Antiviral compounds and compositions and uses thereof

Abstract

The present disclosure relates to compounds which exhibit activity in the inhibition of RNA polymerase as well as pharmaceutical compositions comprising these compounds and methods of treatment of viral infections by administration of these compounds or the pharmaceutical compositions.

Description

FIELD OF THE DISCLOSURE

[001] The present disclosure generally relates to compounds which exhibit activity in the inhibition of RNA polymerase as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions comprising the same. BACKGROUND OF THE DISCLOSURE

[002] Over the past two decades, multiple varieties of viruses that can cause lifethreatening disease in humans and animals have been identified, namely, influenza, Respiratory syncytial virus (RSV), parainfluenza, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV), Ebola virus etc. Amongst, the global pandemic caused by SARS-CoV-2 has resulted in severe respiratory illness throughout the world, wherein severe cases progress to pneumonia and multiorgan failure, which have led to millions of deaths worldwide. Coronaviruses are highly susceptible to mutate into prevalent variants. Although various vaccines have been approved for use since the outbreak of SARS-CoV-2, the vaccinated people are still under risk associated with the emergence of immune escape mutants. Therefore, it is important to develop anti-viral drug to combat existing and emerging coronaviruses.

[003] Coronaviruses are positive-strand RNA viruses encoding 16 nonstructural proteins (nspl to nspl6). A number of the nonstructural proteins coalesce to form a multi-protein replicase-transcriptase complex (RTC). The main replicase-transriptase protein is the RNA-dependent RNA polymerase (RdRp), which is directly involved in the replication and transcription of RNA from an RNA strand. Besides, RdRps are highly conserved throughout variants and viruses, making it a desirable drug target for managing various RNA-viral infections.

[004] Remdesivir, a monopho sphoramidate prodrug of the nucleoside GS-441524, originally developed to treat Ebola virus infections, inhibits the RdRp of SARS-CoV-2. It was the first antiviral approved or authorized for emergency use to treat COVID-19 in several countries. Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe disease and it prevents disease progression in outpatients (Beigel J.H., et al. Remdesivir for the treatment of covid-19 - final report. N. Engl. J. Med. 2020;383(19):1813-1826.; Gottlieb R.L., et al. Early remdesivir to prevent progression to severe covid-19 in outpatients. N. Engl. J. Med. 2021). Vangeel et al. also proved that Remdesivir is effective against different variants of concern of SARS-CoV-2 (Vangeel L., et al. Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022 Feb; 198: 105252.). However, Remdesivir has several drawbacks, such as, limited to intravenous administration, short plasma half-life, uncorrelated plasma exposure and clinical efficacy, low delivery in lung (Sun D. Remdesivir for treatment of COVID-19: combination of pulmonary and IV administration may offer additional benefit. AAPS J. 2020;22:77.).

[005] Accordingly, there is a need in the art to develop improved compounds which exhibit inhibitory activity against RNA polymerase, in particular, an RNA polymerase inhibitor with good oral and pulmonary bioavailability, and high conversion rate to its monophosphate and triphosphate. SUMMARY OF THE DISCLOSURE

[006] The present disclosure provides compounds which are capable of inhibiting RNA polymerase, the pharmaceutical compositions comprising these compounds and methods for the use of such compounds or pharmaceutical compositions for treatment of viral infections.

[007] In one aspect, the present disclosure provides a compound having Formula (I) or Formula (II): (I) (II) or a pharmaceutically acceptable salt thereof, wherein Base is a naturally occurring or modified pyrimidine base or purine base; Q is CH2, CHD or CD2; R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -ORa, -NO2, -N(Ra)2, -C(0)N(Ra)2, -C(0)Ra, -0C(0)Ra, -C(O)ORa, -S(O)Ra, -S(O)2Ra, -S(O)ORa, -S(O)2(ORa), and -S(O)2N(Ra)2; each of R21, R22, R31, R32, and R4 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -ORa, -NO2, -N(Ra)2, -C(0)N(Ra)2, -C(0)Ra, -0C(0)Ra, -C(0)0Ra, -S(O)Ra, and -S(O)2Ra; each R5 is independently selected from the group consisting of hydrogen, hydroxyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Ci-6 alkoxyl, wherein the alkyl, alkenyl, alkynyl and alkoxy are optionally substituted with one or more Rb; or two R5 taken together with the nitrogen atom to which they are bound form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are optionally substituted with one or more R5a; each R5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl or cycloalkyl; or two R5a taken together with the intervening atom(s) therebetween form a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more Rb; L1 is-C(RL)2-; each Rl is independently selected from hydrogen, deuterium, or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl or heteroaryl; L2 is selected from *-OC(O)-, *-OC(O)O-, *-OC(O)N(Ra)-, *-N(Ra)C(O)-, *- O A N(Ra)C(0)0-, or *        , wherein * end of L2 is connected to L1; R6b r6 is RSa'A . R6a is selected from the group consisting of Cs-20 alkyl, Cs-20 alkenyl, CH3(CH2)mO(CH2)n- and RCOCH2(CH2OCH2)PCH2-, each of which is optionally substituted with one or more Rb; R6b is selected from hydrogen, halogen, alkyl, alkenyl or alkoxyl, each of which is optionally substituted with one or more Rb; I-nTa\x G is selected from -N(Ra)-**, -N(Ra)C(RG)2C(0)0-** or ?             , wherein ** end of G is connected to R7; ring A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more Rb; X is selected from -0-, -N(Ra)- or -C(Ra)2-; each Rg is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl and natural amino acid side chain, each of which is optionally substituted with one or more Rb; R7 is selected from the group consisting of Cs-20 alkyl, Cs-20 alkenyl, Cs-20 alkynyl, CH3(CH2)mO(CH2)n- and RcOCH2(CH2OCH2)pCH2-, each of which is optionally substituted with one or more Rb; R8 is selected from the group consisting of hydrogen, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which is optionally substituted with one or more Rb; each Ra is independently selected from hydrogen, halogen or alkyl; each Rb is independently selected from halogen, hydroxyl, cyano, amino, alkyl or alkoxy 1; each Rc is independently selected from hydrogen or alkyl; and each m, n or p is independently an integer of 0 to 20.

[008] In a further aspect, there is provided a compound having a Formula (la) or Formula (Ila): R6 Rt ^R5 N J.J-O-p-o-o nA / ’r K --^R21 r31*7   - K K R32 R22 (la) R7 R8 G L2-L1-O-P-O-Qv°\ / B“e R4' \ / 'R1 K --^R21 o31*<   •- K R R32 R22 (Ila), or a pharmaceutically acceptable salt thereof.

[009] In another aspect, there is provided a compound having a formula selected from: or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In a further aspect, the present disclosure provides a method for treating a viral infection in a patient in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.

[0012] In a further aspect, the present disclosure provides a method for inhibiting RNA polymerase in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.

[0013] In a further aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a viral infection.

[0014] In a further aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for treating a viral infection. DETAILED DESCRIPTION OF THE DISCLOSURE

[0015] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present disclosure as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, the present disclosure controls. All references, patents, patent applications cited in the present disclosure are hereby incorporated by reference in their entireties.

[0016] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural forms of the same unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of compounds. Definitions

[0017] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2nd Edition, University Science Books, Sausalito, 2006; Smith and March March’s Advanced Organic Chemistry, 6th Edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th Edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference.

[0018] At various places in the present disclosure, linking substituents are described. It is specifically intended that each linking substituent includes both the forward and backward forms of the linking substituent. For example, -NR(CR’R”)- includes both -NR(CR’R”)- and -(CR’R”)NR-. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl”, then it is understood that the “alkyl” represents a linking alkylene group.

[0019] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0020] When any variable (e.g., R1) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R1 moieties, then the group may optionally be substituted with up to two R1 moieties and R1 at each occurrence is selected independently from the definition of R1. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0021] As used herein, the term “Ci-j” indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i. For examples, Ci-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms. In some embodiments, the term “C1-12” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.

[0022] As used herein, the term “alkyl”, whether as part of another term or used independently, refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described herein. The term “Ci-j alkyl” refers to an alkyl having i to j carbon atoms. In some embodiments, alkyl groups contain 1 to 10 carbon atoms. In some embodiments, alkyl groups contain 1 to 9 carbon atoms. In some embodiments, alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of “Ci-io alkyl” include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of “Ci-6 alkyl” are methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-l -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like. In some embodiments, alkyl groups contain 9 to 30 carbon atoms. In some embodiments, alkyl groups contain 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms.

[0023] As used herein, the term “alkylcycloalkyl” refers to an alkyl attached to cycloalkyl, including -alkyl-cycloalkyl and alkyl-cycloalkyl-. In some embodiments, alkylcycloalkyl refers to -alkyl-cycloalkyl.

[0024] As used herein, the term “alkylheterocyclyl” refers to an alkyl attached to heterocyclyl, including -alkyl-heterocyclyl and alkyl-heterocyclyl-. In some embodiments, alkylheterocyclyl refers to -alkyl-heterocyclyl.

[0025] As used herein, the term “alkylaryl” refers to an alkyl attached to aryl, including -alkyl-aryl and alkyl-aryl-. In some embodiments, alkylaryl refers to -alkylaryl.

[0026] As used herein, the term “alkylheteroaryl” refers to an alkyl attached to heteroaryl, including -alkyl-heteroaryl and alkyl-heteroaryl-. In some embodiments, alkylheteroaryl refers to -alkyl-heteroaryl.

[0027] As used herein, the term “alkenyl”, whether as part of another term or used independently, refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In some embodiments, alkenyl groups contain 9 to 30 carbon atoms. In some embodiments, alkenyl groups contain 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms. Examples of alkenyl group include, but are not limited to, ethylenyl (or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2 buten-l-yl, 5-hexenyl, and the like.

[0028] As used herein, the term “alkoxyl”, whether as part of another term or used independently, refers to an alkyl group attached to oxygen (-O-alkyl). In some embodiments, alkoxyl groups contain 1 to 10 carbon atoms. In some embodiments, alkoxyl groups contain 1 to 9 carbon atoms. In some embodiments, alkoxyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Example of alkoxyl group include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0029] As used herein, the term “alkynyl”, whether as part of another term or used independently, refers to a linear or branched-chain hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In some embodiments, alkynyl groups contain 9 to 30 carbon atoms. In some embodiments, alkynyl groups contain 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms. Examples of alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0030] As used herein, the term “amino” refers to -NH2 group. Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amino groups.

[0031] As used herein, the term “aryl”, whether as part of another term or used independently, refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl group may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system. In the case of the polycyclic ring system, it may include fused or spiro ring system. For example, a polycyclic aryl may comprise an aromatic ring fused to one or more additional rings such as cycloalkyl or aryl ring. In some embodiments, the aryl is a C6-C12 aryl. In some embodiments, the aryl is a Ce-Cn aryl. In some embodiments, the aryl is Ce-Cio aryl. In some embodiments, the aryl is a C6-C9 aryl. In some embodiments, the aryl is a Ce-Cs aryl. Aryl includes, but are not limited to, aryl groups derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted at one or more ring positions with substituents as described herein.

[0032] As used herein, the term “azido” refers to -N3.

[0033] As used herein, the term “cycloalkyl”, whether as part of another term or used independently, refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring. In the case of polycyclic carbocyclic ring system, it may include fused (for example, fused with another cycloalkyl ring), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. In some embodiments, the cycloalkyl is partially saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 12-membered cycloalkyl. In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1. l]hexane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl- bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted at one or more ring positions with substituents as described herein.

[0034] As used herein, the term “cyano” refers to -CN.

[0035] As used herein, the term “halogen” refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo).

[0036] As used herein, the term “haloalkyl” refers to an alkyl substituted with one or more halogens. In some embodiments, the haloalkyl may contain 1 to 6 carbon atoms. In some embodiments, the haloalkyl may contain 1 to 4 carbon atoms. In some embodiments, the haloalkyl may contain 1 to 3 carbon atoms. Examples of haloalkyl include, but not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromomethyl, tribromomethyl and tetrafluoroethyl.

[0037] As used herein, the term “heteroatom” refers to nitrogen, oxygen, sulfur, phosphorus or silicon, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxides).

[0038] As used herein, the term “heteroaryl”, whether as part of another term or used independently, refers to an aromatic ring having, in addition to carbon atoms, one or more heteroatoms which may be optionally oxidized or quaternized. The heteroaryl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system. In the case of the polycyclic ring system, it may include fused or spiro ring system. For example, a polycyclic heteroaryl may comprise a heteroaryl ring fused to one or more additional rings such as cycloalkyl, heterocyclyl, aryl or heteroaryl ring, or an aryl ring fused to one or more additional rings such as heterocyclyl or heteroaryl ring. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzo thiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridyl, pyridyl 1 -oxide, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted at one or more ring positions with substituents as described herein.

[0039] As used herein, the term “heterocyclyl”, whether as part of another term or used independently, refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur, which may be optionally oxidized or quaternized. In some embodiments, the heterocyclyl is fully saturated. In some embodiments, the heterocyclyl is partially unsaturated. The heterocyclyl group may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system. In the case of the polycyclic ring system, it may include fused, spiro, or bridged ring systems. For example, a polycyclic heterocyclyl may comprise a heterocyclyl ring fused to one or more additional rings such as cycloalkyl or heterocyclyl ring, or a cycloalkyl ring fused to one or more heterocyclyl ring. Examples of heterocyclyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, dihydrofuryl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 9-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 7-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4- to 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 6-membered heterocyclyl. Unless stated otherwise specifically in the specification, a heterocyclyl may be optionally substituted as described below, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclyl is optionally substituted with halogen.

[0040] In some embodiments, the term “3- to 12-membered heterocyclyl” refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The fused, spiro and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyl include, but are not limited to oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclyl include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[ 1,2-a]pyridinyl, [ 1,2,4]triazolo[4,3-a]pyridinyl, [l,2,3]triazolo[4,3-a]pyridinyl groups, and the like. Examples of spiro heterocyclyl include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of bridged heterocyclyl include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, l,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0041] As used herein, the term “hydroxyl” refers to -OH.

[0042] As used herein, the terms “natural amino acid side chain” and “naturally occurring amino acid side chain” refer to side chain of any of the naturally occurring amino acids (i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) usually in the S-configuration (i.e., the L-amino acid).

[0043] As used herein, the term “partially saturated” or “partially unsaturated” refers to a radical that includes at least one double or triple bond. The term “partially saturated” or “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0044] As used herein, the term “purine base” or “pyrimidine base” comprises, but is not limited to, adenine, N6-alkylpurines, N6-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl)), N6-benzylpurine, N6-halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-allylaminopurine, N6-thioallyl purine, N2-alkylpurines, N2-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and / or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C5-alkylpyrimidines, C5-benzylpyrimidines, C5-halopyrimidines, C5-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-5-iodopyrimidine, C6-iodo-pyrimidine, C5-Br-vinyl pyrimidine, C6-Br-vinyl pyriniidine, C5-nitropyrimidine, C5-amino-pyrimidine, N2-alkylpurines, N2-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. The purine and pyrimidine bases are linked to the ribose sugar, or analog thereof, through a nitrogen atom of the base. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

[0045] As used herein, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Typical substituents include, but are not limited to, the functional groups as described herein, such as halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like, each of which may also be similarly substituted. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Unless otherwise indicated, when the term “substituted” is used in conjunction with groups such as alkylaryl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. Compounds

[0046] The present disclosure provides novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the disclosed compounds.

[0047] In one aspect, the present disclosure provides a compound having Formula (I) or Formula (II): (I) (II) or a pharmaceutically acceptable salt thereof, wherein Base is a naturally occurring or modified pyrimidine base or purine base; Q is CH2, CHD or CD2; R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -ORa, -NO2, -N(Ra)2, -C(0)N(Ra)2, -C(0)Ra, -0C(0)Ra, -C(O)ORa, -S(O)Ra, -S(O)2Ra, -S(O)ORa, -S(O)2(ORa), and -S(O)2N(Ra)2; each of R21, R22, R31, R32, and R4 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -ORa, -NO2, -N(Ra)2, -C(0)N(Ra)2, -C(0)Ra, -0C(0)Ra, -C(0)0Ra, -S(O)Ra, and -S(O)2Ra; each R5 is independently selected from the group consisting of hydrogen, hydroxyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Ci-6 alkoxyl, wherein the alkyl, alkenyl, alkynyl and alkoxy are optionally substituted with one or more Rb; or two R5 taken together with the nitrogen atom to which they are bound form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are optionally substituted with one or more R5a; each R5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl or cycloalkyl; or two R5a taken together with the intervening atom(s) therebetween form a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more Rb; L1 is-C(RL)2-; each Rl is independently selected from hydrogen, deuterium, or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl or heteroaryl; L2 is selected from *-OC(O)-, *-OC(O)O-, *-OC(O)N(Ra)-, *-N(Ra)C(O)-, *- O A N(Ra)C(0)0-, or *        , wherein * end of L2 is connected to L1; R6b r6 is RSa'A . R6a is selected from the group consisting of Cs-20 alkyl, Cs-20 alkenyl, CH3(CH2)mO(CH2)n- and RCOCH2(CH2OCH2)PCH2-, each of which is optionally substituted with one or more Rb; R6b is selected from hydrogen, halogen, alkyl, alkenyl or alkoxyl, each of which is optionally substituted with one or more Rb; I-nTa\x G is selected from -N(Ra)-**, -N(Ra)C(RG)2C(0)0-** or ?             , wherein ** end of G is connected to R7; ring A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more Rb; X is selected from -0-, -N(Ra)- or -C(Ra)2-; each Rg is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl and natural amino acid side chain, each of which is optionally substituted with one or more Rb; R7 is selected from the group consisting of Cs-20 alkyl, Cs-20 alkenyl, Cs-20 alkynyl, CH3(CH2)mO(CH2)n- and RcOCH2(CH2OCH2)pCH2-, each of which is optionally substituted with one or more Rb; R8 is selected from the group consisting of hydrogen, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which is optionally substituted with one or more Rb; each Ra is independently selected from hydrogen, halogen or alkyl; each Rb is independently selected from halogen, hydroxyl, cyano, amino, alkyl or alkoxy 1; each Rc is independently selected from hydrogen or alkyl; and each m, n or p is independently an integer of 0 to 20.

