Anti-coronavirus compound as well as composition and application thereof

Abstract

The present disclosure relates to compounds that exhibit activity in the inhibition of RNA polymerases, as well as pharmaceutical compositions comprising these compounds and methods of treating viral infections by administering these compounds or pharmaceutical compositions.

Description

Field of the Invention

[0001] The present disclosure generally relates to compounds that exhibit activity in inhibiting RNA polymerase and pharmaceutical compositions containing such compounds, as well as methods of treatment by administering such compounds or pharmaceutical compositions containing them. Background Art

[0002] In the past two decades, a variety of viruses that can cause life-threatening diseases in humans and animals have been identified, namely influenza virus, respiratory syncytial virus (RSV), parainfluenza virus, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola virus, etc. Among them, the global pandemic caused by SARS-CoV-2 has led to severe respiratory diseases around the world, where severe cases progress to pneumonia and multiple organ failure, which has resulted in millions of deaths worldwide. Coronaviruses are highly prone to mutate into epidemic variants. Although a variety of vaccines have been approved for use since the outbreak of SARS-CoV-2, vaccinated people still face the risk associated with the emergence of immune escape mutants. Therefore, it is very important to develop antiviral drugs to combat existing and emerging coronaviruses.

[0003] Coronaviruses are positive-strand RNA viruses that encode 16 non-structural proteins (nsp1 to nsp16). Many non-structural proteins bind to form a multi-protein replicase-transcriptase complex (RTC). The main replicase-transcriptase protein is the RNA-dependent RNA polymerase (RdRp), which is directly involved in the RNA replication and transcription of RNA strands. In addition, RdRp is highly conserved among various variants and viruses, making it an ideal drug target for controlling the infection of various RNA viruses.

[0004] Remdesivir is a monophospho-adenosine prodrug of the nucleoside GS-441524, originally developed for the treatment of Ebola virus infection, and the drug inhibits the RdRp of SARS-CoV-2. In several countries, it is the first antiviral drug to be approved or authorized for the emergency treatment of COVID-19. Remdesivir improved the clinical outcomes of hospitalized patients with moderate to severe disease and prevented disease progression in outpatients (Beigel J.H. et al., Remdesivir for the treatment of covid-19-final report. N. Engl. J. Med. 2020; 383(19):1813-1826.; Gottlieb R.L. et al., Earlyremdesivir to prevent progression to severe covid-19inoutpatients. 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 remainactive against SARS-CoV-2Omicron and other variants ofconcern. AntiviralRes. February 2022; 198:105252.). However, remdesivir has several drawbacks, such as being limited to intravenous administration, having a short plasma half-life, lack of correlation between plasma exposure and clinical efficacy, and low pulmonary delivery rate (Sun D. Remdesivir for treatment of COVID-19:combination of pulmonary and IVadministration may offer additional benefit. AAPS J. 2020; 22:77.).

[0005] Accordingly, there is a need in the art to develop improved compounds that exhibit inhibitory activity against RNA polymerase, particularly RNA polymerase inhibitors having good oral and pulmonary bioavailability and a high conversion rate to their monophosphate and triphosphate forms. SUMMARY OF THE INVENTION

[0006] The present disclosure provides compounds capable of inhibiting RNA polymerase, pharmaceutical compositions comprising these compounds, and methods of using such compounds or pharmaceutical compositions to treat viral infections.

[0007] In one aspect, the present disclosure provides a compound having formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof,

[0010] in,

[0011] The base is a naturally occurring or modified pyrimidine base or a purine base;

[0012] R 1 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -OR a 、-NO 2 、-N(R a ) 2 、-C(O)N(R a ) 2 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-S(O)R a 、-S(O) 2 R a 、-S(O)OR a 、-S(O) 2 (OR a ) and -S(O) 2 N(R a ) 2 ;

[0013] R 21 , R 22 , R 31 , R 32 and R 4 Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -OR a 、-NO 2 、-N(R a ) 2 、-C(O)N(R a ) 2 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-S(O)R a and -S(O) 2 R a ;

