TW202541816A - Antiviral compounds and compositions and uses thereof - Google Patents

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

Antiviral compounds, their compositions and uses

This disclosure relates generally to compounds that exhibit activity in RNA polymerase inhibition, pharmaceutical compositions comprising such compounds, and methods of treatment by administering such compounds or pharmaceutical compositions comprising such compounds.

Over the past two decades, numerous viruses have been identified that can cause life-threatening diseases in humans and animals, including influenza viruses, respiratory syncytial virus (RSV), parainfluenza viruses, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and Ebola virus. Among these, the global pandemic caused by SARS-CoV-2 has led to severe respiratory illnesses worldwide, with severe cases progressing to pneumonia and multiple organ failure, resulting in millions of deaths globally. Coronaviruses are highly prone to mutating into epidemic variants. Although several vaccines have been approved since the SARS-CoV-2 outbreak, vaccinated individuals still face the risk of developing immune evasion mutants. Therefore, developing antiviral drugs to combat existing and emerging coronaviruses is crucial.

Coronaviruses are positive-sense RNA viruses that encode 16 non-structural proteins (nsp1 to nsp16). Many of these non-structural proteins bind together to form a multi-protein replicase-transcriptionase complex (RTC). The primary replicase-transcriptionase protein is RNA-dependent RNA polymerase (RdRp), which directly participates in RNA replication and transcription of the RNA strand. Furthermore, RdRp is highly conserved across various variants and viruses, making it an ideal drug target for controlling various RNA virus infections.

Remdesivir is a nucleoside GS-441524 monoamino phosphate prodrug, originally developed to treat Ebola virus infection by inhibiting the RdRp of SARS-CoV-2. In several countries, it was the first antiviral drug approved or authorized for emergency treatment of COVID-19. Remdesivir improves clinical outcomes in hospitalized patients with moderate to severe illness and prevents disease progression in outpatients (Beigel JH et al., Remdesivir for the treatment of covid-19 - final report. N. Engl. J. Med. 2020;383(19):1813-1826.; Gottlieb RL et al., Early remdesivir to prevent progression to severe covid-19 in outpatients. N. Engl. J. Med. 2021). Vangeel et al. also demonstrated that remdesivir is effective against different SARS-CoV-2 related variants (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 being limited to intravenous administration, having a short plasma half-life, plasma exposure not being correlated with clinical efficacy, and having a low pulmonary delivery rate (Sun D. Remdesivir for treatment of COVID-19: combination of pulmonary and IV administration may offer additional benefit. AAPS J. 2020;22:77.).

Therefore, this technology requires the development of modified compounds that exhibit inhibitory activity against RNA polymerase, particularly RNA polymerase inhibitors with good oral and pulmonary bioavailability and high conversion rates to its monophosphate and triphosphate.

This disclosure provides compounds capable of inhibiting RNA polymerase, pharmaceutical compositions comprising such compounds, and methods for treating viral infections using such compounds or pharmaceutical compositions.

In one state, this disclosure provides a compound having formula (I) or formula (II): Or a pharmaceutically acceptable salt thereof, wherein the base is a naturally occurring or modified pyrimidine 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, halogenated alkyl, ^-ORa , -NO2, -N( ^Ra ) _{2 ,} -C(O)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 ^; _R21 ^{, R22} , ^R31 , R Each of ^R32 and ^R4 is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, halogenated alkyl, ^-ORa , -NO2, -N( ^Ra ) ₂ , -C(O)N( ^Ra ) ₂ , -C(O) _Ra , -OC(O) ^Ra , -C(O) ^ORa , ^-S (O) ^Ra and -S(O) _2Ra ; Each of ^R5 is independently selected from the group consisting of: hydrogen, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl or _C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl and alkoxy are, as appropriate, substituted by one or more ^{Rb ;} or two R ^5, together with the nitrogen atom to which it is attached, forms a heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group is, as appropriate, substituted by one or more R ^5a ; each R ^5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl; or two R ^5a , together with the intercalation atom between them, form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is, as appropriate, substituted by one or more R ^b ; L ¹ is -C( ^RL ) _2- ; each R ^L is independently selected from hydrogen, deuterium, or an alkyl group, which may be substituted by one or more groups independently selected from halogen, hydroxyl, cyano, cycloalkyl, heterocyclic, aryl, or heteroaryl groups; ^L2 is selected from *-OC(O)-, *-OC(O)O-, *-OC(O)N( ^Ra )-, *-N( ^Ra )C(O)-, *-N( ^Ra )C(O)O-, or The * terminal of ^L2 is connected to ^L1 ; ^R6 is... ^R6a is selected from the group consisting of: _C8-20 alkyl, _C8-20 alkenyl, _CH3 ( _{CH2 ) mO} ( _CH2 ) _n- and ^RcOCH2 ( _CH2OCH2 ) _{pCH2- ,} wherein each is substituted by one or more ^Rb , as appropriate; ^R6b is selected from hydrogen, halogen, alkyl _, alkenyl or alkoxy, wherein each is substituted by one or more ^Rb , as appropriate; G is selected from -N( ^Ra )-**, -N( ^Ra )C( ^RG ) _2C (O)O-** or The **terminus of G is connected to ^R7 ; ring A is heterocyclic or heteroaryl, wherein each is substituted by one or more Rb ^groups as appropriate; X is selected from -O-, -N( ^Ra )-, or -C( ^Ra ) _2- ; each R and ^G is independently selected from the group consisting of: hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, and natural amino acid side chains, wherein each is substituted by one or more Rb ^groups as appropriate; ^R7 is selected from the group consisting of: _C8-20 alkyl, _C8-20 alkenyl, _C8-20 alkynyl, _CH3 ( _CH2 ) _mO ( _{CH2 ) n-} , _and ^RcOCH2 _{( CH2OCH2} ) _pCH2 - where each is substituted by one or more ^Rb as appropriate; ^R8 is selected from the group consisting of: hydrogen, _C1-6 alkyl, _C2-6 alkenyl or _C2-6 alkynyl, where each is substituted by one or more ^Rb as appropriate; each ^Ra is independently selected from hydrogen, halogen or alkyl; each ^Rb is independently selected from halogen, hydroxyl, cyano, amino, alkyl or alkoxy; each ^Rc is independently selected from hydrogen or alkyl; and each m, n or p is independently an integer from 0 to 20.

In another embodiment, a compound having formula (Ia) or formula (IIa) is provided: (Ia) (IIa), or a medically acceptable salt thereof.

In another embodiment, a compound having the following formula is provided: (Ib) (Ic) (Id) (Ie) (IIb) (IIc) (IId) (IIe) or a medically acceptable salt thereof.

In another embodiment, this disclosure provides a pharmaceutical composition comprising the compound of this disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In another embodiment, this disclosure provides a method for treating a viral infection in an individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In another embodiment, this disclosure provides a method for inhibiting RNA polymerase in an individual in need, the method comprising administering to the individual in need a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In another embodiment, this disclosure provides the use of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions in the manufacture of medicaments for the treatment of viral infections.

In another embodiment, this disclosure provides a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment of viral infections.

Please refer to certain embodiments of this disclosure for details, which are illustrated in the appended structures and formulas. Although this disclosure is described in conjunction with the listed embodiments, it should be understood that it is not intended to limit this disclosure to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, or equivalents that may be included within the scope of this disclosure as defined by the claims. Those skilled in the art will recognize many methods or materials similar to or equivalent to those described herein that can be practiced. This disclosure is by no means limited to the methods or materials described. In the event that one or more of the incorporated references and similar materials (including (but not limited to) the defined terms, terminology usages, and described techniques) differ from or contradict this application, this disclosure shall prevail. All references, patents, and patent applications cited in this disclosure are incorporated herein by reference in their entirety.

It should be understood that certain features of this disclosure described in the context of different embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of this disclosure described in the context of a single embodiment for brevity may also be provided separately or in any suitable subcombination. It must be noted that, unless the context expressly requires otherwise, the singular forms "a,""an," and "the" as used in the specification and the scope of the appended claims include their plural forms. Thus, for example, reference to "compound" includes a plurality of compounds. Definitions

The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition inner cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry, as well as the descriptions of specific functional groups and reactivity, can be found in Organic Chemistry, Thomas Sorrell, 2nd ed., University Science Books, Sausalito, 2006; Smith and March, March's Advanced Organic Chemistry, 6th ed., John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd ed., VCH Publishers, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 4th ed., Cambridge University Press, Cambridge, 2004. The full contents of each of these references are incorporated herein by reference.

Linking substituents are described in several places throughout this disclosure. Specifically, each linking substituent is intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes both -NR(CR'R")- and -(CR'R")NR-. Where the structure explicitly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For instance, if the structure requires a linking group and the Markush group definition of that variable lists "alkyl", then it should be understood that "alkyl" indicates a linked alkyl group.

When the bond to a substituent is shown to cross the bonds of two atoms in the ring, the substituent may bond to any atom in the ring. When the listed substituent does not indicate that it bonds to any other atom in the given compound, the substituent may bond via any atom in the formula. Combinations of substituents and/or variables are permissible, provided that the combination produces a stable compound.

When any variable (e.g., ^Ri ) appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for each subsequent occurrence. Thus, for example, if a group is shown to be partially substituted by 0 to 2 ^Ri , the group may, as appropriate, be partially substituted by up to two ^Ri , and ^Ri is chosen independently of the definition of ^Ri for each occurrence. Furthermore, combinations of substituents and/or variables are permissible, provided that such combinations produce a stable compound.

As used herein, the term "C_{_ij}" indicates a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and all integer points in between, where j is greater than i. For example, C _{_1-6} indicates a range of one to six carbon atoms, including one, two, three, four, five, and six carbon atoms. In some embodiments, the term "C _{_1-12} " 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.

As used herein, the term "alkyl," whether used as part of another term or independently, refers to a saturated straight-chain or branched-chain hydrocarbon that may, as appropriate, be independently substituted by one or more of the substituents described herein. The term "C_{_ij}alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 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 "C _{_1-10} alkyl" include (but are not limited to) methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of " _C1-6 alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc. In some embodiments, the alkyl group contains 9 to 30 carbon atoms. In some embodiments, the alkyl group contains 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.

As used herein, the term "alkylcycloalkyl" refers to an alkyl group linked to a cycloalkyl group, including -alkyl-cycloalkyl and alkyl-cycloalkyl-. In some embodiments, alkylcycloalkyl refers to -alkyl-cycloalkyl.

As used herein, the term "alkyl heterocyclic" refers to an alkyl group attached to a heterocyclic group, including -alkyl-heterocyclic and alkyl-heterocyclic-. In some embodiments, alkyl heterocyclic refers to -alkyl-heterocyclic.

As used herein, the term "alkylaryl" refers to an alkyl group attached to an aryl group, including -alkyl-aryl and alkyl-aryl-. In some embodiments, alkylaryl refers to -alkyl-aryl.

As used herein, the term "alkyl heteroaryl" refers to an alkyl group attached to a heteroaryl group, including -alkyl-heteroaryl and alkyl-heteroaryl-. In some embodiments, alkyl heteroaryl refers to -alkyl-heteroaryl.

As used herein, the term "alkenyl," whether used as part of another term or independently, refers to a straight-chain or branched hydrocarbon having at least one carbon-carbon double bond, which may, as appropriate, be independently substituted by one or more substituents described herein, including groups having "cis" and "trans" orientations or substituted "E" and "Z" orientations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 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, or 2 to 3 carbon atoms. In some embodiments, the alkenyl group contains 9 to 30 carbon atoms. In some embodiments, the alkenyl group contains 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 groups include (but are not limited to) ethylenyl (or vinyl), allyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, etc.

As used herein, the term "alkoxy" whether used as part of another term or independently, refers to an alkyl group (-O-alkyl) attached to an oxygen atom. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms. In some embodiments, the alkoxy group contains 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 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 alkoxy groups include (but are not limited to) methoxy, ethoxy, isopropoxy, etc.

As used herein, the term "alkynyl" whether used as part of another term or independently refers to a straight-chain or branched hydrocarbon having at least one carbon-carbon reference bond, which may, as appropriate, be independently substituted by one or more substituents described herein. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 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, or 2 to 3 carbon atoms. In some embodiments, the alkynyl group contains 9 to 30 carbon atoms. In some embodiments, the alkynyl group contains 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 groups include (but are not limited to) ethynyl, 1-propynyl, 2-propynyl, etc.

As used herein, the term "amine" refers to the -NH ₂ group. The amine group may also be substituted by one or more groups (such as alkyl, aryl, carbonyl or other amine groups).

As used herein, the term "aryl," whether used as part of another term or independently, refers to a group derived from a carbohydrogen ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic or polycyclic system (including, but not limited to, bicyclic, tricyclic, or tetracyclic systems). In the case of a polycyclic system, it can include fused or spirocyclic systems. For example, a polycyclic aryl group can comprise an aromatic ring fused to one or more additional rings (such as cycloalkyl or aryl rings). In some embodiments, the aryl group is _C6 - _C12 aryl. In some embodiments, the aryl group is _C6 - _C11 aryl. In some embodiments, the aryl group is _C6 - _C10 aryl. In some embodiments, the aryl group is _C6 - _C9 aryl. In some embodiments, the aryl group is _C6 - _C8 aryl. The aryl group includes (but is not limited to) aryl groups derived from carbohydrocyclic systems of anthracene, anthraquinone, anthracene, azyl, phenyl, thallium, thallium, thallium, as-indacene, s-indacene, dihydroindene, indene, naphthyl, pelyl, phenanthrene, heptaenyl, pyrene, and bitriphenyl. Unless expressly stated otherwise in the specification, the aryl group may, where appropriate, be substituted at one or more ring positions with the substituents described herein.

As used in this article, the term "azido group" refers to -N ₃ .

As used herein, the term "cycloalkyl" whether used as part of another term or independently refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring. In the case of a polycyclic carbocyclic system, it may include fused rings (e.g., fused with another cycloalkyl ring), spirocyclic, or bridged ring systems. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated. Representative cycloalkyl groups include (but are not limited to) those having three to fifteen carbon atoms ( _C3 - _C15 fully saturated cycloalkyl groups or _C3 - _C15 cycloalkenyl groups), three to ten carbon atoms ( _C3 - _C10 fully saturated cycloalkyl groups or _C3 - _C10 cycloalkenyl groups), three to eight carbon atoms ( _C3 - _C8 fully saturated cycloalkyl groups or _C3 - _C8 cycloalkenyl groups), three to six carbon atoms ( _C3 - _C6 fully saturated cycloalkyl groups or _C3 - _C6 cycloalkenyl groups), three to five carbon atoms ( _C3 - _C5 fully saturated cycloalkyl groups or _C3 - _C5 cycloalkenyl groups), or three to four carbon atoms ( _C3 - _C4 fully saturated cycloalkyl groups or C3- _C15 cycloalkenyl groups). A cycloalkyl group consisting of a _4- cycloalkenyl group. In some embodiments, the cycloalkyl group is 3 to 12 members. In some embodiments, the cycloalkyl group is 3 to 10 members. In some embodiments, the cycloalkyl group is 3 to 6 members. In some embodiments, the cycloalkyl group is 5 to 6 members. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, northionyl, decahydronaphthyl, bicyclic[3.3.0]octyl, bicyclic[4.3.0]nonyl, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclic[2.1.1]hexyl, bicyclic[2.2.1]heptyl, bicyclic[2.2.2]octyl, bicyclic[3.2.2]nonyl, bicyclic[3.3.2]decyl, and 7,7-dimethyl-bicyclic[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in the specification, the cycloalkyl group is, as appropriate, substituted at one or more ring positions with the substituents described herein.

As used in this article, the term "cyano" refers to -CN.

As used in this article, the term "halogen" refers to an atom selected from fluorine (or fluorinyl), chlorine (or chlorinyl), bromine (or bromineyl), and iodine (or iodyl).

As used herein, the term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens. In some embodiments, the halogenated alkyl group may contain 1 to 6 carbon atoms. In some embodiments, the halogenated alkyl group may contain 1 to 4 carbon atoms. In some embodiments, the halogenated alkyl group may contain 1 to 3 carbon atoms. Examples of halogenated alkyl groups include (but are not limited to) trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromomethyl, tribromomethyl, and tetrafluoroethyl.

As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, phosphorus, or silicon, including any oxidized form of nitrogen or sulfur, and any quaternary ammonium form of basic nitrogen (including N-oxides).

