3.46(m,2H),3.33(m,4H),1.54(m,2H),1.28(s,16H),0.96-0.86(m,3H). 31 P NMR (162 MHz, methanol-d₄) δ 0.17 (t, J = 6.3 Hz). MS: 570.16 (M+1). Example 28: O-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl)O-((R)-2-(benzyloxy)-3-(octadecyloxy)propyl)S-hydrogen (R) phosphorothioate (28): [ka]

[0398] 1,8-Diazabicyclo[5.4.0]undec-7-ene (12.8 μL, 85.5 μmol) was added via syringe to a vigorously stirred mixture of Intermediate 6-1 (24.7 mg, 3.02 μmol), (2S)-2-benzyloxy-3-octadecoxy-propan-1-ol (37.2 mg, 85.5 μmol), and tetrahydrofuran (0.5 mL) over 1 minute at room temperature. After 30 minutes, concentrated hydrochloric acid (0.18 mL) was added. After 2 hours, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give Compound 28. 1 H NMR (400MHz, methanol-d4) δ7.91(s,1H),7.39-7.18(m,5H),6.98-6.90(m,2H), 4.95(t,J=4.1Hz,1H),4.79(d,J=2.8Hz,1H),4.60(s,1H),4.50-4.30(m,2H), 4.29-4.14(m,1H),3.84-3.75(m,1H),3.55-3.48(m,3H),3.45-3.37(m,3H),3 .20-3.13(m,1H),1.52(s,2H),1.29(d,J=8.3Hz,30H),0.92(t,J=6.7Hz,3H). LCMS:802.4. Intermediate 29-1: (R)-2-((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-yl)oxy)-5-methylisophthalonitrile: [ka]

[0399] A solution of potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 490 μL, 490 μmol) was added via syringe to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (150 mg, 327 μmol) in tetrahydrofuran (0.5 mL) at 0° C. After 5 minutes, a solution of 5-(iodomethyl)isophthalonitrile (437 mg, 1.63 mmol) in tetrahydrofuran (2.0 mL) was added via syringe, and the resulting mixture was allowed to warm to room temperature. After 16 hours, saturated aqueous ammonium chloride (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 10% ethyl acetate in hexanes) to give intermediate 29-1. LCMS: 621.5 [M+Na] + . Intermediate 29-2: (S)-2-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)-5-methylisophthalonitrile: [ka]

[0400] Intermediate 29-2 was synthesized in the same manner as Intermediate 2-2, using Intermediate 29-1 instead of Intermediate 2-1. LCMS: 507.4 [M+Na] + . Intermediate 29-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-(2,6-dicyano-4-methylphenoxy)-3-(octadecyloxy)propyl)phosphate: [ka]

[0401] Intermediate 29-3 and intermediate 26-3 were synthesized in the same manner as for intermediate 23-2, using intermediate 29-2 instead of intermediate 23-1. LCMS: 988.4. Example 29: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(2,6-dicyano-4-methylphenoxy)-3-(octadecyloxy)propyl)hydrogenphosphate (29): [ka]

[0402] Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 300 μL, 300 μmol) was added via syringe to a vigorously stirred mixture of intermediate 29-3 (23.6 mg, 23.9 μmol), 4-(dimethylamino)pyridine (29.2 mg, 239 μmol), water (45.0 μL, 2.50 mmol), and tetrahydrofuran (0.1 mL) at room temperature. After 82 min, chlorotrimethylsilane (38.2 μL, 301 μmol) and concentrated hydrochloric acid (300 μL, 3.60 mmol) were added sequentially. After 140 min, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give compound 29. 1 H NMR (400MHz, methanol-d4) δ8.05(s,1H),7.90-7.70(m,2H),7.32-7.23(m,1H),7.21-7.12(m,1H) ,5.00-4.62(m,3H),4.57-3.40(m,9H),2.37(s,3H),1.56-1.04(m,32H),0.92(t,J=6.6Hz,3H). LCMS:836.4[MH] - . Intermediate 30-1: (S)-N-(1-hydroxy-3-(octadecyloxy)propan-2-yl)benzamide: [ka]

[0403] Benzoyl chloride (10.1 μL, 87.3 μmol) was added via syringe to a vigorously stirred mixture of Intermediate 1-2 (30.0 mg, 87.3 μmol), triethylamine (36.5 μL, 262 μmol), and dichloromethane (0.8 mL) at room temperature. After 30 minutes, the resulting mixture was purified by flash column chromatography on silica gel (0-65% ethyl acetate in hexanes) to give Intermediate 30-1. LCMS: 470.4 [M+Na] + . Example 30: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-benzamido-3-(octadecyloxy)propyl)hydrogenphosphate: (30): [ka]

[0404] Compound 30 was synthesized in the same manner as compound 6, using intermediate 30-1 instead of intermediate 6-3. 1 H NMR (400MHz, methanol-d4) δ8.05(s,1H),7.89-7.83(m,2H),7.56-7.49(m,1H),7.45(dd,J=8. 3,6.7Hz,2H),7.28(d,J=4.8Hz,1H),7.18(d,J=4.7Hz,1H),4.78(d,J=5.2Hz,1H),4.38-4.2 9(m,2H),4.26(t,J=5.3Hz,1H),4.16(dt,J=8.2,4.0Hz,1H),4.12-4.04(m,1H),4.00(t,J=5 .6Hz,2H),3.62-3.25(m,4H),1.61-1.49(m,2H),1.41-1.20(m,30H),0.92(t,J=6.7Hz,3H). LCMS:799.4[MH] - . Intermediate 31-1: (S)-2-((1-hydroxy-3-(octadecyloxy)propan-2-yl)amino)benzoic acid: [ka]

[0405] Potassium phosphate (48.2 mg, 227 μmol) was added to a vigorously stirred mixture of Intermediate 1-2 (30.0 mg, 87.3 μmol), copper(I) iodide (5.0 mg, 26 μmol), 2-bromobenzoic acid (17.6 mg, 87.3 μmol), (±)-1,1′-binaphthalene-2,2′-diol (15.0 mg, 52.4 μmol), and N,N-dimethylformamide (0.6 mL) at room temperature. After 21 h, the resulting mixture was heated to 100 °C. After 150 min, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL), ethyl acetate (20 mL), and aqueous citric acid (10 wt%, 10 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 55% ethyl acetate in hexanes) to give intermediate 31-1. LCMS: 462.4 [MH] - . Example 31: 2-(((2R)-1-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3-(octadecyloxy)propan-2-yl)amino)benzoic acid (31): [ka]