[0014] Q is CH 2 , CHD or CD 2 ;

[0015] Each M is independently selected from hydrogen, a metal ion, -NH 4 or a protonated organic amine;

[0016] L is selected from hydrogen or -C(R 5 ) 2 -L 1 -L 2 ;

[0017] Each R 5 is selected from hydrogen, deuterium or an alkyl group optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0018] L 1 is selected from -OC(O)-*, -OC(O)O-*, -OC(O)N(R a )-*, -N(R a )C(O)-*, -N(R a )C(O)O-

[0019] * or wherein the *-end of L 1 is connected to L 2 ;

[0020] L 2 is selected from hydrogen, R 6 , wherein the *-end of L 2 is connected to L 1 ;

[0021] R 6 is selected from C 9-26 alkyl, C 9-26 alkenyl, C 9-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q -,

[0022] R a OCH 2 (CH 2 OCH 2 ) n CH 2 - wherein the alkyl, alkenyl or alkynyl is optionally substituted by one or more R b ;

[0023] R 7 is selected from C 6-26 alkyl, C 6-26 alkenyl, C 6-26 alkynyl, CH 3 (CH2 ) p O(CH 2 ) q - or

[0024] R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, each of which is optionally substituted by one or more R b substituents;

[0025] R 8 and R 9 each independently selected from C 1-26 alkyl, C 2-26 alkenyl, C 2-26 alkynyl,

[0026] CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, each of which is optionally substituted by one or more R b substituents;

[0027] Provided that when R 8 is methyl and R 9 is hydrogen, then R 7 is selected from C 7-26 alkyl, C 7-26 alkenyl, C 7-26 alkyn

[0028] yl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -;

[0029] Each R a is independently selected from hydrogen, halogen or alkyl;

[0030] Each R bindependently selected from halogen, hydroxyl, cyano, amino or alkyl;

[0031] m is 0, 1, 2 or 3; and

[0032] each of n, p or q is independently an integer between 0 and 20.

[0033] In a further aspect, there is provided a compound having the formula (Ia):

[0034]

[0035] or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0037] In another aspect, the present disclosure provides a method for treating a patient in need of treatment for a viral infection, which comprises administering to the individual an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0038] In another aspect, the present disclosure provides a method for inhibiting RNA polymerase in an individual in need thereof, which comprises administering to the individual in need an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0039] In another aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for the treatment of viral infections.

[0040] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure for the treatment of viral infections. Detailed Description

[0041] For details, refer to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. Although the present disclosure will be described in conjunction with the recited embodiments, it should be understood that the present disclosure is not intended to be limited to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, or equivalents that may be included within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize many methods or materials that can implement the present disclosure that are similar to or equivalent to those described herein. The present disclosure is in no way limited to the methods or materials described. In the event of a difference or conflict between one or more of the incorporated references and similar materials (including, but not limited to, defined terms, term usage, techniques, etc.) and the present application, the present disclosure shall prevail. All references, patents, and patent applications cited in the present disclosure are incorporated herein by reference in their entirety.

[0042] It should be understood that certain features of the present disclosure described in the context of different embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination. It must be noted that, unless the context clearly dictates otherwise, as used in the specification and the appended claims, the singular forms "a / an" and "the" include their plural forms. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0043] Definition

[0044] 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, inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry and specific functional groups and reactivity are described in Organic Chemistry, Thomas Sorrell, 2nd Edition, University Science Books, Sausalito, 2006; Smith and March, March's Advanced Organic Chemistry, 6th Edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th Edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference.

[0045] Throughout this disclosure, linking substituents are described. In particular, 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 a structure clearly requires a linking group, the Markush variables recited with respect to the group are to be understood as linking groups. By way of example, if a structure requires a linking group and the Markush group definition of the variable recites "alkyl", then it is to be understood that the "alkyl" represents a linking alkylene.