As used herein, the term "heteroaryl," whether used as part of another term or independently, refers to an aromatic ring having one or more heteroatoms, in addition to a carbon atom, which may be oxidized or quaternarily ammonium-treated. Heteroaryl groups can be monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) systems. In the case of polycyclic systems, they can include fused-ring or spirocyclic systems. For example, a polycyclic heteroaryl group may comprise a heteroaryl ring fused to one or more additional rings (such as cycloalkyl, heterocyclic, aryl, or heteroaryl rings), or an aryl ring fused to one or more additional rings (such as heterocyclic or heteroaryl rings). In some embodiments, the heteroaryl group is 5 to 10 members. In some embodiments, the heteroaryl group is 5 to 6 members. In some embodiments, the heteroaryl group is 6 members. In some embodiments, the heteroaryl group is 5 members. Examples of heteroaryl groups include (but are not limited to) aziryl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzo-m-dioxocyclopentenyl, benzofuranyl, benzoazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxocycloheptatrienyl, 1,4-benzodialkyl, benzonaphthofuranyl, benzoazolyl, benzo-m-dioxocyclopentenyl, benzodioxocyclohexenyl, benzopiperanyl, benzopiperanone, benzofuranyl, and benzofuranyl. Ketone, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, alkinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanone, furanyl, isothiazolyl, imidazoyl, indazole, indoleyl, isoindoleyl, indolinyl, isoindolinyl, isoquinolinyl, indoleyl alkyl, isozolyl, acetylated, acediazolyl, 2-sideoxy-nitropyrrolyl, acezolyl, epoxyethyl, 1-oxopyridyl, 1-oxopyrimidinyl, 1-oxopyrrolyl, 1-oxopyrrolyl, 1-phenyl-1H-pyrroleyl, phenanthryl, phenanthrylthialyl, phenanthryl, phthalyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridyl 1-oxide, pyrrolyl, pyrimidinyl, phthalyl, quinazolinyl, quinazolinyl, quinolinyl The heteroaryl group may be substituted with one or more ring positions by the substituents described herein, unless otherwise expressly stated in the specification.

As used herein, the term "heterocyclic group," whether used as part of another term or independently, refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of, where apparent, oxidized or quaternarily ammonium-treated: nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic group is fully saturated. In some embodiments, the heterocyclic group is partially unsaturated. The heterocyclic group can be a monocyclic or polycyclic system (including (but not limited to) bicyclic, tricyclic, or tetracyclic systems). In the case of polycyclic systems, it can include fused ring, spirocyclic, or bridged ring systems. For example, a polycyclic heterocyclic group may comprise a heterocyclic ring fused to one or more additional rings (such as cycloalkyl or heterocyclic rings), or a cycloalkyl ring fused to one or more heterocyclic rings. Examples of heterocyclic groups include (but are not limited to) [e.g., y]. alkyl, azirmonobutyl, oxocyclobutyl, dioxopentyl, dihydrofuranyl, thiophenyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolinyl, isoazolinyl, succinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopyridinyl, 2-oxopyridinyl, 2-oxopyridinyl, succinyl, piperidinyl, piperidinyl, 4-piperidinoneyl, pyrrolidinyl, pyrazolidyl The heterocyclic group comprises pyridyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiopyrrinyl, thiohexapyrrinyl, 1-sideoxy-thiopyrrinyl, 1,1-disideoxy-thiopyrrinyl, 1,3-dihydroisobenzofuran-1-yl, 3-sideoxy-1,3-dihydroisobenzofuran-1-yl, methyl-2-sideoxy-1,3-dioxane-4-yl, and 2-sideoxy-1,3-dioxane-4-yl. In some embodiments, the heterocyclic group is 3 to 12 members. In some embodiments, the heterocyclic group is 3 to 9 members. In some embodiments, the heterocyclic basis is a 3- to 8-member heterocyclic basis. In some embodiments, the heterocyclic basis is a 3- to 7-member heterocyclic basis. In some embodiments, the heterocyclic basis is a 3- to 6-member heterocyclic basis. In some embodiments, the heterocyclic basis is a 4- to 6-member heterocyclic basis. In some embodiments, the heterocyclic basis is a 5- to 6-member heterocyclic basis. Unless otherwise expressly stated in the specification, the heterocyclic group may be substituted with one or more substituents (such as lateral, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, halogenated alkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic, heteroaryl, etc.) as described below. In some embodiments, the heterocyclic group may be substituted with one or more substituents (such as lateral, halogen, methyl, ethyl, -CN, -COOH, -COOMe, _-CF3 , -OH, -OMe, _-NH2 or _-NO2 ) as described below. In some embodiments, the heterocyclic group is substituted with one or more substituents (such as halogen, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe). In some embodiments, the heterocyclic group is substituted with halogens.

In some embodiments, the term "3- to 12-membered heterocyclic group" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused ring, spiro ring, and bridge ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclic groups include (but are not limited to) oxo-heterocyclic butyl, 1,1-di-oxythio-heterocyclic butylpyrrolidyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, succinyl, thiazolyl, piperidyl, piperidinyl, pyridinyl, pyridinyl, pyrimidyl, pyridazonyl, triazinonyl, pyridoneyl, pyrazinoneyl, pyrazinonyl, pyridazonyl, triazinonyl, etc. Examples of fused heterocyclic groups include (but are not limited to) phenyl fused-ring or pyridyl fused-ring groups, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinoline, quinazolinyl, and azidoinyl. pteridyl, octobenyl, isooctobenyl, indole, isoindole, indole Examples of spirocyclic groups include (but are not limited to) spiropyranyl, indazoleyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, carbazoleyl, phenazolyl, phenazothiazolyl, phenazinyl, imidazole[1,2-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,3]triazolo[4,3-a]pyridyl, etc. Examples of spirocyclic groups include (but are not limited to) spiropyranyl, spirodicycloyl, etc. Examples of bridging heterocyclic groups include (but are not limited to) morphanyl, hexamethylenetetramine, 3-aza-biscyclic [3.1.0]hexyl, 8-aza-biscyclic [3.2.1]octyl, 1-aza-biscyclic [2.2.2]octyl, 1,4-diaza-biscyclic [2.2.2]octyl (DABCO), etc.

As used in this article, the term "hydroxyl" refers to -OH.

As used herein, the terms "natural amino acid side chain" and "naturally occurring amino acid side chain" refer to the side chain of any naturally occurring amino acid (i.e., alanine, arginine, aspartic acid, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and volcanic acid), which are typically S-configured (i.e., L-amino acids).

As used herein, the terms “partially saturated” or “partially unsaturated” refer to a group that includes at least one double bond or parabola. The terms “partially saturated” or “partially unsaturated” are intended to include a ring with multiple unsaturated sites, but are not intended to include aromatic (i.e., completely unsaturated) portions.

As used herein, the term "purine base" or "pyrimidine base" includes (but is not limited to) adenine, ^N6 -alkylpurine, ^N6 -acetylinine (where the acetylinium group is C(O) (alkyl, aryl, alkylaryl, or arylalkyl)), ^N6 -benzylpurine, ^N6 -halogenated purine, ^N6 -vinylpurine, ^N6 -alkynylpurine, ^{N6 -} acetylinine, ^N6 -hydroxyalkylpurine, ^N6 -allylaminopurine, N6-thioallylpurine, ^N2 -alkylpurine, ^N2 -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine (including 6-azapyrimidine), 2-pyrimidine and/or 4-pyrimidine, uracil, ⁵ -halogenated uracil (including 5-fluorouracil), C5-alkylpyrimidine, ^C5 -benzylpyrimidine, ^C5 -halogenated pyrimidine, ^C5 -vinylpyrimidine, ^C5 -alkynylpyrimidine, ^C5 -acrylpyrimidine, C5 ^- hydroxyalkylpurine, ^C5 -aminopyrimidine, ^C5 -cyanopyrimidine, ^C5-5 -iodopyrimidine, ^C6 -iodopyrimidine, ^C5 - ^Br -vinylpyrimidine, ^C6 -Br-vinylpyrimidine, C5-nitropyrimidine, ^C5 -aminopyrimidine, ^N2 -alkylpurine, N ² -alkyl-6-thiopurine, 5-azacytidine, 5-azauracil, triazolanopyridyl, imidazopyridyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include (but are not limited to) guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Purine and pyrimidine bases are linked to ribose or similar sugars via the nitrogen atom of the base. The oxygen and nitrogen functional groups on the base can be protected as needed or desired. Suitable protective groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, tributyldimethylsilyl and tributyldiphenylsilyl, triphenylmethyl, alkyl and acetyl, such as acetyl and propytyl, methanesulfonyl and p-toluenesulfonyl.

As used herein, the term "substituted," whether or not preceded by the phrase "as the case may be," refers to the substitution of one or more hydrogen atoms in a specified moiety by suitable substituents. Typical substituents include (but are not limited to) functional groups as described herein, such as halogens, hydroxyl groups, amino groups, cyano groups, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, etc., each of which can be substituted in a similar manner. It should be understood that "substitution" or "substituted with" includes the implicit condition that such substitution meets the permissible valence of the substituted atom and that the substitution produces a stable or chemically viable compound, for example, a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. Unless otherwise stated, when the term "substituted" is used in conjunction with a group having two or more substituted moieties (such as alkylaryl), the substituent may be attached to the aryl moieties, alkyl moieties, or both. Unless otherwise stated, a "optionally substituted" group may have suitable substituents at each substituted position of the group, and when more than one position in any given structure is substituted by more than one substituent selected from the specified group, the substituents at each position may be the same or different. Those skilled in the art will understand that, where appropriate, the substituent itself may be substituted. Unless expressly stated as "unsubstituted," references to the chemical part herein should be understood to include substituted variants. For example, a reference to the "aryl" group or part thereof implicitly includes both substituted and unsubstituted variants. (Compound)

This disclosure provides novel compounds of formula (I) and their pharmaceutically acceptable salts, synthetic methods for manufacturing such compounds, pharmaceutical compositions containing such compounds, and various uses of the disclosed compounds.

In one state, this disclosure provides a compound having formula (I) or formula (II): (I) (II) or a pharmaceutically acceptable salt thereof, wherein the base is a naturally occurring or modified pyrimidine 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, halogenated alkyl, _{-OR₂, -NO₂, -N(Ra)₂} ^{, -C} ₍ O)N( ^Ra ) _₂ , -C(O) ^Ra , -OC(O) ^Ra , -C(O) ^OR₂ , -S( _O ) ^Ra , -S(O) ^₂Ra , -S(O) ^OR₂ ( ^OR₂ ) and _-S (O) _₂N ( ^Ra ) _₂ ; ^R₂₁ , ^R₂₂ , ^R₃₁ Each of ^R32 and ^R4 is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, halogenated alkyl, ^-ORa , -NO2, -N( ^Ra ) ₂ , -C(O)N( ^Ra ) ₂ , -C(O) _Ra , -OC(O) ^Ra , -C( ^O ) ^ORa , -S(O) ^Ra and -S(O ⁾ _2Ra ; Each of ^R5 is independently selected from the group consisting of: hydrogen, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl or _C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl and alkoxy are, as appropriate, substituted by one or more ^Rb ; or two R ^5, together with the nitrogen atom to which it is attached, forms a heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group is, as appropriate, substituted by one or more R ^5a ; each R ^5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl; or two R ^5a , together with the intercalation atom between them, form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is, as appropriate, substituted by one or more R ^b ; L ¹ is -C( ^RL ) _2- ; each R ^L is independently selected from hydrogen, deuterium, or an alkyl group, which may be substituted by one or more groups independently selected from halogen, hydroxyl, cyano, cycloalkyl, heterocyclic, aryl, or heteroaryl groups; ^L2 is selected from *-OC(O)-, *-OC(O)O-, *-OC(O)N( ^Ra )-, *-N( ^Ra )C(O)-, *-N( ^Ra )C(O)O-, or The * terminal of ^L2 is connected to ^L1 ; ^R6 is... ^R6a is selected from the group consisting of: _C8-20 alkyl, _C8-20 alkenyl, _CH3 ( _{CH2 ) mO} ( _CH2 ) _n- and ^RcOCH2 ( _CH2OCH2 ) _{pCH2- ,} wherein each is substituted by one or more ^Rb , as appropriate; ^R6b is selected from hydrogen, halogen, alkyl _, alkenyl or alkoxy, wherein each is substituted by one or more ^Rb , as appropriate; G is selected from -N( ^Ra )-**, -N( ^Ra )C( ^RG ) _2C (O)O-** or The **terminus of G is connected to ^R7 ; ring A is heterocyclic or heteroaryl, wherein each is substituted by one or more Rb ^groups as appropriate; X is selected from -O-, -N( ^Ra )-, or -C( ^Ra ) _2- ; each R and ^G is independently selected from the group consisting of: hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, and natural amino acid side chains, wherein each is substituted by one or more Rb ^groups as appropriate; ^R7 is selected from the group consisting of: _C8-20 alkyl, _C8-20 alkenyl, _C8-20 alkynyl, _CH3 ( _CH2 ) _mO ( _{CH2 ) n-} , _and ^RcOCH2 _{( CH2OCH2} ) _pCH2 - where each is substituted by one or more ^Rb as appropriate; ^R8 is selected from the group consisting of: hydrogen, _C1-6 alkyl, _C2-6 alkenyl or _C2-6 alkynyl, where each is substituted by one or more ^Rb as appropriate; each ^Ra is independently selected from hydrogen, halogen or alkyl; each ^Rb is independently selected from halogen, hydroxyl, cyano, amino, alkyl or alkoxy; each ^Rc is independently selected from hydrogen or alkyl; and each m, n or p is independently an integer from 0 to 20.

In another embodiment, a compound having formula (Ia) or formula (IIa) is provided: (Ia) (IIa) or a pharmaceutically acceptable salt thereof, wherein Q, G, ^R1 to ^R8 , ^R21 , ^R22 , ^R31 , ^R32 , ^L1 , ^L2 and the base are as defined above.

In some embodiments, the base is chosen from the following group: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments, the base is chosen from the group consisting of: , , , , , , and .

In some embodiments, ^R1 is selected from hydrogen, hydroxyl, cyano, azido, alkyl, or halogenated alkyl. In some embodiments, ^R1 is selected from hydrogen, hydroxyl, cyano, azido, alkyl (such as _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl, or _C1-2 alkyl) or _C1-6 halogenated alkyl (such as _C1-5 halogenated alkyl, _C1-4 halogenated alkyl, _C1-3 halogenated alkyl, or _C1-2 halogenated alkyl).

In some embodiments, ^R1 is a cyano group.

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), halogenated alkyl (such as _C1-6 halogenated alkyl, _C1-5 halogenated alkyl, _C1-4 halogenated alkyl, _C1-3 halogenated alkyl or _C1-2 halogenated alkyl) or -OC(O) ^Ra .

In some embodiments, each of R ²¹ , R ²² , R ³¹ , and R ³² 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 .

In some embodiments, ^Ra is an alkyl group. In some embodiments, ^Ra is a _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl, or _C1-2 alkyl group. In some embodiments, ^Ra is a methyl group.

In some embodiments, ^R4 is selected from hydrogen, deuterium, halogen, cyano, azido, or halogenated alkyl (such as _C1-6 halogenated alkyl, _C1-5 halogenated alkyl, _C1-4 halogenated alkyl, _C1-3 halogenated alkyl, or _C1-2 halogenated alkyl).

In some implementations, Choose from the following groups: , , , , , , , , , , , , , , , and .

In some embodiments, the base is or ,and for .

In some embodiments, the base is ,and for .

In some embodiments, the compound has formula (Ia): (Ia) or a pharmaceutically acceptable salt thereof, wherein Q, ^R1 to ^R6 , ^R21 , ^R22 , ^R31 , ^R32 , ^L1 , ^L2 and the base are as defined above.

In some embodiments of the compounds of formula (Ia), each ^R5 is independently selected from hydrogen or _C1-6 alkyl (such as _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl or _C1-2 alkyl).

In some embodiments, each ^R5 is independently a _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl, or _C1-2 alkyl. In some embodiments, both ^R5s are methyl. In some embodiments, both ^R5s are ethyl.

In some embodiments, one R ⁵ is hydrogen, and the other R ⁵ is a _C1-6 alkyl. In some embodiments, one R ⁵ is hydrogen, and the other R ⁵ is a _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl, or _C1-2 alkyl.

In some implementations, both ^R5s are hydrogen.

