4-aminopyrrolo [2, 1-f] [1, 2, 4] triazine C-nucleoside compounds and methods for treatment of viral infections

Abstract

The present disclosure provides compounds of Formula I. Also provided are pharmaceutical compositions comprising the compounds of formula I and uses thereof.

Description

Cross Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 499166, filed April 28, 2023. The entire contents of this application are incorporated herein by reference in their entirety. BACKGROUND

[0002] There is a need for compounds and methods for treating viral infections, such as Paramyxoviridae paramyxoviridae ), Pneumoviridae pneumoviridae ), Picornaviridae picornaviridae ), Flaviviridae flaviviridae ), Filoviridae filoviridae ), Arenaviridae arenaviridae ), Orthomyxoviruses orthomyxovirus ), and Coronaviridae coronaviridae ) infections. The present disclosure addresses the aforementioned and other needs.

[0003] The oral route is the preferred route for daily drug administration due to its advantages such as non-invasiveness, patient compliance, and convenience of drug administration. However, oral administration can be limited due to poor physicochemical properties of drug molecules, including low aqueous solubility between pH 2 and pH 7, instability, low permeability, and rapid drug molecule metabolism, all of which factors combine to result in low and erratic oral bioavailability. Oral bioavailability (F%) is, in terms of pharmacology, the fraction of an orally administered drug that reaches the systemic circulation relative to the same dose delivered by intravenous administration. Following intravenous administration, the drug is directly and completely available in the bloodstream and can be distributed via systemic circulation to the point where a pharmacological effect occurs. If a drug is administered orally, it must survive in the intestinal fluid, cross other barriers such as the gastrointestinal (GI) cell layer, and then cross the liver to reach the systemic circulation, which can significantly reduce the amount of administered drug that reaches the bloodstream. Therefore, oral bioavailability is an important property in drug design and development. High oral bioavailability reduces the required amount of administered drug necessary to achieve the desired pharmacological effect, thus reducing the risk of side effects and toxicity in the absorption process. The present disclosure also provides compounds with combined solubility, stability, and permeability properties that result in improved oral bioavailability. SUMMARY

[0004] In one aspect, the present disclosure provides a compound of Formula (I): Formula I or a pharmaceutically acceptable salt thereof, wherein: L is -Y-(CR 1 R 2 )-X-(CR 3 R4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - 、 -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -, -(CR 5 R 6 ) v -SO-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -SO2-(CR 5A R 6A ) w -; Y is O or absent; Z is O or absent; R 1 , R 2 , R 3 , and R 4 are each independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; or R 1 and R 2 groups on the same carbon form a spiro C3-C9carbocyclyl ring or a 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S; R 3 and R 4together with R 22each R 5 independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 23R 5 groups together with R 5 on the adjacent carbon atom form a double bond; or 24R 5 groups together with R 1 on the adjacent carbon atom form a double bond; 25each R 6 independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 26R 5 groups together with R 6 on the same carbon atom form a spiro C3-C9carbocyclyl ring or a 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 27each R 5A independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 28R 5A groups together with R 5A on the adjacent carbon atom form a double bond; or 29R 5A groups together with R 3 on the adjacent carbon atom form a double bond; Each R 6A Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A R on the same carbon 6A The groups together form a spirocyclic C3-C9 carbon ring or a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S; R 7 It can be H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C9 carbocyclic. n is 1, 2, 3, 4, 5, 6, or 7; v can be 0, 1, 2, or 3; w can be 0, 1, 2, or 3; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R 11 It is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Among them, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10 The aryl, 4- to 8-membered heterocyclic, or 5- to 6-membered heteroaryl groups are optionally substituted by one, two, or three independent substituents selected from the group consisting of: C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 -COR 12 -COOR 12 -NR 13 R 14 -OP(=O)(OR) 19 )2, C3-C9 carbon cycloyl groups, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl groups; Where R 11substituents independently selected from the group consisting of carbonyl, halo, cyano, OR 20 , oxo, phenyl, C1-C6haloalkyl, and C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl; each R 8 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 9 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 10 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 12 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 13 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 14 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 19 is independently H or C1-C8alkyl; each R 20 is independently H or C1-C8alkyl; the base is , or ; R 15 is H, C1-C8alkyl, -C(=O)R 17 , or -C(=O)OR 17 ; R 16 is C1-C8alkyl optionally substituted with -OP(=O)(OH)(OR 18 ); each R 17 is independently H, C1-C8alkyl, or C1-C8cycloalkyl; wherein the C1-C8alkyl or C1-C8cycloalkyl of R 17 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -OP(=O)(OH)(OR 18 ), -OR 21 , NR 22 R 23 , and phenyl, wherein R18 substituted with -OP(=0)(OH)(OR 18 ); each R 18 is independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6- membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 18 of the C1-C8alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; each R 21 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 22 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 23 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl.

[0005] In some embodiments of the compound of Formula (I), the base is In some embodiments, the compound of Formula I has the formula la: Formula la.

[0006] In some embodiments of the compounds disclosed herein: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is O or absent; Z is O or absent; R 1 , R2 R 3 and R 4 Each is independently H, -OR 8 , cyano, -NR 9 R 10 , halogenated group, C 1 -C 8 Alkyl, C 2 -C 8 alkenyl, C2-C8 ynyl, C3-C9 carbocyclic, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R 5 Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5 The group and the R on an adjacent carbon atom 5 The groups together form a double bond; Each R 6 Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R 5A Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A The group and the R on an adjacent carbon atom 5A The groups together form a double bond; each R 6A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 is H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl; n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R is H, -C(=O)R 11 , or -C(=O)OR 11 ; R 11 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halo, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 8 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 9 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 10Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 12 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 13 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 14 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 19 Independently H or C1-C8 alkyl; and Each R 20 It is independently H or C1-C8 alkyl.

[0007] In some embodiments of the compounds disclosed herein, L is -Y-(CR) 1 R 2 )-X-(CR 3 R 4 )-Z-; X is non-existent, -(CR) 5 R 6 ) n -、-(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -or-(CR) 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y does not exist; Z does not exist; R 1 R 2 R 3 and R 4 Each group can be independently H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4 to 8 heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5 to 6 heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R 5Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Or R 5 The group and the R on an adjacent carbon atom 5 The groups together form a double bond; Each R 6 Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or Each R 5A Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A The group and the R on an adjacent carbon atom 5A The groups together form a double bond; Each R 6A Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 7 H, C1-C8 alkyl; n is 1, 2, 3, 4, 5, 6, or 7; v can be 0, 1, 2, or 3; w can be 0, 1, 2, or 3; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R 11 It is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 13 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 14 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; and each R 19 is independently H or C1-C8alkyl.

[0008] In some embodiments of the compounds disclosed herein: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n , -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A )w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H or C1-C8 alkyl; each R 5 is independently H or C1-C8 alkyl; or R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; each R 6 is independently H or C1-C8 alkyl; each R 5A is independently H or C1-C8 alkyl; or R 5A groups together with the R 5A group on an adjacent carbon atom form a double bond; each R 6A is independently H or C1-C8 alkyl; R 7 is H, C1-C8 alkyl; n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R is H, -C(=O)R 11 , or -C(=O)OR 11 ; R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14C3-C9 carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H or C1-C8 alkyl; each R 13 is independently H or C1-C8 alkyl; and each R 14 is independently H or C1-C8 alkyl.

[0009] In some embodiments of the compounds disclosed herein, n is 1, 2, 3, or 4.

[0010] In some embodiments of the compounds disclosed herein, v is 0 or 1.

[0011] In some embodiments of the compounds disclosed herein, w is 0 or 1.

[0012] In some embodiments of the compounds disclosed herein: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -, or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H or C1-C8 alkyl; each R 5 is independently H or C1-C8 alkyl; or R 5 groups together with the R 5 group on one adjacent carbon atom form a double bond; each R 6 is independently H or C1-C8 alkyl; each R 5A is independently H or C1-C8 alkyl; or R 5A groups together form a double bond with one adjacent carbon atom; 5A groups together form a double bond; each R 6A is independently H or C1-C8 alkyl; R 7 is H, C1-C8 alkyl; n is 1, 2, 3, or 4; v is 0 or 1; w is 0 or 1; R is H, -C(=O)R 11 , or -C(=O)OR 11 ; R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , C3-C9 carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H or C1-C8 alkyl; each R 13 is independently H or C1-C8 alkyl; and each R 14 is independently H or C1-C8 alkyl.

[0013] In some embodiments, the compounds disclosed herein have the formula Id: Formula Id.

[0014] In some embodiments, the compounds disclosed herein have the formula Ib: Formula Ib.

[0015] In some embodiments, the compounds disclosed herein have the formula Ic: Formula Ic.

[0016] In some embodiments of the compounds disclosed herein, X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -. In some embodiments, X is -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -. In some embodiments, X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NR 7 -, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some embodiments, X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NR 7-CH2-CH=CH-CH2-. In some embodiments, X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 7 -CH2-CH=CH-CH2-. In some embodiments, X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR

[0017] In some embodiments of the compounds disclosed herein, Y is absent.

[0018] In some embodiments of the compounds disclosed herein, Z is absent.

[0019] In some embodiments of the compounds disclosed herein, Y is absent and Z is absent.

[0020] In some embodiments of the compounds disclosed herein, Y is O.

[0021] In some embodiments of the compounds disclosed herein, Z is O.

[0022] In some embodiments of the compounds disclosed herein, Y is O and Z is O.

[0023] In some embodiments of the compounds disclosed herein, L is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -(CH2)2-O-(CH2)2-, -CH2-NR 7 -CH2- or -(CH2)2-CH=CH-(CH2)2-.

[0024] In some embodiments of the compounds disclosed herein, R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR12 -COOR 12 -NR 13 R 14 -OP(=O)(OR) 19 )2, C3-C9 carbon cycloyl groups, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl groups; Where R 11 The substituents C3-C9 carbocyclic groups, 4- to 8-membered heterocyclic groups, 5- to 6-membered heteroaryl groups, and phenyl groups are each independently and optionally substituted by one, two, or three independently selected substituents from the following: carbonyl, halogen, cyano, OR 20 Oxoyl, phenyl, C1-C6 haloalkyl and C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl.

[0025] In some embodiments of the compounds disclosed herein, R 11 It is a C1-C8 alkyl group, a C3-C9 carbocyclic group, or a C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Among them, C1-C8 alkyl, C3-C9 carbocyclic, C6-C 10 The aryl, 4- to 8-membered heterocyclic, or 5- to 6-membered heteroaryl groups are optionally substituted by one, two, or three independent substituents selected from the group consisting of: C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 -COR 12 -COOR 12 -NR 13 R 14 -OP(=O)(OR) 19 2. C3-C9 carbon cycloyl groups, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl groups.

[0026] In some embodiments of the compounds disclosed herein, R 11 It is a C1-C8 alkyl group, a C3-C9 carbocyclic group, or a C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments of the compounds disclosed herein, R 11 It is a C1-C8 alkyl or C3-C9 carbon cycloyl group.

[0027] In some embodiments, the compounds disclosed herein have the formula Id: Formula Id L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H or C1-C8 alkyl; each R 5 is independently H or C1-C8 alkyl; or R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; each R 6 is independently H or C1-C8 alkyl; each R 5A is independently H or C1-C8 alkyl; or R 5A groups together with the R 5A group on an adjacent carbon atom form a double bond; each R 6A is independently H or C1-C8 alkyl; R 7 is H, C1-C8 alkyl; n is 1, 2, 3, or 4; v is 0 or 1; w is 0 or 1.

[0028] In some embodiments of the compounds disclosed herein, L is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -(CH2)2-O-(CH2)2-, -CH2-NR 7 -CH2- or -(CH2)2-CH=CH-(CH2)2-.

[0029] In some embodiments, the compounds disclosed herein have the formula Ib: Formula Ib wherein: L is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -(CH2)2-O-(CH2)2-, -CH2-NR 7 -CH2- or -(CH2)2-CH=CH-(CH2)2-. R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , C3-C9 carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H or C1-C8 alkyl; each R 13 is independently H or C1-C8 alkyl; and each R 14 is independently H or C1-C8 alkyl.

[0030] In some embodiments, the compounds disclosed herein have the formula Ic: Formula Ic wherein: L is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -(CH2)2-O-(CH2)2-, -CH2-NR 7 -CH2- or -(CH2)2-CH=CH-(CH2)2-; R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H or C1-C8alkyl; each R 13 is independently H or C1-C8alkyl; and each R 14 is independently H or C1-C8alkyl.

[0031] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition disclosed herein is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration. In some embodiments, the pharmaceutical composition disclosed herein is for oral administration.

[0032] In another aspect, the present disclosure provides a method of treating or preventing a viral infection in a human in need thereof, wherein the method comprises administering to the human a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0033] In some embodiments, the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof is administered to the human via oral, intramuscular, intravenous, subcutaneous, or inhalation administration.

[0034] In some embodiments, the methods disclosed herein comprise administering to the human at least one additional therapeutic or prophylactic agent. In some embodiments, the additional therapeutic or prophylactic agent is molnupiravir, oseltamivir, nirmatrelvir, or ritonavir.

[0035] In some embodiments of the methods disclosed herein, the viral infection is a coronavirus 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 selected viral polymerase. In some embodiments, the viral infection is selected from the group consisting of 229E virus infection, NL63 virus infection, OC43 virus infection, and HKU1 virus infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID-19). In some embodiments, the viral infection is a SARS-CoV virus infection. In some embodiments, the viral infection is a MERS-CoV virus infection.

[0036] In some embodiments of the methods disclosed herein, the viral infection is a pneumoviridae virus infection. 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.

[0037] In some embodiments of the methods disclosed herein, the viral infection is a picornaviridae virus infection.

[0038] In some embodiments of the methods disclosed herein, the viral infection is an enterovirus infection.

[0039] In some embodiments of the methods disclosed herein, 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.

[0040] In some embodiments of the methods disclosed herein, the Picornaviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the Picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0041] In some embodiments of the methods disclosed herein, the viral infection is a Flaviviridae virus infection. In some embodiments, the Flaviviridae virus infection is a dengue virus infection, a yellow fever virus infection, a West Nile virus infection, tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection. In some embodiments, the viral infection is a Filoviridae virus infection.

[0042] In some embodiments of the methods disclosed herein, the viral infection is a Filoviridae virus infection is an Ebola virus infection or a Marburg virus infection.

[0043] In some embodiments of the methods disclosed herein, the viral infection is an Orthomyxoviridae virus infection. In some embodiments, the viral infection is an influenza virus infection. In some embodiments, the viral infection is an influenza A virus infection or an influenza B virus infection.

[0044] In some embodiments of the methods disclosed herein, the viral infection is a Paramyxoviridae virus infection.

[0045] In some embodiments of the methods disclosed herein, the viral infection is a human parainfluenza virus, a Nipah virus, a Hendra virus, a measles, or a mumps infection.

[0046] In another aspect, the disclosure provides a method of preparing a medicament for treating or preventing a viral infection in a human in need thereof, characterized by using a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0047] In another aspect, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a viral infection in a human in need thereof. In some embodiments, the medicament is used with at least one additional therapeutic or prophylactic agent. In some embodiments, the additional therapeutic or prophylactic agent is monolupiravir, oseltamivir, nirmatrelvir, or ritonavir.

[0048] On the other hand, this disclosure provides a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating or preventing viral infections in persons in need. In some embodiments, the composition comprises at least one additional therapeutic or prophylactic agent. In some embodiments, the additional therapeutic or prophylactic agent is monoupivir, oseltamivir, nirmatrelvir, or ritonavir. Detailed Implementation

[0049] I. SUMMARY The present invention relates to methods and compounds for treating or preventing viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxoviridae, and Coronaviridae families.

[0050] II. DEFINITIONS Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings: "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20 Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl ( n -Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl ( n -Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl ( i -Bu, isobutyl, -CH2CH(CH3)2), 2-butyl ( s -Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl ( t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2) CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0051] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C) 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl group or 2 to 4 carbon atoms (i.e., C44) 2-4 Alkenyl groups are aliphatic groups. Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0052] "Alkyne" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 2-20 alkynyl group), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0053] "Haloalkyl" is an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl moiety of the haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20haloalkyl), 1 to 12 carbon atoms (i.e., C1-C12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, and the like. 12 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, and the like.

[0054] “Aryl” means an aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, and the like.

[0055] “Heteroaryl” means an aromatic group having a single ring, multiple rings, or multiple condensed rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring atoms (i.e., 1 to 20 membered heteroaryl ring), 3 to 12 ring atoms (i.e., 3 to 12 membered heteroaryl ring), or 3 to 8 carbon ring atoms (i.e., 3 to 8 membered heteroaryl ring), or 5 to 6 ring atoms (i.e., 5 to 6 membered heteroaryl ring). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass aryl as defined above or overlap therewith.

[0056] “Carbocyclyl” means a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms having three to twenty carbon atoms, in certain embodiments, three to fifteen carbon atoms, in certain embodiments, three to ten carbon atoms, three to eight carbon atoms, three to seven carbon atoms, or 3 to 6 carbon atoms, and which is either saturated or partially unsaturated and is connected to the rest of the molecule by a single bond. Carbocyclyl includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. Carbocyclyl includes cycloalkyl groups.

[0057] “Cycloalkyl” means a saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C3-C20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-C12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-C10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-C8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-C6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 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 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0058] As used herein, "heterocyclyl" includes those heterocycles described, by way of example and without limitation, in Paquette, Leo A.: Principles of Modern Heterocyclic Chemistry "Chemical Reviews" (W. A. Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7, and 9; "Rodd's Chemistry of Carbon Compounds," 2nd Ed., Vol. 1, Elsevier – Pubs., 2009, and The Chemistry of Heterocyclic Compounds, A Series of Monographs "Rodd's Chemistry of Carbon Compounds," 2nd Ed., Vol. 1, Elsevier – Pubs., 2009, and J. Am. Chem. Soc. (1960) 82:5566. For example, "heterocyclyl" includes "carbocyclyl" as defined herein, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g., O, N, or S). As used herein, a heterocycle or heterocyclyl group has 3 to 20 ring atoms, 3 to 12 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms, or 3 to 6 ring atoms. The term "heterocyclyl" includes saturated and partially unsaturated rings. Substituted heterocyclyl groups include, for example, heterocycles substituted with any of the substituents disclosed herein, including carbonyl groups. Non-limiting examples of carbonyl-substituted heterocyclyl groups are: Exemplary heterocycles include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, and piperidinyl.

[0059] The term "optionally substituted" with reference to a particular moiety of a compound described herein (e.g., an optionally substituted aryl group) means a moiety in which all substituents are hydrogen or in which one or more of the hydrogens can be replaced by a listed substituent.

[0060] Unless otherwise indicated, the carbon atoms of the compounds described herein (e.g., the compounds of Formula I) are intended to be four-valent. If, in some chemical structure representation, a carbon atom does not have a sufficient number of variables attached to produce four valences, it is to be assumed that the remaining carbon substituents needed to provide four valences are hydrogens.

[0061] Unless otherwise indicated, the term "treatment" as used herein means reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to the act of treating as "treatment" is defined above.

[0062] “Prevention” means any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the compounds and compositions disclosed herein can be administered to a subject (including a human) at risk of having a disease or condition. As used herein, the term “prevention” encompasses administration of a compound, composition, or pharmaceutically acceptable salt according to the embodiments disclosed herein before or after exposure of an individual to a virus, but before the appearance of symptoms of viral infection and / or before detection of the virus in the blood. The term also refers to preventing the appearance of symptoms of a disease and / or preventing the virus from reaching detectable levels in the blood. The term includes pre-exposure prophylaxis (PrEP) as well as post-exposure prophylaxis (PEP) and event-driven or “on-demand” prophylaxis. The term also refers to preventing perinatal transmission of a virus from mother to infant by administering to the mother before delivery and to the child within the first few days of life. The term also refers to preventing transmission of a virus through blood transfusion.

[0063] As used herein, the term “therapeutically effective amount” is the amount of a compound of Formula I present in a composition described herein that is required to provide a desired level of drug in secretions and tissues of the airways and lungs, or alternatively, that is required to produce the intended physiological response or desired biological effect in the bloodstream of a subject to be treated when such a composition is administered by a selected route of administration. The precise amount will depend on a number of factors, for example, the specific compound of Formula I, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition and its intended use, and patient considerations such as the severity of the disease, patient cooperation, and the like, and can be readily determined by one of skill in the art based on the information provided herein.

[0064] III. COMPOUNDS Any reference to a compound of the present application described herein is also meant to include a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of a compound of the present application include those derived from appropriate bases such as alkali or alkaline earth metals (e.g., Na + , Li + , K + , Ca +2 , and Mg +2 ), ammonium and NR4 +(salt of a compound of Formula I). The pharmaceutically acceptable salts of nitrogen atoms or amines include: (a) acid addition salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; (b) salts with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, o-benzoic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts derived an elemental anion, such as chloride, bromide and iodide. The pharmaceutically acceptable salts of hydroxyl compounds include the anion of the compound with a suitable cation such as Na + and combinations of NR4 + .

[0065] In some embodiments, R is H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, C6-C 20 aryl, or C2-C 20 heterocyclyl.

[0066] For therapeutic use, the salts of the active ingredient of the compounds of the application will be pharmaceutically acceptable, i.e., they will be salts derived from pharmaceutically acceptable acids or bases. However, salts of acids or bases that are non-pharmaceutically acceptable can also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether derived from a pharmaceutically acceptable acid or base, are within the scope of the present application.

[0067] It is also to be understood that the compositions herein include the compounds of the present application in non-ionized form as well as in zwitterionic form in combination with stoichiometric amounts of water in the hydrate.

[0068] It is noted that the present application encompasses all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of the compounds within the scope of Formula I and pharmaceutically acceptable salts thereof. All mixtures of such enantiomers and diastereomers, other than those of pure R- or S- forms, are within the scope of the present application.

[0069] Compounds of the application exemplified by Formula I can have chiral centers, e.g., chiral carbon or phosphorus atoms. Accordingly, the compounds of the application include all racemic, scalemic, enantiomeric, and atropisomeric mixtures, as well as the individual optical isomers. Further, the compounds of the application include optically isomers that are enriched or resolved at any or all of the asymmetric, chiral atoms. In other words, chiral centers apparent from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and scalemic mixtures, as well as isolated or synthetic individual optical isomers, substantially free of their enantiomeric or scalemic partners, are within the scope of the application. Racemic mixtures are separated into their individual, substantially optically pure isomers by appropriate techniques, such as separation of diastereomeric salts formed with an optically active base, e.g., an acid or a base, followed by conversion of the diastereomeric salts back to the optically active compounds. In most cases, the desired optical isomer is synthesized by a stereospecific reaction using a suitable optically pure starting material.

[0070] The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. "McGraw-Hill Dictionary of Chemical Terms” (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 an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1, D and L, or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, with S, (-), or 1 indicating a compound that is levorotatory and R, (+), or d a compound that is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" mean an equimolar mixture of two enantiomeric species.

[0071] In certain instances, the compounds of the present application can also exist as tautomeric isomers. Although only one tautomeric form can be depicted, all such forms are intended to be included within the scope of the present application. For example, for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, enol-imine tautomers can exist, and all possible tautomeric forms are within the scope of the present application.

[0072] Any formula or structure given herein, including the compounds of Formula I, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I. Various isotopically labeled compounds of the present disclosure, for example, those into which radioactive isotopes such as 3 H, 13 C, and 14 C are incorporated. Such isotopically labeled compounds are useful in metabolic studies, receptor binding assays, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including diagnosis of diseases in humans, or in radiosynthesis of other compounds of this application. In certain embodiments, substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or ameliorated side effects. It is understood that the replacement of hydrogen by deuterium can afford metabolically more stable compounds.

[0073] The present disclosure also includes compounds described herein (e.g., compounds of Formula I) in which one to x hydrogens attached to a carbon atom are 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 prolonging the half-life of any of the compounds described herein (e.g., compounds of Formula I) when administered to a mammal, especially a human. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods known in the art in view of the present disclosure, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0074] Deuterium labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, which involves distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic 18 F-labeled compounds can be used in PET or SPECT studies. Isotopically- labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a

[0075] In some embodiments, the carbon bonded to the 5-position on the tetrahydrofuran ring of Formula I is substituted with one or two deuterium atoms. In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is In some embodiments, the carbon on the base of Formula I is substituted with one or more deuterium atoms. In some embodiments, the base is , or In some embodiments, the base is , or In some embodiments, the base is , or In some embodiments, the base is , or In some embodiments, the base is In some embodiments, the carbon on R 15 of the base of Formula I is substituted with one or more deuterium atoms. In some embodiments, the carbon on R 16 of the base of Formula I is substituted with one or more deuterium atoms. In some embodiments, the carbon on L of Formula I is substituted with one or more deuterium atoms. In some embodiments, the carbon on R of Formula I is substituted with one or more deuterium atoms.

[0076] The concentration of such a heavier isotope, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope indicates that any stable isotope of that atom is intended. Unless otherwise indicated, when a position is designated specifically as "H" or "hydrogen," that position is understood to have its natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to denote deuterium.

[0077] Whenever a compound described herein is substituted with more than one of the same designated group (e.g., "R" or "R"), then unless specified otherwise, it will be understood that the groups can be the same or different.

[0078] wavy line, denotes the position at which a covalent bond is attached to an adjacent substructure, group, moiety, or atom.