[0048] In another aspect, there is provided a compound having a Formula (la) or Formula (Ila): l2-l'-o-p—o-q_.ovb“ '       O p31*7   •- K R32 R22 (la) G L2-L1-O-P-O-Qv°VB^e 3 O R4'\C-X *1 d31<-   1 K R32 R22 (lla) or a pharmaceutically acceptable salt thereof, wherein Q, G, R1 to R8, R21, R22, R31, R32, L1, L2 and Base are defined supra.

[0049] In some embodiments, the Base is selected from the group consisting of:

[0050] In certain embodiments, the Base is selected from the group consisting of:

[0051] In some embodiments, R1 is selected from hydrogen, hydroxyl, cyano, azido, alkyl, or haloalkyl. In some embodiments, R1 is selected from hydrogen, hydroxyl, cyano, azido, alkyl (such as Ci-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl), or C1-6 haloalkyl (such as C1-5 haloalkyl, C1-4 haloalkyl, C1-3 haloalkyl or C1-2 haloalkyl).

[0052] In certain embodiments, R1 is cyano.

[0053] In some embodiments, each of R21, R22, R31, R32, and R4 is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl (such as C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl), haloalkyl (such as C1-6 haloalkyl, C1-5 haloalkyl, C1-4 haloalkyl, C1-3 haloalkyl or C1-2 haloalkyl), or -OC(O)Ra.

[0054] In certain embodiments, each of R21, R22, R31, R32 is selected from hydrogen, deuterium, halogen, hydroxyl, alkyl (such as C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl) or -OC(O)Ra.

[0055] In certain embodiments, Ra is alkyl. In certain embodiments, Ra is C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In certain embodiments, Ra is methyl.

[0056] In some embodiments, R4 is selected from hydrogen, deuterium, halogen, cyano, azido, or haloalkyl (such as C1-6 haloalkyl, C1-5 haloalkyl, C1-4 haloalkyl, C1-3 haloalkyl or C1-2 haloalkyl). r41y y,Ri r2^ Sr21

[0057] In some embodiments, r32 r22 is selected from the group consisting of: In some embodiments, the Base is

[0058] In certain embodiments, the Base is and

[0059]

[0060] In some embodiments, the compound has a Formula (la): Rt ^R5 N ,L2-L1-O-P—O-Q. / °\Z R'Z o p31<:   !• K R R32 R22 (la) or a pharmaceutically acceptable salt thereof, wherein Q, R1 to R6, R21, R22, R31, R32, L1, L2 and Base are defined supra.

[0061] In some embodiments of the compound of Formula (la), each R5 is independently selected from hydrogen or Ci-6 alkyl (such as C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or Ci-2 alkyl).

[0062] In certain embodiments, each R5 is independently C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In certain embodiments, both R5 are methyl. In certain embodiments, both R5 are ethyl.

[0063] In certain embodiments, one R5 is hydrogen, and the other R5 is C1-6 alkyl. In certain embodiments, one R5 is hydrogen, and the other R5 is C1-6 alkyl, C1-5 alkyl, Ci-4 alkyl, C1-3 alkyl or C1-2 alkyl.

[0064] In certain embodiments, both R5 are hydrogen.

[0065] In some embodiments of the compound of Formula (la), two R5 taken together with the nitrogen atom to which they are bound form a heterocyclyl optionally substituted with one or more R5a. In certain embodiments, two R5 taken together with the nitrogen atom to which they are bound form a 5- to 12-membered heterocyclyl (such as 5- to 11-membered heterocyclyl, 5- to 10-membered heterocyclyl, 5- to 9-membered heterocyclyl, 5- to 8-membered heterocyclyl, 5- to 7membered heterocyclyl or 5- to 6-membered heterocyclyl) optionally substituted with one or more R5a.

[0066] In some embodiments of the compound of Formula (la), two R5 taken together with the nitrogen atom to which they are bound form a heterocyclyl selected from the group consisting of: each of which is optionally substituted with one or more R5a.

[0067] In certain embodiments, R5a is selected from alkyl or alkoxyl. In certain embodiments, R5a is selected from Ci-6 alkyl (such as C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl) or C1-6 alkoxyl (such as C1-5 alkoxyl, C1-4 alkoxyl, C1-3 alkoxyl or C1-2 alkoxyl). In certain embodiment, R5a is methyl or         .

[0068] In some embodiments of the compound of Formula (la), each RL is independently selected from hydrogen, deuterium, or alkyl (such as C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl). In certain embodiments, both RL are hydrogen.

[0069] In some embodiments of the compound of Formula (la), L2 is selected from *-OC(O)- or *-OC(O)O-. In certain embodiments, L2 is *-OC(O)O-.

[0070] In some embodiments of the compound of Formula (la), R6a is selected from Cs-2o alkyl or Cs-20 alkenyl, each of which is optionally substituted with one or more Rb. In certain embodiments, R6a is selected from Cs-20 alkyl, Cs-is alkyl, Cs-i5 alkyl, Cs-i3 alkyl, Cs-20 alkenyl, Cs-is alkenyl, Cs-i5 alkenyl or Cs-i3 alkenyl, each of which is optionally substituted with one or more Rb. In certain embodiments, R6a is selected from Cs-i3 alkyl or Cs-i3 alkenyl, each of which is optionally substituted with one or more Rb. In certain embodiments, R6a is Cs-i3 alkyl optionally substituted with one or more Rb.

[0071] In some embodiments of the compound of Formula (la), R6b is selected from hydrogen, halogen or alkyl. In certain embodiments, R6b is selected from hydrogen or alkyl. In certain embodiments, R6b is hydrogen or methyl. In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is Ci-6 alkyl. In certain embodiments, R6b is Ci-6 alkyl, C1-5 alkyl, C1-4 alkyl or C1-3 alkyl. In certain embodiments, R6b is Ci-3 alkyl. In certain embodiments, R6b is methyl.

[0072] In some embodiments, the compound has a Formula (Ila): / R7 G ^-1^0-1=-0-0^ / 0^ / 8666 r=z 0 r31*< K R32 R22 (Ila) or a pharmaceutically acceptable salt thereof, wherein Q, R1 to R8, R21, R22, R31, R32, L1, L2 and Base are defined supra..

[0073] In some embodiments of the compound of Formula (Ila), L2 is selected from *-OC(O)- or *-OC(O)O-.

[0074] In certain embodiments, L2 is *-OC(O)O-.

[0075] In some embodiments of the compound of Formula (Ila), R8 is selected from hydrogen or C1-6 alkyl optionally substituted with one or more Rb. In certain embodiments, R8 is C1-6 alkyl, C1-5 alkyl, C1-4 alkyl or C1-3 alkyl optionally substituted with one or more Rb. In certain embodiments, R8 is C1-3 alkyl optionally substituted with one or more Rb. In certain embodiments, R8 is methyl or isopropyl.

[0076] In some embodiments of the compound of Formula (Ila), G is -N(Ra)-**. In certain embodiments, Ra is selected from hydrogen or alkyl. In certain embodiments, Ra is alkyl. In certain embodiments, Ra is Ci-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In certain embodiments, Ra is methyl.

[0077] In some embodiments of the compound of Formula (Ila), G is -N(Ra)C(RG)2C(O)O-**.

[0078] In some embodiments of the compound of Formula (Ila), each RG is independently selected from the group consisting of hydrogen, C1-6 alkyl, C6-12 aryl, 5-to 12-membered heteroaryl, (C1-3 alkyl)(C3-i2 cycloalkyl), (C1-3 alkyl)(3- to 12membered heterocyclyl), (C1-3 alkyl)(C6-i2 aryl), (C1-3 alkyl)(5- to 12-membered heteroaryl) and natural amino acid side chain, each of which is optionally substituted with one or more Rb.

[0079] In some embodiments of the compound of Formula (Ila), one of RG is hydrogen, and the other RG is selected from C1-6 alkyl, C6-12 aryl, (C1-3 alkyl)(C6-i2 aryl), (C1-3 alkyl)(5- to 12-membered heteroaryl) or natural amino acid side chain, each of which is optionally substituted with one or more Rb.

[0080] In some embodiments of the compound of Formula (Ila), one of RG is hydrogen, and the other RG is (C1-3 alkyl)(C6-i2 aryl) or (C1-3 alkyl)(5- to 12membered heteroaryl), each optionally substituted with one or more Rb. In certain embodiments, Rb is cyano, halogen, hydroxyl, or alkoxyl.

[0081] In some embodiments of the compound of Formula (Ila), one of RG is hydrogen, and the other RG is selected from the group consisting of:

[0082] In some embodiments of the compound of Formula (Ila), one of RG is hydrogen, and the other RG is natural amino acid side chain.

[0083] In some embodiments of the compound of Formula (Ila), one of RG is hydrogen, and the other RG is selected from the group consisting of:

[0084] In some embodiments of the compound of Formula (Ila), both RG are methyl.

[0085] In some embodiments of the compound of Formula (Ila), G is

[0086] In certain embodiments, ring A is selected from the group consisting of:

[0087] In some embodiments of the compound of Formula (Ila), R7 is selected from Cs-2o alkyl or Cs-20 alkenyl, each of which is optionally substituted with one or more Rb.

[0088] In certain embodiments, R7 is selected from Cs-20 alkyl, C10-20 alkyl, C12-20 alkyl, C14-20 alkyl, C16-20 alkyl, Cs-20 alkenyl, C10-20 alkenyl, C12-20 alkenyl, C14-20 alkenyl, or C16-20 alkenyl, each of which is optionally substituted with one or more Rb. In certain embodiments, R7 is selected from C16-20 alkyl or C16-20 alkenyl, each of which is optionally substituted with one or more Rb.

[0089] In certain embodiments, R7 is C16-20 alkyl optionally substituted with one or more Rb.

[0090] In a further aspect, there is provided a compound having a formula selected from: or a pharmaceutically acceptable salt thereof, wherein Q, G, R1 to R8, R21, R22, R31, and R32 are defined supra.

[0091] In a further aspect, the present disclosure provides a compound selected from any compound set forth in Table 1. Table 1 Com poun d No. Compound Structure Com poun d No. Compound Structure 1 0-,             nh2 \ ) S U CH3(CH2)11—o               J—: XN HO OH 47 nh2 I £     W JL    JL         p—q__ n 1   N CH3(CH2)1tf^OX 0  0^     Y SL :----f HO OH 2 0-,             nh2 ' _  Pm CH3(CH2)17—0                 J ( N HO OH 48 nh2 / i 0             \ j JL JL        p—o—« n i CH3(CH2)1(f^O   0  O'"    V X )—[ h<5 6h 3 \           Jc2 CH3(CH2)11—0                 ; : N HO OH 49 nh2 I 0 1 JL      p-o-w n F N> CH^CHzJkT^O^ 0  O*'    Y SL )— / Hd 6h 4 \               nh2 \ /      / ^T^N U. J CH3(CH2)17—0                 J J N HO OH 50 nh2 1   0 "Na      Vk 1. JL        p—o—« n I N CH^CHjJm^^O 0  O'"     Y SL )---- / h6 6h 5 i 0^0 L 1  3      / t'N CH3(CH2)17-Oy^n^^-Ot.oJ n o H 0 \_ / X °                 5---: N h6 dH 51 NH2 I 9               V-N. JL JL / s,    p—o—« n I N ch3(ch2)< o o o^ Y k }-----; Hd 6h 6 YV° °C       Z fx °z w .p-o-. o r n 5—n    Y ch3<ch2)17-o—h      V-I K 0       Hd 6h 52 nh2 /      Z==Z^N =   9 "Nx       Vn. X YY      P—O—« n i N ch3(ch2)<^o      o^Y SL ;-----i Hd Oh 7 1 0^0 oJ                nh2 °\ kL j CH3(CH2)15-ov^N / ^-o~vox! n A H °   \ / X Hd dH 53 nh2 _ /     Z=r^N I 0    "      V~ JL JL / s.   p—n—_ nJ N CH3(CH2)8 / ^O / X^o^ Y nL )----[ HO OH 8 Zz°      z N-, O-x       / Zn X °z W xp-o-i oJ N CH3(CH2)17-O-^H      yZ^n 0       HO 6h 54 NH2 /      Z=>Y^n I 9             VN' JL       p—o—* n l N ch3(ch2)8^^o^ o X' V 7\ }----[ HO OH 9 1 0^0 0                NH2 L JL   'I     a^n ^z °\   y v CH3(CH2)17-O>^              N If    N   'X    \  K o   H  0   \   / >Z °                    ]---: HO OH 55 nh2 /     Z^Z^N = 9          y. X YY      P—O—» n i N ch3(ch2)Z>z o xr”    Y 7\ )-----f HO OH 10 V°z        nh2 y=z °L°    VO / \       P-O^s.         N ^N.          /     A y—HN     )—\ X H3C(H2C)17-O-Z         ho' oh 0 56 nh2 _ /     Z^Z^N w JL        p—o—« n 1 ch3(ch2)8x^o^ o o^ Y x! }----[ HO OH 11 1 OyO 0                nh2 L JL   Cl      / Zn ^Z °x    kJ J CH3(CH2)15-Oy^n^I^-Ot,o 1 N o  H 0   \ / X °                    ;---: HO OH 57 nh2 i ? ~N< Vz J. JL         p—q—_ n 1 N CHatCHzJa^^O^ 0  O'"    V SL )----1 HO OH 12 / —A            NH2 \ /    ZY^n '   YM Ch^CH^-O           J—t XN HO OH 58 nh2 MZ     / Y^N 1 2 .L JL / s.    p—o—« n I N CH3(CH2)Zyy o o^Y 7\ )—I HO OH 13 SL.           NH2 \ /     Z^Z^N \   V. o ^x°Cf N CHg^HaJn-O             J—( XN HO 6h 59 nh2 1   0    "Nx       VN Jl JL / s,   p—o-« n | N CH3(CH2)i0 O X X \\) Y 7k }—i Hd 6h 14 Y Z ' w Xo^^°°Yj^ CH^CH^-O           J—( XN h6 6h 60 nh2 /   n-y^T^N I 0    -N       \-N J ch3(ch2)Y o o o^ Y K i---- / Hd 6h 15 16 62 17 63 18 64 19 65 20 66 21 67 HO oh 22 23 nh2 i o "Nx      SA J. JL         p—n—« n i N CH3(CH2)io O 0  O'"    YA }-----L Hd 6h 69 o I w o I \ ^o- / O^| o z    J o 1 O 1 1 \-\ z zvY^ 24 nh2 I 9           U. JL       p—o—« n 1 N ch3(ch2)8^'o o          Y 7\ ]----I nd 6h 70 1 O^jZ3 T2 o    0^1 1 \ / '      VN'n^ CH3(CH2)15-OxJ<n^^-O-. oJ N S H o y HO &H 25 nh2 Z^Y^n I 0     H2N         Vill j _L JL        p_Q__ n i N CH3(CH2)10 / ^O  0        YA }-----; h<5 5h 71 1 °xf>° o                NH2 0   D- / VS \      VN'n^ ch3(ch2)15-o^n^-o-. oJ n S h o yy HO OH 26 nh2 /   ZY CH3(CH2)9—N p     LA j Jp-O^ 0 I" 'N A°       n HO OH 72 1 °x^0 nh2 P ■; °YPN CH3(CH2)15-O^rN / ^-O-. OJ N A H 0   \__ / \&. ]--i X N h6 oh 27 nh2 /      Z^Z^N CH3(CH2)1i N 0     LA Z >-O-v Oj 'N 1 z° YA 0>0 n HO OH 73 I fA °Y° )= /   0             NH2 HN \    1    „ aZn 0       D—4 1 I ;   \      VN'n^ CH3(CH2)15-Ov^<n^^-O-. oj N o H 0 vJZ-°           5—! xn HO 6h 28 nh2 /   aYn 1 ?   ~N'    Vv CH3(CH2)12 / ^O o o-" YA ]—I A Hd 6h 74 I °X|^O / =N   %           YH2 HN^Z 2) DZZ I CH3(CH2)15-Ov^n^^-Ot,Ox| n O   H   0    \ HO 6h 29 nh2 /     Z^jAn I ?  ~N'    W JL    JL          p_Q—_ n 1    N CH3(CH2)i4 O o o-"    Y\ ]—I A h6 6h 75 I °^° ,N^     o               NH2 A   n^N CH3(CH2),5-OX>^N^^-O-. oj N o H 0 vJZ- HO 6h 30 nh2 Z^Y^n I O H2N          V|!|x JL JL         p_O—■ n i N 0 O-^    V SL }—I h6 6h 76 o T w i J J0 \ o^T o z J Oih.xY □ ° 1 31 nh2 Z^T^N 1    0     H2N        \ N J J.   JL / X.   P—Q—- Q J 'N ch3(ch2)12 / ^o o        VN }—( nd 6h 77 1 0x^0 1 %           J<2 XX o    D—< T 1 CHslCHz^-O^X^^OyAl N o H 0 °                   i N HO 6h 32 ,0-.             nh2 V 1 1 ?    ' Vv Jx JL        p—o—a n f N ch3(ch2)1(<      o o-^ VN }—I Hd 6h 78 1 °x^° o                nh2 XX     D-<^l  ? z \       yN. CH3(CH2)15-O^>\         oj N S H O \_J%. HO OH 33 ' W kz°^°°xx CH3(CH2)n-0              J—[ XN HO OH 79 I cy*0 0                nh2 XX    nV^N 0       D—& I । E \      VN',Z CHafCH^s-O^X.^'yOX'0''! 0 " ° VjS- HO OH 34 nh2 I ° ~Nx     V-O Jx A        p—o—« n i N ch3(ch2)16^^o o o"^ VN )—; HO OH 80 I °y° NC^^x    Ox           1^2 °\    D y Y CH3(CH2)15-Ox^Xn^'\\-o^V,oJ n o  h °   \ / y o           }—( \N HO OH 35 nh2 /     Z^y^n ° y  yO CH.tCH^x^^^^-O-. 0 F N )---( HO OH 81 I °xx>0 Clx^x    0             NH2 yi  'i     / ^Xn yy o    d-< i । CH3(CH2)15-Ov-\n^I’-Ot,oJ n o h ° v_ / y °           :—( XN HO dH 36 nh2 /     Z^Y^N o -N     V-rO \— / HO dH 82 I Ox^O Ox               1^2 XX     n_yXN 0       D—4 1    1 =    \        v-n'iZ CH3(CH2)15-O^^ ^!?-Ot.oj  N II     N    '1     v   >x O   H   °   \ °             }--: XN ho 6h 37 nh2 /     Z^T^N ? ~N'   w ch3(ch2)13. x / vvyo-J O \ X<x )—I h6 6h 83 1 °x-^0 Jk2 L IL i „ -o^S °\ vM CH3(CH2)15-Ox^ u / ^o-Voj n n    n   '1    v   >x o   H   °   \ °                  £---i ho Oh 38 nh2 /     Z^T^N ? ~N'    Vv CH3(CH2)15 xo^o^v°y°J N o \ 7>x )—I h<5 6h 84 1 F °y° X °>        YH2 9 ■;  °Y0 CH3(CH2)15-O^YN / VOy / OJ o H 0 H'x HO 6h HO OH HO OH HO OH HO OH HO OH HO 6h HO 6h HO 6h