In some embodiments of the compound of formula (Ia), the two ^R5 atoms together with the nitrogen atoms they are attached to form a heterocyclic group that is, as appropriate, substituted with one or more ^{R5a atoms} . In some embodiments, the two ^R5 atoms together with the nitrogen atoms they are attached to form a 5- to 12-membered heterocyclic group (such as a 5- to ¹¹ -membered heterocyclic group, a 5- to 10-membered heterocyclic group, a 5- to 9-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group) that is, as appropriate, substituted with one or more R5a atoms.

In some embodiments of the compound of formula (Ia), the two ^R5 atoms, together with the nitrogen atoms they are attached to, form a heterocyclic group selected from the group consisting of: , , , and Each of these may be replaced by one or more R ^5a , depending on the circumstances.

In some embodiments, R ^5a is selected from alkyl or alkoxy groups. In some embodiments, R ^5a is selected from _C1-6 alkyl groups (such as _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl, or _C1-2 alkyl groups) or _C1-6 alkoxy groups (such as _C1-5 alkoxy, _C1-4 alkoxy, _C1-3 alkoxy, or _C1-2 alkoxy groups). In some embodiments, R ^5a is methyl or... .

In some embodiments of compounds of formula (Ia), each R ^L is independently selected from hydrogen, deuterium, or an alkyl group (such as _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl, or _C1-2 alkyl). In some embodiments, both R ^Ls are hydrogen.

In some embodiments of the compounds of formula (Ia), ^L2 is selected from *-OC(O)- or *-OC(O)O-. In some embodiments, ^L2 is *-OC(O)O-.

In some embodiments of the compounds of formula (Ia), ^R6a is selected from _C8-20 alkyl or _C8-20 alkenyl, wherein each is optionally substituted with one or more ^Rb . In some embodiments, ^R6a is selected from _C8-20 alkyl, _C8-18 alkyl, _C8-15 alkyl, _C8-13 alkyl, _C8-20 alkenyl, _C8-18 alkenyl, _C8-15 alkenyl, or _C8-13 alkenyl, wherein each is optionally substituted with one or more ^Rb . In some embodiments, ^R6a is a C8-13 alkyl group substituted with one or _more Rb, wherein each is optionally substituted with one or more ^Rb . In some embodiments, R6a is a _C8-13 alkyl group substituted with one or _more Rb, wherein ^each is optionally substituted with one or more ^Rb .

In some embodiments of the compounds of formula (Ia), R ^6b is selected from hydrogen, halogen, or alkyl. In some embodiments, R ^6b is selected from hydrogen or alkyl. In some embodiments, R ^6b is hydrogen. In some embodiments, R ^6b is a _C1-6 alkyl. In some embodiments, R ^6b is a _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, or _C1-3 alkyl. In some embodiments, R ^6b is a _C1-3 alkyl. In some embodiments, R ^6b is methyl.

In some embodiments, the compound has formula (IIa): (IIa) or a pharmaceutically acceptable salt thereof, wherein Q, ^R1 to ^R8 , ^R21 , ^R22 , ^R31 , ^R32 , ^L1 , ^L2 and the base are as defined above.

In some embodiments of the compound of formula (IIa), ^L2 is selected from *-OC(O)- or *-OC(O)O-.

In some embodiments, ^L2 is *-OC(O)O-.

In some embodiments of compounds of formula (IIa), ^R8 is selected from hydrogen or, where appropriate, a _C1-6 alkyl group substituted with one or more Rb ^ions . In some embodiments, ^R8 is a _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, or, where appropriate, a _C1-3 alkyl group substituted with one or more ^{Rb ions} . In some embodiments, ^R8 is a _C1-3 alkyl group substituted with one or more Rb ^ions . In some embodiments, ^R8 is methyl or isopropyl.

In some embodiments of compounds of formula (IIa), G is -N( ^Ra )-**. In some embodiments, ^Ra is selected from hydrogen or alkyl. In some embodiments, ^Ra is alkyl. In some embodiments, ^Ra is _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl, or _C1-2 alkyl. In some embodiments, ^Ra is methyl.

In some embodiments of the compound of formula (IIa), G is -N( ^Ra )C( ^RG ) _2C (O)O-**.

In some embodiments of compounds of formula (IIa), each R ^G is independently selected from the group consisting of: hydrogen, _C1-6 alkyl, _C6-12 aryl, 5- to 12-membered heteroaryl, ( _C1-3 alkyl)( _C3-12 cycloalkyl), (C1-3 alkyl)(3- to 12-membered heterocyclol), ( _C1-3 alkyl)( _C6-12 aryl), ( _C1-3 alkyl)(5- to 12-membered heteroaryl), and a natural amino acid side chain, wherein each is, as appropriate _, substituted by one or more R ^b .

In some embodiments of the compound of formula (IIa), one R ^G is hydrogen, and the other R ^G is selected from _C1-6 alkyl, _C6-12 aryl, ( _C1-3 alkyl)( _C6-12 aryl), ( _C1-3 alkyl)(5- to 12-membered heteroaryl), or a natural amino acid side chain, wherein each is substituted by one or more R ^b as appropriate.

In some embodiments of compounds of formula (IIa), one R ^G is hydrogen, and the other R ^G is (C _1-3 alkyl)(C _6-12 aryl) or (C _1-3 alkyl)(5 to 12 heteroaryl), wherein each is, as appropriate, substituted with one or more R ^b . In some embodiments, R ^b is cyano, halogen, hydroxyl, or alkoxy.

In some embodiments of the compounds of formula (IIa), one ^RG is hydrogen, and the other ^RG is chosen from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments of the compound of formula (IIa), one ^RG is hydrogen and the other ^RG is a natural amino acid side chain.

In some embodiments of the compounds of formula (IIa), one ^RG is hydrogen, and the other ^RG is chosen from the group consisting of: , , , , , , , , , , , , , and .

In some embodiments of the compound of formula (IIa), G is And X is -O-.

In some implementations, ring A is selected from the following groups: , , , , and .

In some embodiments of compounds of formula (IIa), ^R7 is selected from _C8-20 alkyl or _C8-20 alkenyl, wherein each is, as appropriate, substituted by one or more ^Rb .

In some embodiments, ^R7 is selected from _C8-20 alkyl, _C10-20 alkyl, _C12-20 alkyl, _C14-20 alkyl, _C16-20 alkyl, _C8-20 alkenyl, _C10-20 alkenyl, C12-20 alkenyl, _C14-20 alkenyl, or _C16-20 alkenyl, wherein each is optionally substituted with one or more ^Rb . In some embodiments, ^R7 is selected from _C16-20 alkyl or _{C16-20 alkenyl} , wherein each is optionally substituted with one or more ^Rb .

In some embodiments, ^R7 is a _C16-20 alkyl group that is substituted with one or more ^Rb , as appropriate.

In another aspect, a compound having a formula selected from the group consisting of: (Ib) (Ic) (Id) (Ie) (IIb) (IIc) (IId) (IIe) or its pharmaceutically acceptable salts, wherein Q, G, ^R1 to ^R8 , ^R21 , ^R22 , ^R31 and ^R32 are as defined above.

In another embodiment, this disclosure provides a compound selected from any of the compounds listed in Table 1. Table 1

The compounds described herein are illustrated with reference to general formulas and specific compounds. Furthermore, the compounds disclosed herein may exist in many different forms or derivatives, all of which are within the scope of this disclosure. These compounds include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvent complexes, amorphous forms, various crystalline forms, or polymorphs.

Depending on the choice of substituents, the compounds disclosed herein may contain one or more asymmetric centers, and therefore may exist in various stereoisomeric forms, such as mirror isomers and/or non-mirror isomers. For example, the compounds provided herein may have asymmetric carbon centers, and therefore may have (R) or (S) stereoconfigurations at the asymmetric carbon centers. Thus, the compounds disclosed herein may be in the form of individual mirror isomers, non-mirror isomers, or geometric isomers, or may be in the form of mixtures of stereoisomers.

As used herein, the term "mirror image isomer" refers to two stereoisomers of a compound that are non-superimposed mirror images of each other. The term "non-mirror image isomer" refers to a pair of optical isomers that are not mirror images of each other. Non-mirror image isomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity.

When a particular mirror isomer is preferred, in some embodiments it can be provided as substantially free of the relative mirror isomer, and this can also be referred to as "optical enrichment." As used herein, "optical enrichment" means that the compound consists of a significantly larger proportion of one of the mirror isomers. In some embodiments, the compound consists of at least about 90 wt% of the preferred mirror isomer. In other embodiments, the compound consists of at least about 95 wt%, 98 wt%, or 99 wt% of the preferred mirror isomer. The preferred mirror isomer can be isolated from a racemic mixture by any method known to those skilled in the art, such as by chromatography or crystallization, by synthesis using stereochemically homogeneous starting materials, or by stereoselective synthesis. Depending on the circumstances, derivatization may be performed prior to the separation of stereoisomers. The separation of mixtures of stereoisomers may be carried out as an intermediate step during the synthesis of the compounds provided herein, or may be performed on the final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of the crystalline products or intermediates, if necessary, by derivatization with reagents containing stereocenters of known configurations. Alternatively, absolute stereochemistry may be determined by vibrational circular dichroism (VCD) spectroscopy. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscienc, 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).

In some embodiments, a mixture of non-mirror isomers is provided, such as a mixture of non-mirror isomers enriched with 51% or more of one of the non-mirror isomers, including, for example, one of the non-mirror isomers being 60% or more, 70% or more, 80% or more, or 90% or more.

In some embodiments, unless otherwise specified, the compounds provided herein may have one or more double bonds in the form of Z or E isomers. Additionally, this disclosure also includes compounds that are substantially free of other isomers, and alternatively, compounds that are mixtures of multiple isomers (e.g., racemic mixtures other than mirror isomers).

The compounds disclosed herein may also exist in different tautomer forms, and all such forms are covered within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can be interconverted through a low-energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol, amide-imino, lactamide-amide, imine-enamine isomerization, and cyclic forms, where the proton can occupy two or more positions in the heterocyclic system (e.g., 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole). Valence tautomers include interconversions via rearrangement of some bonding electrons. Tautomers may be in equilibrium or spatially locked into a form by appropriate substitution. Unless otherwise specified, the compounds disclosed herein, identified by name or structure as a particular tautomer, are intended to include other tautomers.

This disclosure is also intended to include all isotopes of atoms in compounds. An isotope of an atom includes atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in compounds disclosed herein are also intended to include their isotopes, such as (but not limited to) ^¹H , ^²H , ^³H , ^¹¹C , ^¹²C , ^¹³C , ^¹⁴C , ^¹⁴N , ^¹⁵N , ^¹⁶O , ^¹⁷O , ^¹⁸O , ^³¹P , ^³²P , ^³²S , ^³³S , ³⁴S, ^³⁶S , ^¹⁷F , ^¹⁸F , ^¹⁹F , ^³⁵Cl , ^³⁷Cl , ^⁷⁹Br , ^⁸¹Br , ^¹²⁴I , ^{¹²⁷I ,} and ^¹³¹I . The isotopically enriched compounds of formula (I) or (II) can be prepared without excessive experimentation by means of familiar techniques known to those skilled in the art or by means of methods similar to those described in the procedures and examples herein, using appropriate isotopically enriched reagents and/or intermediates.

In some embodiments, this disclosure includes compounds of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (IIa), (IIb), (IIc), (IId), or (IIe), wherein one or more hydrogen atoms bonded to carbon atoms are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and, therefore, when administered to individuals, such as mammals, particularly humans, can be used to increase the half-life of any compound of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (IIa), (IIb), (IIc), (IId), or (IIe). See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol.Sci.5(12):524-527 (1984). In view of this disclosure, such compounds can be synthesized by means known to this art, such as by using one or more hydrogen-substituted deuterium starting materials.

The in vivo metabolites of the compounds described herein also fall within the scope of this document. Such products are novel to some extent and not readily apparent compared to prior art. These products can be generated, for example, by oxidation, reduction, hydrolysis, amination, esterification, etc., of the introduced compound, primarily through enzymatic processes. Therefore, this includes novel and less obvious compounds produced by methods comprising exposing the compound to a mammal for a period sufficient to produce its metabolites.

The compounds disclosed herein may be formulated into pharmaceutically acceptable salts or in the form of pharmaceutically acceptable salts. Unless otherwise stated, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

As used herein, the term "pharmaceutically acceptable" indicates that the substance or composition is chemically and/or toxicologically compatible with the other components constituting the formulation and/or the individuals treated with it.

As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" includes salts that retain the bioavailability of the free acids and bases of the specified compound and are not biologically or otherwise undesirable. Forms of pharmaceutically acceptable salts considered include (but are not limited to) single, disodium, trisodium, tetrasodium, etc. Pharmaceutically acceptable salts are non-toxic at the amount and concentration in which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of the compound without impairing its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher drug concentrations.

Pharmaceutically acceptable salts include acid addition salts, such as those containing the following: sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, aminosulfonates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminesulfonates, and quinates. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, aminosulfonic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, fumaric acid, and quinic acid.

When an acidic functional group (such as a carboxylic acid or phenol) is present, pharmaceutically acceptable salts also include alkali addition salts, such as those containing: benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. See, for example, Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Wiley-VCH, Weinheim, Germany, 2002. These salts can be prepared using appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared using standard techniques. For example, the free alkaline form of a compound can be dissolved in a suitable solvent (such as an aqueous solution containing a suitable acid or a water-alcohol solution) and then separated by evaporation of the solution. Therefore, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in this technique, such as treating the free base with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or treating the free base with organic acids, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, piperanosic acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.

Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, such as treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary amine), an alkaline metal hydroxide, or an alkaline earth metal hydroxide. 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 hydroxyethylpyrrolidone, piperidine, succinyl phosphate, or piperazine); and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

It should also be understood that the compounds disclosed herein may exist in non-solvent, solvent-bound (e.g., hydrated) and solid (e.g., crystalline or polycrystalline) forms, and this disclosure is intended to encompass all such forms.

As used herein, the term "solvate" or "solvated form" refers to a solvent addition form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to form solvent compounds by retaining solvent molecules in a crystalline solid state with a fixed molar ratio. If the solvent is water, the resulting solvent compound is a hydrate; and if the solvent is an alcohol, the resulting solvent compound is an alcohol. A hydrate is formed by the combination of one or more water molecules with a molecule of another substance, wherein the water retains its molecular state as _H₂O . Examples of solvents that form solvent compounds include (but are not limited to) water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

As used herein, the terms "crystalline form,""crystallinestructure,""polycrystallineform," and "polymorph" are used interchangeably and refer to the crystalline structures of compounds (or their salts or solvent compounds) that can crystallize in different crystalline arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Crystalline polymorphs of compounds can be prepared by crystallization under different conditions. Synthesis of Compounds

The synthetic procedures described herein illustrate the synthesis of the compounds (including their pharmaceutically acceptable salts). The compounds provided herein can be prepared using any known organic synthetic technique and can be synthesized according to any of a variety of possible synthetic routes; therefore, these procedures are illustrative only and are not intended to limit other possible methods for preparing the compounds provided herein. Furthermore, the steps in these procedures are for better illustration and may be modified where appropriate. Examples of synthesizing the compounds in the examples are provided for research purposes and possibly for submission to regulatory authorities.

The reactions used to prepare the compounds disclosed herein can be carried out in suitable solvents, which can be readily selected by those skilled in organic synthesis. Suitable solvents are those that do not substantially react with the starting materials (reactants), intermediates, or products at the temperatures in which the reaction proceeds, for example, in the range from the solvent's freezing temperature to its boiling temperature. A specific reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

The preparation of the compounds disclosed herein may 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 those skilled in the art. The chemical properties of protecting groups can be found in, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley & Sons, Inc., New York (1999); P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003; and Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th ed., Wiley, 2014. All of these references are incorporated herein by reference in their entirety.

The reaction can be monitored using any suitable method known in this technique. For example, product formation can be monitored using spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g., ^¹H or ^¹³C ), infrared spectroscopy (IR), spectrophotometry (e.g., UV-Vis), mass spectrometry, or chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Those skilled in this technique can use various methods, including high performance liquid chromatography (HPLC). (See "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem., 2004, 6(6)). (874-883, which are incorporated herein by reference in their entirety) and normal-phase silica chromatography were used to purify the compounds.

The known starting materials disclosed herein can be synthesized using or according to the methods known in this art, or can be purchased from commercial suppliers. Unless otherwise indicated, analytical grade solvents and commercially available reagents are used without further purification.

Unless otherwise specified, all reactions disclosed herein are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using dry tubes, and the reaction flasks are typically fitted with rubber septa for introduction of the substrate and reagent via syringe. Glassware is oven-dried and/or heat-dried.