[0079] In certain embodiments, provided herein are compounds of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - 、 -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -, 5 R 6 ) v -SO-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -SO2-(CR 5A R 6A ) w -; Y is O or absent; Z is O or absent; R 1 , R 2 , R 3 , and R 4 are each independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C 1-C 8 Alkyl, C 2 -C 8 alkenyl, C2-C8 ynyl, C3-C9 carbocyclic, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 1 R on the same carbon 2 The groups together form a spirocyclic C3-C9 carbon ring or a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S; R 3 R on the same carbon 4 The groups together form a spirocyclic C3-C9 carbon ring or a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R 5 Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5 The group and the R on an adjacent carbon atom 5 Groups together form a double bond; or R 5 The group and the R on the adjacent carbon atom 1 The groups together form a double bond; Each R 6 Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5 R on the same carbon 6 The groups together form a spirocyclic C3-C9 carbon ring or a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R 5A Independently for H, -OR8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A The group and the R on an adjacent carbon atom 5A Groups together form a double bond; or R 5A The group and the R on an adjacent carbon atom 3 The groups together form a double bond; Each R 6A Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A R on the same carbon 6A The groups together form a spirocyclic C3-C9 carbon ring or a 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S; R 7 It can be H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C9 carbocyclic. n is 1, 2, 3, 4, 5, 6, or 7; v can be 0, 1, 2, or 3; w can be 0, 1, 2, or 3; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R 11 It is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Among them, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10The aryl, 4- to 8-membered heterocyclic, or 5- to 6-membered heteroaryl groups are optionally substituted by one, two, or three independent substituents selected from the group consisting of: C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 -COR 12 -COOR 12 -NR 13 R 14 -OP(=O)(OR) 19 )2, C3-C9 carbon cycloyl groups, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl groups; Where R 11 The substituents C3-C9 carbocyclic groups, 4- to 8-membered heterocyclic groups, 5- to 6-membered heteroaryl groups, and phenyl groups are each independently and optionally substituted by one, two, or three independently selected substituents from the following: carbonyl, halogen, cyano, OR 20 , oxoyl, phenyl, C1-C6 haloalkyl and C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl; Each R 8 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 9 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 10 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 12 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 13 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 14 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 19 Independently H or C1-C8 alkyl; Each R 20 Independently H or C1-C8 alkyl; Alkali is , or ; R 15 It is H, C1-C8 alkyl, -C(=O)R 17 or -C(=O)OR17 ; R 16 is C1-C8 alkyl optionally substituted with -OP(=O)(OH)(OR 18 ); each R 17 is independently H, C1-C8 alkyl, or C1-C8 cycloalkyl; wherein the C1-C8 alkyl or C1-C8 cycloalkyl of R 17 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -OP(=O)(OH)(OR 18 ), -OR 21 , NR 22 R 23 , and phenyl, wherein the phenyl substituent of R 17 is optionally substituted with -OP(=O)(OH)(OR 18 ); each R 18 is independently H, C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C1-C8 alkyl of R 18 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; each R 21 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl; each R 22 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl; each R 23 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl.

[0080] In some embodiments of the compound of Formula I, the base is , or ; wherein R 15 is H, C1-C8 alkyl, -C(=O)R 17 , or -C(=O)OR 17 ; R 16 is C1-C8 alkyl optionally substituted with -OP(=O)(OH)(OR 18 ); each R 17 is independently H, C1-C8 alkyl, or C1-C8 cycloalkyl; each R 18independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C10aryl, or 5- to 6- membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0081] In some embodiments of the compound of Formula I, the base is , or ; wherein R 15 is H, C1-C8alkyl, -C(=O)R 17 , or -C(=O)OR 17 ; R 16 is C1-C8alkyl; each R 17 is independently H, C1-C8alkyl, or C1-C8cycloalkyl.

[0082] In some embodiments of the compound of Formula I, the base is or ; wherein R 16 is C1-C8alkyl optionally substituted with -OP(=O)(OH)(OR 18 ); R 18 is independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C1-C8alkyl of R 18 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; each R 21 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 22 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 23 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl.

[0083] In some embodiments of the compound of Formula I, the base is or ; wherein R 16 is C1-C8alkyl optionally substituted with -OP(=O)(OH)(OR 18 ); each R 18independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C10aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0084] In some embodiments of the compound of Formula I, the base is or ; wherein R 16 is C1-C8alkyl.

[0085] In some embodiments of the compound of Formula I, the base is ; wherein R 16 is C1-C8alkyl optionally substituted with -OP(=O)(OH)(OR 18 ); R 18 independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C1-C8alkyl of R 18 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; each R 21 independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 22 independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 23 independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl.

[0086] In some embodiments of the compound of Formula I, the base is ; wherein R 16 is C1-C8alkyl optionally substituted with -OP(=O)(OH)(OR 18 ); each R 18 independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0087] In some embodiments of the compound of Formula I, the base is ; wherein R 16 is C1-C8alkyl.

[0088] In some embodiments of the compound of Formula I, the base is ; wherein R 16 is C1-C8 alkyl optionally substituted with -OP(=0)(OH)(OR 18 ); R 18 is independently H, C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 18 of the C1-C8 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; each R 21 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl; each R 22 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl; each R 23 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl.

[0089] In some embodiments of the compound of Formula I, the base is ; wherein R 16 is C1-C8 alkyl optionally substituted with -OP(=0)(OH)(OR 18 ); each R 18 is independently H, C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0090] In some embodiments of the compound of Formula I, the base is ; wherein R 16 is C1-C8 alkyl.

[0091] In some embodiments of the compound of Formula I, the base is ; wherein R 15 is H, C1-C8 alkyl, -C(=0)R 17 , or -C(=0)OR 17 ; each R 17 is independently H, C1-C8 alkyl, or C1-C8 cycloalkyl; wherein R 17C1-C8alkyl or C1-C8cycloalkyl of R is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -OP(=O)(OH)(OR 18 ), -OR 21 , NR 22 R 23 , and phenyl, wherein the substituent phenyl of R 17 is optionally substituted with -OP(=O)(OH)(OR 18 ); each R 18 is independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C1-C8alkyl of R 18 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; each R 21 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 22 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 23 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl.

[0092] In some embodiments of the compound of formula I, the base is ; wherein R 15 is H, C1-C8alkyl, -C(=O)R 17 , or -C(=O)OR 17 ; each R 17 is independently H, C1-C8alkyl, or C1-C8cycloalkyl; each R 18 is independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0093] In some embodiments of the compound of formula I, the base is ; wherein R 15 is H, C1-C8alkyl, -C(=O)R 17 , or -C(=O)OR 17 ; and each R 17independently H, C1-C8alkyl, or C1-C8cycloalkyl.

[0094] In some embodiments of the compound of Formula I, the base is ; wherein R 15 is H or C1-C8alkyl.

[0095] In some embodiments of the compound of Formula I, the base is ; wherein R 15 is H.

[0096] In some embodiments, the compound of Formula I has Formula Ia: Formula Ia.

[0097] In some embodiments of the compound of Formula I or Formula Ia, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -, -O-(CR 5A R 6A ) w -, or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is O or absent; Z is O or absent; R 1 , R 2 , R 3 , and R 4 are each independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each R 5 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or each R 5 group together with the R 5 group on the adjacent carbon atom form a double bond; each R 6 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each R 5A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or each R 5A group together with the R 5A group on the adjacent carbon atom form a double bond; each R 6A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 is H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl; n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R 11 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 8 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 9 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 10 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 12 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 13 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 14independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 19 is independently H or C1-C8alkyl; and each R 20 is independently H or C1-C8alkyl.

[0098] In some embodiments of the compound of Formula Ia, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is O or absent; Z is O or absent; each R 1 , R 2 , R 3 , and R 4 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; each R 5 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5 The group and the R on an adjacent carbon atom 5 The groups together form a double bond; Each R 6 Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R 5A Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A The group and the R on an adjacent carbon atom 5A The groups together form a double bond; Each R 6A Independently for H, -OR 8 , cyano, -NR 9 R 10 Halogenated groups, C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C9 carbocyclic groups, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; R 7 It can be H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C9 carbocyclic. n is 1, 2, 3, 4, 5, 6, or 7; v can be 0, 1, 2, or 3; w can be 0, 1, 2, or 3; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R11 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 12 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 12 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 12 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 13 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 14 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 19 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C each R 8 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 9 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 10 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 12 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 13 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 14 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 19 is independently H or C1-C8alkyl; and each R 20 is independently H or C1-C8alkyl.

[0099] L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-. X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 and R 4 are each independently H, cyano, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; each R 5 is independently H, cyano, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; or R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; each R 6 is independently H, cyano, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; or each R 5A is independently H, cyano, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclyl, C6-C 10Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A The group and the R on an adjacent carbon atom 5A The groups together form a double bond; Each R 6A Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 7 H, C1-C8 alkyl; n is 1, 2, 3, 4, 5, 6, or 7; v can be 0, 1, 2, or 3; w can be 0, 1, 2, or 3; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R 11 It is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Among them, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10 The aryl, 4- to 8-membered heterocyclic, or 5- to 6-membered heteroaryl groups are optionally substituted by one, two, or three independent substituents selected from the group consisting of: C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 -COR 12 -COOR 12 -NR 13 R 14 -OP(=O)(OR) 19 )2, C3-C9 carbon cycloyl groups, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl groups; Each R 12 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 13independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 14 independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; and each R 19 independently H or C1-C8alkyl.

[0100] In some embodiments of the compound of Formula I or Formula la: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each R 5 independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; each R 6 independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; or 10 independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C each R 5A independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C R 5A independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 5A independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C each R 6A independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C R 7 is H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R is H, -C(=O)R 11 , or -C(=O)OR 11 ; R 11 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; wherein C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halo, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9 carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl; each R 13 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl; each R 14 is independently H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl; and each R 19 is independently H or C1-C8 alkyl.

[0101] In some embodiments of the compound of Formula Ia: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -, or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H, cyano, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; Each R 5 Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Or R 5 The group and the R on an adjacent carbon atom 5 The groups together form a double bond; Each R 6 Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or Each R 5A Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A The group and the R on an adjacent carbon atom 5A The groups together form a double bond; Each R 6A Independently, it can be H, cyano, halogroup, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, or C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 7 H, C1-C8 alkyl; n is 1, 2, 3, 4, 5, 6, or 7; v can be 0, 1, 2, or 3; w can be 0, 1, 2, or 3; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R 11 It is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 13 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 14 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; and each R 19 is independently H or C1-C8alkyl.

[0102] In some embodiments of the compound of Formula I or Formula la: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A )w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H or C1-C8 alkyl; each R 5 is independently H or C1-C8 alkyl; or R 5 group together with the R 5 group on an adjacent carbon atom to form a double bond; each R 6 is independently H or C1-C8 alkyl; each R 5A is independently H or C1-C8 alkyl; or R 5A group together with the R 5A group on an adjacent carbon atom to form a double bond; each R 6A is independently H or C1-C8 alkyl; R 7 is H, C1-C8 alkyl; n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R is H, -C(=O)R 11 , or -C(=O)OR 11 ; R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H or C1-C8alkyl; each R 13 is independently H or C1-C8alkyl; and each R 14 is independently H or C1-C8alkyl.

[0103] In some embodiments of the compound of Formula Ia: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; each R 1 , R 2 , R 3 , and R 4 is independently H or C1-C8alkyl; each R 5 is independently H or C1-C8alkyl; or R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; each R 6 is independently H or C1-C8alkyl; each R 5A is independently H or C1-C8alkyl; or R 5A groups together with the R 5A group on an adjacent carbon atom form a double bond; each R6A independently H or C1-C8alkyl; R 7 is H, C1-C8alkyl; n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H or C1-C8alkyl; each R 13 is independently H or C1-C8alkyl; and each R 14 is independently H or C1-C8alkyl.

[0104] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, or 4. In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 3. In some embodiments, n is 1 or 4. In some embodiments, n is 2 or 3. In some embodiments, n is 2 or 4. In some embodiments, n is 3 or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0105] In some embodiments of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, or 4. In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 3. In some embodiments, n is 1 or 4. In some embodiments, n is 2 or 3. In some embodiments, n is 2 or 4. In some embodiments, n is 3 or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0106] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, v is 0, 1, or 2. In some embodiments, v is 0 or 1.

[0107] In some embodiments of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, v is 0, 1, or 2. In some embodiments, v is 0 or 1.

[0108] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, w is 0, 1, or 2. In some embodiments, w is 0 or 1.

[0109] In some embodiments of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, w is 0, 1, or 2. In some embodiments, w is 0 or 1.

[0110] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, v is 0, 1, or 2, and w is 0, 1, or 2. In some embodiments, v is 0 or 1, and w is 0 or 1.

[0111] In some embodiments of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, v is 0, 1, or 2, and w is 0, 1, or 2. In some embodiments, v is 0 or 1, and w is 0 or 1.

[0112] In some embodiments of the compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR5A R 6A R w -or-(CR 5 R 6 R v -NR 7 -(CR 5A R 6A R w -; Y is absent; Z is absent; R 1 , R 2 , R 3 and R 4 are each independently H or C1-C8alkyl; each R 5 is independently H or C1-C8alkyl; or R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; each R 6 is independently H or C1-C8alkyl; each R 5A is independently H or C1-C8alkyl; or R 5A groups together with the R 5A group on an adjacent carbon atom form a double bond; each R 6A is independently H or C1-C8alkyl; R 7 is H, C1-C8alkyl; n is 1, 2, 3 or 4; v is 0 or 1; w is 0 or 1; R is H, -C(=O)R 11 or -C(=O)OR 11 ; R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S or 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​12 -COOR 12 -NR 13 R 14 C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H or C1-C8alkyl; each R 13 is independently H or C1-C8alkyl; and each R 14 is independently H or C1-C8alkyl.

[0113] In some embodiments of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -, or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H or C1-C8alkyl; each R 5 is independently H or C1-C8alkyl; or R 5 groups together with the R 5 group on one adjacent carbon atom form a double bond; each R 6 is independently H or C1-C8alkyl; each R 5A is independently H or C1-C8alkyl; or R 5A group together with R 5A group on an adjacent carbon atom forms a double bond; each R 6A is independently H or C1-C8 alkyl; R 7 is H, C1-C8 alkyl; n is 1, 2, 3, or 4; v is 0 or 1; w is 0 or 1; R is H, -C(=O)R 11 , or -C(=O)OR 11 ; R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , C3-C9 carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; each R 12 is independently H or C1-C8 alkyl; each R 13 is independently H or C1-C8 alkyl; and each R 14 is independently H or C1-C8 alkyl.

[0114] In some embodiments, the compound of Formula I or Formula la has Formula lb: Formula lb.

[0115] In some embodiments, the compound of Formula I or Formula la has Formula Ic: Formula Ic.

[0116] In some embodiments of the compound of Formula I, Formula la, Formula lb, and Formula Ic, or a pharmaceutically acceptable salt thereof, R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halo, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the substituents of R 11 C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl, and phenyl are each independently optionally substituted with one, two, or three substituents independently selected from carbonyl, halo, cyano, OR 20 , oxo, phenyl, C1-C6haloalkyl, and C1-C6alkyl, C1-C6alkenyl, and C1-C6alkynyl.

[0117] In some embodiments of the compound of Formula I, Formula la, Formula lb, and Formula Ic, or a pharmaceutically acceptable salt thereof, R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halo, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR19 ) 2, C3-C9 carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

[0118] In some embodiments of the compound of Formula I, Formula la, Formula lb, and Formula lc, or a pharmaceutically acceptable salt thereof, R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0119] In some embodiments of the compound of Formula I, Formula la, Formula lb, and Formula lc, or a pharmaceutically acceptable salt thereof, R 11 is C1-C8 alkyl or C3-C9 carbocyclyl.

[0120] In some embodiments of the compound of Formula I or Formula la, the compound is of Formula Id: Formula Id.

[0121] In some embodiments of the compound of Formula I, Formula la, Formula lb, Formula lc, or Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - 、 -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -, -(CR 5 R 6 ) v -SO-(CR 5A R 6A ) w - or -(CR 5 R 6) v -SO2-(CR 5A R 6A ) w -; Y is O or absent; Z is O or absent; R 1 , R 2 , R 3 , and R 4 are each independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; or R 1 and the R 2 group on the same carbon form a spiro C3-C9carbocyclyl ring or a 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S; R 3 and the R 4 group on the same carbon form a spiro C3-C9carbocyclyl ring or a 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S; each R 5 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; or R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; or R 5 groups together with the R 1 group on an adjacent carbon atom form a double bond; each R 6 is independently H, -OR 8 , cyano, -NR 9 R 10halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 10 halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 5 R 6 groups together with R 5A on the same carbon form a spiro C3-C9carbocyclyl ring or a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 8 each R 9 is independently H, -OR 10 , cyano, -NR 10 R 5A , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 5A aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 5A R 3 groups together with R 6A on the same carbon form a double bond; or 8 R 9 groups together with R 10 on the same carbon form a double bond; 10 each R 5A is independently H, -OR 6A , cyano, -NR 7 R 8 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 9 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 10 R 1 groups together with R 2 on the same carbon form a spiro C3-C9carbocyclyl ring or a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 3 R 4 is H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl; 5 each R 6 is independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; n each R 5independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; each R 10 independently H, C1-C8alkyl, C1-C8haloalkyl, and C3-C6cycloalkyl; n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; and w is 0, 1, 2, or 3.

[0122] In some embodiments of the compound of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is O or absent; Z is O or absent; each R 1 , R 2 , R 3 , and R 4 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; each R 5 is independently H, -OR 8 , cyano, -NR 9 R10 halo, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-Ci0aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; 10 halo, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; each R 6 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; each R 5A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; R 5A groups together with the R 5A group on an adjacent carbon atom form a double bond; each R 6A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; R 7 is H, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl; n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; each R 8 is independently H, Ci-C8alkyl, Ci-C8haloalkyl, and C3-C6cycloalkyl; each R 9 is independently H, Ci-C8alkyl, Ci-C8haloalkyl, and C3-C6cycloalkyl; and each R 10 is independently H, Ci-C8alkyl, Ci-C8haloalkyl, and C3-C6cycloalkyl.

[0123] In some embodiments of the compound of Formula I, Formula la, Formula lb, Formula Ic, or Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H, cyano, halo, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each R 5 is independently H, cyano, halo, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R5 group and R 5 groups form a double bond together; each R 6 is independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or each R 5A is independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A group and R 5A groups form a double bond together; each R 6A is independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 7 is H, C1-C8alkyl; n is 1, 2, 3, 4, 5, 6, or 7; v is 0, 1, 2, or 3; and w is 0, 1, 2, or 3.

[0124] In some embodiments of the compounds of Formula I, Formula la, Formula Ic, and Formula Id, or a pharmaceutically acceptable salt thereof: L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H or C1-C8 alkyl; each R 5 is independently H or C1-C8 alkyl; or R 5 groups together with the R 5 group on an adjacent carbon atom form a double bond; each R 6 is independently H or C1-C8 alkyl; each R 5A is independently H or C1-C8 alkyl; or R 5A groups together with the R 5A group on an adjacent carbon atom form a double bond; each R 6A is independently H or C1-C8 alkyl; R 7 is H, C1-C8 alkyl; n is 1, 2, 3, or 4; v is 0 or 1; and w is 0 or 1.

[0125] In some embodiments of the compounds of Formula I, Formula la, Formula lb, Formula lc, and Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or is absent; Z is O or is absent; and X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -, or -(CR 5 R 6 ) v -NR 7 -(CR5A R 6A ) w - In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or absent; Z is O or absent; and X is -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w - In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or absent; Z is O or absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NR 7 -, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or absent; Z is O or absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NR 7 - or -CH2-CH=CH-CH2-. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or absent; Z is O or absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR7 -CH2- or -CH2-CH=CH-CH2-. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or absent; Z is O or absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3-, or -CH2-CH=CH-CH2-.

[0126] In some embodiments of the compound of Formula I, Formula la, Formula lb, Formula Ic, and Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O; Z is O or absent; and X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w - In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O; Z is O or absent; and X is -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w - In some embodiments, L is -Y-(CR1 R 2 )-X-(CR 3 R 4 -Z-; where Y is O; Z is O or does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NR 7 -、-CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 -Z-; where Y is O; Z is O or does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NR 7 - or -CH2-CH=CH-CH2-. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 -Z-; where Y is O; Z is O or does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; where Y is O; Z is O or does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3- or -CH2-CH=CH-CH2-.

[0127] In some embodiments of compounds of formulas I, Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; where Y does not exist; Z is 0 or does not exist; and X does not exist, –(CR 5 R 6 ) n -、-(CR5 R 6 ) v -O-(CR 5A R 6A ) w -or-(CR) 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; where Y is 0 or does not exist; Z is 0 or does not exist; and X is -(CR 5 R 6 ) n -、-(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -or-(CR) 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 -Z-; where Y does not exist; Z is O or does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NR 7 -、-CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 -Z-; where Y is O; Z is O or does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NR 7 - or -CH2-CH=CH-CH2-. In some implementations, L is -Y-(CR 1 R2 )-X-(CR 3 R 4 )-Z-; wherein Y is O; Z is O or is absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3-, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is absent; Z is O or is absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3-, or -CH2-CH=CH-CH2-.

[0128] In some embodiments of the compounds of Formula I, Formula la, Formula lb, Formula Ic, and Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or is absent; Z is O; and X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w - In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or is absent; Z is O; and X is -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A )w -CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NR 1 R 2 )-Z-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 3 R 4 )-CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 7 R 7 )-CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 1 R 2 )-CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 3 R 4 )-CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 7 R 1 )-CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 2 R 3 )-CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 4 R 7 )-CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 1 R 2 )-CH2- or -CH2-CH=CH-CH2-; wherein Y is O or absent; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 3 R 4 )

[0129] In some embodiments of the compound of Formula I, Formula la, Formula lb, Formula Ic, and Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or absent; Z is absent; and X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or absent; Z is absent; and X is -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or absent; Z is absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NR 7 -, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4)-Z-; wherein Y is O or is absent; Z is absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3-, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or is absent; Z is absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3-, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O or is absent; Z is absent; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3-, or -CH2-CH=CH-CH2-.

[0130] In some embodiments of the compound of Formula I, Formula la, Formula lb, Formula Ic, and Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O; Z is O; and X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -, or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w - In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4)-Z-; wherein Y is O; Z is O; and X is -(CH2)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 5 R 6 ) n -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 5 R 6 ) v -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 5A R 6A ) w -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 5 R 6 ) v -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 7 R 5A ) 6A -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR w R 1 ) 2 -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 3 R 4 ) 7 -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 7 R 1 ) 2 -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 3 R 4 ) 7 -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 1 R 2 ) 3 -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 4 R 7 ) 1 -CH2-CH=CH-CH2-; wherein Y is O; Z is O; and X is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, -CH2-O-CH2-, -CH2-NR 2 R 3 ) 4)-X-(CR

[0131] In some embodiments of the compounds of Formula I, Formula la, Formula lb, Formula Ic, and Formula Id, or a pharmaceutically acceptable salt thereof, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O; Z is O; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3-, or -CH2-CH=CH-CH2-. 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; wherein Y is O; Z is O; and X is -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v -O-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -. In some embodiments, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4-Z-; where Y does not exist; Z does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NR 7 -、-CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 -Z-; where Y does not exist; Z does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NR 7 - or -CH2-CH=CH-CH2-. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 -Z-; where Y does not exist; Z does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -O-, -CH2-O-CH2-, -NCH3-, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-. In some implementations, L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; where Y does not exist; Z does not exist; and X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3- or -CH2-CH=CH-CH2-.

[0132] In some embodiments of compounds of formulas I, Ia, Ib and Ic, or pharmaceutically acceptable salts thereof, L is –(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-; R 11 It is a C1-C8 alkyl group, a C3-C9 carbocyclic group, or a C6-C 10Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Among them, C1-C8 alkyl, C3-C9 carbocyclic, C6-C 10 The aryl, 4- to 8-membered heterocyclic, or 5- to 6-membered heteroaryl groups are optionally substituted by one, two, or three independent substituents selected from the group consisting of: C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 -COR 12 -COOR 12 -NR 13 R 14 -OP(=O)(OR) 19 )2, C3-C9 carbon cycloyl groups, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl groups; Where R 11 The substituents C3-C9 carbocyclic groups, 4- to 8-membered heterocyclic groups, 5- to 6-membered heteroaryl groups, and phenyl groups are each independently and optionally substituted by one, two, or three independently selected substituents from the following: carbonyl, halogen, cyano, OR 20 Oxoyl, phenyl, C1-C6 haloalkyl and C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl.

[0133] In some embodiments of compounds of formulas I, Ia, Ib and Ic, or pharmaceutically acceptable salts thereof, L is –(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-; R 11 It is a C1-C8 alkyl group, a C3-C9 carbocyclic group, or a C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Among them, C1-C8 alkyl, C3-C9 carbocyclic, C6-C 10 The aryl, 4- to 8-membered heterocyclic, or 5- to 6-membered heteroaryl groups are optionally substituted by one, two, or three independent substituents selected from the group consisting of: C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 -COR 12 -COOR 12, -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9 carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

[0134] In some embodiments of the compound of Formula I, Formula la, Formula lb, and Formula lc, or a pharmaceutically acceptable salt thereof, L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-. R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0135] In some embodiments of the compound of Formula I, Formula la, Formula lb, and Formula lc, or a pharmaceutically acceptable salt thereof, L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-. R 11 is C1-C8 alkyl or C3-C9 carbocyclyl.

[0136] In some embodiments of the compound of Formula lb, or a pharmaceutically acceptable salt thereof: Formula lb wherein: L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-. R 11 is C1-C8 alkyl, C3-C9 carbocyclyl, C6-C 10C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

[0137] In some embodiments of the compound of Formula Ib, or a pharmaceutically acceptable salt thereof: Formula Ib wherein: L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-; and R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0138] In some embodiments of the compound of Formula Ib, or a pharmaceutically acceptable salt thereof: Formula Ib wherein: L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-; and R11 C1-C8alkyl or C3-C9carbocyclyl.

[0139] In some embodiments of the compound of Formula Ic, or a pharmaceutically acceptable salt thereof: Formula Ic wherein: L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-; R 11 C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C1-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

[0140] In some embodiments of the compound of Formula Ic, or a pharmaceutically acceptable salt thereof: Formula Ic wherein: L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-; and R 11 C1-C8alkyl, C3-C9carbocyclyl, C6-C10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0141] In some embodiments of the compound of formula Ic or its pharmaceutically acceptable salt: Formula Ic in: L is –(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-; and R 11 It is a C1-C8 alkyl or C3-C9 carbon cycloyl group.

[0142] In some embodiments of the compound of formula Id or its pharmaceutically acceptable salt: FormulaId Where L is –(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-NCH3-CH2-, or -CH2-CH2-CH=CH-CH2-CH2-.

[0143] In some embodiments of the compound of formula Id or its pharmaceutically acceptable salt: FormulaId Where L is –(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -CH2-CH2-O-CH2-CH2- or -CH2-NCH3-CH2-.

[0144] In some embodiments of the compound of formula Id or its pharmaceutically acceptable salt: FormulaId Where L is –(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6- or -CH2-C(CH3)2-CH2-.