[0046] When a bond to a substituent is shown to cross a bond between two atoms in a linking ring, then the substituent may be bonded to any atom on the ring. When a listed substituent does not indicate the atom to which the substituent is bonded to the remainder of a given formula compound, then the substituent may be bonded via any atom in the formula. Combinations of substituents and / or variables are permissible, but only if the combination results in a stable compound.

[0047] When "*" is shown adjacent to an atom of a compound, it indicates that the compound contains the atom as an asymmetric center of (R) or (S) stereoconfiguration.

[0048] When any variable (e.g., R i ) appears more than once in any moiety or formula of a compound, its definition at each occurrence is independent of its definition at each other occurrence. Thus, for example, if a group is shown to be substituted with 0 - 2 R i moieties, then the group may optionally be substituted with up to two R i moieties, and R i is independently selected from the definitions for R i at each occurrence. Also, combinations of substituents and / or variables are admissible only if the combination results in a stable compound.

[0049] As used herein, the term "C i-j " indicates a range of carbon atom numbers, where i and j are integers, and the range of carbon atom numbers includes the endpoints (i.e., i and j) and each integer point therebetween, and where j is greater than i. For example, C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "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.

[0050] Whether used as part of another term or independently, as used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon group, which may optionally and independently be substituted with one or more of the substituents described below. The term "C i-j 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. "C 1-6Examples of "alkyl" are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 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 contains 9 to 30 carbon atoms. In some embodiments, the alkyl 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.

[0051] As used herein, whether used as part of another term or independently, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon double bond, which may optionally and independently be substituted with one or more substituents described herein, and includes groups having "cis" and "trans" conformations, or alternatively, "E" and "Z" conformations. In some embodiments, the alkenyl contains 2 to 12 carbon atoms. In some embodiments, the alkenyl contains 2 to 11 carbon atoms. In some embodiments, the alkenyl 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, 2 to 3 carbon atoms. In some embodiments, the alkenyl contains 9 to 30 carbon atoms. In some embodiments, the alkenyl 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 include, but are not limited to, vinyl (or ethenyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

[0052] As used herein, the term "alkynyl", whether as part of another term or used independently, refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon triple bond, which may optionally and independently be substituted with one or more substituents described herein. In some embodiments, the alkenyl contains 2 to 12 carbon atoms. In some embodiments, the alkynyl contains 2 to 11 carbon atoms. In some embodiments, the alkynyl 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, 2 to 3 carbon atoms. In some embodiments, the alkynyl contains 9 to 30 carbon atoms. In some embodiments, the alkynyl 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 include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0053] As used herein, the term "amino" refers to -NH 2 group. The amino group may also be substituted with one or more groups such as alkyl, aryl, carbonyl, or other amino groups.

[0054] As used herein, the term "aryl", whether as part of another term or used independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members. Examples of "aryl" include (but are not limited to) phenyl, biphenyl, naphthyl, anthracenyl, etc., which may be substituted with one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more additional rings are also included within the scope of the term "aryl". In the case of polycyclic ring systems, only one ring needs to be aromatic (e.g., 2,3-dihydroindole), although all rings may be aromatic (e.g., quinoline). The second ring may also be spiro, fused, or bridged. Examples of polycyclic aryls include (but are not limited to) benzofuranyl, indanyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc. The aryl may be substituted at one or more ring positions with substituents as described above.

[0055] As used herein, the term "azido" refers to -N 3 .

[0056] As used herein, whether used as part of another term or independently, the term "cycloalkyl" refers to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system in which all ring atoms are carbon and the ring system contains at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, 4 to 5 ring-forming carbon atoms. The cycloalkyl may be saturated or partially unsaturated. The cycloalkyl may be substituted. In some embodiments, the cycloalkyl may be a saturated cycloalkyl. In some embodiments, the cycloalkyl may be a partially unsaturated cycloalkyl containing at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl may be monocyclic or polycyclic. Examples of monocyclic cycloalkyls include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of polycyclic cycloalkyls include (but are not limited to) adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, and the like.