[0092] Compounds provided herein are described with reference to both generic formulae and specific compounds. In addition, compounds of the present disclosure may exist in a number of different forms or derivatives, all within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvated forms, amorphous forms, different crystal forms or polymorphs.

[0093] The compounds of present disclosure can comprise one or more asymmetric centers depending on substituent selection, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds provided herein may have an asymmetric carbon center, and thus compounds provided herein may have either the (R) or (S) stereo-configuration at a carbon asymmetric center. Therefore, compounds of the present disclosure may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.

[0094] As used herein, the term “enantiomer” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. The term “diastereomer” refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.

[0095] Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the opposite enantiomer, and may also be referred to as “optically enriched”. “Optically enriched”, as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound provided herein or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, absolute stereochemistry may be determined by Vibrational Circular Dichroism (VCD) spectroscopy analysis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).

[0096] In some embodiments, mixtures of diastereomers, for example mixtures of diastereomers enriched with 51% or more of one of the diastereomers, including for example 60% or more, 70% or more, 80% or more, or 90% or more of one of the diastereomers are provided.

[0097] In some embodiments, compounds provided herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The present disclosure additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers.

[0098] The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imineenamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system (for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole). Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0099] The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to JH, 2H, 3H, nC, 12C, 13C, 14C, 14N, 15N, 16O, 17O, 180,31P, 32P, 32S, 33S, 34S, 36S, 17F, 18F, 19F, 35C1,37C1, 79Br, 81Br, 124I, 127I and 131I. Isotopically-enriched compounds of Formula (I) or Formula (II) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[00100] In some embodiments, the present disclosure includes compounds of Formula (I), (II), (la), (lb), (Ic), (Id), (Ie), (Ila), (lib), (lie), (lid) or (lie) wherein one or more hydrogens attached to a carbon atom is / are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula (I), (II), (la), (lb), (Ic), (Id), (Ie), (Ila), (lib), (lie), (lid) or (lie) when administered to a subject, such as mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). In view of the present disclosure, such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[00101] Also falling within the scope herein are the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield a metabolic product thereof.

[00102] Compounds of the present disclosure can be formulated as or be in the form of pharmaceutically acceptable salts. Unless specified to the contrary, a compound provided herein includes pharmaceutically acceptable salts of such compound.

[00103] As used herein, the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the subjects being treated therewith.

[00104] As used herein, the term “pharmaceutically acceptable salt”, unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.

[00105] Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[00106] Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remington's Pharmaceutical Sciences, 19thed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases.

[00107] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[00108] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[00109] It is also to be understood that the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystal or polymorphic forms), and the present disclosure is intended to encompass all such forms.

[00110] As used herein, the term “solvate” or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[00111] As used herein, the terms “crystal form”, “crystalline form”, “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions. Synthesis of compounds

[00112] Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the Schemes are for better illustration and can be changed as appropriate. The embodiments of the compounds in examples were synthesized for the purposes of research and potentially submission to regulatory agencies.

[00113] The reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by one skilled in the art.

[00114] Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.

[00115] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g / H or 13C), infrared spectroscopy, spectrophotometry (e.g. UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chern. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety), and normal phase silica chromatography.

[00116] The known starting materials of the present disclosure can be synthesized by using or according to the known methods in the art, or can be purchased from commercial suppliers. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification.

[00117] Unless otherwise specified, the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and / or heat dried.

[00118] For illustrative purposes, the Examples section below shows synthetic route for preparing the compounds of the present disclosure as well as key intermediates. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. Use of Compounds

[00119] In an aspect, the present disclosure provides compounds of Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof, which are capable of inhibiting RNA polymerase. Thus, the compounds of the present disclosure or a pharmaceutically acceptable salt thereof are useful as medicinal drugs, and particularly useful as therapeutic or prophylactic agent that are active against various viruses. In some embodiments, the compounds of the present disclosure are therapeutic or prophylactic agent active against caliciviruses, picornaviruses and coronaviruses.

[00120] As used herein, the term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving beneficial or desired clinical results. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it. Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. The term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.

[00121] The term “treatment” is used synonymously with “therapy”. Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.

[00122] As used herein, the term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[00123] In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof for treatment of viral infection.

[00124] In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a viral infection.

[00125] In some embodiments, the compounds of the present disclosure have good inhibitory effect against various coronaviruses. In some embodiments, the compounds of the present disclosure have good inhibitory effect against various coronaviruses with low cytotoxicity.

[00126] In some embodiments, the compounds of the present disclosure have good inhibitory effect against various pneumoviruses. In some embodiments, the compounds of the present disclosure have good inhibitory effect against various pneumoviruses with low cytotoxicity.

[00127] In some embodiments, the compounds of the present disclosure can convert into triphosphate and maintain a high concentration of triphosphate in targeted tissue and cells, such as lung cell and respiratory epidermal cell.

[00128] Therefore, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof for treatment of coronavirus or pneumo virus infection.

[00129] In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a coronavirus infection.

[00130] In another aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a pneumovirus infection. Pharmaceutical Compositions

[00131] For the purposes of administration, in some embodiments, the compounds provided herein are administered as a raw chemical or are formulated as pharmaceutical compositions.

[00132] Therefore, in a further aspect, there is provided pharmaceutical compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.

[00133] In some embodiments, the pharmaceutical compositions of the present disclosure comprise a compound selected from any one of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present disclosure comprise a first compound selected from any one of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula but said first compound and additional compounds are not the same molecules.

[00134] As used herein, the term “pharmaceutical composition” refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject.

[00135] In some embodiments, the pharmaceutical composition of the present disclosure comprises a therapeutically effective amount of one or more compounds of Formula (I) or a pharmaceutically acceptable salt thereof.

[00136] As used herein, the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[00137] In another aspect, there is provided pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.

[00138] As used herein, the term “pharmaceutically acceptable excipient” refers to an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient. The term “pharmaceutically acceptable excipient” also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent”.

[00139] The particular excipient used will depend upon the means and purpose for which the compounds of the present disclosure is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans. In general, safe solvents are nontoxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof.

[00140] In some embodiments, suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, dextrins, or substituted dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[00141] In some embodiments, suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxy methylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). A “liposome” is a small vesicle composed of various types of lipids, phospholipids and / or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

[00142] The pharmaceutical compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.

[00143] A variety of routes are contemplated for the pharmaceutical compositions provided herein, and accordingly the pharmaceutical composition provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets (such as orodispersible tablets or orally disintegrating tablets), pills, oral soluble films, capsules, gelcaps, and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable as liquid dosage forms, and a powder suitable for reconstitution with an appropriate solution as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage form. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form. For nasal or pulmonary administration, aqueous or oily solutions may be acceptable dosage form.

[00144] The quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved. As used herein, the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[00145] In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for oral administration.

[00146] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Suitable pharmaceutically -acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and / or appearance, in either case using conventional coating agents and procedures well known in the art.

[00147] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

[00148] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (such as sucrose, saccharine or aspartame).

[00149] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[00150] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.

[00151] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and / or coloring agent.

[00152] In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for injection administration.

[00153] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[00154] In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for nasal or pulmonary administration. In certain embodiments, the formulation is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.

[00155] In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for inhalation administration.

[00156] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

[00157] In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.

[00158] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[00159] In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.

[00160] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), in “Remington: The Science and Practice of Pharmacy”, Ed. University of the Sciences in Philadelphia, 21st Edition, LWW (2005), which are incorporated herein by reference.

[00161] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The amount of the compounds provided herein in the unit dosage form will vary depending on the condition to be treated, the subject to be treated (e.g., the age, weight, and response of the individual subject), the particular route of administration, the actual compound administered and its relative activity, and the severity of the subject's symptoms.

[00162] In some embodiments, dosage levels of the pharmaceutical compositions of the present disclosure can be between 0.001-1000 mg / kg body weight / day, for example, 0.001-1000 mg / kg body weight / day, 0.001-900 mg / kg body weight / day, 0.001-800 mg / kg body weight / day, 0.001-700 mg / kg body weight / day, 0.001-600 mg / kg body weight / day, 0.001-500 mg / kg body weight / day, 0.001-400 mg / kg body weight / day, 0.001-300 mg / kg body weight / day, 0.001-200 mg / kg body weight / day, 0.001-100 mg / kg body weight / day, 0.001-50 mg / kg body weight / day, 0.001-40 mg / kg body weight / day, 0.001-30 mg / kg body weight / day, 0.001-20 mg / kg body weight / day, 0.001-10 mg / kg body weight / day, 0.001-5 mg / kg body weight / day, 0.001-1 mg / kg body weight / day, 0.001-0.5 mg / kg body weight / day, 0.001-0.4 mg / kg body weight / day, 0.001-0.3 mg / kg body weight / day, 0.001-0.2 mg / kg body weight / day, 0.001-0.1 mg / kg body weight / day, 0.005-0.1 mg / kg body weight / day, 0.01-0.1 mg / kg body weight / day, 0.02-0.1 mg / kg body weight / day, 0.03-0.1 mg / kg body weight / day, 0.04-0.1 mg / kg body weight / day, 0.05-0.1 mg / kg body weight / day, 0.06-0.1 mg / kg body weight / day, 0.07-0.1 mg / kg body weight / day, 0.08-0.1 mg / kg body weight / day, or 0.09-0.1 mg / kg body weight / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosage regimes, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

[00163] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration. In some embodiments, the unit dosage for oral administration contains one or more compounds provided herein in an amount from about 1 mg to about 1000 mg, for example from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 15 mg to about 1000 mg, from about 20 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 30 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 60 mg to about 1000 mg, from about 70 mg to about 1000 mg, from about 80 mg to about 1000 mg, from about 90 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 1 mg to 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 400 mg to about 500 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg and the like. In some embodiments, the dosage unit may be administered to a subject from 1 to 6 times per day depending on the severity of the subject’s symptoms.

[00164] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration in a treatment having a duration of more than 1 week, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, more than 1 year or even longer.

[00165] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for parenteral administration, e.g., administered intravenously, subcutaneously or intramuscularly via injection. In some embodiments, the unit dosage for parenteral administration contains one or more compounds provided herein in an amount from about 0.1 mg to about 500 mg of one or more compounds provided herein, for example from about 0.2 mg to about 500 mg, from about 0.3 mg to about 500 mg, from about 0.4 mg to about 500 mg, from about 0.5 mg to about 500 mg, from about 1 mg to about 500 mg, from about 5 mg to about 500 mg, from about 10 mg to about 500 mg, from about 20 mg to about 500 mg, from about 30 mg to about 500 mg, from about 40 mg to about 500 mg, from about 50 mg to about 500 mg, from about 0.5 mg to about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg to about 200 mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about 90 mg, from about 0.5 mg to about 80 mg, from about 0.5 mg to about 70 mg, from about 0.5 mg to about 60 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 40 mg, from about 1 mg to about 90 mg, from about 5 mg to about 90 mg, from about 10 mg to about 80 mg, from about 20 mg to about 70 mg, from about 30 mg to about 60 mg, or from about 40 mg to about 50 mg, for example about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg and the like.

[00166] In some embodiments, the pharmaceutical composition intended to be administered by injection can be prepared by combining one or more compounds of the present disclosure with sterile, distilled water, sesame or peanut oil, aqueous propylene glycol, so as to form a solution. In some embodiments, the pharmaceutical composition may comprise a surfactant or other solubilizing excipient that is added to facilitate the formation of a homogeneous solution or suspension. In some embodiments, the pharmaceutical composition may further comprise one or more additional agents selected from the group consisting of a wetting agent, a suspending agent, a preservative, a buffer, and an isotonizing agent.

[00167] In some embodiments, the pharmaceutical composition intended to be administered by injection can be administered with a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the pharmaceutical composition provided herein.

[00168] In a further aspect, there is also provided veterinary compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

[00169] The pharmaceutical compositions or veterinary compositions may be packaged in a variety of ways depending upon the method used for administering the drug. For example, an article for distribution can include a container having deposited therein the compositions in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Method of Treatment

[00170] In another aspect, the present disclosure provides a method for treating a viral infection in a patient in need thereof, comprising administering an effective amount of any compound described herein.

[00171] In some embodiments, the viral infection is from an RNA virus. In certain embodiments, the RNA virus is a single stranded or double stranded RNA virus. In further embodiments, the RNA virus is a positive sense RNA virus or a negative sense RNA virus or an ambisense RNA virus.

[00172] In certain embodiments, the viral infection is from a virus selected from the group consisting of Retroviridae virus, Lentiviridae virus, Coronaviridae virus, Picornaviridae virus, Caliciviridae virus, Flaviviridae virus, Togaviridae virus, Bomaviridae, Filoviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae, Arenaviridae, Bunyaviridae, Orthomyxoviridae, and Deltavirus.

[00173] In certain embodiments, the viral infection is from a virus selected from the group consisting of Lymphocytic choriomeningitis virus, Coronavirus, HIV, SARS, Poliovirus, Rhinovirus 16, Hepatitis A, Norwalk virus, Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus, Zika virus, Rubella virus, Ross River virus, Sindbis virus, Chikungunya virus, Boma disease virus, Ebola virus, Marburg virus, Measles virus, Mumps virus, Nipah virus, Hendra virus, Newcastle disease virus, Human respiratory syncytial virus, Rabies virus, Lassa virus, Hantavirus, Crimean-Congo hemorrhagic fever virus, Influenza, Hepatitis D virus, Enterovirus 71, Coxsakie Virus, and Norovirus.

[00174] In certain embodiments, the viral infection is a coronavirus infection.