For illustrative purposes, the following examples illustrate the synthetic routes and key intermediates used to prepare the compounds of this disclosure. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of this disclosure. Although specific starting materials and reagents are described, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified according to this disclosure using familiar chemical reactions well known to those skilled in the art. Uses of the Compounds

In one embodiment, this disclosure provides compounds of formula (I) or formula (II) or their pharmaceutically acceptable salts, which inhibit RNA polymerase. Therefore, the compounds disclosed herein or their pharmaceutically acceptable salts can be used as pharmaceuticals, and in particular as therapeutics or preventative agents active against various viruses. In some embodiments, the compounds disclosed herein are therapeutics or preventative agents active against caliciviruses, microviruses, and coronaviruses.

As used herein, the term "therapy" is intended in its general sense to treat an illness in order to completely or partially relieve one, some, or all of its symptoms, or to correct or counteract the underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, a beneficial or desired clinical outcome includes (but is not limited to): symptom relief, reduction of disease severity, stabilization of disease status (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of disease condition, and remission (partial or complete remission), whether detectable or undetectable. "Therapy" may also mean a prolonged survival compared to the expected survival without therapy. Situations requiring therapy include those where symptoms or conditions are already present, those susceptible to developing symptoms or conditions, and those for the purpose of preventing symptoms or conditions. Unless specifically indicated to the contrary, the term "therapy" also includes prevention. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

The terms “treatment” and “therapy” are used synonymously. Similarly, the term “treatment” can be considered as “the application of therapy,” where “therapy” is defined as in this article.

As used in this article, the term "prophylaxis" is intended to have its usual meaning and includes primary prevention for preventing the development of disease and secondary prevention for temporarily or permanently protecting patients from disease aggravation or the development of new disease-related symptoms once the disease has developed.

In another embodiment, this disclosure provides for the use of the disclosed compounds or their pharmaceutically acceptable salts for the treatment of viral infections.

In another embodiment, this disclosure provides the use of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions in the manufacture of medicaments for the treatment of viral infections.

In some embodiments, the compounds disclosed herein exhibit good inhibitory effects against various coronaviruses. In some embodiments, the compounds disclosed herein exhibit good inhibitory effects against various coronaviruses and low cytotoxicity.

In some embodiments, the compounds disclosed herein exhibit good inhibitory effects against various pneumonia viruses. In some embodiments, the compounds disclosed herein exhibit good inhibitory effects against various pneumonia viruses and low cytotoxicity.

In some embodiments, the disclosed compounds can be converted into triphosphates and maintain high concentrations of triphosphates in target tissues and cells (such as lung cells and respiratory epithelial cells).

Therefore, this disclosure provides for the use of the compounds disclosed herein or their pharmaceutically acceptable salts for the treatment of coronavirus or pneumonia virus infections.

In another embodiment, this disclosure provides the use of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions in the manufacture of a medicament for the treatment of coronavirus infection.

In another embodiment, this disclosure provides the use of the compounds disclosed herein, or their pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of an agent for the treatment of pneumonia virus infection. Pharmaceutical Composition

For administration purposes, in some embodiments the compounds provided herein are administered in their original chemical form or formulated into pharmaceutical compositions.

Therefore, in another embodiment, a pharmaceutical composition comprising one or more of the compounds disclosed herein or their pharmaceutically acceptable salts is provided.

In some embodiments, the pharmaceutical composition disclosed herein comprises a compound selected from either formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition disclosed herein comprises a first compound selected from either formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula, wherein the first compound and the additional compounds are not identical molecules.

As used herein, the term "medicinal composition" refers to a formulation containing the molecules or compounds disclosed herein in a form suitable for administration to an individual.

In some embodiments, the pharmaceutical composition disclosed herein comprises a therapeutically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof.

As used herein, the term "therapeutic effective dose" refers to the amount of a molecule, compound, or combination thereof that treats, improves, or prevents an identified disease or symptom, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any analytical method known in the art. The precise effective dose for an individual will depend on the individual's weight, build, and health status; the nature and severity of the symptom; the rate of administration; the chosen treatment or combination of treatments; and the prescribing physician's judgment. Therapeutic effective doses for a given condition can be determined by routine experiments within the skill and judgment of a clinician.

In another embodiment, a pharmaceutical composition is provided comprising one or more of the compounds disclosed herein or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient suitable for the preparation of pharmaceutical compositions that are generally safe, non-toxic, and biologically and otherwise satisfactory, including excipients acceptable for veterinary and human medical use. As used herein, "pharmaceuticalally acceptable excipient" includes one or more such excipients. The term "pharmaceuticalally acceptable excipient" also includes "pharmaceuticalally acceptable carriers" and "pharmaceuticalally acceptable diluents."

The specific excipients used will depend on the means and purpose of application of the disclosed compounds. Solvents are generally selected based on those deemed safe by those skilled in the art for administration to mammals (including humans). Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof.

In some embodiments, suitable excipients may include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; and preservatives such as octadecyl dimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, and benzyl ammonium chloride. chloride); phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; 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, glutamic acid, and aspartic acid. Histamine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, dextrin, or substituted dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming ions, such as sodium; metal complexes (such as Zn-protein complexes); and/or nonionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, slip agents, processing aids, colorants, sweeteners, aromas, flavorings, and other known additives to provide optimal presentation of the drug (i.e., the compound disclosed herein or its pharmaceutical composition) or to aid in the manufacture of a pharmaceutical product (i.e., a pharmaceutical preparation). Active pharmaceutical ingredients can also be encapsulated in microcapsules, for example, prepared by coagulation techniques or interfacial polymerization, such as hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in gel-like drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (1980). "Liposomes" are small vesicles composed of various types of lipids, phospholipids, and/or surfactants, suitable for delivering drugs (such as compounds disclosed herein and, where appropriate, chemotherapeutic agents) to mammals, including humans. Liposomes are typically arranged in a bilayer, similar to the lipid arrangement in biological membranes.

The pharmaceutical compositions described herein may be in any form that allows the composition to be administered to an individual (including (but not limited to) humans) and formulated in a manner compatible with the intended route of administration.

The pharmaceutical compositions provided herein take into account various routes of administration; therefore, they may be provided in bulk or unit dosage forms depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets (such as orally dispersible tablets or orally disintegrating tablets), pills, oral water-soluble films, capsules, softgels, and capsule-type tablets are acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions are acceptable as liquid dosage forms. For injection, emulsions and suspensions in liquid form and powders suitable for rehydration with appropriate solutions in solid form are acceptable. For inhalation, solutions, sprays, dry powders, and aerosols are acceptable dosage forms. For topical (including cheek and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches are acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams, and sprays are acceptable dosage forms. For intranasal or pulmonary administration, aqueous or oily solutions are acceptable dosage forms.

The amount of active ingredient in a unit dosage form of a combination is the therapeutically effective amount (TDA), and varies depending on the specific treatment involved. As used herein, the term "therapeuticly effective amount" refers to the amount of a molecule, compound, or combination containing such molecule or compound that treats, improves, or prevents an identified disease or condition, or exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, body size, and health status; the nature and severity of the condition; the rate of administration; the chosen treatment or combination of treatments; and the prescribing physician's judgment. Therapeuticly effective amounts for a given condition can be determined by routine experiments within the skill and judgment of a clinician.

In some embodiments, the pharmaceutical composition disclosed herein may be in the form of an oral administration formulation.

In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of tablet formulations. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to regulate their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and/or appearance. In either case, the conventional coating agents and procedures known in this art are used.

In some embodiments, the pharmaceutical composition disclosed herein may be in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin); or in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or oil (e.g., peanut oil, liquid paraffin, or olive oil).

In some embodiments, the pharmaceutical composition disclosed herein may be in the form of an aqueous suspension, which generally contains an active ingredient in fine powder form and one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragali gum, and gum arabic; dispersants or wetting agents, such as lecithin, or condensation products of epoxides and fatty acids. (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecetylated hexadecyl alcohol), or condensation products of ethylene oxide and esters derived from fatty acids and hexyl alcohols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and esters derived from fatty acids and hexyl alcohols (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (e.g., ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate), antioxidants (e.g., ascorbic acid), colorants, flavorings, and/or sweeteners (e.g., sucrose, saccharin, or aspartame).

In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of an oily suspension, which typically contains suspended active ingredients in vegetable oils (such as peanut oil, castor oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). The oily suspension may also contain thickeners, such as beeswax, hard paraffin, or whale wax alcohol. Sweeteners (such as those described above) and flavorings may be added to provide a palatable oral formulation. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

In some embodiments, the pharmaceutical composition disclosed herein may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or any mixture of such oils. Suitable emulsifiers may be, for example, naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybean, lecithin, esters or metaesters derived from fatty acids and hexanoic anhydrides (e.g., sorbitan monooleate), and condensation products of such metaesters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners, flavorings, and preservatives.

In some embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweeteners such as glycerin, propylene glycol, sorbitol, aspartame or sucrose; modifiers; preservatives; flavoring agents and/or colorants.

In some embodiments, the pharmaceutical composition disclosed herein may be in the form of a formulation for injection administration.

In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. The sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic, non-enteric-acceptable diluents or solvents, such as solutions in 1,3-butanediol or prepared as lyophilized powders. Acceptable media and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild, nonvolatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid can also be used in the preparation of injectable formulations.

In some embodiments, the pharmaceutical composition disclosed herein may be in the form of a formulation for nasal or pulmonary administration. In some embodiments, the formulation is administered by rapid inhalation via the nasal passage or by oral inhalation to reach the alveolar sacs.

In some embodiments, the pharmaceutical composition disclosed herein may be in the form of a formulation for inhalation administration.

In some embodiments, the pharmaceutical compositions disclosed herein may be in aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosol form, containing any suitable solvent and, where appropriate, other compounds such as (but not limited to) stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability regulators, and combinations thereof. The carrier and stabilizer vary depending on the specific compound requirements, but generally include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars, or sugar alcohols.

In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of formulations for topical or transdermal administration.

In some 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 formulation of active ingredients and conventionally accepted topical excipients, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide or mixtures thereof.

In some embodiments, the pharmaceutical composition provided herein can be formulated in the form of a transdermal patch, which is familiar to those generally skilled in this art.

In addition to the representative dosage forms mentioned above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in this disclosure. Such excipients and carriers are described in, for example, "Remingtons Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), "Remington: The Science and Practice of Pharmacy," University of the Sciences in Philadelphia, 21st ed., LWW (2005), which are incorporated herein by reference.

In some embodiments, the pharmaceutical compositions disclosed herein may be formulated into unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable for administration in a single dose to human individuals and other mammals, each unit containing a pre-quantitative amount of active substance calculated to bind with a suitable pharmaceutical excipient to produce the desired therapeutic effect. The amount of compounds provided herein in unit dosage forms will vary depending on the condition to be treated, the individual to be treated (e.g., age, weight, and response of the individual), the specific route of administration, the actual compound administered and its relative activity, and the severity of the individual's symptoms.

In some embodiments, the dosage level of the pharmaceutical composition disclosed herein may be from 0.001 to 1000 mg/kg body weight/day, for example, 0.001 to 1000 mg/kg body weight/day, 0.001 to 900 mg/kg body weight/day, 0.001 to 800 mg/kg body weight/day, 0.001 to 700 mg/kg body weight/day, 0.001 to 600 mg/kg body weight/day, 0.001 to 500 mg/kg body weight/day. /day, 0.001 to 400 mg/kg body weight/day, 0.001 to 300 mg/kg body weight/day, 0.001 to 200 mg/kg body weight/day, 0.001 to 100 mg/kg body weight/day, 0.001 to 50 mg/kg body weight/day, 0.001 to 40 mg/kg body weight/day, 0.001 to 30 mg/kg body weight/day, 0.001 to 20 mg/kg body weight/day, 0.001 to 10 mg/kg body weight/day g/kg body weight/day, 0.001 to 5 mg/kg body weight/day, 0.001 to 1 mg/kg body weight/day, 0.001 to 0.5 mg/kg body weight/day, 0.001 to 0.4 mg/kg body weight/day, 0.001 to 0.3 mg/kg body weight/day, 0.001 to 0.2 mg/kg body weight/day, 0.001 to 0.1 mg/kg body weight/day, 0.005 to 0.1 mg/kg body weight/day, 0. The recommended dosage ranges are 0.01 to 0.1 mg/kg body weight/day, 0.02 to 0.1 mg/kg body weight/day, 0.03 to 0.1 mg/kg body weight/day, 0.04 to 0.1 mg/kg body weight/day, 0.05 to 0.1 mg/kg body weight/day, 0.06 to 0.1 mg/kg body weight/day, 0.07 to 0.1 mg/kg body weight/day, 0.08 to 0.1 mg/kg body weight/day, or 0.09 to 0.1 mg/kg body weight/day. In some cases, dosage levels below the lower limit of the aforementioned ranges may be insufficient, while in other cases, larger doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several smaller doses to be administered throughout the day. For further information on administration routes and dosage protocols, see Volume 5, Chapter 25.3 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

In some embodiments, the pharmaceutical composition disclosed herein is formulated for oral administration. In some embodiments, the unit dose for oral administration contains one or more of the compounds provided herein in amounts of: about 1 mg to about 1000 mg, such as about 5 mg to about 1000 mg, about 10 mg to about 1000 mg, about 15 mg to about 1000 mg, about 20 mg to about 1000 mg, about 25 mg to about 1000 mg, about 30 mg to about 1000 mg, about 40 mg to about 1000 mg, about 50 mg to about 1000 mg, about 60 mg to about 1000 mg, about 70 mg to about 1000 mg, about 80 mg to about 1000 mg, about 90 mg to about 1000 mg, about 100 mg to about 1000 mg, about 200 mg to 1000 mg, about 300 mg to about 1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg, about 500 mg to about 1000 mg, about 500 mg to about 1000 mg, about 1 ... From approximately 1000 mg to approximately 1000 mg, approximately 1 mg to 500 mg, approximately 10 mg to approximately 500 mg, approximately 50 mg to approximately 500 mg, approximately 100 mg to approximately 500 mg, approximately 200 mg to approximately 500 mg, approximately 300 mg to approximately 500 mg, approximately 400 mg to approximately 500 mg, for example, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, etc. In some practices, depending on the severity of the individual's symptoms, the dosage unit may be administered to the individual 1 to 6 times daily.

In some embodiments, the pharmaceutical composition disclosed herein is formulated for oral administration in treatment lasting longer than 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or even longer.

In some embodiments, the pharmaceutical composition disclosed herein is formulated for non-enteric administration, such as by intravenous, subcutaneous or intramuscular injection. In some embodiments, the unit dose for non-enteric administration contains one or more of the compounds provided herein, in amounts ranging from about 0.1 mg to about 500 mg, such as about 0.2 mg to about 500 mg, about 0.3 mg to about 500 mg, about 0.4 mg to about 500 mg, about 0.5 mg to about 500 mg, about 1 mg to about 500 mg, about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 20 mg to about 500 mg, about 30 mg to about 500 mg, about 40 mg to about 500 mg, about 50 mg to about 500 mg, about 0.5 mg to about 400 mg, about 0.5 mg to about 300 mg, about 0.5 mg to about 200 mg, about 0.5 mg to about 100 mg, about 0.5 mg to about 9 ... From about 80 mg, about 0.5 mg to about 70 mg, about 0.5 mg to about 60 mg, about 0.5 mg to about 50 mg, about 0.5 mg to about 40 mg, about 1 mg to about 90 mg, about 5 mg to about 90 mg, about 10 mg to about 80 mg, about 20 mg to about 70 mg, about 30 mg to about 60 mg or about 40 mg to about 50 mg, such as 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, etc.

In some embodiments, the pharmaceutical composition intended for injection administration may be prepared by combining one or more of the disclosed compounds with sterile distilled water, sesame oil, peanut oil, or an aqueous solution of propylene glycol to form a solution. In some embodiments, the pharmaceutical composition may contain a surfactant or other solubilizing agent added to promote the formation of a homogeneous solution or suspension. In some embodiments, the pharmaceutical composition may further contain one or more additional reagents selected from the group consisting of: wetting agents, suspending agents, preservatives, buffers, and isotonics.

In some embodiments, the pharmaceutical composition intended for injection may be administered via 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.