[0057] As used herein, the term "cyano" refers to -CN.

[0058] As used herein, the term "halogen" refers to an atom selected from fluorine (fluorine / fluoro), chlorine (chlorine / chloro), bromine (bromine / bromo), and iodine (iodine / iodo).

[0059] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens. In some embodiments, the haloalkyl may contain 1 to 6 carbon atoms. In some embodiments, the haloalkyl may contain 1 to 4 carbon atoms. In some embodiments, the haloalkyl may contain 1 to 3 carbon atoms. Examples of haloalkyls include but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromomethyl, tribromomethyl, and tetrafluoroethyl.

[0060] As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, phosphorus or silicon, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen (including N-oxides).

[0061] As used herein, the term "heteroaryl" refers to an aryl group that has one or more heteroatoms in addition to carbon atoms. The heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl groups include (but are not limited to) thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. The heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused with one or more aryl groups, cycloaliphatic groups or heterocyclic groups, wherein the linking group or the point of attachment is located on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include (but are not limited to) indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0062] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated carbocyclic group, wherein one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, and one or more ring atoms may optionally be independently substituted with one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the heterocyclic group may contain any oxidized form of carbon, nitrogen or sulfur and any quaternized form of basic nitrogen. The "heterocyclic group" also includes a group in which a heterocyclic group is fused with a saturated, partially unsaturated or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, the heterocyclic group can be carbon-linked or nitrogen-linked. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, a group derived from pyrrole can be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). In addition, a group derived from imidazole can be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

[0063] 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 ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spiro, and bridged ring systems are also included within this definition. Examples of monocyclic heterocyclic groups include (but are not limited to) oxetanyl, 1,1-dioxothietanyl pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridone, pyrimidinone, pyrazinonyl, pyrimidinone, pyridazonyl, pyrrolidinyl, triazinonyl, etc. Examples of fused heterocyclic groups include (but are not limited to) phenyl-fused rings or pyridyl-fused rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,3]triazolo[4,3-a]pyridyl, etc. Examples of spiro heterocyclic groups include (but are not limited to) spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclic groups include (but are not limited to) morphanyl, hexamethylenetetramine, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

[0064] As used herein, the term "hydroxyl" refers to -OH.

[0065] As used herein, the term "metal ion" refers to a cation including a metal element. Various metal ions can be used as the metal ions in the present disclosure, including but not limited to any metal selected from alkali metals, alkaline earth metals, lanthanides, transition metals, and mixtures thereof.

[0066] As used herein, the term "partially unsaturated" refers to a group including at least one double bond or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0067] As used herein, the term "protonated organic amine" refers to (R-NH 3 ) +, wherein the R group refers to an organic group.

[0068] As used herein, the term "purine base" or "pyrimidine base" includes, but is not limited to, adenine, N 6 -alkylpurine, N 6 -acylpurine (wherein the acyl group is C(O)(alkyl, aryl, alkylaryl or arylalkyl)), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -alkynylpurine, N 6 -acylpurine, N 6 -hydroxyalkylpurine, N 6 -allylaminopurine, N 6 -thioallylpurine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine (including 6-azacytosine), 2- and / or 4-mercaptopyrimidine, uracil, 5-halouracil (including 5-fluorouracil), C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -alkynylpyrimidine, C 5 -acylpyrimidine, C 5 -hydroxyalkylpurine, C 5 -aminopyrimidine, C 5 -cyanopyrimidine, C 5 -5-iodopyrimidine, C 6 -iodopyrimidine, C 5 -Br-vinylpyrimidine, C 6 -Br-vinylpyrimidine, C 5 -nitropyrimidine, C 5 -aminopyrimidine, N 2 -alkylpurine, N 2-alkyl-6-thiopurine, 5-azacytidinyl, 5-azauridinyl, triazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. The purine and pyrimidine bases are attached to ribose or its analogs through the nitrogen atom of the base. As needed or desired, the oxygen and nitrogen functional groups on the bases may be protected. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl, trityl, alkyl, and acyl groups such as acetyl and propionyl, mesyl, and tosyl.