[00175] In further embodiments, the coronavirus is selected from the group consisting of 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), SARS-CoV-2 (COVID-19), and Feline coronavirus (FCoV).

[00176] In certain embodiments, the coronavirus is SARS-CoV-2.

[00177] In certain embodiments, the coronavirus is feline coronavirus.

[00178] In certain embodiments, the feline coronavirus is feline enteric coronavirus (FECV) or feline infectious peritonitis virus (FIPV).

[00179] In some embodiments, the viral infection is a pneumovirus infection.

[00180] In certain embodiments, the pneumovirus is Human respiratory syncytial virus (RSV).

[00181] In certain embodiments, the pneumovirus is human metapneumo virus (HMPV).

[00182] In some embodiments, the viral infection is from a DNA virus. In certain embodiments, the DNA virus is a single stranded or double stranded DNA virus. In further embodiments, the DNA virus is a positive sense DNA virus or a negative sense DNA virus or an ambisense DNA virus.

[00183] In certain embodiments, the virus is a Myoviridae, Podoviridae, Siphoviridae, Alloherpesviridae, Herpesviridae (including human herpes virus, and Varicella Zozter virus), Malocoherpesviridae, Lipothrixviridae, Rudiviridae, Adenoviridae, Ampullaviridae, Ascoviridae, Asfarviridae (including African swine fever virus), Baculoviridae, Cicaudaviridae, Clavaviridae, Corticoviridae, Fuselloviridae, Globuloviridae, Guttaviridae, Hytrosaviridae, Iridoviridae, Maseilleviridae, Mimiviridae, Nudiviridae, Nimaviridae, Pandoraviridae, Papillomaviridae, Phycodnaviridae, Plasmaviridae, Polydnaviruses, Polyomaviridae (including Simian virus 40, JC virus, BK virus), Poxviridae (including Cowpox and smallpox), Sphaerolipoviridae, Tectiviridae, Turriviridae, Dinodnavirus, Salterprovirus, or Rhizidovirus.

[00184] In some embodiments, methods described herein may inhibit viral replication transmission, replication, assembly, or release, or minimize expression of viral proteins. In one embodiment, described herein is a method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting vims release, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a patient suffering from the virus, and / or contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, with a virally infected cell.

[00185] In a further aspect, the present disclosure provides a method for inhibiting RNA polymerase in a subject in need thereof, comprising administrating an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein to the subject. Combination Therapy

[00186] The compounds of the present disclosure can also be used in combination with one or more additional therapeutic or prophylactic agents. As such, also provided herein are methods for treating viral infections in a subject in need thereof, comprising administering to the subject a compound disclosed herein, as a first active ingredient, and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents, as a second active ingredient. Accordingly, there is also provided pharmaceutical compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient.

[00187] In some embodiments, the second active ingredient include one or more additional therapeutic agents from the same class or group and / or one or ore more additional therapeutic agents from different classes or groups.

[00188] In some embodiments, the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.

[00189] In some embodiments, the second active ingredient can be an antibiotic, a protease inhibitor, an anti-viral agent, an anti-inflammatory agent, an immunomodulatory agent, a kinase inhibitor, an anti-metabolite agent, a lysosomotropic agent, a M2 proton channel blocker, a polymerase inhibitor (e.g., EIDD-2801), a neuraminidase inhibitor, a reverse transcriptase inhibitor, a viral entry inhibitor, an integrase inhibitor, interferons (e.g., types I, II, and III), or a nucleoside analogue.

[00190] In some embodiments, the second active ingredient is an antibiotic. In some embodiments, the antibiotic can be selected from the group consisting of a penicillin antibiotic, a quinolone antibiotic, a tetracycline antibiotic, a macrolide antibiotic, a lincosamide antibiotic, a cephalosporin antibiotic, or an RNA synthetase inhibitor. In some embodiments, the antibiotic is selected from the group consisting of azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem / cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefoxotin, and streptomycin. In some embodiments, the antibiotic is azithromycin.

[00191] In some embodiments, the second active ingredient can be a protease inhibitor. In some embodiments, the protease inhibitor can be selected from the group consisting of nafamostat, camostat, gabexate, epsilon-aminocapronic acid, aprotinin, amprenavir, indinavir, nelfinavir, nirmatrelvir, s-217622, EDP-235, PBI-0451, ritonavir, and saquinavir.

[00192] In some embodiments, the second active ingredient can be an anti-viral agent. In some embodiments, the anti-viral agent can be selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR-576, ZX-7101A, Baloxavir, Ziresovi, molnupiravir, GS-5806 and zalcitabine.

[00193] In some embodiments, the second active ingredient can be an antiinflammatory agent. In some embodiments, the anti-inflammatory agent can be selected from the group consisting of anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast.pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DPI antagonists, DP2 antagonists, PI3K delta inhibitors, GGK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors, bronchodilators (e.g.. muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents; monoclonal antibody therapy such as anti-lgE, anti-TNF, anti- IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies e.g. etanercept and similar agents; antigen non-specific immunotherapies (e.g. interferon or other cytokines / chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists and similar agents), suitable anti-infective agents including antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents and antituberculosis agents.

[00194] In some embodiments, the second active ingredient can be an immunomodulatory agent. In some embodiments, the immunomodulatory agent can be selected from the group consisting of anti-PD-1 or anti-PDL-1 therapeutics including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab, anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453, anti-LAG3 therapeutics including but not limited to relatlimab, LAG525, or TSR-033, anti-4-lBB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutics including but not limited to SGN-40, CP- 870,893 or R07009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists including but not limited to ADU- S100, MK-1454, ASA404, or amidobenzimidazoles, anthracyclines including but not limited to doxorubicin or mitoxanthrone, hypomethylating agents including but not limited to azacytidine or decitabine, other immunomodulatory therapeutics including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some embodiments, the additional therapeutic agent is a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2- naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol.

[00195] In some embodiments, the second active ingredient can be a kinase inhibitor. In some embodiments, the kinase inhibitor can be selected from the group consisting of erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib, Loxo 292, larotrectinib, and quizartinib. EXAMPLES

[00196] For the purpose of illustration, the following examples are included. However, it is to be understood that these examples do not limit the present disclosure and are only meant to suggest a method of practicing the present disclosure. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are deemed to be within the scope of the present disclosure. For example, the synthesis of nonexemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and / or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.

[00197] Chiral HPLC condition: (Column: Daicel CHIRALPAK® IH 250*4.6 mm, 5pm; Mobile Phase A: HEX+0.2%DEA; Mobile Phase B: IPAMEOH+0.2%DEA, Mobile Phase A:Mobile Phase B=80:20 (V / V)).

[00198] The compound in Table 1 may be separated by prep-HPLC or Chiral HPLC to give a pair of isomers comprising Compound No.-Pl and Compound No.-P2. For a pair of Compound No.-Pl and Compound No.-P2, the compound designated as “-P1” is firstly eluted from the column of prep-HPLC or Chiral HPLC and the compound designated as “-P2” is secondly eluted. The structure of a pair of separated Compound No.-Pl and Compound No.-P2 was shown by marking a near the chiral central atom of the corresponding Compound No. structure. For example, ho oh means the structures of 1-P1 and 1-P2 could be: 1-P1 HO OH 1-P2                 or 1-P1

[00199] Similarly, in some embodiments, the compound in Table 1 may be separated by Chiral HPLC to give four isomers comprising Compound No.-Pl, Compound No.-P2, Compound No.-P3 and Compound No.-P4. For these compounds, there are two chiral central atoms in the compound structure. Example 1. Synthesis of Intermediates 1.1 Synthesis of Intermediate la:

[00200] A solution of compound la-1 (50 g, 0.1718 mol, 1 eq) in TMP (400 mL) was stirred for 15 min at 0 °C under N2 atmosphere. To the above mixture was added POCI3 (86.18 g, 0.5670 mol, 3.3 eq) dropwise over 30 min at 0°C. The resulting mixture was stirred for 1.5 h at 25 °C under N2 atmosphere. The reaction was quenched with ice water at 0°C. The resulting mixture was concentrated under vacuum. The concentrated mixture was added acetonitrile (3 L) and filtered to give Intermediate la (50 g, 0.1348 mol, 78%) as a light-yellow solid. The product was used in the next step directly without further purification.

[00201] LCMS: Rt = 0.396 min; m / z= 372 [M+l]+; m / z= 370 [M-l]’

[00202] JH NMR (400 MHz, D2O) 8 8.07 (s, 1H), 7.35-7.33 (m, 1H), 7.12-7.11 (m, 1H), 4.91-4.90 (m, 1H), 4.50 (d, J= 4.6 Hz, 1H), 4.41-4.39 (m, 1H), 4.14-4.10 (m, 2H). 1.2 Synthesis of Intermediate lb: 1b-1 DBDMH, AON, -30 °C Br HCI / dioxane dioxane, 0-25°C 1b-2                                1b-3 Step 1: Synthesis of compound lb-2

[00203] To a solution of compound lb-1 (20.0 g, 96.5 mmol, 1.0 eq) in ACN (200 mL) was added DBDMH (15.2 g, 53.1 mmol, 0.55 eq) under N2 at -30 °C, the mixture was stirred at -20 °C for 2 hrs. Then the reaction mixture was poured into water (200 mL), extracted with EA (200 mL*3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and evaporated in vacuum to get the crude product. The crude product was purified by FCC (EtOAc in PE from 1% to 15%) to give compound lb-2 (27.1 g, 98%) as light yellow oil.

[00204] LCMS: m / z (M+H)+ =286.0

[00205] 'H NMR (400 MHz, CDC13): 6: 7.69 (s, 1H), 6.90 (d, J= 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 1.50 (s, 9H). Step 2: Synthesis of compound lb-3

[00206] To a solution of compound lb-2 (20.0 g, 69.9 mmol) in dioxane (50 mL) was added HCl / dioxane (104.8 mL, 4 M, 419.4 mmol) at 0 °C under N2, then the resulting mixture was stirred at 25 °C for 5 hrs. The mixture was filtered, and the filter cake was washed with MTBE (100 mL), then the filtrate was dried in vacuum to give compound lb-3 (11.3 g, 50.8 mmol, 72.7%) as a white solid. The crude product was used directly for next step without further purification.

[00207] LCMS: m / z =186.0

[00208] 'H NMR (400 MHz, DMSO-de): 6 ppm = 7.24 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H). Step 3: Synthesis of compound lb-4

[00209] To a solution of compound lb-3 (16.0 g, 71.9 mmol) in EtOH (200 mL) was added formamidine acetate (37.4 g, 359.6 mmol) and K3PO4 (76.3 g, 359.6 mmol) at 25 °C under N2, then the mixture was stirred at 78 °C for 16 hrs. The reaction mixture was filtered and the filter cake was washed with EtOH (100 mL*2), then the filtrate was evaporated in vacuum to get the crude product. The crude product was triturated by THF:DCM (1: 3) and filtered. The filter cake was dried in vacuum, and the filtrate was further purified by FCC (10-26% THF in PE) to give compound lb-4 (9.5 g, 44.6 mmol, 62.0%) as light yellow solid.

[00210] LCMS: m / z = 213.0

[00211] 'H NMR (400 MHz, DMSO-de): 6 ppm = 7.84 (br, 2H), 7.82 (s, 1H), 7.81 (d, J= 1.6 Hz, 1H), 6.97 (d, J= 1.6 Hz, 1H). Step 4: Synthesis of compound lb-5

[00212] To a solution of compound lb-4 (21.1 g, 99.0 mmol) in THF (200 mL) was added D2O (10 mL), then it was concentrated to dryness three times. After that, THF (200 mL) and D2O (10 mL) was added into the residue under N2, then the solution was added Pd(dppf)Ch(7.2 g, 9.9 mmol) and TMEDA (2.3 g, 19.8 mmol) at 25 °C. The reaction was stirred at 25 °C for 0.5 hour. After that, the solution was cooled to 0 °C, NaBD4 (8.3 g, 198.0 mmol) was added into the solution, the reaction was stirred at 25 °C for 17 hours. TLC (PE: EA =1:1) showed compound lb-4 was consumed completely and a new spot was detected. The mixture was poured into saturated NH4CI (200 mL). The reaction mixture was extracted with EA (100 mL x 3). The organic phase was washed with brine (100 mL), then dried over Na2SO4 and concentrated to give the residue. The residue was purified by column chromatography on silica gel (EtOAc in PE from 10% to 50%) to give compound lb-5 (7.5 g, 56.3%) as yellow solid.

[00213] LCMS: m / z = 136.2

[00214] 'H NMR (400 MHz, DMSO-rf6):8: 7.80 (s, 1H), 7.70 (s, 2H), 7.61 (d, J= 1.6 Hz, 1H), 6.86 (d, J= 1.6 Hz, 1H). Step 5: Synthesis of Compound lb-6

[00215] A solution of compound lb-5 (4.0 g, 29.5 mmol, 1.0 eq) in DMF (36 mL) was cooled to -5°C~5°C. NIS (6.7 g, 29.5 mmol, 1.0 eq) was added to the above reaction under N2 atmosphere. The reaction was stirred at -5°C~5°C for 2 h. TLC showed the reaction was finished. The reaction mixture was poured in to aqueous NaOH (400 mL, IM) and stirred for another 30 min. The solid crushed out was filtered off and the solid was washed with H2O (50 mL), PE (60 mL), dried in vacuo to give compound lb-6 as a solid (6 g, 77%).

[00216] 'H NMR (400 MHz, DMSO-de) 6: 7.87 (s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H). Step 6: Synthesis of Compound lb-7

[00217] To a solution of compound lb-6 (2.6 g, 9.9 mmol, 1.0 eq) in THF (40 mL) was added TMSC1 (2.4 g, 21.7 mmol, 2.2 eq) under N2 atmosphere and the reaction was stirred at rt for 40 min. The reaction mixture was cooled to -5~5°C, PhMgCl (11.8 mL, 2M, 23.6 mmol) was added to the above reaction mixture and keep the temperature at -5~5°C for another 1.5 h. Then z-PrMgCl-LiCl (9.9 mL, 12.9 mmol, 1.3eq) was added to the above reaction mixture and stirred for another 15 min after addition. A solution of compound A (4.1 g, 9.9 mmol, 1.0 eq) in THF (40 mL) was added to the above reaction mixture at -20—15°C. After addition, the reaction mixture was warmed to rt and stirred for another 1 h. TLC (PE:EA=1:1) showed the reaction was finished, IM HC1 was added to the reaction to modify pH=2~3. EtOAc was added, the two phases were separated, and the organic phase was washed with HC1 (IM) twice. Then the organic phase was washed with saturated NaHCOs, brine, dried over Na2SO4, filtered and concentrated in vacuo to get a crude product, which was purified by column (PE:EA=2:1) to give compound lb-7 (2.0 g) as solid. Step 7: Synthesis of Compound lb-8

[00218] To a solution of compound lb-7 (2.0 g, 3.6 mmol, 1.0 eq) in DCM (24 mL) was added TfOH (1.1 g, 7.2 mmol) at -78°C. After 10 min, TMSOTf (1.7 g, 7.6 mmol, 2.1eq) was added to the above reaction and stirred for another 30 min. TMSCN (1.4 g, 14.4 mmol, 4.0 eq) was then added. After 10 min, TLC (PE: EA=1:1) showed the reaction was finished. TEA was then added to quench the reaction, followed by the addition of NaHCCL to pH ~8. The two phases were separated and the aqueous phase was extracted with DCM. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to get a crude product, which was purified by column to give compound lb-8 (1.4 g, 69%) as solid. Step 8: Synthesis of Compound lb-9

[00219] To a solution of compound lb-8 (1.6 g, 2.8 mmol, 1.0 eq) in DCM (23 mL) was added BCE (11.1 mL, 11.1 M) at-78°C. The reaction mixture was stirred at -40 °C for 2 h. MeOH (10 mL) was added to quench the reaction, followed by the addition of TEA to pH 8~9. The solution was concentrated. Then water (100 mL) was added, the aqueous phase was washed with DCM, and the aqueous phase was concentrated to about 50 mL. Another 100 mL was added and repeat the same procedure seven times. The solid formed was filtered and concentrated in vacuo to give compound lb-9 (0.4 g, 51%) as solid.

[00220] 'H NMR (400 MHz, DMSO-de) 6: 7.9-787 (m, 3H), 6.86 (s, 1H), 6.07 (s, 1H), 5.15 (s, 1H), 4.90-4.87 (m, 1H), 4.62-4.59 (m, 1H), 4.03-4.01(m ,1 H), 3.94-3.90 (m, 1H), 3.63-3.46 (m, 2H). Step 9: Synthesis of Intermediate lb:

[00221] A solution of compound lb-9 (50.0 g, 0.1718 mol, 1 eq) in TMP (400 mL) was stirred for 15 min at 0 °C under N2 atmosphere. To the above mixture was added POCI3 (86.2 g, 56.7 mmol, 3.3 eq) dropwise over 30 min at 0 °C. The resulting mixture was stirred for 1.5 h at 25 °C under N2 atmosphere. The reaction was quenched with ice water at 0°C. The resulting mixture was concentrated under vacuum. The crude product was precipitated by the addition of acetonitrile (3 L). The precipitated solids were collected by filtration to give Intermediate lb (50.0 g, 134.8 mmol, 78%) as a light-yellow solid.