In another embodiment, veterinary compositions are also provided, comprising one or more molecules or compounds disclosed herein, or their pharmaceutically acceptable salts, and veterinary carriers. The veterinary carrier is a substance suitable for administering the composition and may be an inert or veterinarily acceptable solid, liquid, or gaseous substance, and compatible with the active ingredient. These veterinary compositions may be administered non-intestinal, oral, or by any other desired route.

Pharmaceutical or veterinary formulations can be packaged in various ways depending on the method of drug administration. For example, dispensing products may include containers containing a formulation in its appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), capsules, ampoules, plastic bags, metal tubes, etc. Containers may also include tamper-evident components to prevent easy access to the contents. Additionally, the container is labeled with a description of its contents. The label may also include appropriate warnings. The formulation can be packaged in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored under freeze-dried conditions, requiring only the addition of a sterile liquid carrier (e.g., water) immediately before use for injection. Ready-to-use injectable solutions and suspensions are prepared from the previously described types of sterile powders, granules, and tablets. Treatment methods

In another embodiment, this disclosure provides a method for treating a viral infection in a patient in need, the method comprising administering an effective amount of any of the compounds described herein.

In some embodiments, the viral infection originates from an RNA virus. In some embodiments, the RNA virus is a single-stranded or double-stranded RNA virus. In other embodiments, the RNA virus is a positive-sense RNA virus, a negative-sense RNA virus, or a double-sense RNA virus.

In some embodiments, the viral infection originates from viruses selected from the following groups: Retroviridae virus, Lentiviridae virus, Coronaviridae virus, Picornaviridae virus, Caliciviridae virus, Flaviviridae virus, Togaviridae virus, Bomaviridae virus, Filoviridae virus, Paramyxoviridae virus, Pneumomoviridae virus, Rhabdoviridae virus, Arenaviridae virus, Bunyaviridae virus, Orthomyxoviridae virus, and Deltavirus.

In some embodiments, the viral infection originates from a group of viruses selected from the following: Lymphocytic choriomeningitis virus, Coronavirus, HIV, SARS, Poliovirus, Rhinovirus 16, Hepatitis A virus, 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, and Marburg virus. The following viruses are listed: 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 virus, hepatitis D virus, enterovirus 71, Coxsakie virus, and Norovirus.

In some implementations, the viral infection is a coronavirus infection.

In another implementation, the coronaviruses were selected from the following groups: 229E α coronavirus, NL63 α coronavirus, OC43 β coronavirus, HKU1 β 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).

In some implementations, the coronavirus is SARS-CoV-2.

In some implementations, the coronavirus is a feline coronavirus.

In some implementations, the feline coronavirus is feline enteric coronavirus (FECV) or feline infectious peritonitis virus (FIPV).

In some implementations, the viral infection is pneumonia virus infection.

In some implementations, the pneumonia virus is a human respiratory syncytial virus.

In some embodiments, the viral infection originates from a DNA virus. In some embodiments, the DNA virus is a single-stranded or double-stranded DNA virus. In other embodiments, the DNA virus is a positive-sense DNA virus, a negative-sense DNA virus, or a double-sense DNA virus.

In some embodiments, the viruses are from the families Myoviridae, Podoviridae, Siphoviridae, Alloherpesviridae, Herpesviridae (including human herpesvirus and varicella-zoster virus), Malocochherpesviridae, Lipothrixviridae, Rudiviridae, Adenoviridae, Ampullaviridae, Ascoviridae, and Asfarviridae. (Including African swine fever virus), Baculoviridae, Cicaudaviridae, Clavaviridae, Corticoviridae, Fuselloviridae, Globuloviridae, Guttaviridae, Hytrosaviridae, Iridoviridae, Marsie virus. The following families are included: Maseilleviridae, Mimiviridae, Nudiviridae, Nimaviridae, Pandoraviridae, Papillomaviridae, Phycodnaviridae, Plasmaviridae, Polydnavirus, Polyomaviridae (including simian virus 40, JC virus, and BK virus), Poxviridae (including cowpox and smallpox), Sphaerolipoviridae, Tectiviridae, Turriviridae, Dinodnavirus, Salterprovirus, and Rhizidovirus.

In some embodiments, the methods described herein can inhibit viral replication, transmission, replication, assembly, or release, or minimize the expression of viral proteins. In one embodiment, the methods described herein for inhibiting viral transmission, inhibiting viral replication, minimizing the expression of viral proteins, or inhibiting viral release include administering a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof to a patient infected with the virus, and/or bringing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof into contact with virus-infected cells.

In another aspect, this disclosure provides a method for inhibiting RNA polymerase in an individual in need, the method comprising administering to the individual an effective amount of the compound provided herein or a pharmaceutically acceptable salt or pharmaceutical combination thereof. Combination therapy

The compounds disclosed herein can also be used in combination with one or more additional treatments or preventative agents. Accordingly, this document also provides methods for treating viral infections in individuals in need, comprising administering to the individual a compound disclosed herein as a first active ingredient and a therapeutically effective amount of one or more additional treatments or preventative agents as a second active ingredient. Therefore, pharmaceutical compositions are also provided, comprising one or more compounds disclosed herein or their pharmaceutically acceptable salts as a first active ingredient and a second active ingredient.

In some embodiments, the second active ingredient includes one or more additional treatments from the same class or group and/or one or more additional treatments from different classes or groups.

In some embodiments, the second active ingredient has a complementary activity to the compounds provided herein, such that they do not adversely affect each other. Such ingredients are appropriately combined in amounts effective for the intended purpose.

In some embodiments, the second active ingredient may be an antibiotic, protease inhibitor, antiviral agent, anti-inflammatory agent, immunomodulator, kinase inhibitor, antimetabolic agent, lysosomal agent, M2 proton channel blocker, polymerase inhibitor (e.g., EIDD-2801), neuraminic acid inhibitor, reverse transcriptase inhibitor, viral entry inhibitor, integrase inhibitor, interferon (e.g., type I, II and III) or nucleoside analogue.

In some embodiments, the second active ingredient is an antibiotic. In some embodiments, the antibiotic may be selected from the group consisting of: penicillin antibiotics, quinolone antibiotics, tetracycline antibiotics, macrolide antibiotics, lincomycin antibiotics, cephalosporin antibiotics, or RNA synthase inhibitors. In some implementations, the antibiotics are selected from the following group: azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefdroxil, cefazolin, and cephalothin. Cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, ciprofloxacin, levaquin, ofloxacin, tequin, avelox, norfloxacin, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V V), dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tob... The antibiotics include ramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, ceftibuten, cefizoxime, ceftriaxone, cefoxotin, and streptomycin. In some practices, azithromycin is used.

In some embodiments, the second active ingredient may be a protease inhibitor. In some embodiments, the protease inhibitor may be selected from the group consisting of: nafamostat, carmostat, gabexate, ε-aminocaproic acid, aprotinin, amprenavir, indinavir, nelfinavir, nirmatrelvir, S-217622, EDP-235, PBI-0451, ritonavir, and saquinavir.

In some embodiments, the second active ingredient may be an antiviral agent. In some embodiments, the antiviral agent may be selected from the group consisting of: ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, and tenofovir alafenamide. hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapin e) Rilpivirine, Paritaprevir, Simeprevir, Daclatasvir, Grazoprevir, Pibrentasvir, Adefovir, Amprenavir, Ampligen, Apraviroc, Anti-goat antibody, Balavir, Cabotegravir, Cytarabine, Ecoliever, Epigallocatechin gallate 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.

In some embodiments, the second active ingredient may be an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent may be selected from the group consisting of: antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate). furoate, triamcinolone, flunisolide, NSAIDs, leukotriene regulators (e.g., montelukast, zafirlukast, pranlukast), trypsin inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors (such as elastase inhibitors), integrin antagonists (e.g., β-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors (such as sodium cromoglycate, 5-lipoxygenase inhibitors (zyflo), DPI antagonists, DP2 antagonists, PI3Kδ inhibitors, GGK inhibitors, LP... (Lysophospholipid) inhibitors or FLAP (5-lipoxygenase-activated protein) inhibitors, bronchodilators (e.g., muscarinic antagonists, β-2 agonists), methotrexate and similar drugs; monoclonal antibody therapy, such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar drugs; intercellular receptor therapy, such as etanercept and similar drugs; Antigen-specific immunotherapy (e.g., interferon or other intercytokines/chemotransferases, chemotransferase receptor modulators (such as CCR3, CCR4 or CXCR2 antagonists), other intercytokines/chemotransferase agonists or antagonists, TLR agonists and similar reagents), and appropriate anti-infective agents (including antibiotics, antifungals, anthelmintics, antimalarials, antiprotozoal agents and antituberculosis agents).

In some embodiments, the second active ingredient may be an immunomodulator. In some embodiments, the immunomodulator may be selected from the group consisting of: anti-PD-1 or anti-PDL-1 therapies, including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559 or avelumab; anti-TIM3 (anti-HAVcr2) therapies (including (but not limited to) TSR-022 or MBG453); anti-LAG3 therapies (including (but not limited to) relatlimab, LAG525 or TSR-033); anti-4-1BB (anti-CD37, anti-TNFRSF9); and CD40 agonist therapies (including (but not limited to) […]. SGN-40, CP-870, 893, or R07009789), anti-CD47 therapy (including (but not limited to) Hu5F9-G4), anti-CD20 therapy, anti-CD38 therapy, STING agonists (including (but not limited to) ADU-S100, MK-1454, ASA404, or nifedipine benzimidazole), and anthracycline. (Including but not limited to) doxorubicin or mitoxanthrone), demethylators (including but not limited to) azacytidine or decitabine), other immunomodulatory agents (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 treatment is a p2-adrenergic receptor agonist, including (but not limited to) vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol, carmoterol, etanterol, and nalmenterol. Interol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and their salts, such as salmeterol sine naphthaleneate (1-hydroxy-2-naphthoic acid) salt, salbutamol sulfate or formoterol fumarate.

In some embodiments, the second active ingredient may be a kinase inhibitor. In some embodiments, the kinase inhibitor may be selected from the group consisting of: erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatinib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, and abecitabine. maciclib), LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib, Loxo 292, larotrectinib, and quizartinib. Examples

For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit this disclosure and are merely intended to illustrate the methods of practicing this disclosure. Those skilled in the art will recognize that the described chemical reactions are readily adaptable to the preparation of many other compounds of this disclosure, and alternative methods for preparing the compounds of this disclosure are considered to be within the scope of this disclosure. For example, non-exemplary compounds according to this disclosure can be successfully synthesized by modifications readily apparent to those skilled in the art, such as by properly protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art besides those described, and/or by conventionally changing the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds of this disclosure.

HPLC conditions for palmarity: (Column: Daicel ^CHIRALPAK® IH 250mm×4.6mm, 5μm; Mobile phase A: HEX + 0.2% DEA; Mobile phase B: IPAMEOH + 0.2% DEA, Mobile phase A: Mobile phase B = 80:20 (V/V)).

The compounds in Table 1 can be separated by preparative HPLC or paisley HPLC to obtain a pair of isomers, namely compound number -P1 and compound number -P2. For a pair of compound numbers -P1 and -P2, the compound named "-P1" is first dissolved in a preparative HPLC or paisley HPLC column, and then the compound named "-P2" is dissolved. The structures of a pair of separated compound numbers -P1 and -P2 are indicated by the asterisk "*" near the paisley central atom of the corresponding compound number structure. For example, This means that the structures of 1-P1 and 1-P2 can be: or .

Similarly, in some embodiments, the compounds in Table 1 can be separated by palmar HPLC to obtain four isomers, namely compound number-P1, compound number-P2, compound number-P3, and compound number-P4. For these compounds, there are two palmar central atoms in the compound structure. Example 1. Synthesis of Intermediates 1.1 Synthesis of Intermediate 1a :

Under a _nitrogen atmosphere, a solution of compound 1a-1 (50 g, 0.1718 mol, 1 eq) in 400 mL of TMP was stirred for 15 min at 0 °C. _POCl₃ (86.18 g, 0.5670 mol, 3.3 eq) was added dropwise to the mixture over ₃₀ min at 0 °C. The resulting mixture was stirred for 1.5 h at 25 °C under a nitrogen atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was concentrated under vacuum. Acetonitrile (3 L) was added to the concentrated mixture and the mixture was filtered to give intermediate 1a (50 g, 0.1348 mol, 78%), a pale yellow solid. This product was used directly in the next step without further purification.

LCMS: Rt = 0.396 min; m/z= 372 [M+1] ⁺ ; m/z= 370 [M-1] ^-

^¹H NMR (400 MHz, _D₂O ) δ 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 1b : Step 1: Synthesis of compound 1b-2

Under _N2 conditions, DBDMH (15.2 g, 53.1 mmol, 0.55 eq) was added to a solution of compound 1b-1 (20.0 g, 96.5 mmol, 1.0 eq) in ACN (200 mL) at -30 °C, and the mixture was stirred at -20 °C for 2 hours. The reaction mixture was then poured into water (200 mL) and extracted with EA (200 mL × 3). The combined organic phase was washed with brine ( ₂₀₀ mL), dried over _Na2SO4 , filtered, and evaporated under vacuum to give a crude product. The crude product was purified by FCC (1% to 15% EtOAc in PE) to give compound 1b-2 (27.1 g, 98%) as a pale yellow oil.

LCMS: m/z (M+H) ⁺ = 286.0

^¹H NMR (400 MHz, _CDCl₃ ): δ: 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 1b-3

Under _N2 conditions, at 0°C, HCl/dimethyl alkylene (104.8 mL, 4M, 419.4 mmol) was added to a solution of compound 1b-2 (20.0 g, 69.9 mmol) in dimethyl alkylene (50 mL), and the resulting mixture was stirred at 25°C for 5 hours. The mixture was filtered, the filter cake was washed with MTBE (100 mL), and the filtrate was dried under vacuum to give compound 1b-3 (11.3 g, 50.8 mmol, 72.7%) as a white solid. The crude product was used directly in the next step without further purification.

LCMS: m/z = 186.0

^¹H NMR (400 MHz, DMSO _- d⁶ ): δ ppm = 7.24 (d, J = 2.0 Hz, ¹H), 6.92 (d, J = 2.0 Hz, ¹H). Step 3: Synthesis of compounds 1b-4

Under _N2 conditions, at 25°C, formamidine acetate (37.4 g, 359.6 mmol) and _K3PO4 (76.3 g, 359.6 mmol) were added to a solution of compound 1b-3 ₍ 16.0 g, 71.9 mmol) in EtOH (200 mL), and the mixture was then stirred at 78°C for 16 hours. The reaction mixture was filtered, and the filter cake was washed with EtOH (100 mL × 2), followed by vacuum evaporation of the filtrate to obtain the crude product. The crude product was ground with THF:DCM (1:3) and filtered. The filter cake was vacuum dried, and the filtrate was further purified by FCC (10% to 26% THF in PE) to obtain compound 1b-4 (9.5 g, 44.6 mmol, 62.0%), which was a light yellow solid.

LCMS: m/z = 213.0

^¹H NMR (400 MHz, DMSO _- d⁶ ): δ 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 compounds 1b-5

To a solution of compound 1b-4 (21.1 g, 99.0 mmol) in THF (200 mL), _D₂O (10 mL) was added, and the solution was then concentrated to dryness three times. Next, under _N₂ , THF (200 mL) and _D₂O (10 mL) were added to the residue, followed by the addition of Pd(dppf) _Cl₂ (7.2 g, 9.9 mmol) and TMEDA (2.3 g, 19.8 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 hours. The solution was then cooled to 0 °C, and _NaBD₄ (8.3 g, 198.0 mmol) was added. The reaction mixture was stirred at 25 °C for 17 hours. TLC (PE:EA=1:1) showed complete consumption of compound 1b-4 and detection of new spots. The mixture was poured into saturated _NH4Cl (200 mL). The reaction mixture was extracted with EA (100 mL × 3). The organic phase was washed with brine (100 mL), dried and concentrated with _Na2SO4 to obtain the residue. The residue was purified by silica gel column chromatography (10% to 50% EtOAc in PE) to give compound _1b -5 (7.5 g, 56.3%) as a yellow solid.

LCMS: m/z = 136.2

^¹H NMR (400 MHz, DMSO _- d₆ ): δ: 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 1b-6

A solution of compound 1b-5 (4.0 g, 29.5 mmol, 1.0 eq) in DMF (36 mL) was cooled to -5°C to 5°C. NIS (6.7 g, 29.5 mmol, 1.0 eq) was added to the above reaction under a _nitrogen atmosphere. The reaction mixture was stirred at -5°C to 5°C for 2 h. TLC showed the reaction was complete. The reaction mixture was poured into an aqueous solution of NaOH (400 mL, 1 M) and stirred for another 30 min. The pulverized solid was filtered off and washed with _H₂O (50 mL) and PE (60 mL), then dried under vacuum to obtain compound 1b-6 (6 g, 77%) in solid form.