[0406] Compound 31 was synthesized in the same manner as compound 6, using intermediate 31-1 instead of intermediate 6-3. 1H NMR (400 MHz, methanol-d4) δ 7.94 (s, 1H), 7.85 (dd, J = 8.0, 1.7 Hz, 1H), 7.31-7.22 (m, 1H), 7.15-7.00 (m, 2H), 6.79 (d, J = 8.6 Hz, 1H), 6.52 (t, J = 7.5 Hz, 1H), 4.82 (d, J = 5.2 Hz, 1H), 4.42-4.33 (m, 1H), 4.29 (t, J = 5.3 Hz, 1H), 4.25-4.14(m,1H),4.14-4.04(m,1H),4.03-3.95(m,1H),3.95-3.77(m,2H),3.64(dd,J=9.6,4.4Hz,1H),3. 57(dd,J=9.8,4.8Hz,1H),3.46(t,J=6.5Hz,2H),1.61-1.50(m,2H),1.41-1.22(m,30H),0.95-0.87(m,3H). LCMS:815.4[MH] - . Intermediate 32-1: (R)-(2-((3-bromo-5-fluorobenzyl)oxy)-3-(octadecyloxy)propoxy)(tert-butyl)dimethylsilane: Intermediate 33-1: (R)-((1-((3-bromo-5-fluorobenzyl)oxy)-3-(octadecyloxy)propan-2-yl)oxy)(tert-butyl)dimethylsilane: [ka]

[0407] Sodium hydride (60 wt% dispersion in mineral oil, 109 mg, 2.7 mmol) was added to a vigorously stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (500 mg, 1.09 mmol) in tetrahydrofuran (3.0 mL) at 0°C. After 30 min, 1-bromo-3-(bromomethyl)-5-fluorobenzene (438 mg, 1.63 mmol) was added, and the resulting mixture was warmed to room temperature. After 9.5 h, saturated aqueous ammonium chloride solution (6 mL), water (6 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-8% ethyl acetate in hexane) to give a mixture of intermediate 32-1 and intermediate 33-1. LCMS: 667.4 [M+Na] + . Intermediate 32-2: (S)-2-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3-(octadecyloxy)propan-1-ol: Intermediate 33-2: (R)-1-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3-(octadecyloxy)propan-2-ol: [ka]

[0408] Sodium methanesulfinate (47.4 mg, 465 μmol) was added to a vigorously stirred mixture of Intermediate 69-1 (200 mg, 310 μmol), (±)-trans-1,2-diaminocyclohexane (14.9 μL, 124 μmol), trifluoromethanesulfonate copper(I) benzene complex (9.0 mg, 31 μmol), tetrahydrofuran (0.2 mL), and dimethyl sulfoxide (1.0 mL) at room temperature, and the resulting mixture was heated to 110 °C. After 17 h, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL), ethyl acetate (20 mL), and aqueous ammonia (30 wt%, 10 mL) were added sequentially. The organic layer was washed with water (2 × 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.5 mL), and the resulting mixture was stirred at room temperature. Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 929 μL, 930 μmol) was added via syringe. After 30 minutes, saturated aqueous ammonium chloride solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 40% ethyl acetate in hexanes) to give Intermediate 32-2 and Intermediate 33-2. Intermediate 32-2: LCMS: 531.3. Intermediate 33-2: LCMS: 531.3. Example 32: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3-(octadecyloxy)propyl)hydrogenphosphate (32). [ka]

[0409] Compound 32 was synthesized in the same manner as compound 6, using intermediate 32-2 instead of intermediate 6-3. 1H NMR (400MHz, methanol-d4) δ8.09(s,1H),7.73(d,J=1.4Hz,1H),7.56(dt,J=7.9,2.0Hz,1H),7.51(dt,J=9.3,1.8Hz ,1H),7.34(d,J=4.8Hz,1H),7.20(d,J=4.8Hz,1H),4.84(d,J=13.3Hz,1H),4.78(d,J=13.2Hz,1H),4.74(d,J=5.2 Hz,1H),4.42-4.33(m,1H),4.30-4.19(m,2H),4.19-4.05(m,2H),4.05-3.96(m,1H),3.89-3.79(m,1H),3.64-3.5 2(m,2H),3.47(td,J=6.6,2.1Hz,2H),3.14(s,3H),1.63-1.50(m,2H),1.41-1.21(m,30H),0.92(t,J=6.7Hz,3H). LCMS:882.4[MH] - . Example 33: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-1-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3-(octadecyloxy)propan-2-yl)hydrogenphosphate (33). [ka]

[0410] Compound 33 was synthesized in the same manner as compound 6, using intermediate 33-2 instead of intermediate 6-3. 1 H NMR (400MHz, methanol-d4) δ8.03(s,1H),7.71(s,1H),7.67-7.44(m,2H),7.33-7.22(m,1H),7.21-7.15(m,1H),5.37-5.32(m,1H), 4.95-4.68(m,3H),4.41-3.73(m,6H),3.72-3.37(m,4H),3.13(s,3H),1.76-1.40(m,2H),1.37-1.19(m,30H),1.01-0.83(m,3H). LCMS:882.4[MH] - . Intermediate 34-1: (S)-4-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)-2,6-dimethoxybenzonitrile: [ka]

[0411] Sodium hydride (60 wt% dispersion in mineral oil, 68.1 mg, 1.70 mmol) was added to a vigorously stirred solution of (R)-1-(octadecyloxy)-3-(trityloxy)propan-2-ol (WO 2010052718) (400 mg, 682 μmol) in tetrahydrofuran (2.0 mL) at room temperature. After 23 minutes, 4-chloro-2,6-dimethoxybenzonitrile (Li, W; Sun, PJ Org. Chem. 2012, 77, 8362) (202 mg, 1.02 mmol) and N,N-dimethylformamide (3.0 mL) were added sequentially, and the resulting mixture was heated to 90°C. After 31 minutes, the resulting mixture was cooled to room temperature. After 30 minutes, 2-propanol (3.0 mL), methanol (3.0 mL), and concentrated hydrochloric acid (0.6 mL) were added sequentially, and the resulting mixture was heated to 50°C. After 120 minutes, the resulting mixture was cooled to room temperature. Saturated aqueous sodium bicarbonate (30 mL), diethyl ether (100 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 x 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% to 45% ethyl acetate in hexanes) to give intermediate 34-1. LCMS: 506.4. Intermediate 34-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-(4-cyano-3,5-dimethoxyphenoxy)-3-(octadecyloxy)propyl)phosphate: [ka]