[00222] LCMS: m / z= 373 1.3 Synthesis of Intermediate 1c: .OH O ^(CH^nCHa nh2 1c-3 1c-1 1c Step 1: Synthesis of compound lc-3:

[00223] To a mixture of compound lc-1 (1 g, 5.38 mmol, leq) in toluene (20 mL) were added compound lc-2 (478 mg, 5.38 mmol, 1 eq) and PTSA (1.11 g, 6.45 mmol, 1.2 eq), then the mixture was stirred at 130 °C for 16 h. The reaction mixture was quenched with saturated NaHCOa and extracted with EA (50 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC to obtain compound lc-3 (0.98 g, 71%) as a white solid.

[00224] LCMS: m / z= 258.15 [M+l]+

[00225] XH NMR (400 MHz, CDC13) 6 4.10-4.06 (m, 2H), 3.52-3.50 (m, 1H), 1.63 1.57 (m, 2H), 1.34-1.24 (m, 21H), 0.86 (t, J= 6.7 Hz, 3H). Step 2: Synthesis of compound 1:

[00226] To a mixture of compound la (500 mg, 1.348 mmol, 1.0 eq) in DMF (20 mL) were added PPhs (1.13 g, 4.313 mmol, 3.2 eq), TEA (313 mg, 3.099 mmol, 2.3 eq), aldrithion (950 mg, 4.313 mmol, 3.2 eq) and compound lc-3 (1.38 g, 5.391 mmol, 4 eq). The reaction mixture was stirred at 55 °C for 16 h. The reaction mixture was concentrated and the residue was directly purified by column (DCM: MeOH=5:l) to get Compound 1c as a crude product with the purity about 80%, which was further purified again by prep-TLC (DCM: MeOH=5:l) to give Intermediate 1c (23.66 mg, 3%).

[00227] LCMS: m / z= 611.40 [M+l]+; m / z= 609.10 [M-l]'

[00228] 'H NMR (400 MHz, CD3OD) 8 7.85 (s, 1H), 6.99 - 6.86 (m, 2H), 4.81-4.80 (m, 1H), 4.33 - 4.26 (m, 1H), 4.21-4.19 (m, 1H), 4.09 - 3.85 (m, 4H), 3.75-3.72 (m, 1H), 1.57-1.55 (m, 2H), 1.25-1,18 (m, 21H), 0.87 (t, J = 6.7 Hz, 3H).

[00229] The following compounds were synthesized according to the same procedure as for Compound 1c except for using different starting materials or intermediates:

[00230] Intermediate Id: O

[00231] LCMS: [MS+1] =771.55, [MS-1] =769.30

[00232] 'H NMR (400 MHz, CD3OD) 8 7.84 (s, 1H), 7.20-7.14 (m, 2H), 7.14 -7.07 (m, 3H), 6.97 (d, J = 4.7 Hz, 1H), 6.92 (d, J = 4.6 Hz, 1H), 4.79 (d, J = 5.2 Hz, 1H), 4.30 - 4.24 (m, 1H), 4.18 (t, J = 5.3 Hz, 1H), 4.02 - 3.90 (m, 3H), 3.90 - 3.85 (m, 2H), 2.94 (dd, J = 11.1, 5.4 Hz, 1H), 2.81 (dd, J = 11.4, 7.8 Hz, 1H), 1.45 - 1.37 (m, 2H), 1.29-1.18 (m, 30H), 0.87 (t, J= 6.6 Hz, 3H). Example 2. Synthesis of Compounds 2.1 Synthesis of compound 1 o CH3(CH2)11.OAO^C| CH^CH^, 1-2 1-3 CHaCCHzJn-OH 1-1 1a HO OH 1-3 HO OH HO OH 1-P1&1-P2 Step 1: Synthesis of compound 1-2

[00233] To a solution of 1-1 (20.0 g, 107.3 mmol) in hexane (300 mL) was added Py (19.7 g, 248.6 mmol, 20.0 mL) and chloromethyl carbonochloridate (180 g, 139.4 mmol, 12.4 mL) at 0 °C. The mixture was warmed up to 25 °C and stirred at 25 °C for 1 h. The mixture was washed with saturated NH4CI (200 mL). The organic layer was concentrated to get a residue, which was purified by silica gel chromatography (PE / DCM=50 / l to 6 / 1) to give 1-2 (27.0 g, 90% yield) as colorless oil. Step 2: Synthesis of compound 1-3

[00234] To a solution of 1-2 (27.0 g, 96.8 mmol) in acetone (500 mL) was added Nai (58.0 g, 387.0 mmol). The mixture was stirred for 48 h at 40 °C. The mixture was concentrated to get a residue, which was diluted with PE (300 mL), washed with water (200 mL), saturated Na2SO3 (100 mL). The organic layer was concentrated and purified by silica gel chromatography (PE / DCM=50 / l to 6 / 1) to give 1-3 (28.0 g, 78% yield) as yellow oil.

[00235] JH NMR (400 MHz, CDC13) 3 5.97 (s, 2H), 4.24 (t, J = 7.2 Hz, 2H), 1.461.28 (m, 20H), 0.90 (t, J= 6.0 Hz, 3H). Step 3: Synthesis of compound 1-4

[00236] To a solution of Intermediate la (1 g, 2.7 mmol) in pyridine (10.0 mL) was added ls-1 (700 mg, 8.0 mmol), 2,2'-Dithiodipyridine (1.2 g, 5.4 mmol) and PPh3 (1.4 g, 5.4 mmol). The mixture was stirred at 60 °C for 2 h. The mixture was concentrated to get a residue, which was diluted with water (20 mL), extracted with 10% methanol in ethyl acetate (20 mL x 5). The water phase was lyophilized to obtain 1-4 (1.1 g, crude) as yellow solid.

[00237] LCMS: [M+H]+ = 441.3 Step 4: Synthesis of compound 1

[00238] To a solution of 1-4 (600 mg, 1.3 mmol) and 1-3 (2.5 g, 6.8 mmol) in MeOH (12 mL) was added DIEA (880.4 mg, 6.8 mmol) at 25 °C, and the resulting mixture was stirred at 40 °C under argon for 2 h. The mixture was concentrated to get a residue, which was purified by silica gel chromatography (10% MeOH in DCM) to give crude product of compound 1. The product was purified by prep-HPLC (Welch Xtimate C18 21.2*250mm,10 urn, H2O-ACN, 77-77) to give 1-P1 (37 mg, 4.1%), 1-P2 (33.9 mg, 4%).

[00239] LC / MS: [M+H]+ = 683.4 1-P1

[00240] 1H NMR (400 MHz, DMSO-de) 3 7.98-7.78 (m, 3H), 6.90 (d, J = 4.8 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.32 (d, J= 6 Hz, 1H), 5.57-5.48 (m, 2H), 5.41 (d, J = 6.4 Hz, 1H), 4.64 (t, J= 5.2 Hz, 1H), 4.26-3.96 (m, 6H), 3.49-3.36 (m, 4H), 2.912.86 (m, 4H), 1.63-1.54 (m, 2H), 1.31-1.21 (m, 18H), 0.83 (t, J= 6.8 Hz, 3H). 1-P2

[00241] JH NMR (400 MHz, DMSO-76) d 7.99-7.83 (m, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.81 (d, J = 4.4 Hz, 1H), 6.36 (d, J = 6.0 Hz, 1H), 5.57-5.48 (m, 2H), 5.40 (d, J = 6.0 Hz, 1H), 4.67 (t, J= 5.2 Hz, 1H), 4.25-3.91 (m, 6H), 3.48-3.41 (m, 4H), 2.972.91 (m, 4H), 1.63-1.54 (m, 2H), 1.33-1.17 (m, 18H), 0.85 (t, J= 6.8 Hz, 3H).

[00242] The following compounds were synthesized according to the same procedure as for compound 1 except for using different starting materials or intermediates: Compound 2:

[00243] LC / MS [M+H]+= 767.7.

[00244] 1H NMR (400 MHz, DMSO-76) 3 8.05-7.80 (m, 3H), 6.90 (d, J = 4.8 Hz, 1H), 6.82 (t, J = 4.8 Hz, 1H), 6.33 (m, 1H), 5.57-5.48 (m, 2H), 5.40 (t, J = 5.6 Hz, 1H), 4.69-4.62(m, 1H), 4.23-3.92 (m, 6H), 3.56-3.36 (m, 4H), 2.96-2.84 (m, 4H), 1.62-1.56 (m, 2H), 1.31-1.17 (m, 30H), 0.85 (t, J= 6.8 Hz, 3H).

[00245] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio of 57:43. Compound 3:

[00246] LC / MS [M+H]+= 669.6.

[00247] 1H NMR (400 MHz, DMSO-d6) 8 7.98-7.83 (m, 3H), 6.89 (d, J = 4.4 Hz, 1H), 6.82 (d, J= 4.4 Hz, 1H), 6.36-6.31 (m, 1H), 5.53-5.42 (m, 2H), 5.39 (t, J= 4.8 Hz, 1H), 4.69-4.62 (m, 1H), 4.22-4.15 (m, 1H), 4.15-4.03 (m, 3H), 4.01-3.84 (m, 2H), 2.99-2.86 (m, 4H), 1.62-1.52 (m, 2H), 1.31-1.18 (m, 18H), 1.01-0.93 (m, 6H), 0.85 (t, 7=6.8 Hz, 3H).

[00248] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio 1:1. Compound 4:

[00249] LCMS: [M+H]+ = 753.7

[00250] JH NMR (400 MHz, DMSO-d6) 8 7.99-7.81 (m, 3H), 6.89-6.85 (m, 1H), 6.82-6.80 (m, 1H), 6.35-6.30 (m, 1H), 5.53-5.42 (m, 2H), 5.39-5.36 (m, 1H), 4.684.62 (m, 1H), 4.24-4.19(m, 1H), 4.13-4.05 (m, 3H), 4.00-3.90 (m, 2H), 2.96-2.82 (m, 4H), 1.63-1.53 (m, 2H), 1.29-1.18 (m, 30H), 1.01-093(m, 6H), 0.85 (t, J= 6.4 Hz, 3H).

[00251] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio 1:1. Compound 12:

[00252] LCMS: [MS+H]+ = 681.40, [MS-H]’ = 679.40.

[00253] 'H NMR (400 MHz, CD3OD) 8 7.86 (s, 1H), 6.92-6.87 (m, 2H), 5.58-5.51 (m, 2H), 4.87-4.84 (m, 1H), 4.47-4.35 (m, 1H), 4.34-4.24 (m, 1H), 4.23-4.16 (m, 4H), 2.99-2.95 (m, 4H), 1.70-1.57 (m, 2H), 1.56-1.48 (m, 2H), 1.47-1.37 (m, 4H), 1.40-1.28 (m, 18H), 0.90 (t, 7=6.8 Hz, 3H).

[00254] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio ~1:1. Compound 13:

[00255] LCMS: [M+H]+ = 707.6

[00256] 'H NMR (400 MHz, DMSO-76) 3 8.02-7.76 (m, 3H), 6.91-6.88 (m, 1H), 6.84-6.79 (m, 1H), 6.35-6.28 (m, 1H), 5.57-5.47 (m, 2H), 5.42-5.35 (m, 1H), 4.71- 4.61 (m, 1H), 4.25-4.19 (m, 1H), 4.18-4.09 (m, 3H), 4.05-3.93 (m, 2H), 3.01-2.89 (m, 4H), 1.64-1.54 (m, 2H), 1.32-1.11 (m, 22H), 0.85 (t, J= 6.8 Hz, 3H), 0.25-0.21 (m, 4H).

[00257] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio 1:1. Compound 14:

[00258] LCMS: [M+H]+ = 721.6

[00259] 1H NMR (400 MHz, DMSO-d6) 8 7.99-7.78 (m, 3H), 6.88 (d, J = 4.8 Hz, 1H), 6.82-6.79 (m, 1H), 6.33-6.27 (m, 1H), 5.54-5.43 (m, 2H), 5.41-5.36 (m, 1H), 4.69-4.60 (m, 1H), 4.24-4.17 (m, 1H), 4.15-4.06 (m, 3H), 4.02-3.92 (m, 2H), 2.862.7 (m, 4H), 1.85-1.76 (m, 2H), 1.68-1.53 (m, 6H), 1.39-1.17 (m, 22H), 0.85 (t, J = 6.8 Hz, 3H).

[00260] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio 1:1. Compound 15:

[00261] LCMS: [M+H]+ = 683.6

[00262] 1H NMR (400 MHz, DMSO-d6) 8 8.01-7.81 (m, 3H), 6.90 (d, J = 4.8 Hz, 1H), 6.84-6.79 (m, 1H), 6.35-6.27 (m, 1H), 5.54-5.43 (m, 2H), 5.41-5.36 (m, 1H), 4.88-4.77 (m, 1H), 4.69-4.63 (m, 1H), 4.24-4.18 (m, 1H), 4.16-4.08 (m, 1H), 4.033.91 (m, 2H), 3.38-3.35 (m, 2H), 3.32-3.08 (m, 3H), 2.78-2.62 (m, 2H), 1.73-1.51 (m, 2H), 1.49-1.39 (m, 2H), 1.32-1.17 (m, 18H), 0.88-0.81 (m, 3H).

[00263] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio 1:1. Compound 16:

[00264] LC / MS: [M+H]+= 711.7

[00265] JH NMR (400 MHz, DMSO-d6) 8 8.01-7.77 (m, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.83-6.81 (m, 1H), 6.34-6.27 (m, 1H), 5.53-5.45 (m, 2H), 5.39 (t, J= 6 Hz, 1H), 4.85-4.79 (m, 1H), 4.69-4.63 (m, 1H), 4.25-4.19 (m, 1H), 4.16-4.09 (m, 1H), 4.03-3.91 (m, 2H), 3.38-3.34 (m, 2H), 3.28-3.11 (m, 3H), 2.77-2.61 (m, 2 H), 1.731.57 (m, 2H), 1.46-1.39 (m, 2H), 1.33-1.15 (m, 22H), 0.85 (t, J= 7.2 Hz, 3H).

[00266] The compound was separated by Chiral HPLC to give four isomers with the ratio -1:1:1:1. Compound 17:

[00267] LCMS: [MS+H]+ = 641.2, [MS-H]’= 639.2.

[00268] 'H NMR (400 MHz, CD3OD) 8 7.85 (s, 1H), 6.90 (d, J= 4.5 Hz, 1H), 6.87 (d, J= 4.5 Hz, 1H), 5.55-5.51 (m, 2H), 4.93-4.84 (m, 1H), 4.83-4.78 (m, 1H), 4.334.31 (m, 1H), 4.28-4.24 (m, 1H), 4.21-4.12 (m, 2H), 2.92-2.89 (m, 2H), 2.63-2.53 (m, 3H), 1.44-1.41 (m, 2H), 1.24-1.19 (m, 20H), 0.86 (t, J= 6.8 Hz, 3H).

[00269] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio -47:53. Compound 18:

[00270] LC-MS: [M+l]+ = 669.45

[00271] 'H NMR (400 MHz, CD3OD) 8 7.87 (d, J = 1.7 Hz, 1H), 6.94-6.89 (m, 2H), 5.61-5.50 (m, 2H), 4.91-4.90 (m, 1H), 4.86-4.85 (m, 1H), 4.35-4.28 (m, 2H), 4.254.13 (m, 2H), 2.96-2.94 (m, 2H), 2.62-2.59 (m, 3H), 1.49-1.45 (m, 2H), 1.33-1.21 (m, 24H), 0.89 (t, J= 6.7 Hz, 3H). Compound 19:

[00272] LC-MS: [M+l]+ = 697.50

[00273] JH NMR (400 MHz, CD3OD) 8 7.86 (s, 1H), 6.94-6.89 (m, 2H), 5.59-5.53 (m, 2H), 4.91-4.90 (m, 1H), 4.88-4.85 (m, 1H), 4.35-4.24 (m, 2H), 4.22-4.16 (m, 2H), 2.97-2.92 (m, 2H), 2.62-2.59 (m, 3H), 1.49-1.47 (m, 2H), 1.45-1.23 (m, 28H), 0.90 (t, J = 4.0 Hz, 3H).

[00274] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio ~1:1. Compound 20:

[00275] LCMS: [M+H]+ = 739.6

[00276] 1H NMR (400 MHz, DMSO-de) d 8.00-7.83 (m, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.82 (d, J= 4.4 Hz, 1H), 6.34-6.28 (m, 1H), 5.54-5.46 (m, 2H), 5.41-5.38 (m, 1H), 4.69-4.63 (m, 1H), 4.25-4.09 (m, 4H), 4.03-3.92 (m, 2H), 3.67-3.57 (m, 1H), 3.44-3.36 (m, 1H), 3.25-3.13 (m, 2H), 2.76-2.65 (m, 2H), 1.70-1.53 (m, 4H), 1.261.19 (m, 20H), 1.05-1.04 (m, 6H), 0.85 (t, J= 6.8 Hz, 3H).