^¹H NMR (400 MHz, DMSO _- d⁶ ) δ: 7.87 (s, ¹H), 7.80 (br s, ²H), 6.86 (s, ¹H). Step 6: Synthesis of compounds 1b-7

TMSCl (2.4 g, 21.7 mmol, 2.2 eq) was added to a solution of compound 1b-6 (2.6 g, 9.9 mmol, 1.0 eq) in THF (40 mL) under a _nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 40 min. The reaction mixture was cooled to -5°C to 5°C, and PhMgCl (11.8 mL, 2 M, 23.6 mmol) was added to the above reaction mixture, and the temperature was maintained at -5°C to 5°C for another 1.5 h. Then i -PrMgCl·LiCl (9.9 mL, 12.9 mmol, 1.3 eq) was added to the above reaction mixture, and the mixture was stirred for 15 min after the 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°C to -15°C. After addition, the reaction mixture was warmed to room temperature and stirred for 1 h. TLC (PE:EA=1:1) showed that the reaction was complete, and 1M HCl was added to adjust the pH to 2-3. EtOAc was added to separate the two phases, and the organic phase was washed twice with HCl (1M). The organic phase was then washed with saturated _NaHCO3 and brine, dried with _{Na2SO4 ,} filtered and concentrated under vacuum to obtain a crude product, which was purified by column chromatography (PE:EA=2:1) to obtain compound 1b-7 (2.0 g) in solid form. Step 7: Synthesis of compound 1b-8

TfOH (1.1 g, 7.2 mmol) was added to a solution of compound 1b-7 (2.0 g, 3.6 mmol, 1.0 eq) in DCM (24 mL) at -78 °C. After 10 min, TMSOTf (1.7 g, 7.6 mmol, 2.1 eq) was added to the above reaction, and the mixture was stirred for another 30 min. Then, TMSCN (1.4 g, 14.4 mmol, 4.0 eq) was added. After 10 min, TLC (PE:EA = 1:1) showed that the reaction was complete. The reaction was then quenched with TEA, followed by the addition of _NaHCO3 to bring the pH to approximately 8. The two phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried with _{Na₂SO₄ ,} filtered, and concentrated under vacuum to obtain a crude product, which was then purified by column chromatography to obtain a solid compound 1b-8 (1.4 g, 69%). Step 8: Synthesis of compound 1b-9

_BCl₃ (11.1 mL, 11.1 M) was added to a solution of compound 1b-8 (1.6 g, 2.8 mmol, 1.0 eq) in DCM (23 mL) 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 adjust the pH to 8-9. The solution was concentrated. Water (100 mL) was then added, the aqueous phase was washed with DCM, and the aqueous phase was concentrated to approximately 50 mL. Another 100 mL was added, and the same procedure was repeated seven times. The resulting solid was filtered and concentrated under vacuum to give compound 1b-9 (0.4 g, 51%) as a solid.

^¹H NMR (400 MHz, DMSO _-d⁶ ) δ: 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, 1H), 3.94–3.90 (m, 1H), 3.63–3.46 (m, 2H). Step 9: Synthesis of intermediate 1b:

A solution of compound 1b-9 (50.0 g, 0.1718 mol, 1 eq) in TMP (400 mL) was stirred for 15 min at 0 °C under _N2 atmosphere. _POCl3 (86.2 g, 56.7 mmol, 3.3 eq) was added dropwise to the mixture at 0 °C over 30 min. 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 adding acetonitrile (3 L). The precipitate was collected by filtration to give intermediate 1b (50.0 g, 134.8 mmol, 78%), a pale yellow solid.

LCMS: m/z = 373 1.3 Synthesis of intermediate 1c : Step 1: Synthesis of compound 1c-3:

Compound 1c-2 (478 mg, 5.38 mmol, 1 eq) and PTSA (1.11 g, 6.45 mmol, 1.2 eq) were added to a mixture of compound 1c-1 (1 g, 5.38 mmol, 1 eq) in toluene (20 mL), and the mixture was stirred at 130 °C for 16 h. The reaction mixture was quenched with saturated _NaHCO3 and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried with _Na2SO4 , filtered, and concentrated to dryness. The residue was purified by FCC to give compound 1c -3 ₍ 0.98 g, 71%) as a white solid.

LCMS: m/z = 258.15 [M+1]+

^¹H NMR (400 MHz, CDCl₃) δ 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:

To a mixture of compound 1a (500 mg, 1.348 mmol, 1.0 eq) in DMF (20 mL), PPh ₃ (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 1c-3 (1.38 g, 5.391 mmol, 4 eq) were added. The reaction mixture was stirred at 55 °C for 16 h. The reaction mixture was concentrated, and the residue was purified directly by column chromatography (DCM:MeOH=5:1) to obtain compound 1c as a crude product with a purity of about 80%. It was further purified by preparative TLC (DCM:MeOH=5:1) to obtain compound 1c (23.66 mg, 3%).

LCMS: m/z= 611.40 [M+1] ⁺ ; m/z= 609.10 [M-1] ^-

¹ H NMR (400 MHz, CD ₃ OD) δ 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).

Except for the use of different starting materials or intermediates, the following compounds were synthesized according to the same procedure as compound 1c:

Intermediate 1d :

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

¹ H NMR (400 MHz, CD3OD) δ 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 Step 1 : Synthesis of Compounds 1-2

Py (19.7 g, 248.6 mmol, 20.0 mL) and methyl chloroformate (180 g, 139.4 mmol, 12.4 mL) were added to a solution of 1-1 (20.0 g, 107.3 mmol) in hexane (300 mL) at 0 °C. The mixture was heated to 25 °C and stirred at 25 °C for 1 h. The mixture was washed with saturated _NH4Cl (200 mL). The organic layer was concentrated, and the residue was purified by silica gel chromatography (PE/DCM = 50/1 to 6/1) to give 1-2 (27.0 g, 90% yield) as a colorless oil. Step 2 : Synthesis of compounds 1-3

To a solution of 1-2 (27.0 g, 96.8 mmol) in acetone (500 mL), NaI (58.0 g, 387.0 mmol) was added. The mixture was stirred at 40 °C for 48 h. The mixture was concentrated to obtain a residue, which was diluted with PE (300 mL) and washed with water (200 mL) and saturated _Na₂SO₃ (100 mL). The organic layer was concentrated and purified by silica gel chromatography (PE/DCM = 50/1 to 6/1) to _give 1-3 (28.0 g, 78% yield), which was a yellow oil.

^¹H NMR (400 MHz, _CDCl₃ ) δ 5.97 (s, 2H), 4.24 (t, J = 7.2 Hz, 2H), 1.46–1.28 (m, 20H), 0.90 (t, J = 6.0 Hz, 3H). Step 3 : Synthesis of compounds 1–4

To a solution of intermediate 1a (1 g, 2.7 mmol) in pyridine (10.0 mL) , 1s⁻¹ (700 mg, 8.0 mmol), 2,2'-dithiodipyridine (1.2 g, 5.4 mmol), and _PPh₃ (1.4 g, 5.4 mmol) were added. The mixture was stirred at 60 °C for 2 h. The mixture was concentrated to obtain a residue, which was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 5) containing 10% methanol. The aqueous phase was freeze-dried to give 1-4 (1.1 g, crude product) as a yellow solid.

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

DIEA (880.4 mg, 6.8 mmol) was added to a solution of 1-4 (600 mg, 1.3 mmol) and 1-3 (2.5 g, 6.8 mmol) in MeOH (12 mL) at 25 °C, and the resulting mixture was stirred at 40 °C under argon for 2 h. The mixture was concentrated to obtain a residue, which was purified by silica gel chromatography (10% MeOH in DCM) to give the crude product of compound 1. The product was purified by preparative HPLC (Welch Xtimate C18 21.2 mm × 250 mm, 10 μm, _H₂O -ACN, 77-77) to give 1-P1 (37 mg, 4.1%) and 1- P2 (33.9 mg, 4%).

LC/MS: [M+H] ⁺ = 683.4 1-P1

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 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), 2.91–2.86 (m, 4H), 1.63–1.54 (m, 2H), 1.31–1.21 (m, 18H), 0.83 (t, J = 6.8 Hz, 3H). 1-P2

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 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), 2.97–2.91 (m, 4H), 1.63–1.54 (m, 2H), 1.33–1.17 (m, 18H), 0.85 (t, J = 6.8 Hz, 3H).

Except for the use of different starting materials or intermediates, the following compounds were synthesized according to the same procedure as compound 1: Compound 2 :

LC/MS [M+H] ⁺ = 767.7.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 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).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of 57:43. Compound 3 :

LC/MS [M+H] ⁺ = 669.6

1H NMR (400 MHz, DMSO-d6) δ 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, J = 6.8 Hz, 3H).

The compound was separated by palmar HPLC to obtain a pair of isomers in a 1:1 ratio. Compound 4 :

LCMS: [M+H] ⁺ = 753.7

¹ H NMR (400 MHz, DMSO-d6) δ 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), 4.68–4.62 (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).

The compound was separated by palmar HPLC to obtain a pair of isomers in a 1:1 ratio. Compound 12 :

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

¹ H NMR (400 MHz, CD ₃ OD) δ 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, J =6.8 Hz, 3H).

The compound was separated by palmar HPLC to obtain a pair of isomers in a ratio of approximately 1:1. Compound 13 :

LCMS: [M+H] ⁺ = 707.6

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 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).

The compound was separated by palmar HPLC to obtain a pair of isomers in a 1:1 ratio. Compound 14 :

LCMS: [M+H] ⁺ = 721.6

¹ H NMR (400 MHz, DMSO-d6) δ 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), 2.86–2.7 (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).

The compound was separated by palmar HPLC to obtain a pair of isomers in a 1:1 ratio. Compound 15 :

LCMS: [M+H] ⁺ = 683.6

1H NMR (400 MHz, DMSO-d6) δ 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), 4.03–3.91 (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).

The compound was separated by palmar HPLC to obtain a pair of isomers in a 1:1 ratio. Compound 16 :

LC/MS: [M+H] ⁺ = 711.7

¹ H NMR (400 MHz, DMSO-d6) δ 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), 1.73–1.57 (m, 2H), 1.46–1.39 (m, 2H), 1.33–1.15 (m, 22H), 0.85 (t, J = 7.2 Hz, 3H).

The compound was separated by palmar HPLC, yielding four isomers in a ratio of approximately 1:1:1:1. Compound 17 :

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

¹ H NMR (400 MHz, CD ₃ OD) δ 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), 4.33–4.31 (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).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of approximately 47:53. Compound 18 :

LC-MS: [M+1] ⁺ = 669.45

^¹H NMR (400 MHz, _CD₃OD ) δ 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), 4.25–4.13 (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 :

LC-MS: [M+1] ⁺ = 697.50

¹ H NMR (400 MHz, CD ₃ OD) δ 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).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of approximately 1:1. Compound 20 :

LCMS: [M+H] ⁺ = 739.6

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 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), 1.26–1.19 (m, 20H), 1.05–1.04 (m, 6H), 0.85 (t, J = 6.8 Hz, 3H).

The compound was separated by palmar HPLC to obtain a pair of isomers in a 1:1 ratio. Compound 21 :

LCMS: [M+H] ⁺ = 739.7.

¹ H NMR (400 MHz, DMSO-d6) δ 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), 4.24–4.18 (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).

The compound was separated by palmar HPLC to obtain a pair of isomers in a 1:1 ratio. Compound 22 :

LCMS: [M+H] ⁺ = 653.6.

1H NMR (400 MHz, DMSO-d6) δ 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), 4.75–4.61 (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).

The compound was separated by palmar HPLC, yielding four isomers in a ratio of approximately 1:1:1:1. Compound 23 :

LC/MS: [M+H] ⁺ = 655.5

¹ H NMR (400 MHz, DMSO-d6) δ 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), 4.75–4.63 (m, 2H), 4.24–4.12 (m, 2H), 4.06–3.89 (m, 2H), 2.54 (s, 3H), 2.52 (s, 3H), 1.61–1.43 (m, 2H), 1.28–1.18 (m, 21H), 1 0.87–0.82 (m, 3H).

The compound was separated by palmar HPLC, yielding four isomers: compounds 45, 46, 47, and 48, in a ratio of 1:1:1:1. Compound 24 :

LCMS: [M+H] ⁺ = 627.4

¹ H NMR (400 MHz, CD ₃ OD) δ 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).

The compound was separated by palmar HPLC, yielding four isomers: compounds 53, 54, 55, and 56, in a ratio of 1:1:1:1. Compound 26 :

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

¹ H NMR (400 MHz, CD ₃ OD) δ 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), 4.38–4.28 (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).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of approximately 48:52. Compound 33 :

LC-MS: [M+1] ⁺ = 709.30

¹ H NMR (400 MHz, CD ₃ OD) δ 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).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of approximately 55:45. Compound 27 :

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

¹ H NMR (400 MHz, CD3OD) δ 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).

The compound was separated by palmar HPLC to obtain a pair of isomers in a ratio of approximately 43:57. 2.2 Synthesis of Compound 5 Step 1 : Synthesis of compound 5-2 :

To a solution of 5-1 (10 g, 80.3 mmol) in acetone (150 mL), NaI (48.1 g, 321.2 mmol) was added, and the mixture was stirred at 30 °C for 48 h. The mixture was concentrated to obtain a residue, which was diluted with PE (300 mL) and washed with water (200 mL) _and saturated _Na₂SO₃ (3 mL). The organic layer was concentrated to obtain a residue, which was purified by silica gel chromatography (PE/EA = 100/1 to 10/1) to obtain 5-2 (6.1 g, 35%) as a colorless oil. Step 2 : Synthesis of compound 5 :

DIEA (2.0 g, 15.6 mmol, 2.7 mL) was added to a solution of 1d (2 g, 2.5 mmol) and 5-2 (1.6 g, 7.7 mmol) in DMF (10 mL). The mixture was stirred at 70 °C and microwaved for 1 h. The reaction mixture was quenched with water and extracted with EA:THF (1:1). The organic layer was concentrated to obtain a residue, which was purified by a rapid boiling tower and dissolved in DCM:MeOH = 100:1 to 95:5 to obtain a crude product. This crude product was purified by preparative HPLC ((10 mmol NH ₄ HCO ₃ )-ACN, H ₂ O/ACN = 65%-85%, Waters Xbridge C18 OBD 19mm×250mm, 5μm) to obtain compound 5 (217 mg, 10%).

LCMS: [M+H] ⁺ = 859.6

¹ H NMR (400 MHz, DMSO-d6) δ 8.05–7.77 (m, 3H), 7.26–7.14 (m, 5H), 6.92–6.89 (m, 1H), 6.81–6.80 (d, J = 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), 4.65–4.59 (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), 1.45–1.38 (m, 2H), 1.22–1.18 (m, 30H), 0.85 (t, J = 7.2 Hz, 3H).

The compound was separated by palmar HPLC to obtain a pair of isomers in a 1:1 ratio.

Except for the use of different starting materials or intermediates, the following compounds were synthesized according to the same procedure as compound 5: Compound 6 :

LCMS: [M+H] ⁺ = 887.8

¹ H NMR (400 MHz, DMSO-d6) δ 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), 5.38–5.14 (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, J = 6.8 Hz, 3H).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of approximately 60:40. Compound 8 :

LCMS: [M+H] ⁺ = 888.7

1H NMR (400 MHz, DMSO-d6) δ 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), 6.33–6.29 (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, J = 6.4, 3H).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of approximately 33:67. Compound 10 :

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

1H NMR (400 MHz, CD3OD) δ 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), 4.86–4.80 (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).

HPLC: A pair of isomers in a ratio of approximately 50:50. Compound 11 :

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

¹ H NMR (400 MHz, CD ₃ OD) δ 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, J = 6.5 Hz, 3H).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of approximately 40:60. Compound 9 :

LCMS: [MS+H] ⁺ = 860.20

¹ H NMR (400 MHz, CD ₃ OD) δ 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).

The compound was separated by palmar HPLC, yielding a pair of isomers in a ratio of approximately 47:53. Compound 7 :

LCMS: [MS+H] ⁺ = 831.40

¹ H NMR (400 MHz, CD ₃ OD) δ 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), 1.50–1.48 (m, 2H), 1.25–1.23 (m, 26H), 0.89 (t, J = 6.8 Hz, 3H).