[0145] In some embodiments of a compound of Formula I, Formula la, Formula lb, Formula Ic, or Formula Id, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , IV. pharmaceutical formulations The compounds disclosed herein can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, glidants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration, typically will be isotonic. All formulations can optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Pharmaceutically acceptable excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. In some embodiments, the formulation comprises one or more pharmaceutically acceptable excipients. The pH of the formulation ranges from about 3 to about 11, but is typically from about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but is typically from about 3 to 4.

[0146] While it is possible for the compounds of the present disclosure ("active ingredients") to be administered alone, it is preferable to present them as pharmaceutical formulations. Both veterinary and human formulations of the present application comprise at least one active ingredient as defined above, together with one or more acceptable carriers therefore and optionally other therapeutic ingredients, in particular those additional therapeutic ingredients discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject in need thereof.

[0147] These formulations include those suitable for the aforementioned routes of administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods known in the art of pharmacy. Techniques and formulations generally are found in "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with a carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0148] In some embodiments, the pharmaceutical formulations are for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

[0149] In some embodiments, the compounds described herein (e.g., compounds of Formula I) or pharmaceutically acceptable salts thereof described herein have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, the compounds of Formula I have improved bioavailability and thus can be administered by oral administration.

[0150] In some embodiments, formulations of the application 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 a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary or paste.

[0151] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therein.

[0152] For infections of the eye or other external tissues (e.g., mouth and skin), formulations are applied as a topical ointment or cream containing an amount of the active ingredient sufficient to deliver a systemic dose of the drug to the target area, e.g., 0.075% to 20% w / w (including active ingredients in the range of between 0.1% and 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2% w / w to 15% w / w, and most preferably 0.5% w / w to 10% w / w. When formulated in an ointment, the active ingredient can be employed in combination with either a petrolatum base or a water-miscible base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water emulsion base or a water-in-oil base.

[0153] If desired, the water phase of the cream base can include, for example, at least 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400), and mixtures thereof. The topical formulation can desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0154] The oil phase of the emulsions of the present application can be constructed in known manner from known ingredients. While this phase can include only emulsifiers (or emulsifiers), it desirably includes a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included along with a lipophilic emulsifier which acts as a stabilizer. It is also preferable to include both an oil and a fat. The emulsifiers with or without stabilizers together constitute a so-called emulsifying wax, and the wax together with the oil and fat constitute a so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulation.

[0155] Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present application include Tween ® 60, Span ® 80, cetylstearyl alcohol, benzyl alcohol, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate. Additional emulsifiers and emulsion stabilizers suitable for use in the formulations of the present application include Tween ® 80.

[0156] Suitable oils or fats for the formulation are those of either vegetable or animal origin and include hydrogenated vegetable oils, animal oils, white soft paraffin, and mineral oils. Suitable oils or fats include, but are not limited to, almond oil, arachis oil, avocado oil, coconut oil, corn oil, cottonseed oil, jojoba oil, grapefruit seed extract, olive oil, palm oil, peanut oil, safflower oil, sesame oil, sunflower oil, and mixtures thereof. The choice of oil or fat is made according to the desired cosmetic properties to be achieved.

[0157] Pharmaceutical formulations according to the present application comprise a compound according to the present application together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral use the tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended to be administered orally are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient are also acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

[0158] Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0159] Aqueous suspensions according to the application contain the active material 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; and dispersing or wetting agents, such as a naturally occurring phosphatide (for example, soy lecithin), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of an alkylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyoxyethylene ® .

[0160] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil), or in a mineral oil (such as liquid paraffin). Oral suspensions can contain suspending agents (such as sorbitol, cellulose acetate phthalate, or hydrogenated castor oil), and / or sweetening agents (such as those set forth above), and / or flavouring agents. The compositions can be preserved by the addition of an antioxidant (such as ascorbic acid).

[0161] Dispersible powders and granules of the application suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavouring and colouring agents, can also be present.

[0162] The pharmaceutical compositions of this application can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil (such as olive oil or arachis oil), a mineral oil (such as liquid paraffin) or a mixture of these. Suitable emulsifying agents include naturally occurring gums (such as gum acacia and gum tragacanth), 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). The emulsions can also contain sweetening and flavouring agents. Syrups and elixirs can be formulated with sweetening agents (such as glycerol, sorbitol or sucrose) and flavouring agents (such as peppermint, methyl salicylate or orange flavouring).

[0163] The pharmaceutical compositions of this application can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Acceptable solvents and vehicles that can be employed include water, Ringer's solution, isotonic sodium chloride solution and high salt solution.

[0164] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans can contain approximately 1 mg to 1000 mg of the active material compounded with an appropriate and convenient amount of carrier material to make a dosage unit form that is suitably adapted for ingestion, the carrier material being present in about 5 to about 95% (w / w) of the total composition. The pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain about 3 mg to 500 mg of the active ingredient per milliliter of solution in order for a suitable volume to be infused about 30 mL / hr.

[0165] Formulations suitable for topical application to the eye also include drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient preferably is present in such formulations in a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w.

[0166] Formulations suitable for topical application to the eye also include drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient preferably is present in such formulations in a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w.

[0167] Formulations for rectal administration can be provided as suppositories with a suitable base, including for example cocoa butter or salicylates.

[0168] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or intranasal administration have, for example, a particle size that is in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35, or the like, which are administered by rapid inhalation delivery through the nasal passage or by inhalation into the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can deliver the other therapeutic agents. In some embodiments, the compounds used herein are formulated and dosed as a dry powder. In some embodiments, the compounds used herein are formulated and dosed as an aerosolized formulation. In some embodiments, the compounds used herein are formulated for delivery by face mask. In some embodiments, the compounds used herein are formulated for delivery by a face mask inhaler.

[0169] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0170] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

[0171] Formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit- dose formulations are those containing a daily dose or unit daily sub-dose, as herein above described, of an active ingredient.

[0172] It will be appreciated that, in addition to ingredients particularly mentioned herein, the formulations of the application can include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration can include flavouring agents.

[0173] The present application further provides veterinary compositions comprising at least one active ingredient as defined above and a veterinary carrier.

[0174] Veterinary carriers are materials which can be used to administer a composition and which can be solids, liquids, or gases and which are otherwise inert and nontoxic to the subjects and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

[0175] The compounds of the present application are used to provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more compounds of the present application as active ingredients, wherein the release of the active ingredients is controlled and regulated to allow less frequent dosaging or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0176] V. kits Also provided herein are kits comprising a compound disclosed herein, a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. In some embodiments, the kits described herein can comprise a label and / or instructions for using the compound to treat a disease or condition in a subject (e.g., a human) in need thereof. In some embodiments, the disease or condition is a viral infection.

[0177] In some embodiments, the kits can further comprise one or more additional therapeutic agents and / or instructions for using the additional therapeutic agent(s) in combination with the compound of Formula I to treat a disease or condition in a subject (e.g., a human) in need thereof.

[0178] In some embodiments, the kits provided herein comprise individual dosage units of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. Examples of individual dosage units can include pills, tablets, capsules, pre-filled syringes or cartridges for an inhaler or a syringe, IV bags, inhalers, nebulizers, etc., each of which includes a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. In some embodiments, the kits can contain a single dosage unit, and in other embodiments there are multiple dosage units, e.g., the number of dosage units required for a specified regimen or cycle.

[0179] Also provided are articles of manufacture comprising: a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and a container. In some embodiments, the container of the article of manufacture is a vial, jar, ampule, pre-filled syringe, blister pack, tank, flask, bottle, box, intravenous bag, inhaler, or nebulizer.

[0180] VI. administration The compound(s) of the application are administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. In some embodiments, the compounds disclosed herein are administered by inhalation or intravenously. In some embodiments, the compounds disclosed herein are administered orally. It will be appreciated that the preferred route can vary with, for example, the condition of the recipient.

[0181] In the methods of the application for treating viral infections, the compounds of the application can be administered to a person who can be exposed to a virus or who already has a viral infection at any time. In some embodiments, the compounds of the application can be administered prophylactically to a person who is in contact with or at risk of being in contact with a person who has a viral infection, for example, a health care provider. In some embodiments, administration of the compounds of the application can be to a person who tests positive for a viral infection but has not yet shown symptoms of the viral infection. In some embodiments, the compounds of the application can be administered to a person at the onset of symptoms of a viral infection.

[0182] In some embodiments, the methods disclosed herein comprise event- driven administration of a compound described herein (e.g., a compound of Formula I), or a pharmaceutically acceptable salt thereof, to a subject.

[0183] As used herein, the term “event-driven” or “event-driven administration” refers to administration of a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof (1) prior to an event that will expose an individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection); and / or (2) during an event (or more than one repeated event) that will expose an individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection); and / or (3) after an event (or after the final event in a series of repeated events) that will expose an individual to a virus (or will otherwise increase the risk of the individual acquiring a viral infection). In some embodiments, event-driven administration occurs prior to exposure of the subject to a virus. In some embodiments, event-driven administration occurs after exposure of the subject to a virus. In some embodiments, event-driven administration occurs both prior to and after exposure of the subject to a virus.

[0184] In certain embodiments, the methods disclosed herein involve administration prior to and / or after an event that will expose an individual to a virus or otherwise increase the risk of the individual acquiring a viral infection, e.g., as pre-exposure prophylaxis (PrEP) and / or as post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein comprise pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein comprise post-exposure prophylaxis (PEP).

[0185] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered prior to exposure of the subject to a virus.

[0186] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered prior to and after exposure of the subject to a virus.

[0187] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered after exposure of the subject to a virus.

[0188] Examples of event-driven dosing regimens include administration of a compound of Formula I or a pharmaceutically acceptable salt thereof within 24 to 2 hours prior to a virus, followed by administration of a compound of Formula I or a pharmaceutically acceptable salt thereof every 24 hours during exposure, followed by further administration of a compound of Formula I or a pharmaceutically acceptable salt thereof after the last exposure, and a final administration of a compound of Formula I or a pharmaceutically acceptable salt thereof 24 hours later.

[0189] Another example of an event-driven dosing regimen includes administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 hours prior to viral exposure, then daily during exposure, then a final administration (which can be an increased dose, such as a double dose) about 24 hours after the last exposure.

[0190] The specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion of the subject being treated, drug combinations, and the severity of the particular disease undergoing therapy. For example, dosages can be expressed in mg / kg of a compound described herein per kilogram of body weight of the subject. Dosages between about 0.1 mg / kg and 150 mg / kg can be appropriate. In some embodiments, dosages between about 0.1 mg / kg and 100 mg / kg can be appropriate. In other embodiments, dosages between 0.5 mg / kg and 60 mg / kg can be appropriate. Normalization to body weight is particularly useful in adjusting dosages between subjects that differ greatly in size, such as when using a drug in children and adults, or when converting an effective dosage of a non-human subject, such as a dog, to a dosage suitable for a human subject.

[0191] Daily dosages can also be described as the total amount of a compound described herein administered per dose or per day. Daily dosages of a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be between about 1 mg and 4,000 mg, between about 2,000 mg / day to 4,000 mg / day, between about 1 mg / day to 2,000 mg / day, between about 1 mg / day to 1,000 mg / day, between about 10 mg / day to 500 mg / day, between about 20 mg / day to 500 mg / day, between about 50 mg / day to 300 mg / day, between about 75 mg / day to 200 mg / day, or between about 15 mg / day to 150 mg / day.

[0192] The dose or frequency of administration of a compound of the present disclosure can be adjusted during the course of therapy as indicated by the attending physician.

[0193] A compound of the present disclosure can be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once per day.

[0194] The compounds provided herein can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound can include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, a therapeutically effective amount of a compound provided herein includes from about 0.3 mg / day to about 30 mg / day, or from about 30 mg / day to about 300 mg / day, or from about 0.3 mg / day to about 30 mg / day, or from about 30 mg / day to about 300 mg / day.

[0195] The compounds of the disclosure can be combined with one or more additional therapeutic agents in any dosage amount of the compounds of the disclosure (e.g., 1 mg to 1000 mg of the compound). A therapeutically effective amount can include about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose, or such as about 0.01 mg / dose to about 1000 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 10 mg / dose, or such as about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective amounts of the compounds of Formula I are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose. Other therapeutically effective amounts of the compounds of the disclosure are about 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose, 450 mg / dose, 475 mg / dose, 500 mg / dose, 525 mg / dose, 550 mg / dose, 575 mg / dose, 600 mg / dose, 625 mg / dose, 650 mg / dose, 675 mg / dose, 700 mg / dose, 725 mg / dose, 750 mg / dose, 775 mg / dose, 800 mg / dose, 825 mg / dose, 850 mg / dose, 875 mg / dose, 900 mg / dose, 925 mg / dose, 950 mg / dose, 975 mg / dose, or about 1000 mg / dose per dose.

[0196] In some embodiments, the methods described herein comprise administering to the subject an initial daily dose of about 1 mg to 500 mg of a compound provided herein, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0197] When administered orally, the total daily dose to a human subject can be between about 1 mg / day - 4,000 mg / day, between about 1 mg / day - 3,000 mg / day, between 1 mg / day - 2,000 mg / day, about 1 mg / day - 1,000 mg / day, between about 10 mg / day - 500 mg / day, between about 50 mg / day - 300 mg / day, between about 75 mg / day - 200 mg / day, or between about 100 mg / day - 150 mg / day. In some embodiments, the total daily dose to a human subject can be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg / day administered in a single dose. In some embodiments, the total daily dose to a human subject can be about 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, or 800 mg / day administered in a single dose. In some embodiments, the total daily dose to a human subject can be about 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day administered in a single dose. In some embodiments, the total daily dose to a human subject can be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, or 4000 mg / day.In some embodiments, the total daily dose for a human subject can be about 100 mg / day - 200 mg / day, 100 mg / day - 300 mg / day, 100 mg / day - 400 mg / day, 100 mg / day - 500 mg / day, 100 mg / day - 600 mg / day, 100 mg / day - 700 mg / day, 100 mg / day - 800 mg / day, 100 mg / day - 900 mg / day, 100 mg / day - 1000 mg / day, 500 mg / day - 1100 mg / day, 500 mg / day - 1200 mg / day, 500 mg / day - 1300 mg / day, 500 mg / day - 1400 mg / day, 500 mg / day - 1500 mg / day, 500 mg / day - 1600 mg / day, 500 mg / day - 1700 mg / day, 500 mg / day - 1800 mg / day, 500 mg / day - 1900 mg / day, 500 mg / day - 2000 mg / day, 1500 mg / day - 2100 mg / day, 1500 mg / day - 2200 mg / day, 1500 mg / day - 2300 mg / day, 1500 mg / day - 2400 mg / day, 1500 mg / day - 2500 mg / day, 2000 mg / day - 2600 mg / day, 2000 mg / day - 2700 mg / day, 2000 mg / day - 2800 mg / day, 2000 mg / day - 2900 mg / day, 2000 mg / day - 3000 mg / day, 2500 mg / day - 3100 mg / day, 2500 mg / day - 3200 mg / day, 2500 mg / day - 3300 mg / day, 2500 mg / day - 3400 mg / day, 2500 mg / day - 3500 mg / day, 3000 mg / day - 3600 mg / day, 3000 mg / day - 3700 mg / day, 3000 mg / day - 3800 mg / day, 3000 mg / day - 3900 mg / day, or 3000 mg / day - 4000 mg / day.

[0198] In some embodiments, the total daily dose for a human subject can be about 100 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 150 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 200 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 250 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 300 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 350 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 400 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 450 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 550 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 600 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 650 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 700 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 750 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 800 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 850 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 900 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 950 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 1000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 1500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 2000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 2500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 3000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 4000 mg / day administered in a single dose.

[0199] A single dose can be administered every hour, every day, every week, or every month. For example, a single dose can be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. A single dose can also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. A single dose can also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once a week. A single dose can also be administered once a month. In some embodiments, a compound disclosed herein is administered once a day in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice a day in a method disclosed herein. In some embodiments, a compound disclosed herein is administered three times a day in a method disclosed herein.

[0200] In some embodiments, a compound disclosed herein is administered once a day at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, a compound disclosed herein is administered twice a day at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, a compound disclosed herein is administered three times a day at a total daily dose of 100 mg / day to 4000 mg / day.

[0201] The frequency of the dose of a compound of the disclosure will be determined by the needs of the individual patient and can be, for example, once per day or twice or more per day. Administration of the compound continues for as long as treatment of the viral infection is required. For example, the compound can be administered to a person infected with a virus for a period of 20 days to 180 days, or for example, 20 days to 90 days, or for example, 30 days to 60 days.

[0202] Administration can be intermittent, with the patient receiving a certain daily dose of a compound of the disclosure for a period of days or more, followed by the patient not receiving the certain daily dose of the compound for a period of days or more. For example, the patient can receive a dose of the compound every other day or three times a week. Again by way of example, the patient can receive a dose of the compound every day for a period of 1 day to 14 days, followed by the patient not receiving a dose of the compound for a period of 7 days to 21 days, followed by the patient again receiving a certain daily dose of the compound for a subsequent period of, for example, 1 day to 14 days. The alternating periods of administration of the compound followed by no administration of the compound can be repeated as clinically indicated to treat the patient.

[0203] The compounds of the disclosure, or pharmaceutical compositions thereof, can be administered once, twice, three times, or four times daily using any of the suitable modes described above. Also, administration or treatment with the compounds can continue for multiple days; for example, for one treatment cycle, treatment will generally continue for at least 7 days, 14 days, or 28 days. Treatment cycles are well known in cancer chemotherapy, and are typically alternated with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. In other embodiments, the treatment cycles can also be continuous.

[0204] VII. methods of use The disclosure also provides methods of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound described herein.

[0205] In some embodiments, the disclosure provides methods of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject in need thereof a compound described herein.

[0206] In some embodiments, the compounds described herein are administered to humans via oral, intramuscular, intravenous, subcutaneous, or inhalation administration.

[0207] In some embodiments, the disclosure provides methods of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0208] In some embodiments, the disclosure provides methods of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0209] In one embodiment, the disclosure provides methods of inhibiting viral polymerase in a cell, comprising contacting a cell infected with a virus with a compound disclosed herein, whereby viral polymerase is inhibited.

[0210] In one embodiment, the disclosure provides methods of inhibiting viral polymerase in a cell, comprising contacting a cell infected with a virus with a compound disclosed herein and at least one additional active therapeutic agent, whereby viral polymerase is inhibited.

[0211] Also provided herein are uses of the compounds disclosed herein for treating or preventing a viral infection in a subject in need thereof. For example, provided herein are uses of the compounds disclosed herein for treating a viral infection in a subject in need thereof.

[0212] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Thus, in some embodiments, the disclosure provides a method for treating a Paramyxoviridae infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein. Paramyxoviridae viruses include, but are not limited to, a Nipah virus, a Hendra virus, a measles virus, a mumps virus, and a parainfluenza virus.

[0213] In some embodiments, the viral infection is a human parainfluenza virus, a Nipah virus, a Hendra virus, a measles, or a mumps infection.

[0214] In some embodiments, the viral infection is a Pneumoviridae virus infection. Thus, in some embodiments, the disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound provided herein. Pneumoviridae viruses include, but are not limited to, a respiratory syncytial virus and a 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.

[0215] In some embodiments, the 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.

[0216] In some embodiments, the disclosure provides a method for treating an RSV infection in a human in need thereof, the method comprising administering to the human a compound provided herein. In some embodiments, the human has a chronic respiratory syncytial virus infection. In some embodiments, the human has an acute RSV infection.

[0217] In some embodiments, there is provided a method of inhibiting RSV replication, wherein the method comprises administering to a human in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0218] In some embodiments, the disclosure provides a method for reducing viral load associated with an RSV infection, wherein the method comprises administering to a human infected with RSV a compound disclosed herein.

[0219] In some embodiments, the viral infection is a Picornaviridae virus infection. Accordingly, in some embodiments, the disclosure provides a method of treating a Picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound of the disclosure. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), nonparalytic poliomyelitis-like syndrome, epidemic myalgia (an acute, febrile, infectious illness that usually occurs in epidemics), hand-foot-and-mouth syndrome, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the Picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0220] In some embodiments, 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.

[0221] In some embodiments, the disclosure provides a compound for use in treating a Picornaviridae virus infection in a human in need thereof. In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection.

[0222] In some embodiments, the viral infection is a Flaviviridae virus infection. Accordingly, in some embodiments, the disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative Flaviviridae viruses include, but are not limited to, dengue, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0223] In some embodiments, the Flaviviridae virus infection is a dengue virus infection, a yellow fever virus infection, a West Nile virus infection, tick-borne encephalitis, Kyasanur fever, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

[0224] In some embodiments, the present disclosure provides use of a compound disclosed herein for treating a Flaviviridae viral infection in a human in need thereof. In some embodiments, the Flaviviridae viral infection is a Dengue virus infection. In some embodiments, the Flaviviridae viral infection is a Yellow fever virus infection. In some embodiments, the Flaviviridae viral infection is a West Nile virus infection. In some embodiments, the Flaviviridae viral infection is a Zika virus infection. In some embodiments, the Flaviviridae viral infection is a Hepatitis C virus infection.

[0225] In some embodiments, the viral infection is a Filoviridae viral infection. Accordingly, in some embodiments, provided herein is a method of treating a Filoviridae viral infection in a human in need thereof, comprising administering to the human a compound disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (variant Zaire, Bundibugio, Sudan, Tai Forest, or Reston) and Marburg virus. In some embodiments, the Filoviridae viral infection is an Ebola virus infection. In some embodiments, the Filoviridae viral infection is a Marburg virus infection.

[0226] In some embodiments, the present disclosure provides a compound for use in treating a Filoviridae viral infection in a human in need thereof. In some embodiments, the Filoviridae viral infection is an Ebola virus infection. In some embodiments, the Filoviridae viral infection is a Marburg virus infection.

[0227] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, provided herein are methods of treating a coronavirus infection in a human in need thereof, wherein the method comprises administering to the human a compound provided herein. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS-CoV) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, a zoonotic coronavirus (PEDV or HKU CoV isolate, such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0228] In some embodiments, the viral infection is caused by a variant of SARS-CoV-2, such as the B.1.1.7 variant (UK variant), the B.1.351 variant (South African variant), the P.1 variant (Brazilian variant), the B.1.1.7 and E484K variant, the B.1.1.207 variant, the B.1.1.317 variant, the B.1.1.318 variant, the B.1.429 variant, the B.1.525 variant, or the P.3 variant. In some embodiments, the viral infection is caused by the B.1.1.7 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the B.1.351 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the P.1 variant of SARS-CoV-2.

[0229] In some embodiments, the present disclosure provides a compound for use in treating a coronavirus infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, and a zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0230] In some embodiments, the viral infection is an arenavirus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating an arenavirus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the arenavirus infection is a Lassa virus infection or a Junin virus infection.

[0231] In some embodiments, the present disclosure provides a compound for use in treating an arenavirus infection in a human in need thereof. In some embodiments, the arenavirus infection is a Lassa virus infection or a Junin virus infection.

[0232] In some embodiments, the viral infection is a orthomyxovirus infection, e.g., an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0233] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a virus along with one or more additional therapeutic agents. The additional therapeutic agent(s) can be administered to the infected individual simultaneously with, or prior to, or subsequent to, administration of the compound of the present disclosure.

[0234] VIII. combination therapy The compounds described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, also provided herein are methods of treating a viral infection in a subject in need thereof, wherein the methods comprise administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents.

[0235] In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein.

[0236] combination therapy for treating pneumoviridae The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Pneumoviridae viral infections, preferably the other active therapeutic agent has activity against Pneumoviridae viral infections, in particular respiratory syncytial virus infection and / or metapneumovirus infection. Non-limiting examples of these other active therapeutic agents with activity against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam ® ), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents with activity against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and pritelivir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAbs; viral replication inhibitors such as nitazoxanide. Other non-limiting examples of other active therapeutic agents with activity against respiratory syncytial virus infection include EDP-938 and RV-299, and molnupiravir.

[0237] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0238] Non-limiting examples of other active therapeutic agents with activity against metapneumovirus infection include sialidase modulators such as DAS-181; RNA polymerase inhibitors such as ALS-8112; and antibodies for treating metapneumovirus infection such as EV-046113.

[0239] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccine.

[0240] combination therapy for treating picornaviridae The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Picornaviridae viral infections, preferably the other active therapeutic agents have activity against Picornaviridae viral infections, particularly enterovirus infections. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase proteins such as DAS-181; capsid protein VP1 inhibitors such as VVX-003 and AZN-001; viral protease inhibitors such as CW-33; phosphatidylinositol 4 kinase beta inhibitors such as GSK-480 and GSK-533; anti-EV71 antibodies.

[0241] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of Picornaviridae viral infections, including but not limited to EV71 vaccines, TAK-021, and EV-D68 adenoviral vector-based vaccines.

[0242] combination therapy for respiratory infections Many infections by viruses of the families of Pneumoviridae, Picornaviridae, and Coronaviridae are respiratory tract infections. Thus, additional active therapeutic agents for the treatment of respiratory tract symptoms and sequelae of infection can be used in combination with the compounds provided herein. The additional therapeutic agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents for use in combination with the compounds provided herein for the treatment of viral respiratory tract infections include, but are not limited to, bronchodilators and corticosteroids.

[0243] glucocorticoids Glucocorticoids, first introduced as a therapy for asthma in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most effective and consistently effective therapy for this disease, but their mechanism of action is not fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with serious adverse side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th Edition, 2001). A solution to the systemic side effects is to deliver the steroid drug directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to reduce the serious side effects of oral steroids. Non-limiting examples of corticosteroids that can be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol etabonate, loteprednol etabonate ophthalmic solution, hydrocortisone, prednisolone, flurandrenolide, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocinbutte-21 -butylate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide; or a pharmaceutically acceptable salt thereof.