[0069] As used herein, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. It should be understood that "substituted" or "substituted with" includes the implicit condition that such substitution is in accordance with the allowed valences of the atoms being substituted and that the substitution results in a stable or chemically feasible compound, e.g., the compound does not spontaneously undergo transformation such as rearrangement, cyclization, elimination, etc. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from the designated group, the substituents at each position may be the same or different. Those skilled in the art should understand that if appropriate, the substituents themselves may be substituted. Unless expressly stated as "unsubstituted", references herein to chemical moieties should be understood to include substituted variants. For example, a reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0070] Compound

[0071] The present disclosure provides novel compounds of formula (I), their pharmaceutically acceptable salts, synthetic methods for preparing these compounds, pharmaceutical compositions containing these compounds, and various uses of the disclosed compounds.

[0072] In one aspect, the present disclosure provides a compound having formula (I):

[0073]

[0074] or a pharmaceutically acceptable salt thereof,

[0075] wherein

[0076] the base is a naturally occurring or modified pyrimidine base or purine base;

[0077] R 1Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -OR a 、-NO 2 、-N(R a ) 2 、-C(O)N(R a ) 2 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-S(O)R a 、-S(O) 2 R a 、-S(O)OR a 、-S(O) 2 (OR a ) and -S(O) 2 N(R a ) 2 ;

[0078] R 21 , R 22 , R 31 , R 32 and R 4 Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -OR a 、-NO 2 、-N(R a ) 2 、-C(O)N(R a ) 2 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-S(O)R a and -S(O) 2 R a ;

[0079] Q is CH 2 , CHD or CD 2 ;

[0080] Each M is independently selected from hydrogen, metal ions, -NH 4 or protonated organic amines;

[0081] L is selected from hydrogen or -C(R 5 ) 2 -L 1 -L 2 ;

[0082] Each R 5An alkyl selected from hydrogen, deuterium or an alkyl optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0083] L 1 Selected from -OC(O)-*, -OC(O)O-*, -OC(O)N(R a )-*, -N(R a )C(O)-*, -N(R a )C(O)O-* or wherein the *-end of L 1 is connected to L 2 ;

[0084] L 2 Selected from hydrogen, R 6 , wherein the *-end of L 2 is connected to L 1 ;

[0085] R 6 Selected from C 9-26 alkyl, C 9-26 alkenyl, C 9-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q -,

[0086] R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, wherein the alkyl, alkenyl or

[0087] alkynyl is optionally substituted with one or more R b ;

[0088] R 7 Selected from C 6-26 alkyl, C 6-26 alkenyl, C 6-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or

[0089] R a OCH 2 (CH 2 OCH 2 ) n CH 2-, each of which is optionally substituted by one or more R b substituted;

[0090] R 8 and R 9 each independently selected from C 1-26 alkyl, C 2-26 alkenyl, C 2-26 alkynyl,

[0091] CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, each of which is optionally substituted by one or more R b substituted;

[0092] Provided that when R 8 is methyl and R 9 is hydrogen, then R 7 is selected from C 7-26 alkyl, C 7-26 alkenyl, C 7-26 alkyn

[0093] yl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -;

[0094] Each R a is independently selected from hydrogen, halogen or alkyl;

[0095] Each R b is independently selected from halogen, hydroxy, cyano, amino or alkyl;

[0096] m is 0, 1, 2 or 3; and

[0097] each n, p or q is independently an integer between 0 - 20.

[0098] On the other hand, there is provided a compound having the formula (Ia):

[0099]

[0100] or a pharmaceutically acceptable salt thereof, wherein L, R 1 -R 4 , M, the base, and m are as defined above.

[0101] In some embodiments, the base is selected from the group consisting of:

[0102]

[0103]

[0104] In certain embodiments, the base is selected from the group consisting of:

[0105]

[0106] In some embodiments, L is hydrogen.