[0412] 2-Chlorophenyl phosphorodichloridate (625 μL, 3.80 mmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (557 mg, 8.07 mmol), triethylamine (1.12 mL, 8.07 mmol), pyridine (1.0 mL), and acetonitrile (2.5 mL) at room temperature over 1 min. After 25 min, a mixture of Intermediate 34-1 (1.20 g, 2.37 mmol), pyridine (5.0 mL), and acetonitrile (1.5 mL) was added via syringe. After 76 min, Intermediate 1-4 (1.89 g, 5.69 mmol), 1-methylimidazole (567 μL, 7.12 mmol), and acetonitrile (2.0 mL) were added sequentially. After 410 minutes, a solution of citric acid (6.0 g) in water (80 mL) was added, and the aqueous layer was extracted with ethyl acetate (120 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-5% methanol in dichloromethane) to give intermediate 34-2. LCMS: 1009.5. Example 34: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-(4-cyano-3,5-dimethoxyphenoxy)-3-(octadecyloxy)propyl)hydrogenphosphate (34). [ka]

[0413] Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 3.00 mL, 3.0 mmol) was added via syringe to a stirred mixture of Intermediate 34-2 (2.02 g, 2.00 mmol), 4-(dimethylamino)pyridine (733 mg, 6.00 mmol), tetrahydrofuran (1.5 mL), and water (541 μL, 30.0 mmol) at room temperature, and the resulting mixture was heated to 50 °C. After 18 min, the resulting mixture was cooled to room temperature, and chlorotrimethylsilane (381 μL, 3.00 mmol) and concentrated hydrochloric acid (4.80 mL, 58 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in methanol / water) to give Compound 34. 1 H NMR (400MHz, methanol-d4) δ8.10(s,1H),7.37(d,J=4.8Hz,1H),7.16(d,J=4.8Hz,1H),6.34(s,2 H),4.87-4.79(m,1H),4.70(d,J=5.3Hz,1H),4.37(dq,J=4.5,2.5Hz,1H),4.27(ddd,J=11.6,5 .7,3.0Hz,1H),4.21-4.10(m,4H),3.88(s,6H),3.72(dd,J=10.8,4.0Hz,1H),3.66(dd,J=10.8 ,5.8Hz,1H),3.56-3.41(m,2H),1.60-1.48(m,2H),1.39-1.23(m,30H),0.92(t,J=6.7Hz,3H). LCMS:857.4[MH] - . Intermediate 35-1: (R)-1-((tert-butyldiphenylsilyl)oxy)henicosan-2-ol: [ka]

[0414] To a mixture of tert-butyl-[[(2R)-oxiran-2-yl]methoxy]-diphenyl-silane (2.00 g, 6.40 mmol) (Jiri, P.; Istvan, MEtetrahedron Lett. 2006, 47, 5933) and copper(I) iodide (244 mg, 1.28 mmol) in tetrahydrofuran (20 mL) at 0 °C, chloro(octadecyl)magnesium (0.5 M in THF, 19.2 mL, 9.60 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was then quenched with saturated aqueous ammonium chloride solution (50 mL) at 0 °C and diluted with diethyl ether (100 mL). The aqueous phase was then extracted with additional diethyl ether (2 × 50 mL), and the pooled organic fractions were washed with brine (50 mL) and then dried over magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography (0-20% ethyl acetate in hexanes) to give intermediate 35-1. 1 H NMR (400 MHz, chloroform-d) δ 7.67 (dt, J = 7.9, 1.5 Hz, 4H), 7.47-7.35 (m, 6H), 3.75-3.60 (m, 2H), 3.48 (dd, J = 10.0, 7.4 Hz, 1H), 1.45-1.16 (m, 36H), 1.07 (s, 9H), 0.88 (t, J = 6.8 Hz, 3H). Intermediate 35-2: (R)-3-(((1-((tert-butyldiphenylsilyl)oxy)henicosan-2-yl)oxy)methyl)-5-fluorobenzonitrile: [ka]

[0415] Sodium hydride (60 wt% dispersion in mineral oil, 516 mg, 13.5 mmol) was added to a stirred solution of 35-1 (3.06 g, 5.39 mmol) in tetrahydrofuran (24 mL) at 0 °C. After 30 min, 3-(bromomethyl)-5-fluorobenzonitrile (1.73 g, 8.09 mmol) was added, and the resulting mixture was warmed to 55 °C and stirred overnight. The suspension was then cooled to 0 °C, quenched with water (20 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic fractions were washed with brine (25 mL) and dried over magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0–30% ethyl acetate in hexanes) to give intermediate 35-2. 1 H NMR (400MHz, chloroform-d) δ7.73-7.61(m,4H),7.53-7.20(m,9H),4.72(d,J=12.9Hz,1H),4.56(d,J=12.9 Hz,1H),3.83-3.62(m,2H),3.55-3.46(m,1H),1.73-1.15(m,36H),1.08(s,9H),0.91(t,J=6.8Hz,3H). Intermediate 35-3: (R)-3-fluoro-5-(((1-hydroxyhenicosan-2-yl)oxy)methyl)benzonitrile: [ka]

[0416] Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 6.03 mL, 6.03 mmol) was added to a stirred solution of intermediate 35-2 (3.52 g, 5.03 mmol) in tetrahydrofuran (20 mL) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 1 h, at which point water (20 mL) was added and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic fractions were washed with brine (25 mL) and dried over magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0 to 50% ethyl acetate in hexanes) to give intermediate 35-3. 1H NMR (400 MHz, chloroform-d) δ 7.47 (s, 1H), 7.36 (dt, J = 9.1, 1.7 Hz, 1H), 7.32-7.23 (m, 1H), 4.65 (s, 2H), 3.77 (dd, J = 11.6, 3.2 Hz, 1H), 3.63 (dd, J = 11.6, 6.3 Hz, 1H), 3.55 (qd, J = 6.2, 3.2 Hz, 1H), 1.85-1.05 (m, 36H), 0.90 (t, J = 6.7 Hz, 3H). Intermediate 35-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-5-fluorobenzyl)oxy)henicosyl)phosphate: [ka]

[0417] 2-Chlorophenyl phosphorodichloridate (505 μL, 3.07 mmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (455 mg, 6.59 mmol), triethylamine (919 μL, 6.59 mmol), acetonitrile (6 mL), and pyridine (6 mL) at room temperature. After 40 min, intermediate 35-3 (1.42 g, 3.07 mmol) in acetonitrile (6 mL) and pyridine (6 mL) was added and stirred at room temperature for 1 h. Then, (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (864 mg, 2.61 mmol) was added in one portion, and the resulting suspension was stirred at room temperature. After 15 h, the mixture was concentrated, and to the resulting product was added citric acid (20 mL, 20 wt % in water), sodium hydroxide (5 mL, 1N), and ethyl acetate (100 mL). The aqueous phase was extracted with additional ethyl acetate (2 × 50 mL), and the combined organic fractions were washed with brine (50 mL) and dried over magnesium sulfate. After filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0–15% methanol in dichloromethane) to give intermediate 35-4. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.94-7.86 (m, 1H), 7.54-7.32 (m, 5H), 7.24-7.10 (m, 2H), 6.94-6.83 (m, 1H), 6.80-6.70 (m, 1H), 6.37 (s, 2H), 5.44-5.24 (m, 1H), 5.02-4.86 (m, 1H), 4.73-4.30 (m, 5H), 4.29-4.16 (m, 1H), 4.13-4.02 (m, 1H), 3.68-3.52 (m, 1H), 1.69-1.66 (m, 3H), 1.55-1.17 (m, 3H), 0.90 (t, J = 6.6 Hz, 3H). LCMS:965.4. Intermediate 35-5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl((R)-2-((3-cyano-5-fluorobenzyl)oxy)henicosyl)hydrogenphosphate: [ka]