The compound was separated by diametrical HPLC to obtain a pair of isomers in a ratio of approximately 50:50.

compound 62 :

LCMS: [MS+H] ⁺ = 832.15

¹ H NMR (400 MHz, CD ₃ OD) δ 7.87–7.86 (m, 1H), 7.24–7.15 (m, 5H), 7.01–6.83 (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).

Compound 62 was separated by palmar HPLC to obtain a pair of isomers, 62-P1 and 62-P2.

compound 64 :

LCMS: [MS+H] ⁺ = 804.15

^¹H NMR (400 MHz, methanol- d⁴ ) δ 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).

Compound 64 was separated by palmar HPLC to obtain a pair of isomers, 64-P1 and 64-P2:

compound 70 :

LCMS: [MS+H] ⁺ = 770.05

¹ H NMR (400 MHz, methanol- d 4) δ 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).

compound 72 :

LCMS: [MS+H] ⁺ = 817.85

¹ H NMR (400 MHz, methanol- d 4) δ 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, J = 7.0 Hz, 2H), 1.21 (d, J = 53.3 Hz, 26H), 0.91 – 0.86 (m, 3H).

compound 89 :

LCMS: [MS+H] ⁺ = 776.30

¹ H NMR (400 MHz, methanol-d4) δ 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).

compound 91 :

LCMS: [MS+H] ⁺ = 888.30

¹ H NMR (400 MHz, methanol- d 4) δ 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 Step 1 : Synthesis of compound 25-1 :

To a solution of intermediate 1a (15.5 g, 41.8 mmol, crude) and (4-methoxyphenyl)methylamine (5.7 g, 41.6 mmol) in pyridine (150 mL), DIEA (16.4 g, 127.1 mmol, 21.0 mL) and 2,2'-dithiodipyridine (18.5 g, 84.0 mmol) were added. The mixture was stirred at 60 °C for 3 h. The mixture was concentrated to obtain a residue, which was diluted with water (100 mL) and washed with EtOAc (100 mL × 5). The aqueous phase was freeze-dried to give 25-1 (12.5 g, crude), a yellow solid.

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

DIEA (6.7 g, 52.0 mmol, 8.6 mL) was added to a solution of 25-1 (5.0 g, 10.2 mmol) and 1-methyldodecyl chloride methyl carbonate (9.0 g, 30.7 mmol) in DMF (50.0 mL). The mixture was stirred at 80 °C for 4 h. The mixture was poured into saturated _NH4Cl (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layer was concentrated, and the residue was purified by silica gel chromatography (DCM/MeOH = 50/1 to 6/1) to give compound 25-2 (750.0 mg, 10%) as a yellow solid.

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

Add ( _NH₄ ) _₂Ce ( _NO₃ ) _₆ (2.0 g, 3.7 mmol) to a solution of 25⁻² (1.3 g, 1.7 mmol) in MeCN (45 mL) and water (5.0 mL). Stir the mixture at 0 °C for 1 h. Pour the mixture into water (100 mL) and extract with EtOAc (100 mL). The organic layer was washed with saturated _NaHCO3 (20 mL), _dried with _Na2SO4 , filtered, concentrated, and the residue was purified by silica gel chromatography (DCM/MeOH = 50/1 to 2/3) and preparative HPLC (Welch Xtimate C18 OBD, 21.2 mm × 250 mm, 10 μm, 0.05% _NH4HCO3 , _acetonitrile /water = 55%-80%) to give compound 25 (273.6 mg, 25%).

LCMS: [M+H] ⁺ = 627.6.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 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).

The compound was separated by palmar HPLC, yielding four isomers in a ratio of 1:1:1:1.

Except for the use of different starting materials or intermediates, the following compounds were synthesized according to the same procedure as compound 25: Compound 30 :

LC/MS: [M+H] ⁺ = 683.3

¹ H NMR (400 MHz, DMSO-d6) δ 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).

The compound was separated by palmar HPLC, yielding four isomers in a ratio of approximately 1:1:1:1. 2.4 Synthesis of Compound 28 Step 1 : Synthesis of Compound 28-2

_NaBH₄ (8.1 g, 212.1 mmol) was added to a solution of 28-1 (24 g, 106.1 mmol) in MeOH (240 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated _NH₄Cl and extracted with EA (500 mL). The combined organic phase was dried _{with Na₂SO₄} , filtered, and concentrated to give compound 28-2 (24.3 g, crude product), which was a yellow oil and was used directly without further purification. Step 2 : Synthesis of compound 28-3

28s-1 (13.5 g, 104.9 mmol) and pyridine (16.8 g, 212.4 mmol, 17.1 mL) were added to a solution of 28-2 (12.1 g, 52.9 mmol) in THF (120 mL) at -5 °C. The mixture was stirred at -5 °C for 1 h. The mixture was diluted with PE (100 mL) and washed with _NH4Cl (aqueous solution). The combined organic layer was concentrated and purified by silica gel chromatography (PE/DCM = 20/1 to 6/1) to give compound 28-3 (13.0 g, 76.4%) as a colorless oil. Step 3 : Synthesis of compound 28-4

To a solution of 28-3 (7 g, 8.1 mmol) in acetone (70 mL), NaI (13.1 g, 87.3 mmol) was added, and the mixture was stirred at 30 °C for 64 h. The reaction mixture was concentrated, diluted with PE (200 mL), and washed with water (100 mL) _and saturated _Na₂SO₃ (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 .

To a solution of intermediate 1a (4.5 g, 12.1 mmol) in MeOH (45 mL), DIEA (4.7 g, 36.3 mmol, 6.3 mL) was added, and 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 mixture was concentrated and quenched with saturated _NH₄Cl . 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 rapid chromatography (50% MeOH in EA) to give compound 28-5 (4.6 g, 57.8%) as a white solid.

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

DIEA (2.1 g, 15.6 mmol) and BOP (4.6 g, 10.4 mmol) were added 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), and the mixture was stirred at 25 °C for 16 h. The reactants were concentrated and quenched with _NH₄Cl (aqueous solution), extracted with EA/THF (100 mL/100 mL), concentrated, and purified by rapid chromatography (7% MeOH in EA) to give a crude product (1.5 g). The crude product was purified by preparative HPLC (Nanochrom ChromCore C18 21.2 mm × 250 mm, 10 μm, (10 _{mmol NH₄HCO₃} )-ACN, 90%-100%) to give compound 28 (84 mg, 3%).

LC/MS: [M+H] ⁺ = 683.3

¹ H NMR (400 MHz, DMSO-d6) δ 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).

The compound was separated by palmar HPLC, yielding four isomers in a ratio of approximately 1:1:1:1.

Except for the use of different starting materials or intermediates, the following compounds were synthesized according to the same procedure as compound 28: Compound 29 :

LC/MS: [M+H] ⁺ = 711.5

¹ H NMR (400 MHz, MeOD) δ 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), 4.22–4.14 (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).

The compound was separated by palmar HPLC, yielding four isomers in a ratio of approximately 1:1:1:1. Example 3. Biochemical Assay 1 : In vitro antiviral activity against 229E .

The following describes the evaluation of in vitro anti-229E activity and cytotoxicity using MRC5 cells.

Antiviral activity assay: MRC5 cells were seeded at a density of 20,000 cells/well in 96-well plates with 100 μL of assay medium per well and cultured at 37°C and 5% _CO2 . After 24 hours of incubation, the test compound and positive control (remdesivir) were diluted with assay medium and then added to the cells at 50 μL per well. Then, 50 μL of the diluted virus in assay medium was added to each well. The resulting cell cultures were incubated for another 3 days until significant CPE was observed in the virus control (virus-infected cells, untreated with the compound). CPE was measured using CellTiter Glo according to the manufacturer's instructions. The antiviral activity of the compound was calculated based on its protection against virus-induced CPE at various concentrations standardized to a virus control.

The suppression percentage is calculated using the following equation: Suppression (%) = (Original Data CPD – Average VC) / (Average CC – Average VC) × 100.

Cytotoxicity assay : The cytotoxicity of the compound was assessed using the same method as the antiviral activity assay, but without the viral infection step. Cell viability was measured using Cell-Titer Glo according to the manufacturer's manual. Viability % was calculated using the following equation: Viability (%) = (Original data CPD – Mean MC) / (Mean CC – Mean MC) × 100. Original data: CPD: Value of sample treatment wells; Mean VC: Mean of virus control; Mean CC: Mean of cell control (cells without viral infection or untreated with the compound); Mean MC: Mean of culture medium control (culture medium only) wells. Assay 2 : In vitro antiviral activity against SARS-CoV-2 replicants.

The test compound, positive control (remdesivir), and reference compound 1 (((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tris(2,3-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoyl)-L-octylalanate) were serially diluted in DMSO and added to 384-well plates at 0.3 μL/well (8 doses, 3x, duplicated wells). The replicant RNA was generated in vivo in vitro. Huh7 cells transfected with purified SARS-CoV-2 replicant RNA were seeded at 4000 cells/well in 384-well microplates containing serially diluted compound and then cultured at 37°C and 5% _CO2 for 1 day. The final volume of cell culture was 60 μL/well, and the final concentration of DMSO in the test plate was 0.5%.

Fluorescence intensity was measured using Acumen Cellista (TTP LabTech), and the antiviral activity of the compounds was calculated based on the inhibition of GFP expression. Cell viability was measured using CellTiter Glo according to the manufacturer's manual.

The antiviral activity and viability of the compounds are expressed as inhibition % and viability % respectively, and are calculated using the following formulas: Inhibition (%) = (Original Data CPD – Average ZPE) / (Average HPE – Average ZPE) × 100 Viability (%) = (Original Data CPD – Average HPE) / (Average ZPE – Average HPE) × 100 Original Data CPD: Value of the sample treatment wells Average ZPE: Average value of the virus control wells Average HPE: Average value of the medium control wells (medium only)

EC ₅₀ and CC ₅₀ values were calculated using GraphPad Prism software with a log(inhibitor) versus response-variable slope (four parameters) nonlinear regression model. Test 3 : Determination of intracellular nucleoside triphosphates:

Drug uptake and intracellular nucleoside triphosphate were evaluated using the human hepatocellular carcinoma cell line HepG2 and the human lung adenocarcinoma cell line. Cells were incubated in 6-well plates at 37°C in a 5% _CO2-95 % air atmosphere to allow cell attachment. The cell density for HepG2 was 2 × ^10⁶ /well, and for A549 it was 1 × ^10⁶ /well. The incubation media for HepG2 and A549 were Eagle's Minimum Essential Medium (EMEM) and F-12K, respectively, both containing 2% fetal bovine serum (FBS). After cell attachment, the culture medium was removed, and 2.5 mL of fresh culture medium containing 1 μM of the test compound was added to each well. The cells were incubated at 37°C in a 5% CO₂ atmosphere with ₉₅ % air. At specific time points (1 hour, 2 hours, 4 hours, and 6 hours), the culture medium was removed, and the cells were washed twice with 3 mL of ice-cold PBS. After washing, the cells were digested in the wells with 600 μL of ice-cold 70% methanol. The cell lysates were then centrifuged at 4°C and 13,000 rpm for 5 minutes. The supernatant of aliquots (200 μL) was transferred to a clean 96-well plate for LC-MS/MS analysis (Shimazu 20A and API 4000 Qtrap) to determine the intracellular nucleoside triphosphate concentration. Test 4 : In vitro antiviral activity against RSV .

The following describes the evaluation of in vitro anti-RSV activity and cytotoxicity using Hep-2 cells.

Antiviral activity assay : Hep-2 cells were seeded at a density of 6000 cells/well in 96-well plates, with 100 μL of assay medium per well, and cultured at 37°C and 5% _CO2 . After 24 hours of incubation, the test compound and positive control (remdesivir) were diluted with assay medium and then added to the cells, 50 μL per well. Then, 50 μL of RSV A2 virus diluted with assay medium was added to each well. The final concentration of DMSO in the assay medium was 0.5%. The resulting cell cultures were incubated for 5 days. The supernatant from the antiviral activity assay plates was removed, and intracellular viral protein expression was detected by anti-RSV F antibody ELISA. The antiviral activity of the tested compounds was calculated based on their viral replication inhibition rates at different concentrations.

The suppression percentage is calculated using the following equation: Suppression (%) = (Original Data CPD – Average VC) / (Average CC – Average VC) × 100.

Cytotoxicity assay : The cytotoxicity of the compound was assessed using the same method as for antiviral activity assay, but without the viral infection step. Cell viability was measured using CCK8 according to the manufacturer's manual.

Viability (%) is calculated using the following equation: Viability (%) = (Original Data CPD – Mean MC) / (Mean CC – Mean MC) × 100. Original Data CPD: Value of the sample treatment wells Mean VC: Mean value of the virus control wells Mean CC: Mean value of the cell control wells (cells without virus infection or untreated with compounds) Mean MC: Mean value of the medium control wells (medium only)

The EC ₅₀ and CC ₅₀ values were calculated using GraphPad Prism software with a log (inhibitor) comparison response-variable slope (four parameters) nonlinear regression model.

Tables 2 to 4 show the results of tests 3 to 5 for the exemplary compounds disclosed herein. These results indicate that the compounds disclosed herein have good inhibitory activity against various coronaviruses and respiratory syncytial viruses, exhibit low cytotoxicity, show high stability in human liver, and produce more triphosphorylation products in lung cells. Table 2 - In vitro antiviral activity of exemplary compounds against SARS-CoV-2 replicators. Compound number Huh7 (the clone) EC ₅₀ ¹ (nM) CC ₅₀ (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 twenty two A >1000 twenty three A >1000 twenty four 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: 100nM-1000nM, D: ≥1000nM Table 3 - Intracellular nucleoside triphosphates of exemplary compounds Compound number Hep G2 intracellular concentration ¹ (nM) MetaPpp A549 intracellular concentration ¹ (nM) MetaPpp 1h 2h 4h 6h 1h 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 twenty two A A A A B A A A twenty three A A A A B A A A twenty four 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: ≥500 nM, B: 200 nM-500 nM, C: <200 nM. Table 4 - In vitro antiviral activity of illustrative compounds against RSV A2. Compound number RSV A2 Hep-2 EC ₅₀ ¹ (nM) CC ₅₀ (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 twenty two A >1000 twenty three A >1000 twenty four 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: 100nM-1000nM, C: ≥1000nM Detection 5 : Rat Tissue Distribution

Tissue distribution in rats was evaluated using SPF-grade male Sprague-Dawley (SD) rats (n=12 per compound). The compound or positive control (remdesivir) was administered intravenously at a dose of 20 mg/kg. Three animals were sacrificed at specific time points (1 hour, 3 hours, 8 hours, and 24 hours) to collect lung and liver samples.

Liver and lung samples were homogenized using four times the volume of ice-cold 70% methanol (1:4 w:v). 800 μL aliquots of the homogenate were transferred to 1.5 mL tubes and centrifuged at 14000 g , 4 °C for 15 min. After centrifugation, 300 μL of the supernatant was transferred to a 96-well plate and evaporated to dryness under nitrogen. The nitrogen-dried residue was then dissolved in 200 μL of the initial LC mobile phase. The 96-well plate was loaded onto an LC-MS instrument for determining the triphosphate concentrations in the liver and lungs. Table 5 – Rat tissue distribution of illustrative compounds. compound In vivo PK in rats (IV, 20 mg/kg) Liver MetaPpp (nmol/kg) Lung MetaPpp (nmol/kg) 1 h 3 h 8 h 24 h 1 h 3 h 8 h 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 twenty two A A A B A A B C twenty three A A A B A A A C twenty four 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

A: ≥500nM, B: 200nM-500nM, C: <200nM.

The results in Table 5 show that, compared to remdesivir, the compound disclosed herein exhibits higher distribution and better lung selectivity in the lungs. Test 6 : Hemolysis test of SD rat erythrocytes.