[0244] anti-inflammatory agents Other anti-inflammatory agents that act through anti-inflammatory cascades can also be used as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. The use of "anti-inflammatory signal transduction modulators" (AISTMs in this text), such as phosphodiesterase inhibitors (e.g., specific for PDE-4, PDE-5, or PDE-7), transcription factor inhibitors (e.g., block NFκB through IKK inhibition), or kinase inhibitors (e.g., block P38 MAP, JNK, PI3K, EGFR, or Syk) is a logical approach to cutting off inflammation, as these small molecules target a limited number of common intracellular pathways - those signal transduction pathways that are key points of intervention for anti-inflammatory therapy (see review by P.J. Barnes, 2006). These non-limiting additional therapeutic agents include: 5-(2,4-difluoro-phenoxy)-l-isobutyl-lH-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-difluoromethoxy-8-[(methylsulfonyl)amino]-l-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[l-(4-fluorobenzyl)-5-hydroxy-lH-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-l-oxo-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-lH-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-l-(3-phenylpropyl)-5-pyridin-4-yl-lH-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast, PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, EGFR inhibitor); and 4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, EGFR inhibitor).

[0245] beta2-adrenergic receptor agonist bronchodilators Combinations comprising inhaled beta2-adrenergic receptor agonist bronchodilators such as formoterol, salbutamol or salmeterol with the compounds provided herein are also suitable, but not limiting, combinations useful for treating respiratory viral infections.

[0246] Combinations of inhaled beta2-adrenergic receptor agonist bronchodilators such as formoterol or salmeterol with ICS are also used to treat bronchoconstriction and inflammation (Symbicort ® and Advair ® , respectively). Combinations comprising these ICS and beta2-adrenergic receptor agonist combinations and the compounds provided herein are also suitable, but not limiting, combinations useful for treating respiratory viral infections.

[0247] Other examples of beta2 adrenergic receptor agonists are bevonol, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471.

[0248] anticholinergic agents Anticholinergic agents have potential use for the treatment or prevention of bronchoconstriction in the lungs and thus can be used in combination with the compounds provided herein as an additional therapeutic agent for the treatment of viral respiratory infections.These anticholinergic agents include, but are not limited to, antagonists of muscarinic receptors (particularly the M3 subtype) that have proven therapeutic efficacy in humans for the control of cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)-propionyl]-pyrrolidine-2-carbonyl}- pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino- acetyloxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonio-bicyclo[3.2.1]octane (isopropylamine-N,N-diethylglycine); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solfenazin); 2-hydroxymethyl-4-methane-sulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (revatropate); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (darifenacin); 4-azepan-1-yl-2,2-diphenyl-butyramide (buzepide); 7-[3-(2-diethylamino-acetyloxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonio- tricyclo[3.3.1.02,4]nonane (oxitropium-N,N-diethylglycine); 7-[2-(2-diethylamino-acetyloxy)-2,2-di-thiophen-2-yl-acetyloxy]-9,9-dimethyl-3-oxa-9-azonio- tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycine); dimethylamino-acetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N- dimethylglycine); 3-[4,4-bis-(4-fluorophenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl- ethyl)-pyrrolidinium; 1-[1-(3-fluorobenzyl)-piperidin-4-yl]-4,4-bis-(4-fluorophenyl)-imidazolidin-2-one; 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol; 3-[2-(2-diethylamino-acetyloxy)-2,2-dithiophen-2-yl-acetyloxy]-1-(3-phenoxy-propyl)-1-azonio- bicyclo[2.2.2]octane (atropine-N,N-diethylglycine); or (2-diethylamino-acetyloxy)-dithiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; rafenamin, glycopyrronium, umclidinium, tiotropium, aclidinium, benzquinonium.

[0249] mucolytic agents The compounds provided herein can also be combined with mucolytic agents to treat infections and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds can be combined with expectorants to treat infections and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0250] Aerosolized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung disease (Kuzik, et al., 2007, 266). Thus, the compounds provided herein can also be combined with aerosolized hypertonic saline, particularly when the viral infection is complicated by bronchiolitis. The combination of the compounds provided herein with hypertonic saline can also include any of the additional agents discussed above. In one embodiment, aerosolized about 3% hypertonic saline is used. J. Pediatrics 2007, 266). Thus, the compounds provided herein can also be combined with aerosolized hypertonic saline, particularly when the viral infection is complicated by bronchiolitis. The combination of the compounds provided herein with hypertonic saline can also include any of the additional agents discussed above. In one embodiment, aerosolized about 3% hypertonic saline is used.

[0251] combination therapy for treating flaviviridae viral infections The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Flaviviridae viral infections, preferably the other active therapeutic agent has activity against Flaviviridae viral infections.

[0252] For the treatment of dengue viral infections, non-limiting examples of other active therapeutic agents are host cytokine modulators such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors such as celgosivir; platelet-activating factor receptor (PAFR) antagonists such as modipafant; cadherin-5 / factor la modulators such as FX-06; NS4B inhibitors such as JNJ-8359; viral RNA splicing modulators such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0253] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of dengue, including but not limited to TetraVax-DV, Dengvaxia ® , DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2delta30-7169, and DENV-1 PIV.

[0254] combination therapy for treating filoviridae viral infections The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Filoviridae virus infections, preferably the other active therapeutic agents have activity against Filoviridae virus infections, in particular Marburg virus, Ebola virus, and Reston virus infections. Non-limiting examples of these other active therapeutic agents are: ribavirin, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5- (hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9- dimethylquinolo[8,7-h]quinolin-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as Galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cytokine modulators such as GMV-006; Cadherin-5 / Factor la modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0255] Non-limiting active therapeutic agents with activity against Ebola include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cytokine modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick Cl protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0256] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of Ebola, including but not limited to VRC-EBOADC076-00-VP, an adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo + Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0257] The compounds provided herein can also be used in combination with phosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with the translation process by forming base-paired duplexes with specific RNA sequences. Examples of PMOs include, but are not limited to, AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0258] The compounds provided herein are also intended for use with the general care provided to patients infected with an Orthomyxoviridae virus, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common ailments in the patient population, such as anti-malarial agents (including artemether and artemether-lumefantrine combination therapy), typhoid fever vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or Shigella disease vaccines.

[0259] The application will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the application in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters that can be changed or modified to yield essentially the same results.

[0260] combination therapy for treating coronaviridae viral infections In some embodiments, the additional therapeutic agent is a 2,5-oligoadenylate synthetase stimulator, a 5-HT 2a receptor antagonist, a 5-lipoxygenase inhibitor, an ABL family tyrosine kinase inhibitor, an Abl tyrosine kinase inhibitor, an acetaldehyde dehydrogenase inhibitor, an acetyl CoA carboxylase inhibitor, an actin antagonist, an actin modulator, an activity-dependent neuroprotective modulator, an adenosine A3 receptor agonist, an adrenergic receptor antagonist, an adrenomedullin ligand, an adrenomedullin ligand inhibitor, an advanced glycosylation end product receptor antagonist, an advanced glycosylation end product receptor modulator, an AKT protein kinase inhibitor, an alanine proline-rich secreted protein stimulator, an aldose reductase inhibitor, an alkaline phosphatase stimulator, an alpha 2 adrenergic receptor antagonist, an alpha 2B adrenergic receptor antagonist, an AMP-activated protein kinase stimulator, an AMPA receptor modulator, an amyloid deposition inhibitor, an androgen receptor antagonist, an angiotensin II AT-1 receptor antagonist, an angiotensin II AT-2 receptor agonist, an angiotensin II receptor modulator, an angiotensin converting enzyme 2 inhibitor, an angiotensin converting enzyme 2 modulator, an angiotensin converting enzyme 2 stimulator, an angiotensin receptor modulator, an annexin A5 stimulator, an anoctamin 1 inhibitor, an anticoagulant, an antihistamine, an anti-hypoxia agent, an anti-thrombotic agent, an AP 1 transcription factor modulator, an apelin receptor agonist, an APOA 1 gene stimulator, an apolipoprotein A1 agonist, an apolipoprotein B antagonist, an apolipoprotein B modulator, an apolipoprotein C3 antagonist, an aryl hydrocarbon receptor agonist, an aryl hydrocarbon receptor antagonist, an ATP-binding cassette transporter B5 modulator, an axl tyrosine kinase receptor inhibitor, a bactericidal permeability protein inhibitor, a basigin inhibitor, a basigin modulator, a BCL 2 gene inhibitor, a BCL 2L11 gene stimulator, a Bcr protein inhibitor, a beta 1 adrenergic receptor modulator, a beta 2 adrenergic receptor agonist, a beta-arrestin stimulator, a blood coagulation modulator, a BMP10 gene inhibitor, a BMP15 gene inhibitor, a bone morphogenetic protein-10 ligand inhibitor, a bone morphogenetic protein-15 ligand inhibitor, a bradykinin B2 receptor antagonist, a brain-derived neurotrophic factor ligand, a bromodomain-containing protein 2 inhibitor, a bromodomain-containing protein 4 inhibitor, a Btk tyrosine kinase inhibitor, a C-reactive protein modulator, a Ca2+ release-activated Ca2+ channel 1 inhibitor, a cadherin-5 modulator, a calcium-activated chloride channel inhibitor, a calcium channel modulator, a calpain-I inhibitor, a calpain-II inhibitor, a calpain-IX inhibitor, a cannabinoid CB2 receptor agonist, a cannabinoid receptor modulator, a casein kinase II inhibitor, a CASP8-FADD-like modulator inhibitor, a caspase inhibitor, a catalase stimulator, a CCL26 gene inhibitor, a CCR2 chemokine antagonist, a CCR5 chemokine antagonist,CD11a agonist, CD122 agonist, CD3 antagonist, CD4 agonist, CD40 ligand, CD40 ligand modulator, CD40 ligand receptor agonist, CD40 ligand receptor modulator, CD49d agonist, CD70 antigen modulator, CD73 agonist, CD73 antagonist, CD95 antagonist, CFTR inhibitor, CGRP receptor antagonist, Chemokine Receptor Like 1 agonist, Chloride Channel Inhibitor, Chloride Channel Modulator, Cholera Enterotoxin Subunit B Inhibitor, Cholesteryl Ester Transfer Protein Inhibitor, Collagen Modulator, Complement Cls Subcomponent Inhibitor, Complement C3 Inhibitor, Complement C5 Factor Inhibitor, Complement C5a Factor Inhibitor, Complement Factor H Stimulator, Complement Cascade Inhibitor, Complement Factor C2 Inhibitor, Complement Factor D Inhibitor, Connective Tissue Growth Factor Ligand Inhibitor, Coronavirus Nucleoprotein Modulator, Coronavirus Small Envelope Protein Modulator, Coronavirus Spike Glycoprotein Inhibitor, Coronavirus Spike Glycoprotein Modulator, COVID19 Envelope Small Membrane Protein Modulator, COVID19 Nonstructural Protein 8 Modulator, COVID19 Nucleoprotein Modulator, COVID19 Protein 3a Inhibitor, COVID19 Replicase Polyprotein la Inhibitor, COVID19 Replicase Polyprotein la Modulator, COVID19 Replicase Polyprotein lab Inhibitor, COVID19 Replicase Polyprotein lab Modulator, COVID19 Spike Glycoprotein Inhibitor, COVID19 Spike Glycoprotein Modulator, COVID19 Structural Glycoprotein Modulator, CRF-2 Receptor Agonist, CSF-1 Agonist, CSF-1 Antagonist, CX3CR1 Chemokine Antagonist, CXC10 Chemokine Ligand Inhibitor, CXC5 Chemokine Ligand Inhibitor, CXCL1 Gene Modulator, CXCL2 Gene Modulator, CXCL3 Gene Modulator, CXCR1 Chemokine Antagonist, CXCR2 Chemokine Antagonist, CXCR4 Chemokine Antagonist, Cyclin D1 Inhibitor, Cyclin E Inhibitor, Cyclin-Dependent Kinase-1 Inhibitor, Cyclin-Dependent Kinase-2 Inhibitor, Cyclin-Dependent Kinase-5 Inhibitor, Cyclin-Dependent Kinase-7 Inhibitor, Cyclin-Dependent Kinase-9 Inhibitor, Cyclooxygenase 2 Inhibitor, Cyclooxygenase Inhibitor, Cyclophilin Inhibitor, Cysteine Protease Inhibitor, Cytochrome P450 3A4 Inhibitor, Cytokine Receptor Antagonist, Cytotoxic T Lymphocyte Protein Gene Modulator, Cytotoxic T Lymphocyte Protein-4 Inhibitor, Cytotoxic T Lymphocyte Protein-4 Stimulator, DDX3 Inhibitor, Dehydrogenase Inhibitor, Dehydropeptidase-1 Modulator, Deoxyribonuclease I Stimulator, Deoxyribonuclease Gamma Stimulator, Deoxyribonuclease Stimulator, Dihydroceramide Delta 4 Desaturase Inhibitor, Dihydroorotate Dehydrogenase Inhibitor, Dipeptidyl Peptidase I Inhibitor, Dipeptidyl Peptidase III Inhibitor,antagonists, E-selectin antagonists, Ecto NOX disulfide thiol exchanger 2 inhibitors, EGFR gene inhibitors, elongation factor 1 alpha 2 modulators, dndoplasmin modulators, endoribonuclease DICER modulators, endothelin ET-A receptor antagonists, epidermal growth factor receptor antagonists, E-selectin antagonists, estrogen receptor beta agonists, estrogen receptor modulators, eukaryotic initiation factor 4A-I inhibitors, exogenous alpha sialidase modulators, exportin 1 inhibitors, factor la modulators, factor IIa modulators, factor VII antagonists, factor Xa antagonists, factor XIa antagonists, FGF receptor antagonists, FGF-1 ligands, FGF-1 ligand inhibitors, FGF-2 ligand inhibitors, FGF1 receptor antagonists, FGF2 receptor antagonists, FGF3 receptor antagonists, Flt3 tyrosine kinase inhibitors, fractalkine ligand inhibitors, free fatty acid receptor 2 agonists, free fatty acid receptor 3 agonists, furin inhibitors, fyn tyrosine kinase inhibitors, FYVE finger phosphoinositide kinase inhibitors, G protein-coupled bile acid receptor 1 agonists, GABA A receptor modulators, galectin-3 inhibitors, gamma-secretase inhibitors, GDF agonists, gelsolin stimulators, glial cell line-derived neurotrophic factor ligands, glucocorticoid receptor agonists, glutathione peroxidase stimulators, GM-CSF ligand inhibitors, GM-CSF receptor agonists, GM-CSF receptor modulators, griffithsin modulators, growth regulatory protein alpha ligand inhibitors, Grp78 calcium binding protein inhibitors, heat shock protein HSP90 alpha inhibitors, heat shock protein HSP90 beta inhibitors, heat shock proteins inhibitors, heat shock proteins stimulators, hemagglutinin modulators, hemoglobin modulators, hemolysin alpha inhibitors, heparanase inhibitors, heparin agonists, hepatitis B structural protein inhibitors, hepatitis C virus NS5B polymerase inhibitors, HIF prolyl hydroxylase inhibitors, HIF prolyl hydroxylase-2 inhibitors, high mobility group protein B1 inhibitors, histamine H1 receptor antagonists, histamine H2 receptor antagonists, histone deacetylase-6 inhibitors, histone inhibitors, HIV protease inhibitors, HIV-1 gp120 protein inhibitors, HIV-1 protease inhibitors, HIV-1 reverse transcriptase inhibitors, HLA class I antigen modulators, HLA class II antigen modulators, host cytokine modulators, Hsp 90 inhibitors, human papillomavirus E6 protein modulators, human papillomavirus E7 protein modulators, hypoxia-inducible factor inhibitor gene inhibitors, hypoxia-inducible factor-2 alpha modulators, I-kappa B kinase inhibitors, I-kappa B kinase modulators, ICAM-1 stimulators, IgG receptor FcRn large subunit p51 modulators,IL-12 receptor antagonists, IL-15 receptor agonists, IL-15 receptor modulators, IL-17 antagonists, IL-18 receptor accessory protein antagonists, IL-2 receptor agonists, IL-22 agonists, IL-23 antagonists, IL-6 receptor agonists, IL-6 receptor antagonists, IL-6 receptor modulators, IL-7 receptor agonists, IL-8 receptor antagonists, IL12 gene stimulators, IL8 gene modulators, Immunoglobulin G modulators, Immunoglobulin G1 agonists, Immunoglobulin G1 modulators, Immunoglobulin agonists, Immunoglobulin gamma Fc receptor I modulators, Immunoglobulin kappa modulators, Inosine monophosphate dehydrogenase inhibitors, Insulin sensitizers, Integrin agonists, Integrin alpha-4 / beta-7 antagonists, Integrin alpha-V / beta-1 antagonists, Integrin alpha-V / beta-6 antagonists, Interferon agonists, Interferon alpha 14 ligands, Interferon alpha 2 ligands, Interferon alpha 2 ligand modulators, Interferon alpha ligands, Interferon alpha ligand inhibitors, Interferon alpha ligand modulators, Interferon beta ligands, Interferon gamma ligand inhibitors, Interferon gamma receptor agonists, Interferon gamma receptor antagonists, Interferon receptor modulators, Interferon type I receptor agonists, Interleukin 17A ligand inhibitors, Interleukin 17F ligand inhibitors, Interleukin 18 ligand inhibitors, Interleukin 22 ligands, Interleukin-1 beta ligand inhibitors, Interleukin-1 beta ligand modulators, Interleukin-1 ligand inhibitors, Interleukin-2 ligands, Interleukin-29 ligands, Interleukin-6 ligand inhibitors, Interleukin-7 ligands, Interleukin-8 ligand inhibitors, IRAK-4 protein kinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, Jun N-terminal kinase modulators, Kallikrein modulators, Kelch-like ECH-associated protein 1 modulators, Kit tyrosine kinase inhibitors, KLKB1 gene inhibitors, Lactoferrin stimulators, Lanosterol-14 demethylase inhibitors, Lck tyrosine kinase inhibitors, Leukocyte Ig-like receptor A4 modulators, Leukocyte elastase inhibitors, Leukotriene BLT receptor antagonists, Leukotriene D4 antagonists, Leukotriene receptor antagonists, Listeriolysin stimulators, Liver X receptor antagonists, Low molecular weight heparin, Lung surfactant-associated protein B stimulators, Lung surfactant-associated protein D modulators, Lyn tyrosine kinase inhibitors, Lyn tyrosine kinase stimulators, Lysine-specific histone demethylase 1 inhibitors, Macrophage migration inhibitory factor inhibitors, Mannose-binding lectin serine protease inhibitors, Mannose-binding lectin serine protease-2 inhibitors, MAO B inhibitors, MAP kinase inhibitors, MAPK gene modulators, Matrix metalloproteinase modulators,maxi K potassium channel inhibitor, MCL1 gene inhibitor, MEK protein kinase inhibitor, MEK-1 protein kinase inhibitor, melanocortin MC1 receptor agonist, melanocortin MC3 receptor agonist, metalloproteinase-12 inhibitor, METTL3 gene inhibitor, moesin inhibitor, moesin modulator, monocyte chemoattractant protein 1 ligand inhibitor, monocyte differentiation antigen CD14 inhibitor, mRNA cap guanine N7 methyltransferase modulator, mTOR complex 1 inhibitor, mTOR complex 2 inhibitor, mTOR inhibitor, mucin modulator, muscarinic receptor antagonist, myeloperoxidase inhibitor, NACHTLRR PYD domain protein 3 inhibitor, NAD synthetase modulator, NADPH oxidase inhibitor, neuropilin 2 modulator, neuroplastin inhibitor, NFE2L2 gene stimulator, NK cell receptor agonist, NK1 receptor antagonist, NMDA receptor antagonist, NMDA receptor epsilon 2 subunit inhibitor, non-receptor tyrosine kinase TYK2 antagonist, non-nucleoside reverse transcriptase inhibitor, nsp12 polymerase inhibitor, nuclear erythroid 2-related factor 2 stimulator, nuclear factor kappa B inhibitor, nuclear factor kappa B modulator, nuclease stimulator, nucleolin inhibitor, nucleoprotein inhibitor, nucleoprotein modulator, nucleoside reverse transcriptase inhibitor, opioid receptor agonist, opioid receptor antagonist, opioid receptor mu modulator, opioid receptor sigma antagonist 1, ORF1ab polyprotein inhibitor, ornithine decarboxylase inhibitor, outer membrane protein inhibitor, OX40 ligand, p38 MAP kinase alpha inhibitor, p38 MAP kinase inhibitor, p38 MAP kinase modulator, p53 tumor suppressor protein stimulator, palmitoyl protein thioesterase 1 inhibitor, papain inhibitor, PARP inhibitor, PARP modulator, PDE 10 inhibitor, PDE 3 inhibitor, PDE 4 inhibitor, PDGF receptor alpha antagonist, PDGF receptor antagonist, PDGF receptor beta antagonist, peptidyl-prolyl cis-trans isomerase A inhibitor, peroxiredoxin 6 modulator, PGD2 antagonist, PGI2 agonist, P-glycoprotein inhibitor, phosphoinositide 3-kinase inhibitor, phosphoinositide 3-kinase delta inhibitor, phosphoinositide-3 kinase gamma inhibitor, phospholipase A2 inhibitor, plasma kallikrein inhibitor, plasminogen activator inhibitor 1 inhibitor, platelet inhibitor, platelet glycoprotein VI inhibitor, polo-like kinase 1 inhibitor, poly ADP ribose polymerase 1 inhibitor, poly ADP ribose polymerase 2 inhibitor, polymerase cofactor VP35 inhibitor, PPAR alpha agonist, progesterone receptor agonist, programmed cell death protein 1 modulator, prolyl hydroxylase inhibitor, prostaglandin E synthase-1 inhibitor, protease inhibitor, proteasome inhibitor, protein arginine deiminase IV inhibitor, protein tyrosine kinase inhibitor, protein tyrosine phosphatase beta inhibitor,a protein tyrosine phosphatase-2C inhibitor, a proto-oncogene Mas agonist, a purinergic receptor antagonist, a Raf protein kinase inhibitor, a RANTES ligand, a Ras gene inhibitor, a retinoic acid receptor response protein 2 stimulator, a Rev protein modulator, a ribonuclease stimulator, a RIP-1 kinase inhibitor, a RNA helicase inhibitor, a RNA polymerase inhibitor, a RNA polymerase modulator, a S phase kinase-associated protein 2 inhibitor, a SARS coronavirus 3C protease-like inhibitor, a serine protease inhibitor, a serine threonine protein kinase ATR inhibitor, a serine threonine protein kinase TBK1 inhibitor, a serum amyloid A protein modulator, a signal transducing CD24 stimulator, a sirtuin inhibitor, a sodium channel stimulator, a sodium glucose transporter-2 inhibitor, a sphingosine kinase 1 inhibitor, a sphingosine kinase 2 inhibitor, a sphingosine kinase inhibitor, a sphingosine-1-phosphate receptor-1 agonist, a sphingosine-1-phosphate receptor-1 antagonist, a sphingosine-1-phosphate receptor-1 modulator, a sphingosine-1-phosphate receptor-5 agonist, a sphingosine-1-phosphate receptor-5 modulator, a spike glycoprotein inhibitor, a Src tyrosine kinase inhibitor, a STAT-1 modulator, a STAT-3 inhibitor, a STAT-5 inhibitor, a STAT3 gene inhibitor, a stem cell antigen-1 inhibitor, a stimulator of interferon genes stimulator, a sulfatase inhibitor, a superoxide dismutase modulator, a superoxide dismutase stimulator, a Syk tyrosine kinase inhibitor, a T cell immunoreceptor Ig ITIM protein inhibitor, a T cell receptor agonist, a T cell surface glycoprotein CD28 inhibitor, a T cell differentiation antigen CD6 inhibitor, a T cell surface glycoprotein CD8 stimulator, a T cell transcription factor NFAT modulator, a tankyrase-1 inhibitor, a tankyrase-2 inhibitor, a Tek tyrosine kinase receptor agonist, a telomerase modulator, a tetanus toxin modulator, a TGF beta receptor antagonist, a TGFB2 gene inhibitor, a thymic peptide beta 4 ligand, a thyroid hormone receptor beta agonist, a tissue factor inhibitor, a tissue plasminogen activator modulator, a tissue plasminogen activator stimulator, a TLR agonist, a TLR modulator, a TLR-2 agonist, a TLR-2 antagonist, a TLR-3 agonist, a TLR-4 agonist, a TLR-4 antagonist, a TLR-6 agonist, a TLR-7 agonist, a TLR-7 antagonist, a TLR-8 antagonist, a TLR-9 agonist, a TMPRSS2 gene inhibitor, a TNF alpha ligand inhibitor, a TNF alpha ligand modulator, a TNF binding agent, a TNF gene inhibitor, a topoisomerase inhibitor, a transcription factor EB stimulator, a transferrin modulator, a transketolase inhibitor, a translocation-related protein inhibitor, a transmembrane serine protease 2 inhibitor, a transthyretin modulator, a TREM receptor 1 antagonist, a TRP cation channel C1 modulator, a TRP cation channel C6 inhibitor,A TRP cation channel V6 inhibitor, a trypsin 1 inhibitor, a trypsin 2 inhibitor, a trypsin 3 inhibitor, a trypsin inhibitor, a tubulin alpha inhibitor, a tubulin beta inhibitor, a tumor necrosis factor 14 ligand inhibitor, a TYK2 gene inhibitor, a type I IL-1 receptor antagonist, a tyrosine-protein kinase ABL1 inhibitor, a ubiquinol cytochrome C reductase 14 kDa inhibitor, a ubiquitin ligase modulator, an unspecified GPCR agonist, an unspecified cytokine receptor modulator, an unspecified enzyme stimulator, an unspecified gene inhibitor, an unspecified receptor modulator, an urokinase plasminogen activator inhibitor, a vascellar adhesion protein 1 agonist, a vasodilator, a VEGF ligand inhibitor, a VEGF receptor antagonist, a VEGF-1 receptor antagonist, a VEGF-1 receptor modulator, a VEGF-2 receptor antagonist, a VEGF-3 receptor antagonist, a vimentin inhibitor, a vimentin modulator, a VIP receptor agonist, a viral envelope protein inhibitor, a viral protease inhibitor, a viral protease modulator, a viral protein target modulator, a viral ribonuclease inhibitor, a viral structural protein modulator, a vitamin D3 receptor agonist, an X-link inhibitor of an apoptosis protein inhibitor, a xanthine oxidase inhibitor, or a zonulin inhibitor.