[0418] To a solution of 35-4 (2.25 g, 2.23 mmol) and N,N-dimethylpyridin-4-amine (859 mg, 6.99 mmol) in tetrahydrofuran (10 mL) and acetonitrile (5 mL) at room temperature was added cesium fluoride (1062 mg, 6.99 mmol) in water (2.2 mL). The mixture was warmed to 80 °C and stirred for 2 h. Sodium hydroxide (1 N, 2.5 mL) and citric acid (20 wt% in water, 12.5 mL) were then added sequentially, and the mixture was extracted with a 3:2 mixture of 2-methyltetrahydrofuran and ethyl acetate (3 × 50 mL). The pooled organic fractions were then washed with brine (50 mL) and dried over magnesium sulfate. Following filtration and concentration, the residue was purified by flash column chromatography on silica gel (0 to 50% methanol in dichloromethane) to give 35-5. 1 H NMR (400 MHz, methanol-d4) δ 7.88 (s, 1H), 7.50 (s, 1H), 7.45-7.35 (m, 2H), 6.94 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 5.41 (d, J = 6.6 Hz, 1H), 5.06 (dd, J = 6.6, 3.2 Hz, 1H), 4.72 ( d,J=13.0Hz,1H),4.60-4.54(m,1H),4.52(d,J=13.1Hz,1H),4.10-4.02(m,2H),3.90-3 .73(m,2H),3.59-3.44(m,1H),1.72(s,3H),1.48-1.20(m,39H),0.91(t,J=6.8Hz,3H). LCMS:853.5[MH] - . Example 35: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-2-((3-cyano-5-fluorobenzyl)oxy)henicosyl)hydrogenphosphate (35). [ka]

[0419] Concentrated hydrochloric acid (2.00 mL, 24.0 mmol) was added to a solution of 35-5 (1.71 g, 2.00 mmol) in tetrahydrofuran (10 mL). After 3 h, the reaction was cooled to 0 °C and quenched with sodium hydroxide (2.32 mL) and phosphoric acid (0.308 mL). The mixture was extracted with a 3:2 mixture of 2-methyltetrahydrofuran and ethyl acetate (3 × 50 mL). The pooled organic fractions were then washed with brine (50 mL) and dried over magnesium sulfate. Following filtration and concentration, the residue was purified by flash column chromatography on silica gel (0 to 50% methanol in dichloromethane) to give compound 35. 1 H NMR (400MHz, methanol-d4) δ8.05(s,1H),7.51(s,1H),7.47-7.36(m,2H),7.26(d, J=4.7Hz,1H),7.19(d,J=4.8Hz,1H),4.82-4.72(m,2H),4.59(d,J=13.0Hz,1H) ,4.39-4.32(m,1H),4.29-4.14(m,2H),4.14-4.03(m,1H),3.98-3.90(m,1H),3 .90-3.80(m,1H),3.66-3.55(m,1H),1.57-1.21(m,36H),0.92(t,J=6.7Hz,3H). LCMS:813.4[MH] - . Intermediate 36-1: (R)-3-((2-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propoxy)methyl)-5-fluorobenzonitrile: [ka]

[0420] Intermediate 36-1 was prepared in a similar manner to intermediate 33-1, using 5-(bromomethyl)-3-fluorobenzonitrile instead of 1-bromo-3-(bromomethyl)-5-fluorobenzene. LCMS: 614.4 [M+Na]+. Intermediate 36-2: (R)-3-fluoro-5-((2-hydroxy-3-(octadecyloxy)propoxy)methyl)benzonitrile: [ka]

[0421] Intermediate 36-2 was prepared in a similar manner to intermediate 2-2, using intermediate 36-1 instead of intermediate 2-1. LCMS: 478.4. Example 36: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-1-((3-cyano-5-fluorobenzyl)oxy)-3-(octadecyloxy)propan-2-yl)hydrogenphosphate (36): [ka]

[0422] Compound 36 was prepared in a similar manner to compound 33, using intermediate 36-2 instead of intermediate 33-2. H NMR (400 MHz, methanol-d ) δ 8.05 (s, 1H), 7.60-7.37 (m, 3H), 7.24 (d, J = 4.4 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 5.38-5.04 (m, 1H), 4.97-3.87 (m, 9H), 3.83-3.40 (m, 4H), 1.64-1.49 (m, 2H), 1.29 (d, J = 5.6 Hz, 30H), 0.92 (t, J = 6.4 Hz, 3H). LCMS: 829.4 [MH]. Intermediate 37-1: (S)-2-((1-hydroxy-3-(octadecyloxy)propan-2-yl)amino)benzoic acid [ka]

[0423] Potassium phosphate (48.2 mg, 227 μmol) was added to a vigorously stirred mixture of Intermediate 1-2 (30.0 mg, 87.3 μmol), copper(I) iodide (5.0 mg, 26 μmol), (±)-1,1'-bi(2-naphthol) (15.0 mg, 52.4 μmol), 2-bromobenzoic acid (17.6 mg, 87.3 μmol), and N,N-dimethylformamide (0.6 mL) at room temperature. After 21 h, the resulting mixture was heated to 100 °C. After 150 min, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL), ethyl acetate (20 mL), and aqueous citric acid (10 wt%, 10 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 55% ethyl acetate in hexanes) to give intermediate 37-1. LCMS: 462.4 [M-Na] − . Example 37: 2-(((2R)-1-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyan...