[00277] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio 1:1. Compound 21:

[00278] LCMS: [M+H]+ = 739.7.

[00279] 1H NMR (400 MHz, DMSO-d6) 8 7.99-7.81 (m, 3H), 6.90 (d, J =4.4 Hz, 1H), 6.82 (d, J= 4.4 Hz, 1H), 6.33-6.26 (m, 1H), 5.54-5.44 (m, 2H), 5.41-5.37 (m, 1H), 4.87-4.73 (m, 1H), 4.70-4.62 (m, 1H), 4.24^1.18 (m, 1H), 4.16-4.09 (m, 1H), 4.04-3.92 (m, 2H), 3.32-3.24 (m, 2H), 3.22-3.04 (m, 3H), 2.78-2.62 (m, 2H), 1.73- 1.57 (m, 2H), 1.49-1.37 (m, 2H), 1.33-1.16(m, 26H), 0.85 (t, J= 6.8 Hz, 3H).

[00280] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio 1:1. Compound 22:

[00281] LCMS: [M+H]+ = 653.6.

[00282] 1H NMR (400 MHz, DMSO-d6) 8 8.03-7.73 (m, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.82 (m, 1H), 6.36-6.31 (m, 1H), 5.56-5.43 (m, 2H), 5.41-5.35 (m, 1H), 4.754.61 (m, 2H), 4.24-4.12 (m, 2H), 4.06-3.92 (m, 2H), 3.06-2.92 (m, 4H), 1.79-1.65 (m, 4H), 1.61-1.42 (m, 2H), 1.31-1.14 (m, 17H), 0.84 (t, J= 4.8 Hz, 3H).

[00283] The compound was separated by Chiral HPLC to give Four isomers with the ratio -1:1:1:1. Compound 23:

[00284] LC / MS: [M+H]+ = 655.5

[00285] 'H NMR (400 MHz, DMSO-d6) 8 8.01-7.71 (m, 3H), 6.91-6.88 (m, 1H), 6.83-6.80 (m, 1H), 6.35-6.31 (m, 1H), 5.54-5.45 (m, 2H), 5.41-5.35 (m, 1H), 4.754.63 (m, 2H), 4.24-4.12 (m, 2H), 4.06-3.89 (m, 2H), 2.54 (s, 3H), 2.52 (s, 3H), 1.611.43 (m, 2H), 1.28-1.18 (m, 21H), 1 0.87-0.82(m, 3H).

[00286] The compound was separated by Chiral HPLC to give four isomers Compounds 45, 46, 47, and 48 with the ratio 1:1:1:1. Compound 24:

[00287] LCMS: [M+H]+ = 627.4

[00288] 'H NMR (400 MHz, CD3OD) 8 7.87 (s, 1H), 6.93-6.91 (m, 1H), 6.89-6.88 (m, 1H), 5.60-5.51 (m, 2H), 4.84-4.72 (m, 2H), 4.35-4.27 (m, 2H), 4.22-4.13 (m, 2H), 2.64-2.61 (m, 6H), 1.64-1.47 (m, 2H), 1.41-1.19 (m, 17H), 0.88 (t, J= 7.2 Hz, 3H).

[00289] The compound was separated by Chiral HPLC to give four isomers Compounds 53, 54, 55, and 56) with the ratio 1:1:1:1. Compound 26:

[00290] LCMS: [MS+H]+ =613.2, [MS-H]’= 611.1.

[00291] 'H NMR (400 MHz, CD3OD) 8 7.85 (s, 1H), 6.91 (d, J= 4.4 Hz, 1H), 6.87 (d, J= 4.5 Hz, 1H), 5.58-5.54 (m, 1H), 5.54-5.50 (m, 1H), 4.83-4.81 (m, 1H), 4.384.28 (m, 1H), 4.27-4.23 (m, 1H), 4.22-4.11 (m, 2H), 3.84-3.74 (m, 3H), 2.94-2.84 (m, 2H), 2.63-2.53 (m, 3H), 1.45-1.39 (m, 2H), 1.26-1.19 (m, 14H), 0.86 (t, J= 6.6 Hz, 3H).

[00292] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio -48:52. Compound 33:

[00293] LC-MS: [M+l]+ = 709.30

[00294] 'H NMR (400 MHz, CD3OD) 8 7.86 (s, 1H), 6.92-6.87 (m, 2H), 5.57-5.50 (m, 2H), 4.84-4.81 (m, 1H), 4.86-4.85 (m, 1H), 4.35-4.28 (m, 1H), 4.25-4.13 (m, 4H), 3.01-2.92 (m, 4H), 1.66-1.61 (m, 2H), 1.30-1.26 (m,18H), 1.21-1.14 (m, 4H), 0.89-0.86 (m, 9H).

[00295] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio - 55:45. Compound 27:

[00296] LCMS: [MS+1]+ = 641.40, [MS-1]- = 639.35.

[00297] 'HNMR (400 MHz, CD3OD) 8 7.85 (s, 1H), 6.91-6.87 (m, 2H), 5.57-5.52 (m, 2H), 4.87-4.84 (m, 1H), 4.18-4.14 (m, 4H), 3.80-3.78 (m,3H), 2.93-2.90 (m, 2H), 2.60-2.55 (m, 3H), 1.46-1.44 (m, 2H), 1.24-1.21 (m, 18H), 0.89 (t, J = 6.8 Hz, 3H).

[00298] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio -43:57. 2.2 Synthesis of compound 5 HO OH 5 Step 1: Synthesis of compound 5-2:

[00299] To a solution of 5-1 (10 g, 80.3 mmol) in acetone (150 mL) was added Nai (48.1 g, 321.2 mmol), the mixture was stirred at 30 °C for 48 h. The mixture was concentrated to give a residue, which was diluted with PE (300 mL), washed with water (200 mL), saturated Na2SO3 (3 mL). The organic layer was concentrated to give a residue, which was purified by silica gel chromatography (PE / EA=100 / l tol0 / l) to obtain 5-2 (6.1 g, 35%) as a colorless oil. Step 2: Synthesis of compound 5:

[00300] To a solution of Id (2 g, 2.5 mmol) and 5-2 (1.6 g, 7.7 mmol) in DMF (10 mL) was added DIEA (2.0 g, 15.6 mmol, 2.7 mL). The mixture was stirred at 70 °C under microwave for 1 h. The reaction mixture was quenched with water, extracted with EA:THF (1:1). The organic layer was concentrated to give a residue, which was purified by flash column eluted with DCM:MeOH=100:l to 95:5 to obtain a crude product, which was purified by prep-HPLC (10 mmol NH^HCCD-ACN, H2O / ACN=65%-85%,Waters Xbridge C18 OBD 19*250mm,5um) to obtain compound 5 (217 mg, 10%).

[00301] LCMS: [M+H]+ = 859.6

[00302] 'H NMR (400 MHz, DMSO-d6) 8 8.05-7.77 (m, 3H), 7.26-7.14 (m, 5H), 6.92-6.89 (m, 1H), 6.81-6.80 (d, 7 = 4.4 Hz, 1H), 6.31-6.29 (m, 1H), 5.99-5.92 (m, 1H), 5.37-5.28 (m, 2H), 5.24-5.21 (m, 1H), 4.65^.59 (m, 1 H), 4.15-4.09 (m, 1H), 4.01-3.78 (m, 6H), 3.75-3.72 (m, 3H), 2.99-2.91 (m, 1H), 2.84-2.78 (m, 1H), 1.451.38 (m, 2H), 1.22-1.18 (m, 30H), 0.85 (t, 7= 7.2 Hz, 3H).

[00303] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio 1:1.

[00304] The following compounds were synthesized according to the same procedure as for compound 5 except for using different starting materials or intermediates: Compound 6:

[00305] LCMS: [M+H]+ = 887.8

[00306] 'H NMR (400 MHz, DMSO-d6) 8 8.04-7.81 (m, 3H), 7.27-7.14 (m, 5H), 6.93-6.89 (m, 1H), 6.83-6.79 (m, 1H), 6.33-6.29 (m, 1H), 6.01-5.92 (m, 1H), 5.385.14 (m, 3H), 4.83-4.74 (m, 1H), 4.66-4.58 (m, 1H), 4.16-4.07 (m, 1H), 3.96-3.59 (m, 6H), 3.01-2.89 (m, 1H), 2.86-2.77 (m, 1H), 1.48-1.36 (m, 2H), 1.29-1.11 (m, 36H), 0.85-0.79 (t, 7= 6.8 Hz, 3H).

[00307] The compound was separated by Chiral HPLC to give a pair of isomers with the ration -60:40. Compound 8:

[00308] LCMS: [M+H]+ = 888.7

[00309] 1H NMR (400 MHz, DMS0-d6) 8 8.42-8.37 (m, 2H), 7.99-7.82 (m, 3H), 7.66-7.60 (m, 1H), 7.29-7.24 (m, 1H), 6.92-6.88 (m, 1H), 6.82-6.80 (m, 1H), 6.336.29 (m, 1H), 6.07-5.99 (m, 1H), 5.39-5.21 (m, 3H), 4.82-4.73 (m, 1H), 4.66-4.60 (m, 1H), 4.16-4.08(m, 1H), 4.01-3.68(m, 6H), 3.02-2.94(m, 1H), 2.86-2.81(m, 1H), 1.47-1.44(m, 2H), 1.28-1.18(m, 36H), 0.86-0.81 (t, 7 = 6.4, 3H).

[00310] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio -33:67. Compound 10:

[00311] LCMS: [MS+1]+ = 940.5, [MS-1]- = 938.4.

[00312] 1H NMR (400 MHz, CD3OD) 8 7.92 (d, J = 6.9 Hz, 1H), 7.48-7.45 (m, 1H), 7.30-7.202 (m, 1H), 7.10-7.08 (m, 2H), 7.00-6.95 (m, 3H), 5.44-5.31 (m, 2H), 4.864.80 (m, 1H), 4.75-4.71 (m, 1H), 4.27-4.20 (m, 1H), 4.12-3.93 (m, 6H), 3.70 (d, J = 4.7 Hz, 3H), 3.11-3.04 (m, 2H), 1.45-1.37 (m, 2H), 1.26-1.10 (m, 36H), 0.88 (t, J = 6.8 Hz, 3H).

[00313] HPLC: a pair of isomers with the ratio about 50:50. Compound 11:

[00314] LCMS: [MS+H]+ = 832.20, [MS-H]’= 830.05.

[00315] 'H NMR (400 MHz, CD3OD) 8 8.35 (s, 2H), 7.85 (s, 1H), 7.72-7.62 (m, 1H), 7.32 (dd, J= 7.5, 5.3 Hz, 1H), 6.94-6.82 (m, 2H), 5.49-5.35 (m, 2H), 4.79 (d, J = 5.3 Hz, 1H), 4.29-4.19 (m, 1H), 4.17-4.09 (m, 2H), 4.09-3.97 (m, 4H), 3.76 (s, 3H), 3.10-3.00 (m, 1H), 2.95-2.83 (m, 1H), 1.57-1.45 (m, 2H), 1.29-1.21 (m, 26H), 0.87 (t, 7=6.5 Hz, 3H).

[00316] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio -40:60. Compound 9:

[00317] LCMS: [MS+H]+=860.20

[00318] 'H NMR (400 MHz, CD3OD) 8 8.35 (s, 2H), 7.85 (s, 1H), 7.74-7.71 (m, 1H), 7.37-7.27 (m, 1H), 6.92-6.86 (m, 2H), 5.42-5.39 (m, 2H), 4.54-4.44 (m, 1H), 4.30-4.20 (m, 1H), 4.07-4.03 (m, 2H), 4.02-3.99 (m, 4H), 3.76 (s, 3H), 3.28-2.88 (m, 2H), 1.51 (m, 2H), 1.25-1.24 (m, 30H), 0.89 (t, J=6.8 Hz, 3H).

[00319] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio -47:53. Compound 7:

[00320] LCMS: [MS+H]+=831.40

[00321] 'H NMR (400 MHz, CD3OD) 8 7.85 (s, 1H), 7.24-7.20 (m, 2H), 7.17-7.12 (m, 3H), 6.92-6.88 (m, 2H), 5.41-5.31 (m, 2H), 4.78-4.74 (m, 1H), 4.28-4.18 (m, 1H), 4.15-3.84 (m, 6H), 3.75 (s, 3H), 3.04-2.95 (m, 1H) 2.86-2.78 (m, 1H), 1.501.48 (m, 2H), 1.25-1.23 (m, 26H), 0.89 (t, J= 6.8 Hz, 3H).

[00322] The compound was separated by Chiral HPLC to give a pair of isomers with the ratio -50:50.

[00323] Compound 62:

[00324] LCMS: [MS+H]+ = 832.15

[00325] 'H NMR (400 MHz, CD3OD) 8 7.87-7.86 (m, 1H), 7.24-7.15 (m, 5H), 7.016.83 (m, 1H), 5.46-5.30 (m, 2H), 4.83-4.77 (m, 1H), 4.28-4.22 (m, 1H), 4.16-3.86 (m, 6H), 3.77 (s, 3H), 3.03-3.01 (m, 1H), 2.88-2.80 (m, 1H), 1.52-1.50 (m, 2H), 1.42-1.02 (m, 26H), 0.95-0.83 (t, J= 6.6 Hz, 3H).

[00326] The compound 62 was separated by Chiral HPLC to give a pair of isomers 62-P1 and 62-P2. HO OH 62-P1&62-P2

[00327] Compound 64:

[00328] LCMS: [MS+H]+ = 804.15

[00329] 'H NMR (400 MHz, Methanol-J4) 8 7.87 (d, J= 1.4 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.16 (ddt, J= 8.1, 5.5, 1.5 Hz, 3H), 6.89 (s, 1H), 5.44 - 5.32 (m, 2H), 4.79 (d, J = 5.4 Hz, 1H), 4.24 (dtd, J = 6.4, 4.0, 3.5, 1.6 Hz, 1H), 4.15 - 3.99 (m, 5H), 3.95 -3.86 (m, 1H), 3.77 (d, J = 4.0 Hz, 3H), 3.06 - 2.96 (m, 1H), 2.84 (ddd, J= 13.6, 10.1, 8.3 Hz, 1H), 1.51 (q, J= 6.7 Hz, 2H), 1.25 (d, J = 10.9 Hz, 22H), 0.89 (t, J= 6.8 Hz, 3H).

[00330] The compound 64 was separated by Chiral HPLC to give a pair of isomers 64-P1 and 64-P2: HO OH

[00331] Compound 70:

[00332] LCMS: [MS+H]+ = 770.05

[00333] JH NMR (400 MHz, Methanol-J4) 8 7.88 (s, 1H), 6.89 (d, J= 2.0 Hz, 1H), 5.57 (dd, J = 12.9, 5.1 Hz, 2H), 4.40 - 4.35(m, 2H), 4.24 (ddd, J = 9.4, 6.3, 4.1 Hz, 2H), 4.06 (d, J = 6.6 Hz, 2H), 3.78 (d, J = 3.1 Hz, 3H), 3.67 (dd, J = 11.4, 3.2 Hz, 1H), 1.61 (t, J= 7.1 Hz, 2H), 1.41 (dd, J= 6.4, 4.0 Hz, 6H), 1.36-1.26 (m, 26H), 0.87 (d, J =7.0 Hz, 3H).

[00334] Compound 72:

[00335] LCMS: [MS+H]+ = 817.85

[00336] 'H NMR (400 MHz, Methanol-J4) 8 7.84 (dd, J= 3.7, 0.8 Hz, 1H), 7.34 -7.25 (m, 4H), 7.24 (d, J = 0.8 Hz, 1H), 6.89 (s, 1H), 5.55 - 5.48 (m, 2H), 4.79 (d, J = 5.4 Hz, 1H), 4.31-4.07 (m, 6H), 3.98 (dq, J= 12.2, 6.2 Hz, 1H), 3.77 (dd, J= 2.9, 0.8 Hz, 3H), 1.47 (q, 7= 7.0 Hz, 2H), 1.21 (d, J = 53.3 Hz, 26H), 0.91-0.86 (m, 3H).

[00337] Compound 89:

[00338] LCMS: [MS+H]+ =776.30

[00339] 'H NMR (400 MHz, Methanol-d4) 8 7.87 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 21.6, 7.6 Hz, 5H), 6.89 (s, 1H), 5.43 - 5.32 (m, 2H), 4.79 (d, J = 5.3 Hz, 1H), 4.24 (s, 1H), 4.16 - 3.97 (m, 6H), 3.77 (d, J = 4.0 Hz, 3H), 3.01 (dt, J = 9.7, 6.8 Hz, 1H), 2.87 - 2.81 (m, 1H), 1.51 (d, J = 7.9 Hz, 2H), 1.26 (d, J = 7.5 Hz, 18H), 0.89 (t, J = 6.6 Hz, 3H).