[0261] In some embodiments, the compounds and compositions of the present disclosure can be administered in combination with a Sars-Cov-2 treatment such as parenteral fluids (including dextrose saline and lactated Ringer’s), nutrients, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin / clavulanic acid, trimethoprim / sulfamethoxazole, R-327, and cephalosporin antibiotics such as ceftriaxone and cefuroxime), antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K, vitamin D, cholecalciferol, vitamin C, and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids (such as dexamethasone, methylprednisolone, prednisone, mometasone), immunomodulatory drugs (e.g., interferons), vaccines, and pain relievers.

[0262] In some embodiments, the additional therapeutic agent is an Abl tyrosine kinase inhibitor such as radotinib or imatinib.

[0263] In some embodiments, the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor such as ADX-629.

[0264] In some embodiments, the additional therapeutic agent is an adenosine A3 receptor agonist such as piclidenoson.

[0265] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand such as adrenomedullin.

[0266] In some embodiments, the additional therapeutic agent is a p38 MAPK + PPAR gamma agonist / insulin sensitizer, such as KIN-001.

[0267] In some embodiments, the additional therapeutic agent is a PPAR alpha agonist, such as DWTC-5101 (fenofibrate choline).

[0268] In some embodiments, the additional therapeutic agent is a cyclophilin inhibitor, such as rencofilstat.

[0269] In some embodiments, the additional therapeutic agent is a p38 MAP kinase inhibitor, such as PRX-201 or Gen-1124.

[0270] In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as caficrestat.

[0271] In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin.

[0272] In some embodiments, the additional therapeutic agent is an annexin A5 stimulator, such as AP-01 or SY-005.

[0273] In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064MM.

[0274] In some embodiments, the additional therapeutic agent is an anticoagulant, such as heparins (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparinux.

[0275] In some embodiments, the additional therapeutic agent is an androgen receptor antagonist, such as bicalutamide, dehydroepiandrosterone, enzalutamide, or apalutamide.

[0276] In some embodiments, the additional therapeutic agent is an anti-hypoxia agent, such as crocetin disodium salt.

[0277] In some embodiments, the additional therapeutic agent is an anti-thrombotic agent, such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tenecteplase.

[0278] In some embodiments, the additional therapeutic agent is an antihistamine, such as clemastine or clemastine.

[0279] In some embodiments, the additional therapeutic agent is an apolipoprotein Al agonist, such as CER-001.

[0280] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as icosapent ethyl.

[0281] In some embodiments, the additional therapeutic agent is an axl tyrosine kinase receptor inhibitor, such as binimetinib.

[0282] In some embodiments, the additional therapeutic agent is a corticosteroid / beta 2 adrenergic receptor agonist, such as budesonide + formoterol fumarate.

[0283] In some embodiments, the additional therapeutic agent is a BET bromodomain inhibitor / APOA1 gene stimulator, such as apabetalone.

[0284] In some embodiments, the additional therapeutic agent is a blood coagulation modulator, such as lanadelumab.

[0285] In some embodiments, the additional therapeutic agent is a bradykinin B2 receptor antagonist, such as icatibant.

[0286] In some embodiments, the additional therapeutic agent is an EGFR gene inhibitor / Btk tyrosine kinase inhibitor, such as abivertinib.

[0287] In some embodiments, the additional therapeutic agent is a Btk tyrosine kinase inhibitor, such as ibrutinib or zanubratinib.

[0288] In some embodiments, the additional therapeutic agent is a calpain-I / II / IX inhibitor, such as BLD-2660.

[0289] In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as onternabez or PPP-003.

[0290] In some embodiments, the additional therapeutic agent is a Ca2+ release-activated Ca2+ channel 1 inhibitor, such as zegocractin (CM-4620).

[0291] In some embodiments, the additional therapeutic agent is an ATR inhibitor, such as berzosertib.

[0292] In some embodiments, the additional therapeutic agent is a cadherin-5 modulator, such as FX-06.

[0293] In some embodiments, the additional therapeutic agent is a casein kinase II inhibitor, such as silmitasertib.

[0294] In some embodiments, the additional therapeutic agent is a caspase inhibitor, such as emricasan.

[0295] In some embodiments, the additional therapeutic agent is a catalase stimulator / superoxide dismutase stimulator, such as MP-1032.

[0296] In some embodiments, the additional therapeutic agent is a CCR2 chemokine antagonist / CCR5 chemokine antagonist, such as cenicriviroc. In some embodiments, the additional therapeutic agent is a CCR5 chemokine antagonist, such as maraviroc or leronlimab.

[0297] In some embodiments, the additional therapeutic agent is a CD122 agonist / IL-2 receptor agonist, such as bempegaldesleukin. In some embodiments, the additional therapeutic agent is a CD73 agonist / interferon beta ligand, such as FP-1201.

[0298] In some embodiments, the additional therapeutic agent is a cholesteryl ester transfer protein inhibitor, such as dalcetrapib.

[0299] In some embodiments, the additional therapeutic agent is a galectin serine protease / complement Cls subcomponent inhibitor / myeloperoxidase inhibitor, e.g., RLS-0071.

[0300] In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor / leukotriene BLT receptor antagonist, such as nomacopan.

[0301] In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab, STSA-1002, zilucoplan.

[0302] In some embodiments, the additional therapeutic agent is a CXCR4 chemokine antagonist, such as plerixafor or motixafin.

[0303] In some embodiments, the additional therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidyl-prolyl cis-trans isomerase A inhibitor, such as alisporivir.

[0304] In some embodiments, the additional therapeutic agent is a cysteine protease inhibitor, such as SLV-213.

[0305] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, brequinar, RP-7214, or emvododstat.

[0306] In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as Metablok.

[0307] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor / IL-17 antagonist, such as vedolizumab.

[0308] In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.

[0309] In some embodiments, the additional therapeutic agent is a deoxyribonuclease I stimulator, such as GNR-039 or dornase alfa.

[0310] In some embodiments, the additional therapeutic agent is a NET inhibitor, such as NTR-441.

[0311] In some embodiments, the additional therapeutic agent is a dihydroceramide delta 4 desaturase inhibitor / sphingosine kinase 2 inhibitor, such as opaganib.

[0312] In some embodiments, the additional therapeutic agent is a DNA methyltransferase inhibitor, such as azacitidine.

[0313] In some embodiments, the additional therapeutic agent is an LXR antagonist, such as larsucosterol.

[0314] In some embodiments, the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brensocatib.

[0315] In some embodiments, the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044.

[0316] In some embodiments, the additional therapeutic agent is an elongation factor 1 alpha 2 modulator, such as plinabulin.

[0317] In some embodiments, the additional therapeutic agent is a eukaryotic initiation factor 4A-I inhibitor, such as zotatifin.

[0318] In some embodiments, the additional therapeutic agent is an exo-alpha sialidase modulator, such as DAS-181.

[0319] In some embodiments, the additional therapeutic agent is an exporter 1 inhibitor, such as selinexor.

[0320] In some embodiments, the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567.

[0321] In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor / IL-12 receptor antagonist / IL-23 antagonist, such as apilimod di mesylate.

[0322] In some embodiments, the additional therapeutic agent is a GABA A receptor modulator, such as brivaracetam.

[0323] In some embodiments, the additional therapeutic agent is a glucocorticoid receptor agonist, such as ciclesonide, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005.

[0324] In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim.

[0325] In some embodiments, the additional therapeutic agent is a GPCR agonist, such as esuberaprost sodium.

[0326] In some embodiments, the additional therapeutic agent is a Griffithsin modulator, such as Q-Griffithsin.

[0327] In some embodiments, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast.

[0328] In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, levocetirizine hydrochloride.

[0329] In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine.

[0330] In some embodiments, the additional therapeutic agent is a heat shock protein stimulator / insulin sensitizer / PARP inhibitor, such as BGP-15.

[0331] In some embodiments, the additional therapeutic agent is a histone inhibitor, such as STC-3141.

[0332] In some embodiments, the additional therapeutic agent is a histone deacetylase-6 inhibitor, such as CKD-506.

[0333] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase-2 inhibitor, such as desidustat.

[0334] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase inhibitor, such as vadadustat.

[0335] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist, such as reparixin.

[0336] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist, such as CYT-107.

[0337] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist / interleukin-7 ligand, such as efineptakin alfa.

[0338] In some embodiments, the additional therapeutic agent is an IL-22 agonist, such as efmardocokin alfa.

[0339] In some embodiments, the additional therapeutic agent is an IL-22 agonist / interleukin 22 ligand, such as F-652.

[0340] In some embodiments, the additional therapeutic agent targets IL-33, such as toripalimab.

[0341] In some embodiments, the additional therapeutic agent is an IL-15 agonist, such as nogapendekinalfa.

[0342] In some embodiments, the additional therapeutic agent is an integrin alpha-V / beta-1 antagonist / integrin alpha-V / beta-6 antagonist, such as bexotegrast.

[0343] In some embodiments, the additional therapeutic agent is an interferon alpha 2 ligand, such as interferon alpha-2b or Virafin.

[0344] In some embodiments, the additional therapeutic agent is an interferon beta ligand, such as interferon beta-1a follow-on biologic, interferon beta-1b, or SNG-001.

[0345] In some embodiments, the additional therapeutic agent is an interferon receptor modulator, such as peginterferon lambda-1a.

[0346] In some embodiments, the additional therapeutic agent is an interleukin-2 ligand, such as Aldesleukin.

[0347] In some embodiments, the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, such as zimlovisertib.

[0348] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example the additional therapeutic agent is baricitinib, filgotinib, gandotinib, tofacitinib, or nezulcitinib (TD-0903).

[0349] In some embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor, such as alvelestat.

[0350] In some embodiments, the additional therapeutic agent is a pulmonary surfactant-associated protein D modulator, such as AT-100.

[0351] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as donidalorsen.

[0352] In some embodiments, the additional therapeutic agent is a lysine-specific histone demethylase 1 / MAO B inhibitor, such as valfendstat.

[0353] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease inhibitor, for example conestat alfa.

[0354] In some embodiments, the additional therapeutic agent is a maxi K potassium channel inhibitor, such as ENA-001.

[0355] In some embodiments, the additional therapeutic agent is a MEK protein kinase inhibitor, such as zapnometinib.

[0356] In some embodiments, the additional therapeutic agent is a MEK-1 protein kinase inhibitor / Ras gene inhibitor, such as anidulanol.

[0357] In some embodiments, the additional therapeutic agent is a melanocortin MC1 receptor agonist, such as PL-8177.

[0358] In some embodiments, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, such as resometacain.

[0359] In some embodiments, the additional therapeutic agent is a matrix metalloproteinase-12 inhibitor, such as FP-025.

[0360] In some embodiments, the additional therapeutic agent is a NACHT LRR PYD domain protein 3 inhibitor, such as dapansutrile, DFV-890, or ZYIL-1.

[0361] In some embodiments, the additional therapeutic agent is a NADPH oxidase inhibitor, such as isuzinaxib.

[0362] In some embodiments, the additional therapeutic agent is a neuropilin 2 modulator, such as efzofitimod.

[0363] In some embodiments, the additional therapeutic agent is an NK1 receptor antagonist, such as aprepitant or tradipitant.

[0364] In some embodiments, the additional therapeutic agent is an NMDA receptor antagonist, such as crocetin or ifenprodil.

[0365] In some embodiments, the additional therapeutic agent is a nuclear factor kappa B inhibitor / p38 MAP kinase inhibitor, such as zenuzolac.

[0366] In some embodiments, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine.

[0367] In some embodiments, the additional therapeutic agent is an opioid receptor sigma antagonist 1, such as MR-309.

[0368] In some embodiments, the additional therapeutic agent is a PGD2 antagonist, such as asapiprant.

[0369] In some embodiments, the additional therapeutic agent is a PDGF receptor antagonist / TGF beta receptor antagonist / p38 MAP kinase inhibitor, such as deupirfenidone.

[0370] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as mavacamten.

[0371] In some embodiments, the additional therapeutic agent is a phosphoinositide 3-kinase inhibitor / mTOR complex inhibitor, such as dactolisib.

[0372] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, such as sirolimus.

[0373] In some embodiments, the additional therapeutic agent is a phosphoinositide-3-kinase delta / gamma inhibitor, such as duveltitib.

[0374] In some embodiments, the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor, such as TM-5614.

[0375] In some embodiments, the additional therapeutic agent is a protein tyrosine phosphatase beta inhibitor, such as riloxadifen.

[0376] In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor, such as DNL-758 or SIR-0365.

[0377] In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as obefazimod.

[0378] In some embodiments, the additional therapeutic agent is a S-phase kinase-associated protein 2 inhibitor, such as niclosamide, CP-COV3, SCAI-502, or DWRX-2003.

[0379] In some embodiments, the additional therapeutic agent is a signal transducing protein CD24 stimulator, such as EXO-CD24.

[0380] In some embodiments, the additional therapeutic agent is a sodium glucose transporter-2 inhibitor, such as dapagliflozin propanediol.

[0381] In some embodiments, the additional therapeutic agent is a sodium channel inhibitor, such as solnatide.

[0382] In some embodiments, the additional therapeutic agent is a sphingosine-1-phosphate-1 agonist / sphingosine-1-phosphate-5 agonist, for example, ozanimod.

[0383] In some embodiments, the additional therapeutic agent is a non-steroidal anti-inflammatory drug, such as Ampion.

[0384] In some embodiments, the additional therapeutic agent is a superoxide dismutase stimulator, such as avasopasem manganese.

[0385] In some embodiments, the additional therapeutic agent is a Syk tyrosine kinase inhibitor, such as fostamatinib disodium salt.

[0386] In some embodiments, the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist, such as AV-001.

[0387] In some embodiments, the additional therapeutic agent is a TGFB2 gene inhibitor, such as trabedersen.

[0388] In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.

[0389] In some embodiments, the additional therapeutic agent is a TLR-3 agonist, such as resiquimod.

[0390] In some embodiments, the additional therapeutic agent is a TLR-4 antagonist, such as ApTLR-4FT, EB-05, or etokimab.

[0391] In some embodiments, the additional therapeutic agent is a TLR-7 / 8 antagonist, such as enpatoran.

[0392] In some embodiments, the additional therapeutic agent is a TLR-2 / 6 agonist, such as INNA-051.

[0393] In some embodiments, the additional therapeutic agent is a TLR-7 agonist, such as PRTX-007 or APR-002.

[0394] In some embodiments, the additional therapeutic agent is a TLR agonist, such as PUL-042.

[0395] In some embodiments, the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.

[0396] In some embodiments, the additional therapeutic agent is a TLR-2 / 4 antagonist, such as VB-201.

[0397] In some embodiments, the additional therapeutic agent is a TNF alpha ligand inhibitor, such as pegipanermin.

[0398] In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anakinra.

[0399] In some embodiments, the additional therapeutic agent is a TREM receptor 1 antagonist, such as nangibotide.

[0400] In some embodiments, the additional therapeutic agent is a trypsin inhibitor, such as ulinastatin.

[0401] In some embodiments, the additional therapeutic agent is a tubulin inhibitor, such as sabizabulin, CCI-001, PCNT-13, CR-42-24, albendazole, entabulin, SAR-132885, or ON-24160.

[0402] In some embodiments, the additional therapeutic agent is a VIP receptor agonist, such as aviptadil.

[0403] In some embodiments, the additional therapeutic agent is a xanthine oxidase inhibitor, such as allopurinol.

[0404] In some embodiments, the additional therapeutic agent is a vasodilator, such as iloprost, epoprostenol (VentreProst), vazegepant, TXA-127, USB-002, ambrisentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamole.

[0405] In some embodiments, the additional therapeutic agent is a vitamin D3 receptor agonist, such as cholecalciferol.

[0406] In some embodiments, the additional therapeutic agent is a zonulin inhibitor, such as larazotide acetate.

[0407] In some embodiments, the additional therapeutic agent is a synthetic retinoic acid derivative, such as fenretinide.

[0408] In some embodiments, the additional therapeutic agent is a glucose metabolism inhibitor, such as WP-1122 or WP-1096.

[0409] In some embodiments, the additional therapeutic agent is adalimumab, AT-H201, 2- deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer, AZD-1656, belapectin, bitespiramycin, bursine, budesonide, CNM-AgZn-17, Codivir, CT-38, danicopan, dimethyl dodecyl aminopterin, DW-2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, genistein, GLS-1200, hzVSF-v13, imidazole acetamide glutarate, IMM-101, MAS-825, MRG-001, Nasitrol, Nylexa, olesoxorhmbin, OP-101, OPN-019, Orynotide rhesus theta defensin-1, pyronaridine + artesunate, sulfonamides, RPH-104, sodium pyruvate, Sulforadex, tafenoquine, TB-006, telacebec, Tempol, TL-895, thiomersal, trimodulin, XC-221, XC-7, tucatinib, glycine metformin, lucinactant, EOM-613, molmsmod, ivermectin, leflunomide, ibuproxam, RBT-9, raloxifene, prothione, gemicabine, or idronoxil.

[0410] In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as AK-119.

[0411] In some embodiments, the additional therapeutic agent is a CD95 protein fusion, such as asunercept.

[0412] In some embodiments, the additional therapeutic agent is a complement factor C2 modulator, such as ARGX-117.

[0413] In some embodiments, the additional therapeutic agent is a complement C3 inhibitor, such as AMY-101 or NGM-621.

[0414] In some embodiments, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor, such as EB-06.

[0415] In some embodiments, the additional therapeutic agent is a cytotoxic T-lymphocyte protein-4 fusion protein, such as abatacept.

[0416] In some embodiments, the additional therapeutic agent is an anti-Staphylococcus aureus antibody, such as tosatoxumab.

[0417] In some embodiments, the additional therapeutic agent is an anti-LPS antibody, such as IMM-124-E.

[0418] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand inhibitor, such as emapakalimab.

[0419] In some embodiments, the additional therapeutic agent is a basigin inhibitor, such as meplumab.

[0420] In some embodiments, the additional therapeutic agent is a CD3 antagonist, such as foralumab.

[0421] In some embodiments, the additional therapeutic agent is a connective tissue growth factor ligand inhibitor, such as PRS-220, panobacumab.

[0422] In some embodiments, the additional therapeutic agent is a complement C5a factor inhibitor, such as BDB-1 or vercylyzumab.

[0423] In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab.

[0424] In some embodiments, the additional therapeutic agent is a mannose-binding lectin serine protease-2 inhibitor, for example nasolizumab.

[0425] In some embodiments, the additional therapeutic agent is a GM-CSF modulator, such as STSA-1005, resmetirom, namodumab, plinabulin, otilimab, or rontalizumab.

[0426] In some embodiments, the additional therapeutic agent is a heat shock protein inhibitor / IL-6 receptor antagonist, such as siltuximab.

[0427] In some embodiments, the additional therapeutic agent is an IL-6 receptor antagonist, such as clazakizumab, levilimab, olokizumab, tocilizumab, or sirukumab.

[0428] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist, such as BMS-986253.

[0429] In some embodiments, the additional therapeutic agent is an interleukin-1 beta ligand inhibitor, such as canakinumab.

[0430] In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as ipafrinacab.

[0431] In some embodiments, the additional therapeutic agent is an anti-ILT7 antibody, such as daxdilimab.

[0432] In some embodiments, the additional therapeutic agent is a monocyte differentiation antigen CD14 inhibitor, such as atibuclimab.

[0433] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as lanadelumab.

[0434] In some embodiments, the additional therapeutic agent is a platelet glycoprotein VI inhibitor, such as glenzocimab.

[0435] In some embodiments, the additional therapeutic agent is a T-cell differentiation antigen CD6 inhibitor, such as itolizumab.

[0436] In some embodiments, the additional therapeutic agent is a TNF alpha ligand inhibitor / TNF binding agent, such as infliximab.

[0437] In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as AVTX-002.

[0438] In some embodiments, the additional therapeutic agent is IMC-2 (valacyclovir + celecoxib) or AXA-1125.

[0439] In some embodiments, the additional therapeutic agent is COVID-HIG.

[0440] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful for treating and / or preventing COVID-19.

[0441] Non-limiting examples of such agents include corticosteroids, such as dexamethasone, hydrocortisone, methylprednisolone, or prednisone; interleukin-6 (IL-6) receptor blockers, such as tocilizumab or sarilumab; Janus kinase (JAK) inhibitors, such as baricitinib, ruxolitinib, or tofacitinib; and antiviral agents, such as molnupiravir, sotrovimab, or remdesivir.

[0442] In additional embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with two or more agents useful for treating COVID-19. Agents useful for treating and / or preventing COVID-19 include, but are not limited to, a compound of the disclosure and two additional therapeutic agents, such as nirmatrelvir and ritonavir, casirivimab and imdevimab, or ruxolitinib and tofacitinib.

[0443] In some embodiments, the additional therapeutic agent is an antiviral agent. In some embodiments, the antiviral agent is an entry inhibitor. In some embodiments, the antiviral agent is a protease inhibitor. In some embodiments, the antiviral agent is an RNA polymerase inhibitor. In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0444] In some embodiments, the antiviral agent is selected from the group consisting of angiotensin converting enzyme 2 inhibitors, angiotensin converting enzyme 2 modulators, angiotensin converting enzyme 2 stimulators, angiotensin II AT-2 receptor agonists, angiotensin II AT-2 receptor antagonists, angiotensin II receptor modulators, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, SARS-CoV-2 envelope small membrane protein inhibitors, SARS-CoV-2 envelope small membrane protein modulators, SARS-CoV-2 MPro inhibitors, SARS-CoV-2 non-structural protein 8 modulators, SARS-CoV-2 nucleoprotein inhibitors, SARS-CoV-2 nucleoprotein modulators, SARS-CoV-2 protein 3a inhibitors, SARS-CoV-2 replicase polyprotein 1a inhibitors, SARS-CoV-2 replicase polyprotein 1a modulators, SARS-CoV-2 replicase polyprotein 1ab inhibitors, SARS-CoV-2 replicase polyprotein 1ab modulators, SARS-CoV-2 spike glycoprotein inhibitors, SARS-CoV-2 spike glycoprotein modulators, SARS-CoV-2 structural glycoprotein modulators, papain inhibitors, protease inhibitors, protease modulators, RNA polymerase inhibitors, RNA polymerase modulators, RNA-dependent RNA polymerase (RdRp) inhibitors, SARS coronavirus 3C protease-like inhibitors, SARS-CoV-2 nsp14 methyltransferase inhibitors, 3CLpro / Mpro inhibitors, transmembrane serine protease 2 inhibitors, transmembrane serine protease 2 modulators, viral envelope protein inhibitors, viral protease inhibitors, viral protease modulators, viral protein target modulators, viral ribonuclease inhibitors, and viral structural protein modulators.

[0445] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor.

[0446] In some embodiments, the additional therapeutic agent is an angiotensin converting enzyme 2 inhibitor, such as SBK-001.

[0447] In some embodiments, the additional therapeutic agent is an angiotensin converting enzyme 2 modulator, such as neumifil or JN-2019.

[0448] In some embodiments, the additional therapeutic agent is an entry inhibitor, such as MU-UNMC-1.

[0449] In some embodiments, the additional therapeutic agent is an angiotensin converting enzyme 2 stimulator, such as alunacedase alfa.

[0450] In some embodiments, the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, such as VP-01.

[0451] In some embodiments, the additional therapeutic agent is an ACE II receptor antagonist, such as DX-600.

[0452] In some embodiments, the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127.

[0453] In some embodiments, the additional therapeutic agent is a transmembrane serine protease 2 modulator, such as BC-201, N-0385.

[0454] In some embodiments, the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004.

[0455] In some embodiments, the additional therapeutic agent is an RNAi agent, such as ARO-COV or SNS-812.

[0456] 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., inactivated SARS-CoV-2 vaccine), a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, a viral vector vaccine, a cellular vaccine, or a dendritic cell vaccine.

[0457] In some embodiments, the additional therapeutic agent is a vaccine, such as tozinameran, NVX-CoV2373, elasomeran, KD-414, Ad26.COV2-S, Vaxzevria, SCB-2019, AKS-452, VLA-2001, HDT-301, S-268019, MVC-COV1901, mRNA-1273.214, mRNA-1273.213, mRNA-1273.222, NVX-CoV2515, Covaxin, BBIBP-CorV, GBP-510, mRNA-1273.351 + mRNA-1273.617 (SARS-CoV-2 multivalent mRNA vaccine, COVID-19), Ad5-nCoV, Omicron-based COVID-19 vaccine (mRNA vaccine, COVID-19), mRNA-1073, mRNA-1273.214, mRNA-1230, mRNA-1283, Omicron-based COVID-19 vaccine, SARS-CoV-2 protein subunit recombinant vaccine, Sputnik M, ZyCoV-D, COVID-19 XWG-03, mRNA-1273.529, mRNA-1010, CoronaVac, AZD-2816, Sputnik V, Inactivated SARS-CoV-2 vaccine (Vero cells, COVID-19), DS-5670, PHH-1V, INO-4800, UB-612, Coronavirus vaccine (whole virus particles, inactivated / purified), ReCOV, MT-2766, ARCT-154, SP-0253, CORBEVAX, mRNA-1273.211. ZF-2001, Sputnik Light, recombinant protein vaccine (COVID-19 / SARS-CoV-2 infection), VSV vector-based vaccine targeting spike glycoprotein (COVID-19), VLA-2101, GRT-R912, GRAd-COV2, VPM-1002, COViran Barekat, Ad5-nCoV-IH, ARCoV, Covax-19, recombinant SARS-CoV-2 vaccine (protein subunit / CHO cells, COVID-19), BBV-154, RAZI Cov Pars, COVID-19 vaccine (inactivated / Vero cells / IM, SARS-CoV-2 infection), COVID-19 vaccine (inactivated, Vero cells / IM), BNT-162b2 s01, BNT-162b4, BNT-162b5, BNT-162b2 Omi, BNT-162b2 bivalent, CIGB-66, mRNA-1273.617, Mycobacterium w, ERUCOV-VAC, AG-0301-COVID19, fakhravac, AV-COVID-19, Peptide vaccine (COVID-19), Nanocovax, SARS-CoV-2 vaccine (inactivated / Vero cells / IM, COVID-19), QAZCOVID-IN, S-875670 nasal vaccine, VTP-500, or BNT162b5.