Claims

1. Formula I: 【Chemistry 231】 or a pharma- ceutically acceptable salt thereof, wherein Z １ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＡ R ＺＢ - or -CR ＺＡ R ＺＢ -CR ＺＣ R ＺＤ - and Z ２ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＥ R ＺＦ - or -CR ＺＥ R ＺＦ -CR ＺＧ R ＺＨ - and R ＺＡ , R ＺＣ , R ＺＤ , R ＺＥ , R ＺＧ , and R ＺＨ are each independently H, halo, C １ ~C ３ Alkyl, or C １ ~C ３ is haloalkyl, R ＺＢ and R ＺＦ are each independently halo, C １ ~C ３ Alkyl, or C １ ~C ３ is haloalkyl, X is a bond, —O—, —OCO—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) -, - (CR １２Ａ R １２Ｂ ) ｑ -O-(CR １２Ａ R １２Ｂ ) ｑ -, -S-, (CR １２Ａ R １２Ｂ ) ｐ -NR １２Ｃ - (CR １２Ａ R １２Ｂ ) ｐ - or (CR １２Ａ R １２Ｂ ) ｐ -NR １２Ｃ CO-(CR １２Ａ R １２Ｂ ) ｐ -, wherein Each R １２Ａ are independently H, C １ ~C ６ alkyl, or phenyl; or R ２ and R １２Ａ is linked to a 4- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S; Formation, Each R １２Ｂ are independently H or C １ ~C ６ is alkyl, or R on the same carbon １２Ａ and R １２Ｂ are bonded together to form C ３ ~C ６ Forming a cycloalkylene, R １２Ｃ is H, C １ ~C ３ Alkyl, -COR １２Ｄ , or -SO ２ R １２Ｅ or R １２Ｃ and R １ are joined together to have 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally 1 to 4 R １２Ｆ forming a 5- to 6-membered heterocyclyl substituted with a group, Each R １２Ｆ are independently oxo or halo, or two R on adjacent carbons １２Ｆ are linked to form a fused phenyl optionally substituted with 1 or 2 substituents independently selected from F and Cl; R １２Ｄ is C １ ~C ３ Alkyl, C ６ ~C １０ aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R １２Ｄ optionally 1, 2, or 3 R １２Ｇ is substituted with a group, Each R １２Ｇ is independently １ ~C ３ Alkyl, phenyl, halo, C １ ~C ３ Alkoxy, Cyano, C １ ~C ３ Haloalkyl, or -COOR １２Ｈ and R １２Ｈ is H or C １ ~C ３ is alkyl, R １２Ｅ is H or C １ ~C ３ is alkyl, R １３ is H, C １ ~C ６ alkyl, or phenyl; R １４ is H, C １ ~C ６ alkyl, or phenyl; each q is independently 1 or 2; each p is independently 0, 1, or 2; X １ is a bond, —O—, NR Ｘ , or -CONR Ｘ - or -S-, R Ｘ is H, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, or -C(O)R ＸＡ and R ＸＡ is C １ ~C ３ is alkyl, X ２ is —O— or —S—, X ３ is —O— or —S—, X ４ is ═O or ═S, R １ is H, C １ ~C ２０ Alkyl, C ３ ~C １０ Cycloalkyl, C ６ ~C １０ aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, S, and O, or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R １ is not H, then R １ The group optionally contains one, two, or three R １Ａ is substituted with a group, Each R １Ａ is independently １ ~C ３ Alkyl, phenyl, halo, C １ ~C ３ Alkoxy, cyano, -SO ２ R １Ｂ , -COOR １Ｂ , or C １ ~C ３ haloalkyl, or two R on the same or adjacent carbons １Ａ are joined together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, S, and O; R １Ｂ is H or C １ ~C ３ is alkyl, R ２ is H or C １ ~C ３ is alkyl, Y is a bond, phenylene, or C ３ ~C ６ is cycloalkylene, R ３ is H, C １ ~C ３ Alkyl, halo, C １ ~C ３ Haloalkyl, or C ３ ~C ６ is cycloalkyl, Each R ４ are independently H, C １ ~C ３ Alkyl, halo, C １ ~C ３ Haloalkyl, or C ３ ~C ６ cycloalkyl, or or two R on adjacent carbon atoms ４ the groups, together with the carbons to which they are attached, form a carbon-carbon double bond, Each R ５ are independently H, C １ ~C ３ Alkyl, halo, C １ ~C ３ Haloalkyl, Young Or C ３ ~C ６ cycloalkyl, or R on adjacent carbon atoms ４ Groups and R ５ the groups, together with the carbons to which they are attached, form a carbon-carbon triple 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 an integer from 7 to 21; X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - if (a) Z １ is a bond, -CR ＺＡ R ＺＢ - or -CR ＺＡ R ＺＢ -CR ＺＣ R ＺＤ - or (b) Z ２ is a bond, -CR ＺＥ R ＺＦ - or -CR ＺＥ R ＺＦ -CR ＺＧ R ＺＨ - or (c) R ２ and R １２Ａ combine to form a 4- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S; (d) X １ is a bond, NR Ｘ , or -CONR Ｘ - or -S-, (e) X ２ is -S- or (f) X ３ is -S- or (g) X ４ is =S or (h) R １ is C １ ~C ２０ Alkyl, C ３ ~C １０ cycloalkyl; 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C ６ ~C １０ aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R １ The group is composed of three R １Ａ is substituted with a group, (i) R on adjacent carbon atoms ４ Groups and R ５ The groups, together with the carbons to which they are attached, form a carbon-carbon triple bond, or (j) at least one R １Ａ is -SO ２ R １Ｂ Or -COOR １Ｂ or (k) m is 7, 8, or 9; However, the compound is as follows: 【Chemistry 1】 (wherein R is CH 3 (CH 2 ) 15 O(CH 2 ) 3 -- or CH 3 (CH 2 ) 17 O(CH 2 ) 2 --), A compound, or a pharma- ceutically acceptable salt thereof.

2. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ 2. The compound of claim 1, wherein R 1 is -R 2 , or a pharma- ceutically acceptable salt thereof.

3. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and Z １ is a bond, -CR ＺＡ R ＺＢ - or -CR ＺＡ R ＺＢ -CR ＺＣ R ＺＤ 3. The compound according to claim 1 or 2, wherein: -, or a pharma- ceutically acceptable salt thereof.

4. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and Z ２ is a bond, -CR ＺＥ R ＺＦ - or -CR ＺＥ R ＺＦ -CR ＺＧ R ＺＨ 3. The compound according to claim 1 or 2, wherein:

5. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and R ２ and R １２Ａ or a pharma- ceutically acceptable salt thereof. The compound of claim 1 or 2, wherein:

6. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and X １ is a bond, NR Ｘ , or -CONR Ｘ 3. The compound according to claim 1 or 2, which is -, or -S-, or a pharma- ceutically acceptable salt thereof.

7. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and X ２ The compound according to claim 1 or 2, wherein is -S-, or a pharma- ceutically acceptable salt thereof.

8. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and X ３ The compound according to claim 1 or 2, wherein is -S-, or a pharma- ceutically acceptable salt thereof.

9. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and X ４ 3. The compound of claim 1 or 2, wherein: is =S, or a pharma- ceutically acceptable salt thereof.

10. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and R １ is C １ ~C ２０ Alkyl, C ３ ~C １０ cycloalkyl; 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C ６ ~C １０ aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R １ The group is composed of three R １Ａ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein the compound is substituted with a group.

11. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and R on adjacent carbon atoms ４ Groups and R ５ 3. The compound of claim 1 or 2, wherein the groups, together with the carbon to which they are attached, form a carbon-carbon triple bond, or a pharma- ceutically acceptable salt thereof.

12. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and At least one R １Ａ is -SO ２ R １Ｂ , -COOR １Ｂ 3. The compound of claim 1 or 2, wherein:

13. X is a bond, —O—, —(CR １２Ａ R １２Ｂ ) ｑ -, -O(CR １２Ａ R １２Ｂ ) ｑ --or--OCR １２Ａ R １２Ｂ - (CR １３ =CR １４ ) - and 3. The compound of claim 1 or 2, wherein m is 7, 8, or 9, or a pharma- ceutically acceptable salt thereof.

14. Z １ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＡ R ＺＢ - or -CR ＺＡ R ＺＢ -CR ＺＣ R ＺＤ - and Z ２ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＥ R ＺＦ - or -CR ＺＥ R ＺＦ -CR ＺＧ R ＺＨ - and R ＺＡ , R ＺＣ , R ＺＤ , R ＺＥ , R ＺＧ , and R ＺＨ are each independently H, halo, C １ ~C ３ Alkyl, or C １ ~C ３ is haloalkyl, R ＺＢ and R ＺＦ are each independently halo, C １ ~C ３ Alkyl, or C １ ~C ３ is haloalkyl, X is -OCO-, -(CR １２Ａ R １２Ｂ ) ｑ -O-(CR １２Ａ R １２Ｂ ) ｑ -, -S-, (CR １２Ａ R １２Ｂ ) ｐ -NR １２Ｃ - (CR １２Ａ R １２Ｂ ) ｐ - or (CR １２Ａ R １２Ｂ ) ｐ -NR １２Ｃ CO-(CR １２Ａ R １２Ｂ ) ｐ -, wherein Each R １２Ａ are independently H, C １ ~C ６ alkyl, or phenyl; or R ２ and R １２Ａ combine to form a 4- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S; Each R １２Ｂ are independently H or C １ ~C ６ is alkyl, or R on the same carbon １２Ａ and R １２Ｂ are bonded together to form C ３ ~C ６ Forming a cycloalkylene, R １２Ｃ is H, C １ ~C ３ Alkyl, -COR １２Ｄ , or -SO ２ R １２Ｅ or R １２Ｃ and R １ are joined together to have 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally 1 to 4 R １２Ｆ forming a 5- to 6-membered heterocyclyl substituted with a group, Each R １２Ｆ are independently oxo or halo, or two R on adjacent carbons １２Ｆ are linked to form a fused phenyl optionally substituted with 1 or 2 substituents independently selected from F and Cl; R １２Ｄ is C １ ~C ３ Alkyl, C ６ ~C １０ aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R １２Ｄ optionally 1, 2, or 3 R １２Ｇ is substituted with a group, Each R １２Ｇ is independently １ ~C ３ Alkyl, phenyl, halo, C １ ~C ３ Alkoxy, Cyano, C １ ~C ３ Haloalkyl, or -COOR １２Ｈ and R １２Ｈ is H or C １ ~C ３ is alkyl, R １２Ｅ is H or C １ ~C ３ is alkyl, R １３ is H, C １ ~C ６ alkyl, or phenyl; R １４ is H, C １ ~C ６ alkyl, or phenyl; each q is independently 1 or 2; each p is independently 0, 1, or 2; X １ is a bond, —O—, NR Ｘ , or -CONR Ｘ - or -S-, R Ｘ is H, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, or -C(O)R ＸＡ and R ＸＡ is C １ ~C ３ is alkyl, X ２ is —O— or —S—, X ３ is —O— or —S—, X ４ is ═O or ═S, R １ is H, C １ ~C ２０ Alkyl, C ３ ~C １０ Cycloalkyl, C ６ ~C １０ aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; R １ is not H, then R １ The group optionally contains one, two, or three R １Ａ is substituted with a group, Each R １Ａ is independently １ ~C ３ Alkyl, phenyl, halo, C １ ~C ３ Alkoxy, cyano, -SO ２ R １Ｂ , -COOR １Ｂ , or C １ ~C ３ haloalkyl, or two R on the same or adjacent carbons １Ａ are joined together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, S, and O; R １Ｂ is H or C １ ~C ３ is alkyl, R ２ is H or C １ ~C ３ is alkyl, Y is a bond, phenylene, or C ３ ~C ６ is cycloalkylene, R ３ is H, C １ ~C ３ Alkyl, halo, C １ ~C ３ Haloalkyl, or C ３ ~C ６ is cycloalkyl, Each R ４ are independently H, C １ ~C ３ Alkyl, halo, C １ ~C ３ Haloalkyl, or C ３ ~C ６ cycloalkyl, or or two R on adjacent carbon atoms ４ the groups, together with the carbons to which they are attached, form a carbon-carbon double bond, Each R ５ are independently H, C １ ~C ３ Alkyl, halo, C １ ~C ３ Haloalkyl, or C ３ ~C ６ cycloalkyl, or R on adjacent carbon atoms ４ Groups and R ５ the groups, together with the carbons to which they are attached, form a carbon-carbon triple 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, The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein m is an integer from 7 to 21.

15. X is (CR １２Ａ R １２Ｂ ) ｐ -NR １２Ｃ - (CR １２Ａ R １２Ｂ ) ｐ - or (CR １２Ａ R １２Ｂ ) ｐ -NR １２Ｃ CO-(CR １２Ａ R １２Ｂ ) ｐ 15. The compound according to claim 1 or 14, wherein: -, or a pharma- ceutically acceptable salt thereof.

16. X is -(CR １２Ａ R １２Ｂ ) ｐ -NR １２Ｃ CO-(CR １２Ａ R １２Ｂ ) ｐ 16. The compound of claim 1, 14, or 15, wherein:

17. X is -(CR １２Ａ R １２Ｂ ) ｐ -NR １２Ｃ - (CR １２Ａ R １２Ｂ ) ｐ 16. The compound of claim 1, 14, or 15, wherein:

18. 18. The compound of any one of claims 1 and 14-17, or a pharma- ceutically acceptable salt thereof, wherein each p is independently 0 or 1.

19. 19. The compound of any one of claims 1 and 14 to 18, or a pharma- ceutically acceptable salt thereof, wherein each p is 0.