[00340] Compound 91:

[00341] LCMS: [MS+H]+ = 888.30

[00342] 'H NMR (400 MHz, Methanol-J4) 8 7.86 (s, 1H), 7.18 (dd, J = 17.6, 12.4 Hz, 5H), 6.89 (d, J= 4.4 Hz, 1H), 5.37 (dd, J = 27.9, 10.8 Hz, 2H), 4.77 (d, J= 5.4 Hz, 1H), 4.56 (s, 1H), 4.23 (s, 1H), 4.03 (d, J= 17.4 Hz, 6H), 3.76 (d, J= 4.5 Hz, 3H), 3.01 (s, 1H), 2.84 (s, 2H), 1.50 (s, 2H), 1.26 (s, 34H), 0.88 (d, J = 6.0 Hz, 3H). 2.3 Synthesis of compound 25 25-2 HO OH 25 Step 1: Synthesis of compound 25-1:

[00343] To a solution of Intermediate la (15.5 g, 41.8 mmol, crude) and (4-methoxyphenyl)methanamine (5.7 g, 41.6 mmol) in pyridine (150 mL) was added DIEA (16.4 g, 127.1 mmol, 21.0 mL) and 2,2'-dithiodipyridine (18.5 g, 84.0 mmol). The mixture was stirred at 60 °C for 3 h. The mixture was concentrated to give a residue, which was diluted with water (100 mL), washed with EtOAc (100 mL x 5). The water phase was lyophilized to obtain 25-1 (12.5 g, crude) as a yellow solid.

[00344] LCMS: [M+H]+ = 491.4 Step 2: Synthesis of compound 25-2

[00345] To a solution of 25-1 (5.0 g, 10.2 mmol) and chloromethyl 1-methyldodecyl carbonate (9.0 g, 30.7 mmol) in DMF (50.0 mL) was added DIEA (6.7 g, 52.0 mmol, 8.6 mL). The mixture was stirred at 80 °C for 4 h. The mixture was poured into saturated NH4CI (100 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were concentrated and the residue was purified by silica gel chromatography (DCM / MeOH=50 / l to 6 / 1) to give compound 25-2 (750.0 mg, 10%) as a yellow solid.

[00346] LCMS: [M+H]+ = 747.6 Step 3: Synthesis of compound 25

[00347] To a solution of 25-2 (1.3 g, 1.7 mmol) in MeCN (45 mL) and water (5.0 mL) was added (NH4)2Ce(NO3)6 (2.0 g, 3.7 mmol). The mixture was stirred at 0 °C for 1 h. The mixture was poured into water (100 mL), extracted with EtOAc (100 mL). The organic layer was washed with saturated NaHCOs (20 mL), dried over Na2SO4, filtered, concentrated to give a residue, which was purified by silica gel chromatography (DCM / MeOH=50 / l to 2 / 3) and prep-HPLC (Welch Xtimate C18 OBD, 21.2*250mm, lOum, 0.05% NH4HCO3, acetonitrile / water=55-80%) to give compound 25 (273.6 mg, 25%).

[00348] LCMS: [M+H]+ = 627.6.

[00349] JH NMR (400 MHz, DMSO-de) d 8.02-7.76 (m, 3H), 6.90 (d, J = 4.8 Hz, 1H), 6.85-6.82 (m, 1H), 6.31 (d, J = 6.0 Hz, 1H), 5.51-5.44 (m, 2H), 5.39-5.35 (m, 1H), 5.03-5.00 (m, 2H), 4.71-4.65 (m, 2H), 4.22^4.19 (m, 1H), 4.14-4.09 (m, 1H), 4.01-3.88 (m, 2H), 1.61-1.41 (m, 2H), 1.21-1.14 (m, 21H), 0.85 (t, J= 6.8 Hz, 3H).

[00350] The compound was separated by Chiral HPLC to give four isomers with the ratio 1:1:1:1.

[00351] The following compounds were synthesized according to the same procedure as for compound 25 except for using different starting materials or intermediates: Compound 30:

[00352] LC / MS: [M+H]+ = 683.3

[00353] 1H NMR (400 MHz, DMSO-d6) 8 8.03-7.80 (m, 3H), 6.92-6.89 (m, 1H), 6.85-6.81 (m, 1H), 6.32-6.27 (m, 1H), 5.51-5.43 (m, 2H), 5.36 (brs, 1H), 5.05-4.97 (m, 2H), 4.72-4.63 (m, 2H), 4.24-4.18 (m, 1H), 4.14-4.08 (m, 1H), 4.00-3.90 (m, 2H), 1.61-1.42 (m, 2H), 1.31-1.15 (m, 29H), 0.85 (t, J= 7.2 Hz, 3H).

[00354] The compound was separated by Chiral HPLC to give four isomers with the ratio -1:1:1:1. 2.4 Synthesis of compound 28 CH3(CH2)12^O ------- CH3(CH2)i2' / 28-1                         28-2 I ° ’ CH3(CH2)12'^O^^O^I  _ 28-4 ^NH.HCI 1                   1 A 28s~2 r O Cl ^0^01          |   o 1        28s-1                       JL X ^OH --------------* CH3(CH2)i2^^O O Cl 28-3 nh2 I O      HO 1a                  JL    JL          p—q—_ (-,1 N ----► CH3(CH2)12 / O O O     VX ;—1 HO OH 28-5 nh2 / Vn. n o \ HO 6h Step 1: Synthesis of compound 28-2

[00355] To a solution of 28-1 (24 g, 106.1 mmol) in MeOH (240 mL) was added NaBH4(8.1 g, 212.1 mmol) at 0 °C, the mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated NH4CI, extracted with EA (500 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated to give compound 28-2 (24.3 g, crude) as a yellow oil, which was used directly without further purification. Step 2: Synthesis of compound 28-3

[00356] To a solution of 28-2 (12.1 g, 52.9 mmol) in THF (120 mL) were added 28s-1 (13.5 g, 104.9 mmol) and pyridine (16.8 g, 212.4 mmol, 17.1 mL) at -5 °C. The mixture was stirred at -5 °C for 1 h. The mixture was diluted PE (100 mL), washed with NH4CI (aq). The combined organic layers were concentrated and purified by silica gel chromatography (PE / DCM=20 / l to 6 / 1) to give compound 28-3 (13.0 g, 76.4%) as a colorless oil. Step 3: Synthesis of compound 28-4

[00357] To a solution of 28-3 (7 g, 8.1 mmol) in acetone (70 mL) was added Nai (13.1 g, 87.3 mmol), the mixture was stirred at 30 °C for 64 h. The reaction was concentrated, diluted with PE (200 mL), washed with water (100 mL), saturated Na2SOs (10 mL). The organic layer was concentrated and purified by silica gel chromatography (7% DCM in PE) to give compound 28-4 (7.1 g, 78.9%) as a colorless oil. Step 4: Synthesis of compound 28-5.

[00358] To a solution of Intermediate la (4.5 g, 12.1 mmol) in MeOH (45 mL) was added DIEA (4.7 g, 36.3 mmol, 6.3 mL), the mixture was stirred at 25 °C for 5 min. Then 28-4 (10.0 g, 24.2 mmol) was added dropwise, and the mixture was stirred at 65 °C for 2 h. The reaction was concentrated and quenched with saturated NH4CI. The reaction mixture was extracted with EA / THF (100 mL / 100 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (50% MeOH in EA) to give compound 28-5 (4.6 g, 57.8%) as a white solid.

[00359] LCMS: [M+H]+ = 656.3 Step 5: Synthesis of compound 28

[00360] To a solution of 28-5 (1.7 g, 2.6 mmol) and 28s-2 (3.1 g, 38.8 mmol) in DMF (17 mL) were added DIEA (2.1 g, 15.6 mmol) and BOP (4.6 g, 10.4 mmol), the mixture was stirred at 25 °C for 16 h. The reaction was concentrated and quenched with NH4CI (aq), extracted with EA / THF (100 mL / 100 mL), concentrated and purified by flash chromatography (7% MeOH in EA) to obtain a crude product (1.5 g), which was purified by prep-HPLC (Nanochrom ChromCore C18 21.2*250mm, lOum, (10 mmol NH4HCO3)-ACN, 90%~100%) to give compound 28 (84 mg, 3%).

[00361] LC / MS: [M+H]+ = 683.3

[00362] 'H NMR (400 MHz, DMSO-d6) 8 8.01-7.82 (m, 3H), 6.91-6.88 (m, 1H), 6.82-6.80 (m, 1H), 6.32 (brs, 1H), 5.54-5.44 (m, 2H), 5.38 (brs, 1H), 4.73-4.63 (m, 2H), 4.24-4.12 (m, 2H), 4.05-3.88 (m, 2H), 2.54-2.51 (m, 6H), 1.65-1.42 (m, 2H), 1.33-1.14 (m, 25H), 0.84 (t, J = 7.2 Hz, 3H).

[00363] The compound was separated by Chiral HPLC to give four isomers with the ratio -1:1:1:1.

[00364] The following compounds were synthesized according to the same procedure as for compound 28 except for using different starting materials or intermediates: Compound 29:

[00365] LC / MS: [M+H]+ = 711.5

[00366] JH NMR (400 MHz, MeOD) 8 7.87 (d, J = 2.4 Hz, 1H), 6.94-6.92 (m, 1H), 6.90-6.88 (m, 1H), 5.60-5.52 (m, 2H), 4.87-4.74 (m, 2H), 4.37-4.27 (m, 2H), 4.224.14 (m, 2H), 2.65-2.64 (m, 3H), 2.62-2.61 (m, 3H), 1.69-1.46 (m, 2H), 1.35-1.24 (m, 29H), 0.89 (t, J = 7.2 Hz, 3H).

[00367] The compound was separated by Chiral HPLC to give four isomers with the ratio -1:1:1:1. Example 3. Biochemical Assays Assay 1: In vitro anti-viral activities against 229E

[00368] The in vitro anti-229E activity and cytotoxicity were evaluated using MRC5 cell as follows.

[00369] Anti-virial activity assay: The MRC5 cells were seeded in 96-well plates, in 100 pl per well of assay medium, at a density of 20000 cells / well and cultured at 37 °C and 5% CO2. After incubation for 24 hours, the test compounds and a positive control (Remdesivir) were diluted with assay medium and then added into the cells, 50 pl per well. Then 50 pl per well of assay medium diluted virus was added. The resulting cell culture are incubated for additional 3 days until virus infection in the virus control (cells infected with virus, without compound treatment) displays significant CPE. The CPE are measured by CellTiter Gio following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.

[00370] The % inhibition was calculated by the following equation: Inhibition (%) = (Raw data CPD - Average VC) / (Average CC - Average VC) *100.

[00371] Cytotoxicity assay: The cytotoxicity of compounds is assessed under the same method as in the anti-virial activity assay, but without the step of virus infection. Cell viability is measured with Cell-Titer Gio following the manufacturer’s manual. The % Viability was calculated by the following equation: Viability (%) = (Raw data CPD -Average MC) / (Average CC - Average MC) *100. Raw data CPD: values of the sample-treated wells Average VC: average value of virus control Average CC: average value of cell control (cells without virus infection or compound treatment) Average MC: average value of medium control (medium only) wells. Assay 2: In vitro anti-viral activities against SARS-CoV-2 Replicon

[00372] The test compounds, a positive control (Remdesivir) and Reference Compound 1 (octyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)-L-alaninate) were serially diluted in DMSO and added into 384-well plates 0.3 pl per well (8 doses, 3 fold, in duplicate wells). The replicon RNA was generated in vitro transcript. Huh7 cells transfected with purified SARS-CoV-2 replicon RNAs were seeded 4000 / well in 384 microplates containing serially diluted compounds, then cultured at 37°C and 5% CO2 for 1 day. The final volume of the cell culture was 60pl per well, and the final concentrations of DMSO in the test plates was 0.5%.

[00373] Fluorescence intensity was determined using Acumen Cellista (TTP LabTech), and the antiviral activity of compounds was calculated based on the inhibition of expression of GFP. Cell viability was measured with CellTiter Gio following the manufacturer’s manual.

[00374] The antiviral activity and viability of compounds were expressed as % Inhibition and % Viability, respectively, and calculated with the formulas below: Inhibition (%) = (Raw data CPD - Average ZPE) / (Average HPE - Average ZPE) *100 Viability (%) = (Raw data CPD - Average HPE) / (Average ZPE- Average HPE) * 100 Raw data CPD: values of the sample-treated wells Average ZPE: average value of virus control Average HPE: average value of medium control (medium only) wells.

[00375] EC50 and CC50 values was calculated using the GraphPad Prism software using the nonlinear regression model of log (inhibitor) vs. response — Variable slope (four parameters). Assay 3: Determination of intracellular nucleoside triphosphates:

[00376] The human hepatocellular carcinoma cell line HepG2 and human lung adenocarcinoma cell line were used to evaluate the drug cell uptake and intracellular nucleoside triphosphates. Cells were incubated in 6 well plate at 37°C in a 5% CO2 -95% air atmosphere over allow the cells to attach. The cell density was 2xl06 / well for HepG2 and lxl06 / well for A549. The incubation medium for HepG2 and A549 were Eagle's Minimum Essential Medium (EMEM) and F-12K, respectively, both containing 2% Fetal bovine serum (FBS). After cell attached, the culture medium was removed and 2.5mL fresh medium which containing test compound at IpM was add to each well for incubation at 37°C in a 5% CO2 - 95% air atmosphere. At each specific time point (1, 2, 4, 6h), remove the culture medium and wash the cells with 3mL ice-cold PBS twice. After washing, the cells were digested from the plate wells with 600pL ice-cold 70% methanol. The cell lysates were then centrifuged at 4°C, 13000rpm for 5min. An aliquot of (200pL) the supernatant was transferred to a clean 96 well plate for LC- MS / MS (Shimazu 20A and API 4000 Qtrap) analysis to determine the concentration of intracellular nucleoside triphosphates. Assay 4: In vitro anti-viral activities against RSV

[00377] The in vitro anti-RSV activity and cytotoxicity were evaluated using Hep-2 cell as follows.

[00378] Anti-virial activity assay: The Hep-2 cells were seeded in 96-well plates, in 100 pl per well of assay medium, at a density of 6000 cells / well and cultured at 37 °C and 5% CO2. After incubation for 24 hours, the test compounds and a positive control (Remdesivir) were diluted with assay medium and then added into the cells, 50 pl per well. Then 50 pl per well of assay medium diluted RSV A2 virus was added. The final concentration of DMSO in the assay medium is 0.5%. The resulting cell culture are incubated for 5 days. The supernatant of antiviral activity test plate was removed, and the intracellular viral protein expression was detected by anti-RSV F antibody ELISA assay. The antiviral activity of the tested compounds was calculated based on the virus replication inhibition rate of the tested compounds at different concentrations.

[00379] The % inhibition was calculated by the following equation: Inhibition (%) = (Raw data CPD - Average VC) / (Average CC - Average VC) *100.

[00380] Cytotoxicity assay: The cytotoxicity of compounds is assessed under the same method as in the anti-virial activity assay, but without the step of virus infection. Cell viability is measured with CCK8 following the manufacturer’s manual.

[00381] The % Viability was calculated by the following equation: Viability (%) = (Raw data CPD - Average MC) / (Average CC - Average MC) *100. Raw data CPD: values of the sample-treated wells Average VC: average value of virus control Average CC: average value of cell control (cells without virus infection or compound treatment) Average MC: average value of medium control (medium only) wells.

[00382] EC50 and CC50 values was calculated using the GraphPad Prism software using the nonlinear regression model of log (inhibitor) vs. response - Variable slope (four parameters).