The test compound was dissolved in brine at 1 mg/mL and continuously diluted in brine to prepare a working solution with the desired concentration. Pure Triton X-100 was mixed in water (2:98, v:v) to prepare 2% Triton X-100. Rat whole blood was transferred to a 50 mL tube and centrifuged at 2000 rpm for 10 minutes, then the supernatant was discarded. The precipitated red blood cells were gently resuspended in brine and centrifuged at 3000 rpm for 10 minutes. The supernatant was discarded. This process was repeated until the supernatant was colorless and transparent, and the washed red blood cells (RBCs) were resuspended in an equal volume of brine. RBCs were counted and their density adjusted to 2 × ^10⁸ cells/mL. 300 μL of RBCs and the working solution of the test compound were aliquoted into a dish. For positive and negative controls, 300 μL of saline or 2% Triton X-100 was added, respectively. The final concentrations of the test compound were 70 μg/mL, 23.33 μg/mL, 7.77 μg/mL, 2.59 μg/mL, 0.86 μg/mL, and 0.29 μg/mL. After incubation at 37°C for 45 min, each sample was centrifuged, and the absorbance from the supernatant of each sample was measured using a UV spectrophotometer (wavelength = 540 nm). Hemolysis percentage = 100 × [(Absorbance of sample – Absorbance of negative control) / (Absorbance of positive control – Absorbance of negative control)]. Table 6 - Hemolysis test of illustrative compounds compound hemolysis 70 µg/mL 20.33 µg/mL 7.77 µg/mL 2.59 µg/mL 0.86 µg/mL 0.29 µg/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 twenty two B A A A A A twenty four 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 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

A: <10%, B: 10%-30%; C: >30%

The hemolysis test results in Table 6 indicate that the compounds disclosed herein exhibit good safety.

The foregoing description is intended to be merely an explanation of the principles of this disclosure. Furthermore, since many modifications and variations are obvious to those skilled in the art, it is not intended to limit the invention to the exact structure and process described above. Therefore, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the appended patent applications.

Claims (80)

A compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, Wherein the base is a naturally occurring or modified pyrimidine 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, halogenated alkyl, ^-ORa , -NO2, -N( ^Ra ) ₂ , -C(O) _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 ; ^R21 , ^R22 , ^R31 , ^R32 and R Each of ^{the four} groups is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, halogenated alkyl, ^-ORa , -NO2, -N( ^Ra ) _{2 ,} -C(O)N( ^Ra ) ₂ , -C(O) ^Ra , -OC(O) ^Ra , -C(O) ^ORa , -S(O) ^Ra and -S(O) _2Ra ^; Each of the ^four groups is independently selected from the group consisting of: hydrogen, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl or _C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl and alkoxy are, as appropriate, substituted by one or more ^Rb ; or two Rb. ^5, together with the nitrogen atom to which it is attached, forms a heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group is, as appropriate, substituted by one or more R ^5a ; each R ^5a is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl; or two R ^5a , together with the atoms between them, form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is, as appropriate, substituted by one or more R ^b ; L ¹ is -C( ^RL ) _2- ; each R ^L is independently selected from hydrogen, deuterium, or an alkyl group, which may be substituted by one or more groups independently selected from halogen, hydroxyl, cyano, cycloalkyl, heterocyclic, aryl, or heteroaryl groups; ^L2 is selected from *-OC(O)-, *-OC(O)O-, *-OC(O)N( ^Ra )-, *-N( ^Ra )C(O)-, *-N( ^Ra )C(O)O-, or The * terminal of ^L2 is connected to ^L1 ; ^R6 is... ^R6a is selected from the group consisting of: _C8-20 alkyl, _C8-20 alkenyl, _CH3 ( _{CH2 ) mO} ( _CH2 ) _n- and ^RcOCH2 ( _CH2OCH2 ) _{pCH2- ,} wherein each is substituted by one or more ^Rb , as appropriate; ^R6b is selected from hydrogen, halogen, alkyl _, alkenyl or alkoxy, wherein each is substituted by one or more ^Rb , as appropriate; G is selected from -N( ^Ra )-**, -N( ^Ra )C( ^RG ) _2C (O)O-** or The **terminus of G is connected to ^R7 ; ring A is heterocyclic or heteroaryl, wherein each is substituted by one or more Rb ^groups as appropriate; X is selected from -O-, -N( ^Ra )-, or -C( ^Ra ) _2- ; each R and ^G is independently selected from the group consisting of: hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, and natural amino acid side chains, wherein each is substituted by one or more Rb ^groups as appropriate; ^R7 is selected from the group consisting of: _C8-20 alkyl, _C8-20 alkenyl, _C8-20 alkynyl, _CH3 ( _CH2 ) _mO ( _{CH2 ) n-} , _and ^RcOCH2 _{( CH2OCH2} ) _pCH2 - where each is substituted by one or more ^Rb as appropriate; ^R8 is selected from the group consisting of: hydrogen, _C1-6 alkyl, _C2-6 alkenyl or _C2-6 alkynyl, where each is substituted by one or more ^Rb as appropriate; each ^Ra is independently selected from hydrogen, halogen or alkyl; each ^Rb is independently selected from halogen, hydroxyl, cyano, amino, alkyl or alkoxy; each ^Rc is independently selected from hydrogen or alkyl; and each m, n or p is independently an integer from 0 to 20. If the compound of claim 1 or its pharmaceutically acceptable salt has formula (Ia) or formula (IIa): . The compound of claim 2 or its pharmaceutically acceptable salt, wherein the base is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . Such as the compound of claim 3 or its pharmaceutically acceptable salt, wherein the base is selected from the group consisting of: , , , , , , and . The compound of claim 2 or its pharmaceutically acceptable salt, wherein ^R1 is selected from hydrogen, hydroxyl, cyano, azido, alkyl or halogenated alkyl. Such as the compound in claim 5 or its pharmaceutically acceptable salt, wherein R ¹ is a cyano group. The compound of claim 2 or its pharmaceutically acceptable salt, wherein each of R ²¹ , R ²² , R ³¹ , R ³² and R ⁴ is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, halogenated alkyl or -OC(O) ^Ra . The compound of claim 7 or its pharmaceutically acceptable salt, wherein each of ^R21 , ^R22 , ^R31 , and ^R32 is selected from hydrogen, deuterium, halogen, hydroxyl, alkyl, or -OC(O) ^Ra . Such as the compound of claim 8 or its pharmaceutically acceptable salt, wherein ^Ra is an alkyl group. Such as the compound in claim 9 or its pharmaceutically acceptable salt, wherein ^Ra is methyl. The compound of claim 2 or its pharmaceutically acceptable salt, wherein ^R4 is selected from hydrogen, deuterium, halogen, cyano, azido, or halogenated alkyl. Such as the compound in claim 2 or its pharmaceutically acceptable salt, wherein Choose from the following groups: , , , , , , , , , , , , , , , and . The compound or its pharmaceutically acceptable salt as described in any of the preceding claims, wherein the base is... or ,and for . Such as the compound of claim 13 or its pharmaceutically acceptable salt, wherein the base is ,and for . The compound of claim 2 or its pharmaceutically acceptable salt has the formula (Ia): (Ia). The compound of claim 15 or its pharmaceutically acceptable salt, wherein each R ⁵ is independently selected from hydrogen or _C1-6 alkyl. The compound of claim 16 or its pharmaceutically acceptable salt, wherein each R ⁵ is independently a _C1-6 alkyl group. Such as the compound of claim 17 or its pharmaceutically acceptable salt, wherein each R ⁵ is independently a _C1-3 alkyl group. Such as the compound of claim 18 or its pharmaceutically acceptable salt, wherein both R ⁵ are methyl. Such as the compound in claim 18 or a pharmaceutically acceptable salt thereof, wherein both R ⁵ are ethyl. The compound of claim 15 or its pharmaceutically acceptable salt, wherein one R ⁵ is hydrogen and the other R ⁵ is a _C1-6 alkyl group. Such as the compound or its pharmaceutically acceptable salt as claimed in claim 15, wherein both R ⁵ are hydrogen. The compound of claim 15 or its pharmaceutically acceptable salt, wherein the two ^R5 atoms together with the nitrogen atoms thereon form a heterocyclic group, which may be substituted by one or more ^{R5a atoms} . The compound of claim 23 or its pharmaceutically acceptable salt, wherein the two ^R5 atoms, together with the nitrogen atoms thereon, form a heterocyclic group selected from the group consisting of: , , , and Each of these may be replaced by one or more R ^5a , depending on the circumstances. The compound of claim 23 or 24 or its pharmaceutically acceptable salt, wherein R ^5a is selected from alkyl or alkoxy groups. Such as the compound of claim 25 or its pharmaceutically acceptable salt, wherein R ^5a is methyl or . Such as the compound of claim 15 or its pharmaceutically acceptable salt, wherein each R ^L is independently selected from hydrogen, deuterium or alkyl. Such as the compound or its pharmaceutically acceptable salt in claim 27, wherein both R and ^L are hydrogen. Such as the compound of claim 15 or its pharmaceutically acceptable salt, wherein ^L2 is selected from *-OC(O)- or *-OC(O)O-. Such as the compound of claim 29 or its pharmaceutically acceptable salt, wherein ^L2 is *-OC(O)O-. The compound of claim 15 or its pharmaceutically acceptable salt, wherein R ^6a is selected from a _C8-20 alkyl or _C8-20 alkenyl group, wherein each is, as appropriate, substituted by one or more R ^b groups. The compound of claim 31 or its pharmaceutically acceptable salt, wherein R ^6a is selected from a _C8-13 alkyl or _C8-13 alkenyl group, wherein each is, as appropriate, substituted by one or more R ^b groups. The compound of claim 32 or its pharmaceutically acceptable salt, wherein R ^6a is a C _8-13 alkyl group substituted with one or more R ^b, as appropriate. The compound or its pharmaceutically acceptable salt from any of claims 15 to 33, wherein R ^6b is selected from hydrogen, halogen or alkyl. Such as the compound of claim 34 or its pharmaceutically acceptable salt, wherein R ^6b is selected from hydrogen or alkyl. Such as the compound or its pharmaceutically acceptable salt as claimed in claim 35, wherein R ^6b is hydrogen. The compound of claim 35 or its pharmaceutically acceptable salt, wherein R ^6b is a _C1-6 alkyl group. Such as the compound of claim 37 or its pharmaceutically acceptable salt, wherein R ^6b is a _C1-3 alkyl group. Such as the compound of claim 38 or its pharmaceutically acceptable salt, wherein R ^6b is methyl. The compound of claim 2 or its pharmaceutically acceptable salt has the formula (IIa): (IIa). Such as the compound of claim 40 or its pharmaceutically acceptable salt, wherein ^L2 is selected from *-OC(O)- or *-OC(O)O-. Such as the compound of claim 41 or its pharmaceutically acceptable salt, wherein ^L2 is *-OC(O)O-. Such as the compound of claim 40 or its pharmaceutically acceptable salt, wherein ^R8 is selected from hydrogen or, where appropriate, a _C1-6 alkyl group substituted with one or more ^Rb . Such as the compound of claim 43 or its pharmaceutically acceptable salt, wherein ^R8 is a _C1-3 alkyl group substituted with one or more ^Rb , as appropriate. Such as the compound of claim 44 or its pharmaceutically acceptable salt, wherein R ⁸ is methyl or isopropyl. Such as the compound of claim 40 or its pharmaceutically acceptable salt, wherein G is -N( ^Ra )-**. Such as the compound of claim 46 or its pharmaceutically acceptable salt, wherein ^Ra is selected from hydrogen or alkyl. Such as the compound of claim 47 or its pharmaceutically acceptable salt, wherein ^Ra is an alkyl group. Such as the compound of claim 48 or its pharmaceutically acceptable salt, wherein ^Ra is methyl. Such as the compound of claim 40 or its pharmaceutically acceptable salt, wherein G is -N( ^Ra )C( ^RG ) _2C (O)O-**. The compound of claim 50 or its pharmaceutically acceptable salt thereof, wherein each R ^G is independently selected from the group consisting of: hydrogen, _C1-6 alkyl, _C6-12 aryl, 5- to 12-membered heteroaryl, ( _C1-3 alkyl)( _C3-12 cycloalkyl), ( _C1-3 alkyl)(3- to 12-membered heterocycloyl), ( _C1-3 alkyl)( _C6-12 aryl), ( _C1-3 alkyl)(5- to 12-membered heteroaryl), and a natural amino acid side chain, wherein each is, where appropriate, substituted with one or more R ^b . The compound of claim 51 or its pharmaceutically acceptable salt, wherein one ^RG is hydrogen and the other ^RG is selected from a _C1-6 alkyl, _C6-12 aryl, ( _C1-3 alkyl)( _C6-12 aryl), ( _C1-3 alkyl)(5- to 12-membered heteroaryl) or a side chain of a native amino acid, wherein each is, as appropriate, substituted by one or more ^Rb . The compound of claim 52 or its pharmaceutically acceptable salt, wherein one ^RG is hydrogen and the other ^RG is (C _1-3 alkyl)(C _6-12 aryl) or (C _1-3 alkyl)(5 to 12 heteroaryl), wherein each is, as appropriate, substituted with one or more ^Rb . Such as the compound of claim 53 or its pharmaceutically acceptable salt, wherein ^Rb is a cyano, halogen, hydroxyl, or alkoxy group. For example, the compound of claim 53 or its pharmaceutically acceptable salt, wherein one ^RG is hydrogen, and the other ^RG is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . The compound of claim 51 or its pharmaceutically acceptable salt, wherein one ^RG is hydrogen and the other ^RG is a natural amino acid side chain. For example, the compound or its pharmaceutically acceptable salt as claimed in claim 56, wherein one ^RG is hydrogen, and the other ^RG is selected from the group consisting of: , , , , , , , , , , , , , and . Such as the compound or its pharmaceutically acceptable salt as claimed in claim 40, wherein G is... And X is -O-. For example, the compound or its pharmaceutically acceptable salt as claimed in claim 58, wherein ring A is selected from the group consisting of: , , , , and . The compound of claim 40 or its pharmaceutically acceptable salt, wherein ^R7 is selected from a _C8-20 alkyl or _{C8-20 alkenyl} group, wherein each is, as appropriate, substituted with one or more Rb ^groups . The compound of claim 60 or its pharmaceutically acceptable salt, wherein ^R7 is selected from a _C16-20 alkyl or _C16-20 alkenyl group, wherein each is, as appropriate, substituted with one or more Rb ^groups . The compound of claim 61 or its pharmaceutically acceptable salt, wherein ^R7 is a _C16-20 alkyl group substituted with one or more ^Rb , as appropriate. The compound of claim 2 or its pharmaceutically acceptable salt has a formula selected from the group consisting of: (Ib) (Ic) (Id) (Ie) (IIb) (IIc) (IId) (IIe) . Such as the compound in claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from any of the compounds listed in Table 1. A pharmaceutical composition comprising a compound of any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable delivery vehicle. Such as the pharmaceutical composition in claim 65, wherein the pharmaceutical composition is formulated for oral administration, injection administration, nasal administration or pulmonary administration. A method for treating a viral infection in an individual in need, the method comprising administering to the individual an effective amount of a compound of any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 65 to 66. The method of claim 67, wherein the viral infection is from an RNA virus. The method of claim 68, wherein the RNA virus is a single-stranded or double-stranded RNA virus. The method of claim 68, wherein the viral infection originates from a virus selected from the group consisting of: Retroviridae virus, Lentiviridae virus, Coronaviridae virus, Picornaviridae virus, Caliciviridae virus, Flaviviridae virus, Togaviridae virus, Bomaviridae virus, Filoviridae virus, Paramyxoviridae virus, Pneumomoviridae virus, Rhabdoviridae virus, Arenaviridae virus, Bunyaviridae virus, Orthomyxoviridae virus, and Deltavirus. The method of claim 68, wherein the viral infection originates from a virus selected from the group consisting of: Lymphocytic choriomeningitis virus, Coronavirus, HIV, SARS, Poliovirus, Rhinovirus 16, Hepatitis A virus, 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. The following viruses are listed: 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 virus, hepatitis D virus, enterovirus 71, Coxsakie virus, and Norovirus. The method of claim 71, wherein the viral infection is a coronavirus infection. The method of claim 72, wherein the coronavirus is selected from the group consisting of: 229E α coronavirus, NL63 α coronavirus, OC43 β coronavirus, HKU1 β 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). The method of claim 73, wherein the coronavirus is SARS-CoV-2. The method of request item 73, wherein the coronavirus is a feline coronavirus. The method of claim 75, wherein the feline coronavirus is feline enteric coronavirus (FECV) or feline infectious peritonitis virus (FIPV). The method of claim 71, wherein the viral infection is a human respiratory fusion cell virus. A method for inhibiting RNA polymerase in an individual in need, the method comprising administering to the individual an effective amount of a compound of any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 65 to 66. Use of a compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 65 to 66, for the manufacture of an agent for the treatment of viral infections. The compound of any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 65 to 66, is used for the treatment of viral infections.