20. R １２Ｃ is H, C １ ~C ３ Alkyl, or -COR １２Ｄ 20. The compound according to any one of claims 1 and 14 to 19, wherein:

21. R １２Ｄ is methyl, or a pharma- ceutically acceptable salt thereof.

22. R １２Ｃ is H, methyl, or -COCH ３ 22. The compound according to any one of claims 1 and 14 to 21, wherein:

23. R １２Ｃ and R １ are joined together to have 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally 1 to 4 R １２Ｆ R 1 , R 2 , R 3 , R 4 , R 5 , R 6 １２Ｆ are independently oxo or halo, or two R on adjacent carbons １２Ｆ are linked to form a fused phenyl optionally substituted with 1 or 2 substituents independently selected from F and Cl, or a pharma- ceutically acceptable salt thereof.

24. Each p is 0 and X is -NR １２Ｃ - and R １２Ｃ and R １ are joined together, 【Chemistry 232】 24. The compound of claim 23, which forms:

25. X is a bond, —O—, —S—, or —CH ２ O-, -NH-, -N(C(O)CH ３ ) -, -NCH ３ -, or -N(CH ３ 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein:

26. Z １ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＡ R ＺＢ - or -CR ＺＡ R ＺＢ -CR ＺＣ R ＺＤ - and Z ２ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＥ R ＺＦ - or -CR ＺＥ R ＺＦ -CR ＺＧ R ＺＨ - and R ＺＡ , R ＺＣ , R ＺＤ , R ＺＥ , R ＺＧ , and R ＺＨ are each independently H or C １ ~C ３ is alkyl, R ＺＢ and R ＺＦ are each independently １ ~C ３ 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, which is alkyl.

27. Z １ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＡ R ＺＢ - or -CR ＺＡ R ＺＢ -CR ＺＣ R ＺＤ - and Z ２ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＥ R ＺＦ - or -CR ＺＥ R ＺＦ -CR ＺＧ R ＺＨ - and R ＺＡ , R ＺＣ , R ＺＤ , R ＺＥ , R ＺＧ , and R ＺＨ are each independently H or methyl; R ＺＢ and R ＺＦ and R are both methyl, or a pharma- ceutically acceptable salt thereof.

28. Z １ is a bond, -CH ２ --, --CH ２ -CH ２ - or -CR ＺＡ R ＺＢ - and Z ２ is a bond, -CH ２ --, --CH ２ -CH ２ -, -CR ＺＥ R ＺＦ - and R ＺＡ and R ＺＥ are each independently H or methyl; R ＺＢ and R ＺＦ and R are both methyl, or a pharma- ceutically acceptable salt thereof.

29. Z １ is a bond, -CH ２ --, --CH ２ -CH ２ - or -CH(CH ３ )-, and Z ２ is a bond, -CH ２ --, --CH ２ -CH ２ - or -CH(CH ３ 29. The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein:

30. Z １ Ha-CH ２ - and Z ２ Ha-CH ２ 30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein:

31. Z １ -C(CH ３ ) H-; Z ２ Ha-CH ２ 30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein:

32. Z １ Ha-CH ２ - and Z ２ -C(CH ３ 30. The compound according to any one of claims 1 to 29, wherein R is H-, or a pharma- ceutically acceptable salt thereof.

33. Z １ Ha-CH ２ - and Z ２ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein: is a bond.

34. Z １ is a bond, and Z ２ Ha-CH ２ 30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein:

35. X １ is a bond, —O—, —NR ｘ or S, or a pharma- ceutically acceptable salt thereof.

36. X １ is a bond, -O-, or S, or a pharma- ceutically acceptable salt thereof.

37. X １ is a bond or -O-, or a pharma- ceutically acceptable salt thereof.

38. X １ The compound of any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof, wherein: is a bond.

39. X １ is -NR ｘ Or -CONR Ｘ 35. The compound according to any one of claims 1 to 34, wherein: -, or a pharma- ceutically acceptable salt thereof.

40. R ｘ is C １ ~C ３ Alkyl or -C(O)R ＸＡ 40. The compound according to any one of claims 1 to 39, wherein:

41. R ｘ is C １ ~C ３ 41. The compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, which is alkyl.

42. R ｘ is methyl, or a pharma- ceutically acceptable salt thereof.

43. R ｘ is -C(O)R ＸＡ 43. The compound according to any one of claims 1 to 42, wherein:

44. R ＸＡ is methyl, or a pharma- ceutically acceptable salt thereof.

45. X １ is O; or a pharma- ceutically acceptable salt thereof.

46. X １ is S; or a pharma- ceutically acceptable salt thereof.

47. A compound according to any one of claims 1 to 38, wherein the compound is a compound of formula Ia or a pharma- ceutically acceptable salt thereof 【Chemistry 233】

48. X ２ is S; or a pharma- ceutically acceptable salt thereof.

49. X ２ is O; or a pharma- ceutically acceptable salt thereof.

50. X ３ is S; or a pharma- ceutically acceptable salt thereof.

51. X ３ is O; or a pharma- ceutically acceptable salt thereof.

52. X ４ is S; or a pharma- ceutically acceptable salt thereof.

53. X ４ is O; or a pharma- ceutically acceptable salt thereof.

54. R ２ is H; or a pharma- ceutically acceptable salt thereof.

55. R ２ is C １ ~C ３ 54. The compound of any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, which is alkyl.

56. R ２ 56. The compound according to any one of claims 1 to 53 and 55, or a pharma- ceutically acceptable salt thereof, wherein:

57. R １ H, 【Chemical 234】 57. The compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

58. R １ is H; or a pharma- ceutically acceptable salt thereof.

59. R １ optionally 1, 2, or 3 R １Ａ C substituted by a group ６ ~C １０ 57. The compound of any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, which is aryl.

60. X ２ is O and X ３ is O and X ４ is O, and R ２ is H, and R １ optionally 1, 2, or 3 R １Ａ C substituted with a group ６ ~C １０ 60. The compound of claims 47 and 59, which is aryl.

61. Each R ６ and R ７ is H; or a pharma- ceutically acceptable salt thereof.

62. R ３ is H or C １ ~C ３ is alkyl, Each R ４ are independently H or C １ ~C ３ Is it an alkyl group? Each R ５ are independently H or C １ ~C ３ is alkyl, or R on adjacent carbon atoms ４ Groups and R ５ the groups, together with the carbons to which they are attached, form a carbon-carbon triple bond; 62. The compound according to any one of claims 1 to 61, or a pharma- ceutically acceptable salt thereof, wherein m is an integer from 8 to 20.

63. R ３ is H, Each R ４ is H or Each R ５ is H, or R on adjacent carbon atoms ４ Groups and R ５ the groups, together with the carbons to which they are attached, form a carbon-carbon triple bond; 63. The compound according to any one of claims 1 to 62, or a pharma- ceutically acceptable salt thereof, wherein m is an integer from 10 to 20.

64. R ３ is H, Each R ４ is H, Each R ５ is H, 64. The compound according to any one of claims 1 to 63, or a pharma- ceutically acceptable salt thereof, wherein m is an integer from 14 to 20.