[0458] In some embodiments, the additional therapeutic agent is a protease inhibitor. For example, in some embodiments, the additional therapeutic agent is a 3C-like cysteine protease inhibitor (3CLpro, also known as main protease, Mpro), papain-like protease inhibitor (PLpro), serine protease inhibitor, or transmembrane serine protease 2 inhibitor (TMPRSS2).

[0459] In some embodiments, the additional therapeutic agent is a 3CLpro / Mpro inhibitor such as ABBV-903, AB-343, CDI-873, GC-373, GC-376, pomotrelvir, PBI-0451, UCI-1, bofutrelvir (FB-2001, DC-402234), DC-402267, GDI-4405, HS-10517, RAY-1216, MPI-8, SH-879, SH-580, EDP-235, VV-993, CDI-988, MI-30, nirmatrelvir, ensitrelvir, ASC-11, ASC-11 + ritonavir, EDDC-2214, SIM-0417, PF-07817883, senolvid, senolvid + ritonavir, SYH-2055, ISM-3312, CDI-45205, LHP-803 (COR-803), ALG-097111, TJC-642, CVD-0013943, olgotrelvir (STI-1558), eravacycline, cynarine, or prexasertib.

[0460] In some embodiments, the additional therapeutic agent is a papain-like protease inhibitor (PLpro) such as SBFM-PL4 or GRL-0617.

[0461] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp13 inhibitor such as EIS-4363.

[0462] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp14 inhibitor such as TO-507.

[0463] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 spike protein (S) and protease modulator such as ENU-200.

[0464] In some embodiments, the additional therapeutic agent is a protease inhibitor such as ALG-097558 or MRX-18.

[0465] In some embodiments, the additional therapeutic agent is a serine protease inhibitor such as ulpatisant, nafamostat, camostat mesylate, nafamostat mesylate, or camostat.

[0466] In some embodiments, the additional therapeutic agent is a 3CLpro / cross-membrane serine protease 2 inhibitor such as SNB-01 (pentarlandir) or SNB-02.

[0467] In some embodiments, the additional therapeutic agent is a viral protease inhibitor such as Pan-Corona, Cov-X, or bepridil.

[0468] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, or an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0469] In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor such as remdesivir, NV-CoV-2, NV-CoV-2-R, NV-CoV-1 encapsulated remdesivir, CMX-8521, GS-621763, GS-5245, GS-441524, DEP remdesivir, ATV-006, deuterated remdesivir (VV-116), LGN-20, CMX-521, SHEN-26, and the compounds disclosed in WO2022142477, WO2021213288, WO2022047065.

[0470] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor such as molnupiravir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galidesivir.

[0471] In some embodiments, the additional therapeutic agent is a viral entry inhibitor such as brilacidin.

[0472] In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for example an antibody that binds to SARS or MERS.

[0473] In some embodiments, the additional therapeutic agent is an antibody, for example a monoclonal antibody. For example, the additional therapeutic agent is an antibody against SARS-CoV-2, a neutralizing nanobody, an antibody targeting the SARS-CoV-2 spike protein, a fusion protein, a multispecific antibody, and an antibody capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibody).

[0474] 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).

[0475] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 viral antibody.

[0476] In some embodiments, the antibody is ABBV-47D11, COVI-GUARD (STI-1499), C144-LS+C135-LS, DIOS-202, DIOS-203, DIOS-301, DXP-604, JMB-2002, LY-CovMab, bamlanivimab (LY-CoV555), GIGA-2050, IBI-314, S309, SAB-185, etesevimab (CB6), COR-101, JS016, VNAR, VIR-7832 and / or sotrovimab (VIR-7831), casirivimab+imdevimab (REGN-COV2 or REGN10933+RGN10987), BAT2020, BAT2019, 47D11, YBSW-015, or PA-001.

[0477] In some embodiments, the additional therapeutic agent is STI-9199 (COVI-SHIELD), STI-9167, or AR-701 (AR-703 and AR-720).

[0478] In some embodiments, the additional therapeutic agent is BRII-196, BRII-198, ADG-10, adintrevimab (ADG-20), ABP-300, BA-7208, BI-767551, BHV-1200, CT-P63, JS-026, sofontamab (GSK-4182136), tixagamumab + cilgavimab (AZD-7442), regdanvimab, SAB-301, AOD-01, plutavimab (COVI-AMG), 9MW-3311 (MW-33), DXP-593, BSVEQAb, Anti-SARS-CoV-2 IgY, COVID-EIG, CSL-760, F-61, REGN-3048-3051, SARS-CoV-2 monoclonal antibody (COVID-19, ADM-03820), enzuvimab (HFB-30132A), INM-005, SCTA01, TY-027, XAV-19, ambarvimab + lormetegovir, SCTA-01, bebtelovimab, beludavimab, IBI-O123, IGM-6268, FYB-207, FS-2101, RBT-0813, REGN-14256, REGN-14284, SPKM-001, XVR-011, TB202-3, TB181-36, TB339-031, LMN-301, LQ-050, COVAB-36, MAD-0004J08, STI-2099, TATX-03, TZLS-501, ZCB-11, or ACV-200-17.

[0479] In some embodiments, the additional therapeutic agent is an engineered ACE-2-IgGl-Fc fusion protein targeting SARS-Cov-2 RBD, such as EU-129, bivalent ACE2-IgG Fc null fusion protein (SI-F019).

[0480] In some embodiments, the additional therapeutic agent is an ACE2-Fc receptor fusion protein, such as HLX-71.

[0481] In some embodiments, the additional therapeutic agent is ensovibep.

[0482] In some embodiments, the additional therapeutic agent is SYZJ-001.

[0483] In some embodiments, the additional therapeutic agent is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 + ritonavir) or lopinavir + ritonavir.

[0484] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor, such as efavirenz.

[0485] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as azvudine.

[0486] In some embodiments, the additional therapeutic agent is Abbv-990, ABBV-903, 2b-11, 5-aminolevulinic acid phosphate, AGP-600, AIP-502, ALG-150150, BAT-2022, NED-260, ALG-097431, bardoxolone, clofoquine, CR-405, delcetravir, D4-102-01, D4-102-02, ESFAM-289, ENOB-CV-01, ENOB-CV-11, EIS-10700, EV-300, beta-521, GEA-001, SIM-0417, monupiravir, Pan-Corona, Tollovir, nirmatrelvir + ritonavir (Paxlovid ®), favipiravir, favipiravir + cathepsin inhibitor (TNX-3900), GC-376, upamostat, LeSoleil-01, LeSoleil-02+, benfovir, WY-116, WY-993, SNB-01, EDP-235, Cov-X, emtricitabine, MPI-8, masitinib, ALG-097558, ASC-11, PBI-0451, nafamostat, nafamostat mesylate, CDI-45205, LHP-803 (COR-803), ALG-097111, BC-201, SH-879, CDI-873, CDI-988, remdesivir, NV-CoV-2-R, NV-CoV-1 encapsulated remdesivir, NA-831 + remdesivir, DEP remdesivir, GS-621763, GS-5245, GLS-5310, benipavir, QLS-1128, ASC-10, SBFM-PL4, camostat mesylate, UCI-1, FB-2001 (DC-402234), ebselen, SH-580, LeSoleil-01, LeSoleil-02+, MRX-18, MXB-9, MI-09, MI-30, SNB-02, SJP-002C, TJC-642, ENU-200, CVD-0013943, GS-441524, bepridil, MXB-004, eravacycline, GRL-0617, camostat, GC-373, nitazoxanide, cinalikine, preseptal, RAY-1216, SACT-COVID-19, MP-18, EIDD-1931, EDDC-2214, nitric oxide, apabetalone, AnQlar, SBK-001, LQ-050, CG-SpikeDown, baloxavir, HLX-71, HT-002, HY-209, HY-3000, HSC-1553, FYB-207, ensitrelvir, SYZJ-001, EU-129, neumifil, JN-2019 (KG-2019), LCB-99, AR-701, vostesyl, PLM-402, PJS-539, CTB-ACE2, TB181-36, TB202-3, ABP-300, XVR-011, MSP-008-22, MU-UNMC-1, MU-UNMC-2, MIC-1930, MLT-103, Mpro inhibitor (AnixaBiosciences), PBF-4554, alunasketel alpha, VP-01, TRV-027, DX-600, TXA-127, NVX-CoV2515, rapamycin, RCYM-002, RCYM-003, riamilovir, SARS-Cov-2 PL pro inhibitor (Enanta), SBP-502, STB-R040, THY-01, tozinkev, irasozane, Ad5-nCoV, BBIBP-CorV, CoronaVac, MVC-COV1901, NVX-CoV2373, soliab, Sputnik V, TEE-001, Tyme-19, Vaxzevria, ZF-2001, or ZyCoV-D.

[0487] Any of the compounds of the present application can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0488] Co-administration of a compound of the present application with one or more other active therapeutic agents generally refers to the administration of a compound of the present application and one or more other active therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of both the compound of the present application and the one or more other active therapeutic agents are present in the body of the patient.

[0489] Co-administration includes administration of a unit dose of a compound of the present application prior to or following administration of a unit dose of one or more other active therapeutic agents, for example, within seconds or minutes or hours of administration of the one or more other active therapeutic agents. For example, a unit dose of a compound of the present application 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 application. In some cases, it can be desirable to administer a unit dose of a compound of the present application first, followed by administration of a unit dose of one or more other active therapeutic agents hours (e.g., 1-12 hours) later. In other cases, it can be desirable to administer a unit dose of one or more other active therapeutic agents first, followed by administration of a unit dose of a compound of the present application hours (e.g., 1-12 hours) later.

[0490] Combination therapy can provide "synergy" and "additive effects", i.e., the effect achieved when the active ingredients used together is greater than the predicted sum of the effects that each compound produces when used individually. Synergy can result from, for example, the combined action of two or more compounds that act on the same or different pathways, or mechanisms of action. Synergistic effects can also result from the actions of two or more compounds that have complementary actions.

[0491] EXAMPLES Scheme I Scheme I shows the general synthesis of the compounds of the present disclosure, starting from the reaction of nucleoside SI-1 with anhydride SI-2 to give intermediate SI-3. Subsequent treatment of SI-3 with 2-methyl-6-nitrobenzoic anhydride gives the final compound SI-4.

[0492] Example 1: ((7R,9R)-9-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-9-cyano-2,5- dioxooctahydrofuro[3,4-b][1,4]dioxepin-7-yl)methyl isopropyl carbonate (C1) Example 2: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]dioxin-8-yl)methyl isopropyl carbonate To a solution of (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]dioxol-4-carbonitrile (3000 mg, 9.0 mmol) (Siegel et al., J. Med. Chem. 2017, 60, 1648-1661) in toluene (20 mL) was added N,N- dimethylformamide dimethyl acetal (2158 mg, 18 mmol) and heated at 50 °C for 1 h. After the reaction was complete, the solvent was evaporated under pressure, the residue was dissolved in ethyl acetate (100 mL). The solvent was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate and concentrated to give intermediate N'-[7-[(3aR,4R,6R,6aR)-4-cyano-6- (hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,1- f][1,2,4]triazin-4-yl]-N,N-dimethyl-formamidine Intermediate 1a. LCMS: MS m / z: 387.2 To a solution of intermediate la (850 mg, 2.2 mmol) in dichloromethane (20 mL) was added pyridine (1 mL). The reaction mixture was cooled to 0 °C and a solution of isopropyl chloroformate (270 mg, 2.2 mmol) in dichloromethane (5 mL) was slowly added, once the addition was complete, the cold bath was removed and stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL), washed with water, brine and concentrated to get intermediate lb which was used directly for the next step without purification. LCMS: MS m / z: 473.2 (M+1).

[0493] To a solution of intermediate lb (1300 mg, 2.8 mmol) in tetrahydrofuran (10 mL) cooled with ice bath was slowly added concentrated HCl (1.3 mL, 43 mmol) and the reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL) and neutralized with saturated sodium bicarbonate. The organic layer was separated, washed with water, brine and concentrated. The residue was purified by flash chromatography using dichloromethane and methanol as eluents to get intermediate lc.1H NMR (400 MHz, Acetonitrile-d3) δ 7.94 (s, 1H), 6.84 (d, J = 4.6 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 6.33 (s, 3H), 4.83 - 4.69 (m, 3H), 4.45 - 4.31 (m, 2H), 4.26 - 4.14 (m, 2H), 3.67 (d, J = 5.1 Hz, 1H), 1.22 (t, J = 6.7 Hz, 6H). LCMS: MS m / z: 378.1 To a mixture of intermediate lc (200 mg, 0.53 mmol) and succinic anhydride (106 mg, 1.06 mmol) in THF (5 mL) was added 4-dimethylaminopyridine (13 mg, 0.11 mmol). The mixture was stirred at room temperature for 30 min. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over MgS04and concentrated to get intermediate Id which was used without further purification. LCMS: MS m / z: 478.1 (M+1).

[0494] Intermediate 1d (47.7 mg, 0.10 mmol) was first dissolved in DMF (1 mL) and then diluted with 11 mL DCM. The solution was added dropwise to a solution of 2-methyl-6-nitrobenzoic anhydride (103 mg, 0.30 mmol) and 4-dimethylaminopyridine (110 mg, 0.90 mmol) in DCM (4 mL) over 8 hours. The reaction was further stirred at room temperature for 16 hours. The reaction mixture was then concentrated. The residue was purified by high performance liquid chromatography using water and acetonitrile as eluents to give compound C1. 1 H NMR (400MHz, DMSO-d6) δ 7.99-7.95 (br, 2H), 7.94 (s, 1H), 6.94 (d, J = 5.0Hz, 1H), 6.86 (d, J = 4.7Hz, 1H), 6.02 (d, J = 6.2Hz, 1H), 5.41-5.35 (m,1H), 4.75 – 4.58 (m, 2H), 4.50-4.41 (m, 1H), 4.34-4.26 (m, 1H), 2.83 – 2.62(m, 4H), 1.24 – 1.09 (m, 6H)。LCMS:MS m / z: 446.3 (M+1)。

[0495] Example 3: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 10-cyano-4,4-dimethyl-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]dioxin-8-yl)methyl isopropyl carbonate (C3) Example 4: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 10-cyano-4-methyl-2,6-dioxooctahydro-2H-furo[3,4-b][1,4,7]dioxazin-8-yl)methyl isopropyl carbonate (C4) （C2） Compound C2 was synthesized in a similar manner to ((7R,9R)-9-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-9-cyano-2,5-dioxooctahydrofuro[3,4- b][1,4]dioxepin-7-yl)methyl isopropyl carbonate (C1, Example 1) using glutaric anhydride instead of succinic anhydride. 1H NMR (400MHz, DMSO-d6) δ 8.08 (br, 1H), 8.02 (br, 1H), 7.97 (s, 1H), 6.96 (d, J = 4.6Hz, 1H), 6.93 (d, J = 4.6Hz, 1H), 5.99 (d, J = 7.1Hz, 1H), 5.46 (dd, J = 7.0, 5.9Hz, 1H), 4.74 (hept, J = 6.3Hz, 1H), 4.56 (td, J = 5.6, 3.3Hz, 1H), 4.49 (dd, J = 12.2, 3.4Hz, 1H), 4.33 (dd, J = 12.2, 5.5Hz, 1H), 2.80 - 2.69 (m, 2H), 2.47-2.36 (m, 2H), 2.34 - 2.24 (m, 1H), 1.98-1.87 (m, 1H), 1.22 (d, J = 6.2Hz, 3H), 1.19 (d, J = 6.2Hz, 3H). LCMS: MS m / z: 474.02 (M+1).

[0496] Scheme II Example 5: ((10aR,11R,13R,13aR)-13-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 13-cyano-4,4-dimethyl-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]dioxin-8-yl)methyl isopropyl carbonate (C5) ​ Compound C3 was synthesized in a similar manner to ((7R,9R)-9-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-9-cyano-2,5-dioxooctahydrofuro[3,4-b][1,4]dioxin-7- yl)methyl isopropyl carbonate (C1, Example 1) using 3,3-dimethylpentanedioic anhydride instead of succinic anhydride. 1H NMR (400MHz, DMSO-d6) δ 8.09 (br, 1H), 8.02 (br, 1H), 7.96 (s, 1H), 6.96 (d, J = 4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 5.95 (d, J = 7.1Hz, 1H), 5.40 (t, J = 6.7Hz, 1H), 4.74 (hept, J = 6.2Hz, 1H), 4.56 - 4.46 (m, 2H), 4.37 - 4.27 (m, 1H), 2.57-2.52 (m, 2H), 2.43-2.35 (m, 2H), 1.26 - 1.17 (m, 12H). LCMS: MS m / z: 502.02 (M+1).

[0497] ​ ​ ​ Compound C4 was synthesized in a similar manner to ((7R,9R)-9-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-9-cyano-2,5-dioxooctahydrofuro[3,4-b][1,4]dioxin-7- yl)methyl isopropyl carbonate (C1, Example 1) using 4-methylmorpholine-2,6-dione instead of succinic anhydride. 1 H NMR (400MHz, DMSO-d6) δ 8.04 (br, 2H), 7.94 (s, 1H), 6.94 (d, J = 4.6Hz, 1H), 6.83 (d, J = 4.7Hz, 1H), 6.18 (d, J = 6.1Hz, 1H), 5.49 (dd, J = 6.1, 4.3Hz, 1H), 4.73 (p, J = 6.1Hz, 1H), 4.63 (d, J = 4.3Hz, 1H), 4.51 - 4.45 (m, 1H), 4.32 (dd, J = 12.0, 5.3Hz, 1H), 3.63 (d, J = 9.6Hz, 4H), 2.43 (s, 3H), 1.21-1.17 (m, 6H). LCMS: MS m / z: 489.24 (M+1).

[0498] ​ Scheme II illustrates the general synthesis of compounds of the disclosure, starting from the reaction of diacid SI I -1 with 1,1'-carbonyldiimidazole to give reagent SI I -2. Reaction between SI I -2 and nucleoside SI I -3 can further give intermediate SI I -4. Subsequent treatment of SI I -4 with 2-methyl-6-nitrobenzoic anhydride gives final compound SI I -5.

[0499] ​ Base) -13-cyano-2,9-dioxododecahydrofuro[3,4-b][l,4]dioxacyclododec-11-yl)methyl isopropyl carbonic acid ester (C5) Example 6: ((9aR,10R,12R,12aR)-12-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)- 12-cyano-2,8-dioxodecahydro-2H-furo[3,4-b][l,4]dioxacycloundec-10-yl)methyl isopropyl carbonic acid ester (C6) To a stirred solution of suberic acid (2.0 g, 11 mmol) in THF (30 mL) was added 1,1'-carbonyldiimidazole (5.0 g, 31 mmol) at room temperature. The reaction mixture was stirred overnight, intermediate 5a precipitated, which was then filtered and air dried. To a suspension of intermediate 5a (604 mg, 2.2 mmol) in anhydrous 1,4-dioxane (100 mL) was added ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isopropyl carbonate (755 mg, 2.0 mmol) at room temperature with vigorous stirring. A catalyst of 1,8-diazabicyclo[5.4.0]undec-7-ene (3 drops) was added to the reaction medium and the mixture was allowed to react at 80 °C for 15 to 20 hours. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over MgS04and concentrated. The residue was purified by high performance liquid chromatography using water and acetonitrile to give intermediate 5b. LCMS: MS m / z: 534.06 (M+1).

[0500] Intermediate 5b (53.4 mg, 0.10 mmol) was first dissolved in DMF (1 mL) and then diluted with 11 mL of DCM. The solution was added dropwise to a solution of 2-methyl-6-nitrobenzoic anhydride (103 mg, 0.30 mmol) and 4-dimethylaminopyridine (110 mg, 0.90 mmol) in DCM (4 mL) over 8 hours. The reaction was further stirred at room temperature for 16 hours. The reaction mixture was then concentrated. The residue was purified by high performance liquid chromatography using water and acetonitrile as eluents to give compound C5. 1 H NMR (400MHz, DMSO- d 6) δ 7.95 (s, 3H), 6.94 (d, J = 4.6Hz, 1H), 6.85(d, J = 4.6Hz, 1H), 6.02 (d,J = 6.3Hz, 1H), 5.55 (dd, J = 6.3, 4.1Hz, 1H), 4.72(hept, J = 6.3Hz, 1H), 4.61 (q, J = 4.3Hz, 1H), 4.46 (dd, J = 12.1, 3.5Hz, 1H), 4.29 (dd, J = 12.1, 5.2Hz, 1H), 2.61-2.53 (m, 2H), 2.31-2.21 (m, 2H), 1.93 –1.76 (m, 2H), 1.63 – 1.41 (m, 4H), 1.29-1.26 (m, 2H), 1.20 (d, J = 6.2Hz, 3H), 1.18 (d, J = 6.2Hz, 3H). LCMS: MS m / z: 516.06 (M+1).

[0501] Example 7: ((8aR,9R,l lR,l laR)-l l-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)- 11-cyano-2,7-dioxodecahydrofuro[3,4-b][l,4]dioxacyclonon-9-yl)methyl isopropyl carbonic acid ester (C7) Example 8: ((9aR,10R,12R,12aR)-12-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)- 12-cyano-2,8-dioxooctahydro-2H,6H-furo[3,4-b][l,4,8]trioxacycloundec-10-yl)methyl isopropyl carbonic acid ester (C8) Scheme III Compound C6 was synthesized using adipic acid instead of octanoic acid, in a manner similar to ((10aR,11R,13R,13aR)-13-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-13-cyano-2,9-dioxododecanofurano[3,4-b][1,4]dioxanedodecyl-11-yl)methylisopropyl carbonate (Example 5, C5). 1 H NMR (400MHz, DMSO- d 6) δ 8.06 (br, 1H), 8.00 (br, 1H), 7.96 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.85(d, J = 4.6Hz, 1H), 6.05 (d, J = 6.9Hz, 1H), 5.55 (dd, J = 6.8, 5.0Hz, 1H), 4.74(p, J = 6.2Hz, 1H), 4.64 – 4.59 (m, 1H), 4.47 (dd, J= 12.1, 3.5Hz, 1H), 4.32(dd, J = 12.1, 5.4Hz, 1H), 2.56 – 2.43 (m, 2H), 2.35 – 2.23 (m, 2H), 2.04-1.91(m, 2H), 1.85-1.72 (m, 2H), 1.24-1.16 (m, 6H)。LCMS:MS m / z: 502.07 (M+1)。

[0502] Example 9: ((10aR,11R,13R,13aR)-13-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)- 13-cyano-2,9-dioxo-2,3,4,7,8,9,10a,l l,13,13a-decahydrofuro[3,4-b][l,4]dioxacyclododec-11-yl)methyl isopropyl carbonic acid ester (C9) Scheme IV Compound C7 was synthesized in a similar manner to ((10aR,11R,13R,13aR)-13-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-13-cyano-2,9-dioxododecahydrofuro[3,4-b][1,4]dioxacyclododec-11-yl)methyl isopropyl carbonate (Example 5, C5) using heptanedioic acid instead of octanedioic acid. 1 H NMR (400MHz, DMSO-d6) δ 8.06 (br, 1H), 8.00 (br, 1H), 7.96 (s, 1H), 6.95 (d, J = 4.6Hz, 1H),6.87 (d, J = 4.6Hz, 1H), 6.03 (d, J = 6.9Hz, 1H), 5.51 (dd, J = 6.9, 5.1Hz,1H), 4.73 (hept, J = 6.2Hz, 1H), 4.57 (td, J = 5.2, 3.2Hz, 1H), 4.48 (dd, J =12.2, 3.3Hz, 1H), 4.29 (dd, J = 12.2, 5.4Hz, 1H), 2.69-2.59 (m, 2H), 2.39 –2.27 (m, 2H), 1.81-1.57 (m, 5H), 1.21 (d, J = 6.2Hz, 3H), 1.18 (d, J = 6.2Hz,3H), 0.94-0.82 (m, 1H)。LCMS:MS m / z: 488.02 (M+1)。

[0503] Example 10: (7aR,8R,10R,10aR)-8-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)- 10-(hydroxymethyl)-2,6-dioxooctahydro-2H-furo[3,4-b][l,4]dioxanon-8- carbonitrile (C10) Example 11: (7aR,8R,10R,10aR)-8-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)- 10-(hydroxymethyl)-4,4-dimethyl-2,6-dioxooctahydro-2H-furo[3,4-b][l,4]dioxanon-8- carbonitrile Scheme V Compound C8 was synthesized in a similar manner as ((10aR,11R,13R,13aR)-13-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-13-cyano-2,9-dioxododecahydrofuro[3,4-b][1,4]dioxacyclododec-11-yl)methyl isopropyl carbonate (Example 5, C5) using 3-(2-carboxyethoxy)propanoic acid instead of suberic acid. 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (br, 1H), 8.00 (br, 1H), 7.96 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 6.86 (d, J = 4.6 Hz, 1H), 6.02 (d, J = 6.6 Hz, 1H), 5.63 (dd, J = 6.5, 4.2 Hz, 1H), 4.72 (h, J = 6.2 Hz, 1H), 4.61 (q, J = 4.3 Hz, 1H), 4.46 (dd, J = 12.2, 3.6 Hz, 1H), 4.30 (dd, J = 12.1, 5.3 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.80 - 3.66 (m, 2H), 2.83-2.74 (m, 2H), 2.53-2.45 (m, 2H), 1.23-1.16 (m, 6H). LCMS: MS m / z: 504.00 (M+1).

[0504] Example 12: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)- 10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][l,4]dioxanon-8-yl)methyl ethyl carbonic acid ester Scheme III illustrates a general synthesis of esterification of alcohol SIII-1 with vinyl acid SIII-2 using a carbodiimide reagent (e.g., N,N'-diisopropylcarbodiimide) and 4-dimethylaminopyridine to give intermediate SIII-3, which is further subjected to ring closing metathesis with a suitable catalyst (e.g., Hoveyda-Grubbs II catalyst) to give final compound SIII-4.