[00383] Tables 2-4 show the results of exemplary compounds of the present disclosure for Assays 3-5, respectively. It shows the compounds of present disclosure have good inhibitory effect against various coronaviruses and respiratory syncytial viruses with low cytotoxicity, show higher stability in human liver and produce more triphosphorylated products in lung cells. Table 2 In vitro anti-viral activities against SARS-CoV-2 Replicon for exemplary compounds Compound No. Replicon Huh7 EC501 (nM) CC50 (nM) Remdesivir A >1000 1 A >1000 2 A >1000 3 A >1000 4 A >1000 5 A >1000 6 A >1000 7 A >1000 8 A >1000 9 A >1000 10 B >1000 11 A >1000 12 A >1000 13 A >1000 14 A >1000 15 A >1000 16 A >1000 17 A >1000 18 A >1000 19 A >1000 22 A >1000 23 A >1000 24 A >1000 25 A >1000 26 A >1000 27 A >1000 28 A >1000 29 A >1000 30 A >1000 32 A >1000 34 A >1000 45 A >1000 46 A >1000 47 A >1000 48 A >1000 53 A >1000 54 A >1000 55 A >1000 56 A >1000 62 A >1000 62-P1 A >1000 62-P2 A >1000 64 A >1000 66 A >1000 67 A >1000 68 A >1000 69 A >1000 70 A >1000 71 A >1000 72 A >1000 1 A: <100nM, B: lOOnM-lOOOnM, D: >1000nM Table 3 Intracellular nucleoside triphosphates for exemplary compounds Compound No. Hep G2 Intra-cell Concentration1 (nM) MetaPpp A549 Intra-cell Concentration1 (nM) MetaPpp Ih 2h 4h 6h Ih 2h 4h 6h Remdesivir C B A A C C C C 3 A A B A B A A A 12 A A A A B A A A 17 A A A A C B A B 18 C A A A 19 C A A A C c C B 22 A A A A B A A A 23 A A A A B A A A 24 A A A A A A A A 27 A A A A C B B B 28 A A A A C A A A 29 A A A A C C A A 30 A A A A C B A A 32 B A A A C B A A 1 A: >500nM, B: 200~500nM, C: <200nM. Table 4 In vitro anti-viral activities against RSV A2 for exemplary compounds Compound No. RSV A2 Hep-2 ECso1 (nM) CC50(nM) Remdesivir A >1000 1 C >10000 3 B >10000 5 A >1000 7 A >1000 9 A >10000 11 A >10000 15 B >10000 17 A >1000 18 A >1000 19 A >1000 22 A >1000 23 A >1000 24 A >1000 25 A >1000 26 A >1000 27 A >1000 28 A >1000 29 A >1000 30 A >1000 32 A >1000 62 A >1000 62-P1 A >1000 62-P2 A >1000 64 A >1000 64-P1 A >1000 64-P2 A >1000 67 A >1000 1 A: <100nM, B: lOOnM-lOOOnM, C: >1000nM Assay 5: Rat tissue distribution

[00384] SPF-grade male Sprague-Dawley (SD) rats (n=12 for each compound) were used for rat tissue distribution assessment. The compounds or positive control (remdesivir) were administrated at 20mg / kg dose level via intravenous injection. After each specified time points (1, 3, 8 and 24 hour), 3 animals were sacrificed to collect lung and liver samples.

[00385] Liver and lung samples were homolyzed with 4 volume of ice cold 70% methanol (1:4 w:v). An aliquot of 800pL homogenate were transferred to 1.5mL tube for centrifugation at 14000g, 4°C with 15min. After centrifugation, 300pL supernatants were transferred to a 96 well plate and were evaporated to dryness with nitrogen gas. The nitrogen dried residues were then dissolved with 200pL of initial LC mobile phase. The 96 well plates were loaded to a LC-MS instrument for the determination of triphosphate concentration in liver and lung. Table 5 Rat tissue distribution for exemplary compounds Compound In-vivo PK Rat (IV, 20mg / kg) Liver MetaPpp (nmol / kg) Lung MetaPpp (nmol / kg) 1 h 3h 8h 24 h 1 h 3h 8h 24 h Remdesivir A A A B C C C C 3 A A A C B C C C 5 B A A B B A A c 6 C A A B C A A c 7 A A A C A A A B 10 C B A C C B A C 15 A A A C A A B C 17 A A A B B B C C 18 A A A A A A A A 22 A A A B A A B C 23 A A A B A A A C 24 A A A A C B C A 27 A A A B B B A C 28 A A A A C B C B 29 A A A A A C C A 30 A A A A B C c C

[00386] A: >500nM, B: 200~500nM, C: <200nM.

[00387] The results in Table 5 showed that the compounds of present disclosure have higher distribution in lung and better lung selectivity than remdesivir. Assay 6: Hemolysis test in SD rat red blood cells

[00388] Test compounds were dissolved in saline at Img / mL and serial diluted in saline as working solution with desired concentration. Mix pure Triton X-100 in water (2:98, v:v) to prepare 2% Triton X-100. Rat whole blood was transferred to a 50mL tube and centrifuge the blood at 2000rmp for 10 minutes, then discard the supernatant. Gently resuspend the precipitated red blood cells in saline, centrifuge at 3000 rpm for 10 minutes. Discard the supernatant. Repeat the above process until the supernatant is colorless and transparent and resuspend the washed red blood cell (RBC) in an equal volume of saline. Count the RBC and adjust the density of RBC to 2* 108 cells / mL. Aliquot 300pL RBC and working solution of tests compound to the plate. For the positive and negative control, 300pL saline or 2% Triton X-100 were added respectively. The final concentrations of test compounds were 70pg / mL, 23.33pg / mL, 7.77pg / mL, 2.59pg / mL, 0.86pg / mL, and 0.29pg / mL. After incubation at 37°C for 45 minutes, centrifuge each sample and measure the absorbance of the supernatant from 107 each sample using UV spectrometer (wavelengh=540 nm). Percent Hemolysis = 100 * [(Absorbance of sample - Absorbance of negative control) / (Absorbance of positive control - Absorbance of negative control)]. Table 6 Hemolysis test for exemplary compounds Compound Hemolysis 70 Pg / mL 20.33 Pg / mL 7.77 pg / mL 2.59 pg / mL 0.86 pg / mL 0.29 pg / mL 1 B A A A A A 5 A A A A A A 7 A A A A A A 15 A A A A A A 17 A A A A A A 22 B A A A A A 24 A A A A A A 25 A A A A A A 27 A A A A A A 30 A A A A A A 62 A A A A A A 64 A A A A A A 66 A A A A A A 67 A A A A A A 68 A A A A A A 69 A A A A A A 70 A A A A A A

[00389] A:<10%, B:10%~30%; C:>30%

[00390] The hemolysis test results in Table 6 showed that the compounds of present disclosure exhibit good safety. Assay 7: In vitro anti-viral activities against HMPV

[001] The in vitro anti-HMPV activity and cytotoxicity were evaluated using LLC-MK2 cell as follows.

[002] Anti-viral activity assay: The LLC-MK2 cells were seeded in 96-well plates, in 100 pl per well of assay medium, at a density of 10,000 cells / well and cultured at 37 °C and 5% CO2. After overnight incubation, the test compounds and a positive control (ALS-8112) were diluted with assay medium containing 5 pg / ml trypsin and then added into the cells, 50 pl per well. Then 50 pl per well of assay medium containing 5 pg / ml trypsin diluted HMPV virus was added. The final concentrations of DMSO and trypsin in the assay medium were 0.5% and 2.5 pg / ml, respectively. The resulting cell culture was incubated at 33 °C and 5% CO2for 3 days. The GFP intensity was measured by Acumen Cellista. The antiviral activity of the tested compounds was calculated based on the virus replication inhibition rate of the tested compounds at different concentrations.

[003] The % inhibition was calculated by the following equation: Inhibition (%) = (Raw data CPD - Average VC) / (Average CC - Average VC) * 100.

[004] Cytotoxicity assay: The cytotoxicity of compounds was assessed under the same method as in the anti-viral activity assay, but without the step of virus infection. Cell viability was measured with CCK8 following the manufacturer’s manual.

[005] The % Viability was calculated by the following equation: Viability (%) = (Raw data CPD - Average MC) / (Average CC - Average MC) * 100. Raw data CPD: values of the sample-treated wells Average VC: average value of virus control (cells infected with virus, without compound treatment) wells Average CC: average value of cell control (cells without virus infection or compound treatment) Average MC: average value of medium control (medium only) wells.

[006] EC50 and CC50 values were calculated using the GraphPad Prism software using the nonlinear regression model of log (inhibitor) vs. response — Variable slope (four parameters). Table 7: In vitro anti-viral activities against HMPV for exemplary compounds Compound HMPV LLC-MK 2 EC50 (nM) CC50 (nM) Remdesivir C >1000 7 A >1000 23 A >1000 24 A >1000 32 A >1000 62-P1 A >1000 62-P2 A >1000 63 A >1000 64-P1 B >1000 64-P2 B >1000

[007] 1 A: <100nM, B: IQOnM-lOOOnM, C: >1000nM

[008] The result in Table 7 shows the compounds of present disclosure have good inhibitory effect against HMPV with low cytotoxicity.

[009] The foregoing description is considered as illustrative only of the principles of the present disclosure. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow.

Claims

WHAT CLAIMED IS:

1. A compound having Formula (I) or Formula (II):(I)(II)or a pharmaceutically acceptable salt thereof, whereinBase is a naturally occurring or modified pyrimidine base or purine base;Q is CH2, CHD or CD2;R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -ORa, -NO2, -N(Ra)2, -C(0)N(Ra)2, -C(O)Ra, -OC(O)Ra, -C(O)ORa, -S(O)Ra, -S(O)2Ra, -S(O)ORa, -S(O)2(ORa), and -S(O)2N(Ra)2;each of R21, R22, R31, R32, and R4 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -ORa, -NO2, -N(Ra)2, -C(0)N(Ra)2, -C(O)Ra, -OC(O)Ra, -C(O)ORa, -S(O)Ra, and -S(O)2Ra;each R5 is independently selected from the group consisting of hydrogen, hydroxyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Ci-6 alkoxyl, wherein the alkyl, alkenyl, alkynyl and alkoxy are optionally substituted with one or more Rb; ortwo R5 taken together with the nitrogen atom to which they are bound form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are optionally substituted with one or more R5a;each R5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl or cycloalkyl; ortwo R5a taken together with the intervening atom(s) therebetween form a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more Rb;L1 is-C(RL)2-;each Rl is independently selected from hydrogen, deuterium, or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl or heteroaryl;L2 is selected from *-OC(O)-, *-OC(O)O-, *-0C(0)N(Ra)-, *-N(Ra)C(0)-, *-OAN(Ra)C(0)0-, or           , wherein * end of L2 is connected to L1;R6 isR6bR6a is selected from the group consisting of Cs-20 alkyl, Cs-20 alkenyl, CH3(CH2)mO(CH2)n- and RCOCH2(CH2OCH2)PCH2-, each of which is optionally substituted with one or more Rb;R6b is selected from hydrogen, halogen, alkyl, alkenyl or alkoxyl, each of which is optionally substituted with one or more Rb;G is selected from -N(Ra)-**, -N(Ra)C(RG)2C(0)0-** or, wherein** end of G is connected to R7;ring A is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more Rb;X is selected from -0-, -N(Ra)- or -C(Ra)2-;each Rg is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl and natural amino acid side chain, each of which is optionally substituted with one or more Rb;R7 is selected from the group consisting of Cs-20 alkyl, Cs-20 alkenyl, Cs-20 alkynyl,CH3(CH2)mO(CH2)n- and RCOCH2(CH2OCH2)PCH2-, each of which is optionally substituted with one or more Rb;R8 is selected from the group consisting of hydrogen, Ci-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which is optionally substituted with one or more Rb;each Ra is independently selected from hydrogen, halogen or alkyl;each Rb is independently selected from halogen, hydroxyl, cyano, amino, alkyl or alkoxy 1;each Rc is independently selected from hydrogen or alkyl; andeach m, n or p is independently an integer of 0 to 20.

2. The compound of claim 1, having a Formula (la) or Formula (Ila):R® ^R5 NL2-L1-O-P—O-QR4' R31*q Base / "'R1 ^--Sr21 R32 R22(la)G 2 4     ।                  BaseT2-L1-O-P—O-Q.      ,□31*3   - KR32 R22 (lla)or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the Base is selected from the group consisting of:

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the base is selected from the group consisting of:

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen, hydroxyl, cyano, azido, alkyl, or haloalkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R1 is cyano.

7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each of R21, R22, R31, R32, and R4 is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, haloalkyl, or -OC(O)Ra.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein each of R21, R22, R31, R32 is selected from hydrogen, deuterium, halogen, hydroxyl, alkyl or -OC(O)Ra.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Ra is alkyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein Ra is methyl.

11. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, deuterium, halogen, cyano, azido, or haloalkyl.

12. The compound of claim 2, or a pharmaceutically acceptable salt thereof, whereinis selected from the group consisting of:

13. The compound of any one of preceding claims, or a pharmaceutically acceptable14. The compound of claim 13, or a pharmaceutically acceptable salt thereof,15. The compound of claim 2, having a Formula (la):R® ^R5 N L2-L1-o-p-o-QvOyBase R4' \ 1'^ d31<; K R R32 R22(la)or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from hydrogen or Ci-6 alkyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently Ci-6 alkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently C1-3 alkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein both R5 are methyl.

20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein both R5 are ethyl.

21. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein one R5 is hydrogen, and the other R5 is Ci-6 alkyl.

22. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein both R5 are hydrogen.

23. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein two R5 taken together with the nitrogen atom to which they are bound form a heterocyclyl optionally substituted with one or more R5a.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein two R5 taken together with the nitrogen atom to which they are bound form a heterocyclyl selected from the group consisting of:each of which is optionally substituted with one or more R5a.

25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt thereof, wherein R5a is selected from alkyl or alkoxyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof,) Qwherein R5a is methyl or         .

27. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each RL is independently selected from hydrogen, deuterium, or alkyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein both RL are hydrogen.

29. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from *-OC(O)- or *-OC(O)O-.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein L2 is *-OC(O)O-.

31. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R6a is selected from Cs-20 alkyl or Cs-20 alkenyl, each of which is optionally substituted with one or more Rb.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R6a is selected from Cs-i3 alkyl or Cs-i3 alkenyl, each of which is optionally substituted with one or more Rb.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R6a is Cs-i3 alkyl optionally substituted with one or more Rb.

34. The compound of any one of claims 15 to 33, or a pharmaceutically acceptable salt thereof, wherein R6b is selected from hydrogen, halogen or alkyl.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, R6b is hydrogen.

36. The compound of claim 34, or a pharmaceutically acceptable salt thereof, R6b is methyl.

37. The compound of claim 2, having a Formula (Ila):^R7GL2-L1-O-P—O-Q.RZ O R^.^ R32 R22 (iia)or a pharmaceutically acceptable salt thereof.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from *-OC(O)- or *-OC(O)O-.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein L2 is *-OC(O)O-.

40. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R8 is selected from hydrogen or Ci-6 alkyl optionally substituted with one or more Rb.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R8 is C1-3 alkyl optionally substituted with one or more Rb.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R8 is methyl or isopropyl.

43. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein G is -N(Ra)-**.

44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein Ra is selected from hydrogen or alkyl.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein Ra is methyl.

46. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein G is -N(Ra)C(RG)2C(0)0-**.

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein each RG is independently selected from the group consisting of hydrogen, Ci-6 alkyl, Ce-12 aryl, 5- to 12-membered heteroaryl, (C1-3 alkyl)(C3-i2 cycloalkyl), (C1-3 alkyl)(3- to 12-membered heterocyclyl), (C1-3 alkyl)(C6-i2 aryl), and (C1-3 alkyl)(5- to 12-membered heteroaryl), each of which is optionally substituted with one or more Rb.

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein one of RG is hydrogen, and the other RG is selected from C1-6 alkyl, C6-12 aryl, (C1-3 alkyl)(C6-i2 aryl), or (C1-3 alkyl)(5- to 12-membered heteroaryl), each of which is optionally substituted with one or more Rb.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein one of RG is hydrogen, and the other RG is selected from the group consisting of:

50. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein both RG are methyl.

51. The compound of claim 37, or a pharmaceutically acceptable salt thereof,wherein G isand X is -O-.

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of:

53. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from Cs-20 alkyl or Cs-20 alkenyl, each of which is optionally substituted with one or more Rb.

54. The compound of claim 53, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from C16-20 alkyl or C16-20 alkenyl, each of which is optionally substituted with one or more Rb.

55. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein R7 is C16-20 alkyl optionally substituted with one or more Rb.

56. The compound of claim 2, having a formula selected from:(lib)or a pharmaceutically acceptable salt thereof.

57. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any compound set forth in Table 1.

58. A pharmaceutical composition comprising the compound of any one of claims 157 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

59. The pharmaceutical composition of claim 58, which is formulated for oral administration, injection administration, nasal administration, or pulmonary administration.

60. A method for treating a viral infection in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 58-59 to the subject, wherein the viral infection is from an RNA virus selected from the group consisting of Retroviridae virus, Lentiviridae virus, Coronaviridae virus, Picornaviridae virus, Caliciviridae virus, Flaviviridae virus, Togaviridae virus, Bomaviridae, Filoviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae, Arenaviridae, Bunyaviridae, Orthomyxoviridae, Deltavirus, Lymphocytic choriomeningitis virus, Coronavirus, HIV, SARS, Poliovirus, Rhinovirus 16, Hepatitis A, Norwalk virus, Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus, Zika virus, Rubella virus, Ross River virus, Sindbis virus, Chikungunya virus, Boma disease virus, Ebola virus, Marburg virus, Measles virus, Mumps virus, Nipah virus, Hendra virus, Newcastle disease virus, Human respiratory syncytial virus, Rabies virus, Lassa virus, Hantavirus, Crimean-Congo hemorrhagic fever virus, Influenza, Hepatitis D virus, Enterovirus 71, Coxsakie Virus, human metapneumo virus, Norovirus, 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), SARS-CoV-2 (COVID-19), Feline coronavirus (FCoV), feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV).

61. A method for inhibiting RNA polymerase in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 58-59 to the subject.

62. Use of a compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 58-59, in the manufacture of a medicament for treating a viral infection.

63. A compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 58-59, for treating a viral infection.