65. R ３ is H, Each R ４ is H, Each R ５ is H, 65. The compound according to any one of claims 1 to 64, wherein m is 17, 18, or 19, or a pharma- ceutically acceptable salt thereof.

66. 66. The compound of any one of claims 1 to 65, or a pharma- ceutically acceptable salt thereof, wherein m is 17.

67. 66. The compound of any one of claims 1 to 65, or a pharma- ceutically acceptable salt thereof, wherein m is 18.

68. 66. The compound of any one of claims 1 to 65, or a pharma- ceutically acceptable salt thereof, wherein m is 19.

69. Each R １Ａ is independently １ ~C ３ Alkyl, cyano, halo, or C １ ~C ３ 69. The compound of any one of claims 1 to 68, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

70. Each R １Ａ is independently halo or cyano, or a pharma- ceutically acceptable salt thereof.

71. Each R １Ａ is independently fluoro, chloro, or cyano, or a pharma- ceutically acceptable salt thereof.

72. The compound is 【Chemistry 235】 【Chemistry 236】 【Chemical 237】 【Chemical 238】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

73. The compound is 【Chemical 239】 【Chemistry 240】 【Chemistry 241】 【Chemical 242】 【Chemical 243】 【Chemical 244】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

74. The compound is 【Chemistry 245】 【Chemical Formula 246】 【Chemical 247】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

75. The compound is 【Chemical 248】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

76. The compound is 【Chemical 249】 【Chemistry 250】 【Chemistry 251】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

77. The compound is 【Chemistry 252】 【Chemistry 253】 【Chemical 254】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

78. The compound is 【255】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

79. The compound is 【256】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

80. The compound has the formula: 【Chemistry 257】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

81. The compound has the formula: 【Chemistry 258】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

82. The compound has the formula: 【Chemical 259】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

83. The compound has the formula: 【Chemistry 260】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

84. The compound has the formula: 【Chemical 261】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

85. The compound has the formula: 【Chemical 262】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

86. The compound has the formula: 【Chemical 263】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

87. The compound is 【Chemical 264】 【Chemistry 265】 72. The compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

88. 88. A pharmaceutical formulation comprising a pharma- ceutical effective amount of a compound according to any one of claims 1 to 87, or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier or excipient.

89. 89. The pharmaceutical formulation of claim 88, wherein the pharmaceutical formulation is for subcutaneous administration.

90. 89. The pharmaceutical formulation of claim 88, wherein the pharmaceutical formulation is for intravenous administration.

91. 89. The pharmaceutical formulation of claim 88, wherein the pharmaceutical formulation is for oral administration.

92. 90. The pharmaceutical formulation of claim 88, wherein the pharmaceutical formulation is for administration by inhalation.

93. 88. A composition for the treatment or prevention of a viral infection in a human in need thereof, comprising a compound according to any one of claims 1 to 87, or a pharma- ceutically acceptable salt thereof.

94. 94. The composition of claim 93, wherein the composition is administered to the human orally, intravenously, subcutaneously, or by inhalation.

95. 95. The composition of claim 93 or 94, wherein the composition is administered in combination with at least one additional therapeutic or prophylactic agent.

96. The composition of any one of claims 93 to 95, wherein the viral infection is a coronavirus infection.

97. The composition of any one of claims 93 to 96, wherein the viral infection is a zoonotic coronavirus infection.

98. 98. The composition of any one of claims 93-97, wherein the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase, and SARS-CoV-2.

99. 99. The composition of any one of claims 93-98, wherein the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase, and SARS-CoV-2.

100. 100. The composition of any one of claims 93-99, wherein the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase, and SARS-CoV-2.

101. 101. The composition of any one of claims 93-100, wherein the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase, and SARS-CoV-2.

102. 97. The composition of any one of claims 93 to 96, wherein the viral infection is selected from the group consisting of a 229E viral infection, an NL63 viral infection, an OC43 viral infection, and an HKU1 viral infection.

103. The composition of any one of claims 93 to 101, wherein the viral infection is a SARS-CoV-2 infection.

104. The composition of any one of claims 93 to 101, wherein the viral infection is a SARS virus infection.

105. The composition of any one of claims 93 to 101, wherein the viral infection is a MERS virus infection.

106. The composition of any one of claims 93 to 95, wherein the viral infection is a Pneumoviridae virus infection.

107. The composition of claim 106, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

108. The composition of claim 106, wherein the Pneumoviridae virus infection is a human metapneumovirus infection.

109. The composition of any one of claims 93 to 95, wherein the viral infection is a Picornaviridae virus infection.

110. 110. The composition of claim 109, wherein the viral infection is an enterovirus infection.

111. 111. The composition of claim 109 or 110, wherein the viral infection is selected from the group consisting of a Coxsackie A virus infection, a Coxsackie A virus infection, an Enterovirus D68 infection, an Enterovirus B69 infection, an Enterovirus D70 infection, an Enterovirus A71 infection, and a poliovirus infection.

112. The composition of claim 109, wherein the Picornaviridae virus infection is a human rhinovirus infection.

113. The composition of any one of claims 93 to 95, wherein the viral infection is a Flaviviridae virus infection.

114. The composition of claim 113, wherein the Flaviviridae virus infection is a Dengue virus infection, a Yellow Fever virus infection, a West Nile virus infection, a Tick-borne encephalitis, a Kunjin Japanese encephalitis, a St. Louis encephalitis, a Murray Valley encephalitis, an Omsk hemorrhagic fever, a Bovine viral diarrhea, a Zika virus infection, or an HCV infection.

115. The composition of any one of claims 93 to 95, wherein the viral infection is a Filoviridae virus infection.

116. The composition of claim 115, wherein the Filoviridae virus infection is an Ebola virus infection or a Marburg virus infection.

117. The composition of any one of claims 93 to 95, wherein the viral infection is an orthomyxovirus infection.

118. The composition of claim 117, wherein the viral infection is an influenza virus infection.

119. 119. The composition of claim 117 or 118, wherein the viral infection is an influenza A virus infection or an influenza B virus infection.

120. The composition of any one of claims 93 to 95, wherein the viral infection is a Paramyxoviridae viral infection.

121. 121. The composition of claim 120, wherein the viral infection is a human parainfluenza virus infection, a Nipah virus infection, a Hendra virus infection, a measles virus infection, or a mumps virus infection.

122. A method for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof, comprising using a compound according to any one of claims 1 to 87, or a pharma- ceutically acceptable salt thereof.

123. 90. Use of a compound according to any one of claims 1 to 87, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.

124. 124. The use of claim 123, wherein the pharmaceutical agent is used in combination with at least one additional therapeutic agent.

125. 94. The composition of claim 93, wherein the composition is used in combination with at least one additional therapeutic agent.

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