[0505] Example 13: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)- 10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][l,4]dioxanon-8-yl)methyl methyl carbonic acid ester ​ ​ To a suspension of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isopropyl carbonate (377 mg, 1.0 mmol) in DCM (5 mL) was added 4-pentenoic acid (200 mg, 2.0 mmol), N,N'-diisopropylcarbodiimide (DIC, 252 mg, 2.0 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol). The reaction was stirred at room temperature overnight. The reaction solution was then poured into saturated NaHC03solution and extracted with DCM three times. The organic layers were then combined, dried, concentrated, and purified by flash chromatography using dichloromethane and ethyl acetate as eluents to give intermediate 9a. 1 H NMR (400MHz, DMSO-d6) δ 7.94 (s,3H), 6.94 (d, J = 4.6Hz, 1H), 6.79 (d, J = 4.6Hz, 1H), 6.11 (d, J = 5.8Hz,1H), 5.82 (dddt, J = 25.0, 16.7, 10.3, 6.3Hz, 2H), 5.43 (dd, J = 5.9, 4.4Hz,1H), 5.14 - 4.91 (m, 4H), 4.73 (hept, J = 6.3Hz, 1H), 4.60 (q, J = 4.4Hz,1H), 4.46 (dd, J = 12.2, 3.4Hz, 1H), 4.31 (dd, J = 12.1, 5.2Hz, 1H), 2.61 -2.51 (m, 2H), 2.50 - 2.42 (m, 2H), 2.41 - 2.24 (m, 4H), 1.22-1.18 (m, 6H). LCMS: MS m / z: 542.07 (M+1).

[0506] To a suspension of intermediate 9a (118 mg, 0.22 mmol) in toluene (100 mL) was added Hoveyda-Grubbs II catalyst (27 mg, 0.044 mmol) and 1,4-benzoquinone (4.7 mg, 0.044 mmol). The reaction was heated to reflux for 48 hours. The reaction mixture was then cooled and concentrated. The residue was purified by high performance liquid chromatography using water and acetonitrile as eluents to give compound C9 as a mixture of E / Z isomers. 1H NMR (400MHz, DMSO-d6) δ 8.15 - 7.85 (m, 3H), 6.95-6.94 (m, 1H), 6.85-6.81 (m, 1H), 6.01-5.94 (d, J =5.8Hz, 1H), 5.56 - 5.27 (m, 3H), 4.77 - 4.66 (m, 1H), 4.62-4.57 (m, 1H), 4.46-4.42 (m, 1H), 4.30-4.26 (m, 1H), 2.82 - 2.50 (m, 4H), 2.40 - 2.26 (m, 2H), 2.23-2.16 (m, 2H), 1.26 - 1.12 (m, 6H). LCMS: MS m / z: 514.01 (M+1).

[0507] ​ Scheme IV illustrates the general synthesis of compounds of the present disclosure, starting with the Cbz protection of nucleoside SIV-1 under basic conditions (e.g., 1-methylimidazole) to give SIV-2, which undergoes deprotection of the acetonide under acidic conditions (e.g., concentrated HC1) to give SIV-3. Nucleoside SIV-3 is then reacted with anhydride SIV-4 under basic conditions (e.g., DBN, DMAP) to generate intermediate SIV-5, which is subsequently treated with 2-methyl-6-nitrobenzoic anhydride to give cyclic intermediate SIV-6. The Cbz group in SIV-6 is then deprotected to give final compound SIV-7.

[0508] ​ ​ To a solution of (3aR,4R,6R,6aR)-4-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-carbonitrile (9.13 g, 27.6 mmol) and 1-methylimidazole (17.7 mL, 220 mmol) in DCM (276 mL) was added benzyl chloroformate (16.1 mL, 110 mmol) over 35 min at 0 °C in a 500 mL three necked flask equipped with an internal temperature probe (T = 0 °C). intTo a solution of intermediate 10a (16.0 g, 26.7 mmol) in THF (320 mL) at 0 °C was added concentrated HC1 12M (57.6 mL, 702 mmol) over 5 min (T = 2.6 °C to 7.5 °C). The mixture was allowed to warm to r.t. over 30 min and stirred at r.t. for 1.5 h. After 30 min, 1-methylimidazole (4.44 mL, 55.1 mmol) and benzyl chloroformate (4.01 mL, 27.6 mmol) were added and stirred at r.t. for 15 h. HC1 1M (100 mL) was added and the layers were separated. The organic layer was washed with HC1 1M (100 mL). The aqueous layer was washed with DCM (2 x 50 mL). The combined organic layers were washed with NaHC03(100 mL), brine (100 mL), dried over Na2S04and concentrated. The residue was purified by normal phase chromatography (0-20% ethyl acetate in DCM) to give intermediate 10b. 1 H NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 8.42 (s, 1H), 7.49 (d, J = 7.1 Hz, 2H), 7.45 - 7.27 (m, 9H), 7.03 (d, J = 4.7 Hz, 1H), 5.38 (d, J = 6.3 Hz, 1H), 5.27 (s, 2H), 5.06 (d, J = 12.2 Hz, 1H), 5.02 (d, J = 12.2 Hz, 1H), 4.98 (dd, J = 6.3, 2.8 Hz, 1H), 4.68 - 4.61 (m, 1H), 4.34 (dd, J = 11.8, 3.9 Hz, 1H), 4.20 (dd, J = 11.8, 5.7 Hz, 1H), 1.64 (s, 3H), 1.37 (s, 3H). LCMS: MS m / z: 600.4 (M+1).

[0509] To a solution of intermediate 10a (16.0 g, 26.7 mmol) in THF (320 mL) at 0 °C was added concentrated HC1 12M (57.6 mL, 702 mmol) over 5 min (T = 2.6 °C to 7.5 °C). The mixture was allowed to warm to r.t. over 30 min and stirred at r.t. for 1.5 h. After 30 min, 1-methylimidazole (4.44 mL, 55.1 mmol) and benzyl chloroformate (4.01 mL, 27.6 mmol) were added and stirred at r.t. for 15 h. HC1 1M (100 mL) was added and the layers were separated. The organic layer was washed with HC1 1M (100 mL). The aqueous layer was washed with DCM (2 x 50 mL). The combined organic layers were washed with NaHC03(100 mL), brine (100 mL), dried over Na2S04and concentrated. The residue was purified by normal phase chromatography (0-20% ethyl acetate in DCM) to give intermediate 10b. int To a solution of intermediate 10a (16.0 g, 26.7 mmol) in THF (320 mL) at 0 °C was added concentrated HC1 12M (57.6 mL, 702 mmol) over 5 min (T = 2.6 °C to 7.5 °C). The mixture was allowed to warm to r.t. over 30 min and stirred at r.t. for 1.5 h. After 30 min, 1-methylimidazole (4.44 mL, 55.1 mmol) and benzyl chloroformate (4.01 mL, 27.6 mmol) were added and stirred at r.t. for 15 h. HC1 1M (100 mL) was added and the layers were separated. The organic layer was washed with HC1 1M (100 mL). The aqueous layer was washed with DCM (2 x 50 mL). The combined organic layers were washed with NaHC03(100 mL), brine (100 mL), dried over Na2S04and concentrated. The residue was purified by normal phase chromatography (0-20% ethyl acetate in DCM) to give intermediate 10b. intTo the solution of intermediate 10a (1.0 g, 1.8 mmol) in THF (20 mL) was added 1,5-diazabicyclo[4.3.0]non-5-ene (0.5 mL, 4.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, then at room temperature for 2 h. Water (20 mL) was added and the mixture was concentrated. Ethyl acetate (20 mL) and HC1 0.5 M (20 mL) were added, the layers were separated. The aqueous layer was extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04and concentrated. The residue was purified by normal phase chromatography (0-10% MeOH in DCM) to give intermediate 10b. 1 H NMR (400MHz, DMSO-d6) δ 11.04 (s, 1H), 8.38 (s, 1H), 7.49 (m, 2H), 7.46 - 7.31 (m, 8H), 7.30 (d, J = 4.7Hz, 1h), 7.00 (d, J = 4.7Hz, 1H), 6.44 (d, J = 6.1Hz, 1H), 5.48 (d, J = 5.8Hz, 1H), 5.26 (s, 2H), 5.13 (s, 2H), 4.70 - 4.62 (m, 1H), 4.49 - 4.39 (m, 1H), 4.33 - 4.19 (m, 2H), 3.93 (dd, J = 11.1, 6.0Hz, 1H). LCMS: MS m / z: 560.3 (M+1).

[0510] In a 250 mL round bottom flask, 1,5-diazabicyclo[4.3.0]non-5-ene (382 uL, 3.09 mmol) was added to a solution of intermediate 10b (6.07 g, 10.3 mmol) and glutaric anhydride (1.18 g, 10.3 mmol) in THF (172 mL). The mixture was stirred at room temperature for 2 h. Water (30 mL) was added and concentrated. Ethyl acetate (150 mL) and HC1 0.5 M (100 mL) were added, the layers were separated. The aqueous layer was extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04and concentrated to give intermediate 10c which was used directly in the next step. LCMS: MS m / z: 674.3 (M+1).

[0511] 2-Methyl-6-nitrobenzoic anhydride (11.6 g, 33.0 mmol), 4-dimethylaminopyridine (12.3 g, 98.9 mmol), and DCM (1.10 L) were charged into a 3 L round-bottom flask. Intermediate 10c (7.40 g, 11.0 mmol) was dissolved in DCM (549 mL) and loaded into a 1 L feeding funnel, and added dropwise to the reaction mixture over 30 hours. The mixture was stirred for 1 hour, then concentrated to half its original volume (approximately 700 mL), washed with semi-saturated NaHCO3 (300 mL) and 10% citric acid solution (300 mL), then washed with brine (100 mL), and dried over sodium sulfate. The residue was purified by normal-phase chromatography (0–10% EtOAc in DCM solution) and by reversed-phase chromatography (5–80% ACN in AmF solution (10 mM ammonium formate aqueous solution)) to give intermediate 10d. 1 H NMR(400MHz, DMSO-d6) δ 11.14 (s, 1H), 8.39 (s, 1H), 7.53 – 7.46 (m, 2H), 7.45 –7.29 (m, 9H), 7.12 (d, J = 4.8Hz, 1H), 5.94 (d, J = 7.0Hz, 1H), 5.51 – 5.43 (m,1H), 5.26 (s, 2H), 5.15 (d, J = 12.2Hz, 1H), 5.12 (d, J = 12.2Hz, 1H), 4.62 (dd, J = 8.9, 5.5Hz, 1H), 4.54 (dd, J = 12.2, 3.3Hz, 1H), 4.39 (dd, J = 12.2, 5.5Hz,1H), 2.80 – 2.69 (m, 2H), 2.47 – 2.35 (m, 2H), 2.35 – 2.20 (m, 1H), 1.97 –1.85 (m, 1H). LCMS: MS m / z: 656.3 (M+1).

[0512] Intermediate 10d (1.71 g, 2.59 mmol) and EtOAc (32 mL) were charged into a 250 mL round-bottom flask. The mixture was degassed with nitrogen for 2 min, and 10% loaded palladium / carbon (325 mg, 0.309 μmol) was added, followed by further degassed with nitrogen for 5 min. H2 gas from a balloon was bubbled into the mixture using a fine needle for 5 min, and the black suspension was stirred at room temperature under an H2 atmosphere for 16 h. The mixture was washed with nitrogen for 2 min, filtered through diatomaceous earth, washed with EA (10 mL) and MeOH (10 mL), and concentrated to dryness. The residue was co-evaporated with DCM / heptane (1:1, 20 mL) to give compound C10. 1 H NMR (400MHz, DMSO-d6) δ 8.15 – 7.98 (m, 2H), 7.98 (s, 1H), 6.94 (d, J = 4.6Hz, 1H), 6.92(d, J = 4.6Hz, 1H), 5.87 (d, J = 7.0Hz, 1H), 5.45 (dd, J = 6.9, 5.4Hz, 1H),5.17 (t, J = 5.7Hz, 1H), 4.34 (dd, J = 9.2, 4.1Hz, 1H), 3.75 – 3.60 (m, 2H),2.79 – 2.69 (m, 2H), 2.45 – 2.22 (m, 3H), 1.96 – 1.84 (m, 1H). LCMS: MS m / z: 388.2 (M+1).

[0513] ​ ​ （C11） Compound C11 was synthesized in a manner similar to (7aR,8R,10R,10aR)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-10-(hydroxymethyl)-2,6-dioxooctahydro-2H-furano[3,4-b][1,4]dioxane-8-carboxynitrile (Example 10, C10), using 3,3-dimethylglutaric anhydride instead of glutaric anhydride. 1 H NMR (400MHz, DMSO-d6) δ 8.13 – 7.99 (m, 2H), 7.97 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 5.86 (d, J= 7.1 H, 1Hz), 5.40 – 5.32 (m, 1H), 5.16 (t, J =5.7Hz, 1H), 4.30 (dt, J = 6.0, 4.1Hz, 1H), 3.76 – 3.60 (m, 2H), 2.52 (dd, J =8.5, 1.7Hz, 2H), 2.37 (t, J = 12.7Hz, 2H), 1.22 (s, 3H), 1.18 (s, 3H). LCMS: MS m / z: 416.2 (M+1).

[0514] ​ Scheme V shows a general synthesis of compounds of the disclosure, starting from the reaction of 2',3'-cyclized nucleoside SV-1 with chloroformate SV-2 to give final compound SV-3.

[0515] ​ ​ （C12） A flame dried microwave reaction vial (0.5 mL - 2 mL) was charged with (7aR,8R,10R,10aR)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10- (hydroxymethyl)-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]dioxine-8-carbonitrile (Example 10, C10, 25.5 mg, 65.8 umol), 4-dimethylaminopyridine (24.6 mg, 197 umol), DCM (823 uL) and the mixture was cooled to 0 °C using an ice bath. Ethyl chloroformate (8.35 uL, 92.2 umol) (as a 10 vol% solution in DCM for accurate volume control) was added and the mixture was stirred for 20 minutes. Ethyl chloroformate (3.58 uL, 39.5 umol) (as a 10 vol% solution in DCM for accurate volume control) was added and stirred for 15 minutes. The reaction mixture was diluted with DCM (5 mL), washed with water (3 mL) and concentrated to dryness. Purification by reverse phase chromatography (30 g C18 column, 5 to 45% ACN / 10 mM ammonium formate gradient) gave compound C12. 1 H NMR (400MHz, DMSO-d6) δ 8.16 – 7.98 (m, 2H), 7.96 (s, 1H), 6.95 (d, J= 4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 5.98 (d, J = 7.1Hz, 1H), 5.46 (dd, J = 7.0, 5.9Hz, 1H), 4.60 –4.46 (m, 2H), 4.33 (dd, J = 12.2, 5.3Hz, 1H), 4.18 – 4.03 (m, 2H), 2.80 - 2.69(m, 2H), 2.47 – 2.35 (m, 2H), 2.34 – 2.21 (m, 1H), 1.99 – 1.85 (m, 1H), 1.19(t, J = 7.1Hz, 3H)。LCMS:MS m / z: 460.2 (M+1)。

[0516] ​ ​ （C13） Compound C13 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methylethyl carbonate (Example 12, C12) using methyl chloroformate instead of ethyl chloroformate. 1 H NMR (400MHz, DMSO-d6) δ 8.18 – 7.98 (m, 2H), 7.95 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 5.98 (d, J = 7.1Hz, 1H), 5.46 (dd, J = 7.0, 5.8Hz, 1H), 4.61 –4.45 (m, 2H), 4.34 (dd, J = 12.1, 5.2Hz, 1H), 3.69 (s, 3H), 2.81 - 2.69 (m,2H), 2.46 – 2.34 (m, 2H), 2.34 – 2.20 (m, 1H), 1.97 – 1.84 (m, 1H)。LCMS:MS m / z: 446.2 (M+1)。

[0517] Example 14: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-cyano-4,4-dimethyl-2,6-dioxooctahydro-2H- furo[3,4-b][1,4]diazepin-8-yl)methyl ethyl carbonate (C14) Example 15: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-cyano-4,4-dimethyl-2,6-dioxooctahydro-2H- furo[3,4-b][1,4]diazepin-8-yl)methyl methyl carbonate (C15) Scheme VI Compound C14 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10- (4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H- furo[3,4-b][1,4]dioxin-8-yl)methylethyl carbonate (Example 12, C12) using C11 (Example 11) in place of C10 (Example 10). 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (br, 1H), 8.03 (br, 1H), 7.95 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 6.91 (d, J = 4.6 Hz, 1H), 5.95 (d, J = 7.1 Hz, 1H), 5.45 - 5.34 (m, 1H), 4.51 (dt, J = 6.8, 3.1 Hz, 2H), 4.32 (dd, J = 12.9, 6.1 Hz, 1H), 4.16 - 4.01 (m, 2H), 2.55 - 2.51 (m, 2H), 2.38 (dd, J = 12.7, 6.5 Hz, 2H), 1.22 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.18 (s, 3H). LCMS: MS m / z: 488.2 (M+1).

[0518] Example 16: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4] diazepin-8-yl)methyl (tetrahydro-2H-pyran-4-yl) carbonate (C16) Example 17: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4] diazepin-8-yl)methyl (2-(pyridin-4-yl)propan-2-yl) carbonate (C17) Example 18: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4] diazepin-8-yl)methyl isobutyl carbonate Compound C15 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10- (4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H- furo[3,4-b][1,4]dioxin-8-yl)methylethyl carbonate (Example 12, C12) using methyl chloroformate in place of ethyl chloroformate and C11 (Example 11) in place of C10 (Example 10). 1H NMR (400MHz, DMSO-d6) δ 8.11 (br, 1H), 8.02 (br, 1H), 7.95 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.91 (d, J = 4.6Hz, 1H), 5.94 (d, J = 7.1Hz, 1H), 5.44 - 5.36 (m, 1H), 4.56 - 4.48 (m, 2H), 4.34 (dd, J = 13.1, 6.2Hz, 1H), 3.69 (s, 3H), 2.56 - 2.51 (m, 2H), 2.38 (dd, J = 12.8, 6.3Hz, 2H), 1.22 (s, 3H), 1.18 (s, 3H). LCMS: MS m / z: 474.2 (M+1).

[0519] Example 19: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4] diazepin-8-yl)methyl (2-morpholinoethyl) carbonate (C19) Scheme VI illustrates a general synthesis of compounds of the disclosure, starting from the reaction of alcohol SVI-1 with 4-nitrophenyl chloroformate under basic conditions (e.g., triethylamine) to give intermediate SVI-2, which can be reacted with 2',3'-cyclic nucleoside SVI-3 under basic conditions (e.g., triethylamine) to give final compound SVI-4.

[0520] Example 20: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4] diazepin-8-yl)methyl cyclopentyl carbonate Example 21 : ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4] diazepin-8-yl)methyl (2-ethylbutyl) carbonate (C21 ) ​ A 25 mL round bottom flask was charged with tetrahydro-4-pyrane alcohol (187 uL, 1.92 mmol), 4-dimethylaminopyridine (4.78 mg, 38.4 umol), flushed with nitrogen, and EtOAc (9.60 mL) was added, the mixture was cooled to 0 °C using an ice bath, and 4-nitrophenyl chloroformate (439 mg, 2.11 mmol) was added in one portion. The mixture was allowed to warm to room temperature over 3 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water, dried over sodium sulfate, and concentrated. Purification by normal phase chromatography (25 g SiO2column, 0 to 30% EtOAc / hexanes gradient) gave intermediate 16a.

[0521] A flame-dried microwave reaction vial (0.5 mL - 2 mL) was charged with intermediate 16a (14.7 mg, 54.9 umol), (7aR,8R,10R,10aR)-8-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-10-(hydroxymethyl)-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxine-8-carbonitrile (Example 10, C10, 21.2 mg, 54.9 umol), 4- dimethylaminopyridine (13.7 mg, 110 umol), and DCM (686 uL), followed by Et3N (15.4 uL, 110 umol), and the reaction mixture was stirred at room temperature for 16 hours. Water (5 drops) was added, and the mixture was concentrated to dryness. Purification by reverse phase chromatography (30 g C18 column, 5 to 45% ACN / 10 mM ammonium formate gradient) afforded compound C16. 1 HNMR (400MHz, DMSO-d6) δ 8.22 - 7.99 (m, 2H), 7.97 (s, 1H), 6.96 (d, J = 4.6 Hz, 1H), 6.92 (d, J = 4.6 Hz, 1H), 5.98 (d, J = 7.1 Hz, 1H), 5.46 (dd, J = 6.9, 6.0 Hz, 1H), 4.77 - 4.66 (m, 1H), 4.59 - 4.48 (m, 2H), 4.34 (dd, J = 12.2, 5.5 Hz, 1H), 3.82 - 3.71 (m, 2H), 3.45 - 3.35 (m, 2H), 2.80 - 2.69 (m, 2H), 2.46 - 2.35 (m, 2H), 2.35 - 2.21 (m, 1H), 1.99 - 1.78 (m, 3H), 1.61 - 1.46 (m, 2H). LCMS: MS m / z: 516.3 (M+1).

[0522] ​ ​ ​ Compound C17 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]diazepin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using 2-(pyridin-4-yl)propan-2-ol instead of tetrahydro-4-pyranol. 1 H NMR (400MHz, DMSO-d6) δ 8.46 – 8.39 (m, 2H), 8.11 (br, 1H),8.04 (br, 1H), 8.00 (s, 1H), 7.28 – 7.21 (m, 2H), 6.99 (d, J = 4.7Hz, 1H),6.96 (d, J = 4.6Hz, 1H), 6.04 (d, J = 7.0Hz, 1H), 5.48 – 5.43 (m, 1H), 4.55 –4.44 (m, 2H), 4.27 (dd, J = 12.3, 5.3Hz, 1H), 2.80 – 2.70 (m, 2H), 2.47 –2.37 (m, 2H), 2.28 (dd, J = 10.0, 3.8Hz, 1H), 1.97 – 1.88 (m, 1H), 1.69 (s,3H), 1.65 (s, 3H)。LCMS:MS m / z: 551.3 (M+1)。

[0523] ​ ​ （C18） Compound C18 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]diazepin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using 2-methylpropan-1-ol instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.18 - 7.96 (m, 2H), 7.95 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 6.92 (d, J = 4.6 Hz, 1H), 5.99 (d, J = 7.1 Hz, 1H), 5.45 (dd, J = 6.9, 6.0 Hz, 1H), 4.61 - 4.54 (m, 1H), 4.51 (dd, J = 12.2, 3.3 Hz, 1H), 4.34 (dd, J = 12.2, 5.5 Hz, 1H), 3.88 (dd, J = 8.9, 5.2 Hz, 1H), 3.84 (dd, J = 8.9, 5.1 Hz, 1H), 2.80 - 2.69 (m, 2H), 2.47 - 2.35 (m, 2H), 2.35 - 2.21 (m, 1H), 1.99 - 1.80 (m, 2H), 0.86 (dd, J = 6.7, 1.0 Hz, 6H). LCMS: MS m / z: 488.2 (M+1).

[0524] ​ ​ ​ Compound C19 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using 2-morpholinoethan-1-ol instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.10 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H),6.95 (d, J =4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 5.99 (d, J = 7.1Hz, 1H),5.51 - 5.39 (m, 1H), 4.57 (dt, J = 8.8, 4.4Hz, 1H), 4.51 (dd, J = 12.2,3.1Hz, 1H), 4.34 (dd, J = 12.2, 5.4Hz, 1H), 4.22 - 4.09 (m, 2H), 3.56 - 3.50(m, 4H), 2.79 - 2.69 (m, 2H), 2.55 - 2.51 (m, 2H), 2.46 - 2.21 (m, 7H), 1.97- 1.85 (m, 1H). LCMS: MS m / z: 545.3 (M+1).

[0525] ​ ​ （C20） Compound C20 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using cyclopentanol instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.18 - 7.96 (m, 2H), 7.95 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 6.92 (d, J = 4.6 Hz, 1H), 5.98 (d, J = 7.1 Hz, 1H), 5.44 (dd, J = 6.9, 6.1 Hz, 1H), 5.01 - 4.91 (m, 1H), 4.54 (td, J = 5.6, 3.4 Hz, 1H), 4.49 (dd, J = 12.2, 3.3 Hz, 1H), 4.30 (dd, J = 12.2, 5.4 Hz, 1H), 2.80 - 2.68 (m, 2H), 2.47 - 2.34 (m, 2H), 2.34 - 2.20 (m, 1H), 1.99 - 1.86 (m, 1H), 1.86 - 1.72 (m, 2H), 1.71 - 1.45 (m, 6H). LCMS: MS m / z: 500.2 (M+1).

[0526] ​ ​ ​ Compound C21 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using 2-ethylbutan-1-ol instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.10 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H),6.95 (d, J = 4.6Hz, 1H), 6.91 (d, J = 4.6Hz, 1H), 5.98 (d, J = 7.1Hz, 1H),5.45 (dd, J = 7.0, 6.0Hz, 1H), 4.56 (td, J = 5.6, 3.5Hz, 1H), 4.51 (dd, J =12.1, 3.3Hz, 1H), 4.34 (dd, J = 12.1, 5.5Hz, 1H), 4.10-3.90 (m, 2H), 2.79 –2.67 (m, 2H), 2.46 – 2.34 (m, 2H), 2.34 – 2.20 (m, 1H), 1.99 – 1.80 (m, 1H),1.53 – 1.41 (m, 1H), 1.32 – 1.21 (m, 4H), 0.82 (t, J = 7.5Hz, 6H)。LCMS:MS m / z: 516.2 (M+1).

[0527] Example 22: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 10-Cyano-2,6-dioxooctahydro-2H-furano[3,4-b][1,4]dioxane-non-8-yl)methyl(2-methoxy-2- Methylpropyl carbonate (C22) Compound C22 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10- (4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H- furo[3,4-b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using 2-methoxy-2-methylpropan-1-ol instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.18 - 7.98 (m, 2H), 7.96 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 5.99 (d, J = 7.1Hz, 1H), 5.46 (dd, J = 6.9, 6.1Hz, 1H), 4.62 - 4.54 (m, 1H), 4.51 (dd, J = 12.2, 3.3Hz, 1H), 4.37 (dd, J = 12.2, 5.6Hz, 1H), 4.01 (d, J = 11.2Hz, 1H), 3.96 (d, J = 11.1Hz, 1H), 3.09 (s. 3H), 2.80 - 2.68 (m, 2H), 2.47 - 2.34 (m, 2H), 2.34 - 2.20 (m, 1H), 1.98 - 1.85 (m, 1H), 1.09 (s, 6H). LCMS: MS m / z: 518.3 (M+1).

[0528] Example 23: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 10-Cyano-2,6-dioxooctahydro-2H-furano[3,4-b][1,4]dioxane-non-8-yl)methyl(tetrahydrofuran-3- (C23) carbonate Compound C23 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using tetrahydrofuran-3-ol instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.15 - 7.98 (m, 2H), 7.96 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 6.92 (d, J = 4.6 Hz, 1H), 5.99 (d, J = 7.1 Hz, 1H), 5.46 (dd, J = 7.0, 6.0 Hz, 1H), 5.16 - 5.10 (m, 1H), 4.60 - 4.47 (m, 2H), 4.34 (dd, J = 12.2, 5.4 Hz, 1H), 3.81 - 3.65 (m, 4H), 2.79 - 2.68 (m, 2H), 2.46 - 2.34 (m, 2H), 2.34 - 2.19 (m, 1H), 2.19 - 2.06 (m, 1H), 1.99 - 1.84 (m, 2H). LCMS: MS m / z: 502.2 (M+l).

[0529] Example 24: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 10-Cyano-2,6-dioxooctahydro-2H-furano[3,4-b][1,4]dioxane-non-8-yl)methyl((1-cyanocyclopropane) (C24) methyl carbonate Compound C24 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, CI 6) using 1-(hydroxymethyl)cyclopropane-1-carbonitrile instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.17 - 7.99 (m, 2H), 7.98 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 6.93 (d, J = 4.6 Hz, 1H), 6.00 (d, J = 7.1 Hz, 1H), 5.48 (dd, J = 7.0, 6.0 Hz, 1H), 4.59 (td, J = 5.6, 3.3 Hz, 1H), 4.54 (dd, J = 12.1, 3.3 Hz, 1H), 4.39 (dd, J = 12.1, 5.5 Hz, 1H), 4.13 (s, 2H), 2.81 - 2.69 (m, 2H), 2.47 - 2.35 (m, 2H), 2.34 - 2.20 (m, 1H), 1.99 - 1.86 (m, 1H), 1.40 - 1.23 (m, 2H), 1.23 - 1.08 (m, 2H). LCMS: MS m / z: 511.2 (M+1).

[0530] Example 25: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 10-Cyano-2,6-dioxooctahydro-2H-furano[3,4-b][1,4]dioxane-non-8-yl)methyl(1,1-difluoro-2- Methylpropyl-2-yl)carbonate (C25) Compound C25 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using 1,1-difluoro-2-methylpropan-2-ol in place of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.16 - 7.97 (m, 2H), 7.96 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 6.92 (d, J = 4.6 Hz, 1H), 6.16 (t, J = 55.5 Hz, 1H), 5.99 (d, J = 7.1 Hz, 1H), 5.45 (dd, J = 7.0, 6.0 Hz, 1H), 4.58 - 4.53 (m, 1H), 4.51 (dd, J = 12.1, 3.3 Hz, 1H), 4.33 (dd, J = 12.1, 5.5 Hz, 1H), 2.80 - 2.69 (m, 2H), 2.47 - 2.34 (m, 2H), 2.34 - 2.20 (m, 1H), 1.98 - 1.85 (m, 1H), 1.44 (s, 3H), 1.42 (s, 3H). LCMS: MS m / z: 524.3 (M+1).

[0531] Example 26: 2-(((((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazine- 7-yl)-10-cyano-2,6-dioxooctahydro-2H-furano[3,4-b][1,4]dioxane-non-8-yl)methoxy)carbonyl Ethyl 2-methylpropionate (C26) Compound C26 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using ethyl 2-hydroxy-2-methylpropanoate instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.18 - 7.99 (m, 2H), 7.97 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 5.99 (d, J = 7.1Hz, 1H), 5.44 (dd, J = 6.9, 6.2Hz, 1H), 4.58 - 4.52 (m, 1H), 4.49 (dd, J = 12.2, 3.1Hz, 1H), 4.35 (dd, J = 12.3, 5.6Hz, 1H), 4.13 - 3.98 (m, 2H), 2.81 - 2.68 (m, 2H), 2.47 - 2.34 (m, 2H), 2.34 - 2.20 (m, 1H), 1.97 - 1.86 (m, 1H), 1.49 (s, 3H), 1.46 (s, 3H), 1.08 (t, J = 7.1Hz, 3H). LCMS: MS m / z: 546.2 (M+1).

[0532] Example 27: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 10-Cyano-2,6-dioxooctahydro-2H-furano[3,4-b][1,4]dioxane-non-8-yl)methyl(1,3-difluoropropane- 2-yl)carbonate (C27) Compound C27 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using 1,3-difluoropropan-2-ol instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.17 - 7.98 (m, 2H), 7.96 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 6.92 (d, J = 4.6 Hz, 1H), 5.99 (d, J = 7.1 Hz, 1H), 5.47 (dd, J = 7.0, 5.9 Hz, 1H), 5.19 - 5.02 (m, 1H), 4.78 - 4.51 (m, 6H), 4.41 (dd, J = 12.0, 5.5 Hz, 1H), 2.80 - 2.69 (m, 2H), 2.47 - 2.35 (m, 2H), 2.35 - 2.20 (m, 1H), 1.99 - 1.84 (m, 1H). LCMS: MS m / z: 510.2 (M+l).

[0533] Example 28: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 10-Cyano-2,6-dioxooctahydro-2H-furano[3,4-b][1,4]dioxane-non-8-yl)methyl((1S,2R,4S)- 1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)carbonate (C28) Compound C28 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) by replacing tetrahydro-4-pyranol with (1S,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol. 1H NMR (400MHz, DMSO-d6) δ 8.13 - 7.98 (m, 2H), 7.98 - 7.94 (m, 1H), 6.99 - 6.93 (m, 1H), 6.93 - 6.89 (m, 1H), 6.03 - 5.94 (m, 1H), 5.49 - 5.41 (m, 1H), 4.62 - 4.45 (m, 2H), 4.45 - 4.27 (m, 1H), 4.18 - 4.09 (m, 1H), 2.82 - 2.68 (m, 2H), 2.47 - 2.35 (m, 2H), 2.35 - 2.17 (m, 1H), 2.00 - 1.84 (m, 1H), 1.70 - 1.52 (m, 4H), 1.48 - 1.34 (m, 1H), 1.21 - 1.12 (m, 1H), 1.12 - 0.85 (m, 7H), 0.77 - 0.58 (m, 3H). LCMS: MS m / z: 568.3 (M+1).

[0534] Example 29: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]diazepin-8-yl)methyl neopentyl carbonate （C29） Compound C29 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using 2,2-dimethylpropan-1-ol instead of tetrahydro-4-pyranol. 1H NMR (400MHz, DMSO-d6) δ 8.16 - 8.06 (br, 1H), 8.07 - 7.97 (br, 1H), 7.95 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 5.99 (d, J = 7.1Hz, 1H), 5.45 (dd, J = 7.0, 6.0Hz, 1H), 4.59 - 4.54 (m, 1H), 4.51 (dd, J = 12.2, 3.4Hz, 1H), 4.36 (dd, J = 12.1, 5.7Hz, 1H), 3.81 (d, J = 10.2Hz, 1H), 3.77 (d, J = 10.2Hz, 1H), 2.79 - 2.72 (m, 2H), 2.47 - 2.35 (m, 2H), 2.34 - 2.21 (m, 1H), 1.97 - 1.86 (m, 1H), 0.87 (s, 9H). LCMS: MS m / z: 502.3 (M+1).

[0535] Example 30: ((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]diazepin-8-yl)methyl (tetrahydro-2H-pyran-4- yl) carbonate (C33) 10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]diazepin-8-yl)methyl ((1R,3s,5S)- 8-methyl-8-azabicyclo[3.2.1]oct-3-yl) carbonate formate salt (C30) Example 31: methyl (2S,3R)-3-(((((7aR,8R,10R,10aR)-10-(4-aminopyrrolo[2,1-f][1,2, 4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4-b][1,4]diazepin-8-yl)methoxy)carbonyl) oxy)-2-(dimethylamino)butanoate 2,2,2-trifluoroacetate salt (C31) Compound C30 was synthesized in a similar manner to ((7aR,8R,10R,10aR)-10-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-10-cyano-2,6-dioxooctahydro-2H-furo[3,4- b][1,4]dioxin-8-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Example 16, C16) using (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol instead of tetrahydro-4-pyranol. The reaction crude mixture was purified by HPLC using 5% to 100% ACN / 10 mM ammonium formate gradient to give C30 as a formate salt. 1H NMR (400MHz, DMSO-d6) δ 8.24 (s,1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.91(d, J = 4.6Hz, 1H), 5.98 (d, J = 7.0Hz, 1H), 5.45 (dd, J = ...

Claims

1. A compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: Y is O or is absent; L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v - O-(CR 5A R 6A ) w - 、 - (CR 5 R 6 ) v - NR 7 - (CR 5A R 6A ) w -, -(CR 5 R 6 ) v - SO-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v - SO2-(CR 5A R 6A ) w - ; Z is O or is absent; n is 1, 2, 3, 4, 5, 6, or 7; R 1 , R 2 , R 3 , and R 4 are each independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; or R 1 R 2 group together with an R 2 group on the same carbon atom form a spiro C3-C9 carbocyclyl ring or a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 3 R 4 group together with an R 4 group on the same carbon atom form a spiro C3-C9 carbocyclyl ring or a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each R is independently H, -OR 5 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5 group together with the R 5 group on an adjacent carbon atom forms a double bond; or R 5 group together with R 1 group on the adjacent carbon atom forms a double bond; each R is independently H, -OR 6 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5 R 6 group together with an R 6 group on the same carbon atom form a spiro C3-C9 carbocyclyl ring or a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each R is independently H, -OR 5A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A group together with the R 5A group on an adjacent carbon atom forms a double bond; or R 5A group together with the R 3 group on an adjacent carbon atom forms a double bond; each R is independently H, -OR 6A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A R 6A group together with an R 6A group on the same carbon to form a spiro C3-C9 carbocyclyl ring or a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 is H, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula la: R is H, -C(=0)R 11 or -C(=0)OR 11 ; R 11 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2 C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8- membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 10 , -COR 12 , -COOR 12 , -NR 12 , -SR 13 , -N=NR 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein R 11 each substituent of the substituent group of C3-C9carbocyclyl, 4- to 8-membered heterocyclyl, 5- to 6-membered heteroaryl and phenyl is independently optionally substituted with one, two or three substituents independently selected from the group consisting of carbonyl, halo, cyano, OR 20 , oxo, phenyl, C1-C6haloalkyl and C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl; Each R 8 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 9 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 10 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 12 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 13 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 14 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; each R is independently H or C1-C8alkyl; 19 independently H or C1-C8alkyl; each R is independently H or C1-C8alkyl; 20 independently H or C1-C8alkyl; The base is 、 or ; R 15 is H, C1-C8alkyl, -C(=O)R 17 or -C(=O)OR 17 ; R 16 C1-C8alkyl optionally substituted with -OP(=O)(OH)(OR 18 ); each R is independently H, C1-C8alkyl, or C1-C8cycloalkyl; wherein R 17 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR 17 ), -OR 18 , NR 21 R 22 , and phenyl, wherein the substituent phenyl of R 23 is optionally substituted with -OP(=O)(OH)(OR 18 ); and 18 each R is independently H, C1-C8alkyl, or C1-C8cycloalkyl; wherein R 17 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR 17 ), -OR 18 , NR 21 R 22 , and phenyl, wherein the substituent phenyl of R 23 is optionally substituted with -OP(=O)(OH)(OR 18 ); and 18 each R is independently H, C1-C8alkyl, or C1-C8cycloalkyl; wherein R 17 is optionally substituted with one, two, or three substituents independently selected from halogen, cy each R is independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 18 is independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 10 is independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 18 is independently H, C1-C8alkyl, C3-C8carbocyclyl, C6-C10aryl, or Each R 21 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 22 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 23 It can be independently H, C1-C8 alkyl, C1-C8 haloalkyl and C3-C6 cycloalkyl.

2. The compound of claim 1, wherein the base is: . Formula la.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: Y is O or is absent; L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n - -(CR 5 R 6 ) v -0-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Z is O or is absent; n is 1, 2, 3, 4, 5, 6, or 7; R 1 , R 2 , R 3 , and R 4 are each independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; each R is independently H, -OR 5 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5 group together with the R 5 group on an adjacent carbon atom forms a double bond; each R is independently H, -OR 6 is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each R is independently H, -OR 5A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or R 5A group together with R 5A group on an adjacent carbon atom forms a double bond; each R is independently H, -OR 6A is independently H, -OR 8 , cyano, -NR 9 R 10 , halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 is H, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: R is H, -C(=0)R 11 or -C(=0)OR 11 ; R 11 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8- membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6- membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8- membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6- membered heteroaryl containing 1, Among them, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C9 carbocyclic, C6-C 10 The aryl, 4- to 8-membered heterocyclic, or 5- to 6-membered heteroaryl groups are optionally substituted by one, two, or three independent substituents selected from the group consisting of: C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 12 -COR 12 -COOR 12 -NR 13 R 14 -OP(=O)(OR) 19 )2, C3-C9 carbon cycloyl groups, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl groups; Each R 8 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 9 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 10 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 12 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 13 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 14 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 19 Independently H or C1-C8 alkyl; and each R is independently H or C1-C8alkyl. 20 independently H or C1-C8alkyl. Y is absent; L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n - -(CR 5 R 6 ) v -0-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Z is absent; n is 1, 2, 3, 4, 5, 6, or 7; R 1 , R 2 , R 3 , and R 4 are each independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, each R is independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 5 independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or R 5 group together with the R 5 group on the adjacent carbon atom forms a double bond; each R is independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 6 independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, each R is independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 5A independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, R 5A group together with R 5A group on an adjacent carbon atom forms a double bond; each R is independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; or 6A independently H, cyano, halo, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, R 7 is H, C1-C8alkyl; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: R is H, -C(=0)R 11 or -C(=0)OR 11 ; R 11 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8- membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6- membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8- membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6- membered heteroaryl containing 1, C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8- membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; Each R 12 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 13 Independently, it can be H, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C6 cycloalkyl; Each R 14 Independently, it is H, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C6 cycloalkyl; and each R is independently H or C1-C8alkyl. 19 independently H or C1-C8alkyl. Y is absent; L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n - -(CR 5 R 6 ) v -0-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Z is absent; n is 1, 2, 3, 4, 5, 6, or 7; R 1 , R 2 , R 3 , and R 4 are each independently H or Ci-C8alkyl; Each R 5 Independently H or C1-C8 alkyl; or R 5 group together with the R 5 group on an adjacent carbon atom forms a double bond; each R is independently H or C1-C8alkyl; 6 independently H or C1-C8alkyl; Each R 5A Independently H or C1-C8 alkyl; or R 5A group together with the R 5A group on an adjacent carbon atom forms a double bond; each R is independently H or C1-C8alkyl; 6A independently H or C1-C8alkyl; R 7 is H, C1-C8alkyl; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or 4. R is H, -C(=0)R 11 or -C(=0)OR 11 ; R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 is C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2 C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein each of the C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 10 12 12 12 13 14 , C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein each of the C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR​​​​​ each R is independently H or C1-C8alkyl; 12 independently H or C1-C8alkyl; Each R 13 Independently H or C1-C8 alkyl; and each R is independently H or C1-C8alkyl. 14 independently H or C1-C8alkyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein v is 0 or 1.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein w is 0 or 1.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein: Y is absent; L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is absent, -(CR 5 R 6 ) n - -(CR 5 R 6 ) v -0-(CR 5A R 6A ) w - or -(CR 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Z is absent; n is 1, 2, 3, or 4; R 1 , R 2 , R 3 and R 4 are each independently H or Ci-C8alkyl; Each R 5 Independently H or C1-C8 alkyl; or R 5 group together with the R 5 group on an adjacent carbon atom forms a double bond; each R is independently H or C1-C8alkyl; 6 independently H or C1-C8alkyl; Each R 5A Independently H or C1-C8 alkyl; or R 5A group together with the R 5A group on an adjacent carbon atom forms a double bond; each R is independently H or C1-C8alkyl; 6A independently H or C1-C8alkyl; R 7 is H, C1-C8alkyl; v is 0 or 1; w is 0 or 1; 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Id: R is H, -C(=0)R 11 or -C(=0)OR 11 ; R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 is C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2 C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein each of the C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 10 aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein each of the C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, each R is independently H or C1-C8alkyl; 12 independently H or C1-C8alkyl; Each R 13 Independently H or C1-C8 alkyl; and each R is independently H or C1-C8alkyl. 14 independently H or C1-C8alkyl. Formula Id.

12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Ib: Formula Ib.

13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Ic: Formula Ic.

19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NCH3-, or -CH2-CH=CH-CH2-.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X is absent, -(CR 5 R 6 ) n -, -(CR 5 R 6 ) v - O-(CR 5A R 6A ) w -, or -(CR 5 R 6 ) v - NR 7 - (CR 5A R 6A ) w -.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein X is -(CR 5 R 6 ) n - or -(CR 5 R 6 ) v - or -(CR 5A R 6A ) w - or -(CR 5 R 6 ) v - or -(CR 7 R 5A ) 6A - or -(CR w .

16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 15, wherein X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -0-, -CH2-0-CH2-, -NR 7 -CH2-, -CH2-CH=CH-CH2-, or -CH2-CH=CH-. 7 -CH2-, -CH2-CH=CH-CH2-, or -CH2-CH=CH-CH2-.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 16, wherein X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -CH2-O-CH2-, -NR 7 -CH2-CH=CH-CH2-.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 17, wherein X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -C(CH3)2-, -0-, -CH2-0-CH2-, -NCH3-, -CH2-NR 7 -CH2- or -CH2-CH=CH-CH2-.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein Y is absent.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Z is absent.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Y is absent and Z is absent. ​ 23. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-19, wherein Y is O.

24. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-19 and 23, wherein Z is O.

25. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-19, 23, and 24, wherein Y is O and Z is O.

26. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 25, wherein L is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -(CH2)2-O-(CH2)2-, -CH2-NR 7 -CH2- or -(CH2)2-CH=CH-(CH2)2-.

27. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 5 and 12 to 26, wherein R 11 is Ci-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl, 5- to 6-membered heteroaryl, and phenyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein R 11 each substituent of the substituent group of C3-C9carbocyclyl, 4- to 8-membered heterocyclyl, 5- to 6-membered heteroaryl and phenyl is independently optionally substituted with one, two or three substituents independently selected from the group consisting of carbonyl, halo, cyano, OR 20 , oxo, phenyl, C1-C6haloalkyl and C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl.

28. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 5 and 12 to 27, wherein R 11 is Ci-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl, 5- to 6-membered heteroaryl, and phenyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 10 R 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , -OP(=O)(OR 19 )2, C3-C9carbocyclyl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

29. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 28, wherein R 11 is Ci-C8alkyl, C3-C9carbocyclyl, C6-C 10 aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

30. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 29, wherein R 11 is Ci-C8alkyl or C3-C9carbocyclyl.

31. The compound or pharmaceutically acceptable salt thereof of claim 11, wherein the compound is of Formula Id: Formula Id L is -Y-(CR 1 R 2 )-X-(CR 3 R 4 )-Z-; X is non-existent, -(CR) 5 R 6 ) n -、-(CR 5 R 6 ) v -O-(CR 5A R 6A ) w -or-(CR) 5 R 6 ) v -NR 7 -(CR 5A R 6A ) w -; Y is absent; Z is absent; R 1 , R 2 , R 3 , and R 4 are each independently H or Ci-C8alkyl; Each R 5 Independently H or C1-C8 alkyl; or R 5 group together with the R 5 group on an adjacent carbon atom forms a double bond; each R is independently H or C1-C8alkyl; 6 independently H or C1-C8alkyl; Each R 5A Independently H or C1-C8 alkyl; or R 5A group together with the R 5A group on an adjacent carbon atom forms a double bond; each R is independently H or C1-C8alkyl; 6A independently H or C1-C8alkyl; R 7 is H, C1-C8alkyl; n is 1, 2, 3, or 4; v is 0 or 1; w is 0 or 1.

32. The compound of claim 31, wherein L is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -(CH2)2-O-(CH2)2-, -CH2-NR 7 -CH2- or -(CH2)2-CH=CH-(CH2)2-.

33. The compound or pharmaceutically acceptable salt thereof of any one of claim 12, wherein the compound is of Formula Ib: Formula Ib wherein: L is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -(CH2)2-0-(CH2)2-, -CH2-NR 7 -CH2- or -(CH2)2-CH=CH-(CH2)2-; R 11 It is a C1-C8 alkyl group, a C3-C9 carbocyclic group, or a C6-C 10 Aryl, 4- to 8-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5- to 6-membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein each of the C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 10 12 12 12 13 14 , C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein each of the C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR​​​​​ each R is independently H or C1-C8alkyl; 12 independently H or C1-C8alkyl; Each R 13 Independently H or C1-C8 alkyl; and each R is independently H or C1-C8alkyl. 14 independently H or C1-C8alkyl.

34. The compound or pharmaceutically acceptable salt thereof of any one of claim 13, wherein the compound is of Formula Ic: Formula Ic wherein: L is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2-C(CH3)2-CH2-, -(CH2)2-0-(CH2)2-, -CH2-NR 7 -CH2- or -(CH2)2-CH=CH-(CH2)2-; R 11 is C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 10 is C1-C8alkyl, C3-C9carbocyclyl, C6-C10aryl, 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5- to 6-membered heteroaryl containing 1, 2 C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein each of the C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 10 aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8alkyl, halogen, cyano, carbonyl, -N3, -OR 12 , -COR 12 , -COOR 12 , -NR 13 R 14 , C3-C9carbocyclyl, 4 to 8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein each of the C1-C8alkyl, C3-C9carbocyclyl, 4 to 8 membered heterocyclyl, each R is independently H or C1-C8alkyl; 12 independently H or C1-C8alkyl; Each R 13 Independently H or C1-C8 alkyl; and each R is independently H or C1-C8alkyl. 14 independently H or C1-C8alkyl.

35. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

36. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of claims 1-35 and one or more pharmaceutically acceptable excipients.

37. The pharmaceutical composition of claim 36, wherein the pharmaceutical formulation is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

38. The pharmaceutical composition of claim 36 or 37, wherein the pharmaceutical formulation is for oral administration.

39. A method of treating or preventing a viral infection in a human in need thereof, wherein the method comprises administering to the human a compound or pharmaceutically acceptable salt thereof of any one of claims 1-35, or a pharmaceutical composition of any one of claims 35-38.

40. The method of claim 39, wherein the compound or pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the human via oral, intramuscular, intravenous, subcutaneous, or inhalation administration.

41. The method of claim 39 or 40, wherein the method comprises administering to the human at least one additional therapeutic or prophylactic agent.

42. The method of claim 41, wherein the additional therapeutic or prophylactic agent is molnupiravir, oseltamivir, nirmatrelvir, or ritonavir.

43. The method of any one of claims 39-42, wherein the viral infection is a coronavirus infection.

44. The method of any one of claims 39-43, wherein the viral infection is a zoonotic coronavirus infection.

45. The method of any one of claims 39-44, 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-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

46. The method of any one of claims 39-44, 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-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

47. The method of any one of claims 39-44, 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-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

48. The method of any one of claims 39-44, 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-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

49. The method of any one of claims 39-43, wherein the viral infection is selected from the group consisting of: 229E virus infection, NL63 virus infection, OC43 virus infection, and HKU1 virus infection.

50. The method of any one of claims 39-43, wherein the viral infection is a SARS-CoV-2 infection (COVID-19).

51. The method of any one of claims 39-43, wherein the viral infection is a SARS-CoV virus infection.

52. The method of any one of claims 39-43, wherein the viral infection is a MERS-CoV virus infection.

53. The method of any one of claims 39-42, wherein the viral infection is a Pneumoviridae virus infection.

54. The method of claim 53, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

55. The method of claim 53, wherein the Pneumoviridae virus infection is a human metapneumovirus infection.

56. The method of any one of claims 39-42, wherein the viral infection is a Picornaviridae virus infection.

57. The method of any one of claims 39-42, wherein the viral infection is an enterovirus infection.

58. The method of any one of claims 39-42, wherein the viral infection is selected from the group consisting of: Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

59. The method of claim 56, wherein the Picornaviridae virus infection is a human rhinovirus infection (HRV).

60. The method of any one of claim 56, wherein the Picornaviridae virus infection is a HRV-A, HRV-B, or HRV-C infection.

61. The method of any one of claims 39-42, wherein the viral infection is a Flaviviridae virus infection.

62. The method of any one of claim 61, wherein the Flaviviridae virus infection is a dengue virus infection, a yellow fever virus infection, a West Nile virus infection, tick-borne encephalitis, Kyasanur Forest disease, Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or an HCV infection.

63. The method of any one of claims 39-42, wherein the viral infection is a Filoviridae virus infection.

64. The method of any one of claim 63, wherein the Filoviridae virus infection is an Ebola virus infection or a Marburg virus infection.

65. The method of any one of claims 39-42, wherein the viral infection is an Orthomyxoviridae virus infection.

66. The method of any one of claims 39-42, wherein the viral infection is an Influenza virus infection.

67. The method of any one of claims 39-42, wherein the viral infection is an Influenza A virus infection or an Influenza B virus infection.

68. The method of any one of claims 39-42, wherein the viral infection is a Paramyxoviridae virus infection.

69. The method of any one of claims 39-42, wherein the viral infection is a human parainfluenza virus, a Nipah virus, a Hendra virus, a measles, or a mumps infection.

70. A method of making a medicament for treating or preventing a viral infection in a human in need thereof, comprising The compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof.

71. Use of a compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a viral infection in a human in need thereof.

72. The use of claim 71, wherein the medicament is used with at least one additional therapeutic or prophylactic agent.

73. The use of claim 72, wherein the additional therapeutic or prophylactic agent is monolupiravir, oseltamivir, nirmatrelvir, or ritonavir.

74. A composition comprising a compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof for use in treating or preventing a viral infection in a human in need thereof.

75. The composition of claim 74, wherein the composition comprises at least one additional therapeutic or prophylactic agent.

76. The composition of claim 75, wherein the additional therapeutic or prophylactic agent is monolupiravir, oseltamivir, nirmatrelvir, or ritonavir.

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