[0107] In certain embodiments, m is 0, 1, or 3.

[0108] In certain embodiments, M is hydrogen.

[0109] In some embodiments, L is -C(R 5 ) 2 -L 1 -L 2 .

[0110] In some embodiments, the two Rs 5 are both hydrogen or deuterium.

[0111] In certain embodiments, one R 5 is hydrogen, and the other R 5 is an alkyl optionally substituted with aryl.

[0112] In certain embodiments, one R 5 is hydrogen, and the other R 5 is methyl, ethyl,

[0113] In some embodiments, L 1 is selected from -OC(O)-*, -OC(O)O-*, -OC(O)NH-*, -OC(O)N(CH 3 )-*, -NHC(O)-*, -N(CH 3 )C(O)-*, -NHC(O)O-*, -N(CH 3 )C(O)O-* or

[0114] In certain embodiments, L 1is -OC(O)-*, -OC(O)O-* or

[0115] In some embodiments, L 2 is R 6 .

[0116] In some embodiments, R 6 is a straight-chain C 9-26 alkyl, a straight-chain C 9-26 alkenyl, a straight-chain C 9-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

[0117] In certain embodiments, R 6 is a straight-chain C 14-22 alkyl. In certain embodiments, R 6 is a straight-chain C 16-20 alkyl.

[0118] In certain embodiments, R 6 is a straight-chain C 14-22 alkenyl. In certain embodiments, R 6 is a straight-chain C 16-20 alkenyl.

[0119] In certain embodiments, R 6 is a straight-chain C 14-22 alkenyl having 1-6 double bonds.

[0120] In certain embodiments, R 6 is a straight-chain C 14-22 alkenyl having 1-6 double bonds, and each double bond is in the Z configuration.

[0121] In certain embodiments, R 6 is selected from the group consisting of:

[0122]

[0123] In some embodiments, R 6 is CH 3 (CH 2 ) p O(CH 2 ) q -.

[0124] In certain embodiments, R 6 is CH 3 (CH 2 ) p O(CH 2 ) q -, where p is an integer from 3 to 20, and q is an integer from 1 to 6.

[0125] In certain embodiments, R 6 is selected from CH 3 (CH 2 ) 5 O(CH 2 ) 2 -, CH 3 (CH 2 ) 5 O(CH 2 ) 3 -, CH 3 (CH 2 ) 5 O(CH 2 ) 4 -, CH 3 (CH 2 ) 5 O(CH 2 ) 5 -, CH 3 (CH 2 ) 6 O(CH 2 ) 3 -, CH 3 (CH 2 ) 7 O(CH 2 ) 3 -, CH 3 (CH 2 ) 8 O(CH 2 ) 3 -, CH 3 (CH 2 ) 9 O(CH 2 ) 3 -, CH 3 (CH 2 ) 10 O(CH 2 ) 3 -, CH 3 (CH 2 ) 11 O(CH 2 ) 3 -, CH 3 (CH 2 )12 O(CH 2 ) 3 -, CH 3 (CH 2 ) 13 O(CH 2 ) 3 -, CH 3 (CH 2 ) 14 O(CH 2 ) 3 -, CH 3 (CH 2 ) 15 O(CH 2 ) 3 -, CH 3 (CH 2 ) 16 O(CH 2 ) 3 -, CH 3 (CH 2 ) 17 O(CH 2 ) 3 -, CH 3 (CH 2 ) 18 O(CH 2 ) 3 -, or CH 3 (CH 2 ) 19 O(CH 2 ) 3 -.

[0126] In some embodiments, R 6 is R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

[0127] In certain embodiments, R 6 is R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, and n is an integer from 1 to 6.

[0128] In certain embodiments, R 6 is R a OCH 2 (CH 2 OCH 2 )n CH 2 -, where R a is hydrogen, methyl or ethyl.

[0129] In certain embodiments, R 6 is selected from the group consisting of: CH 3 OCH 2 (CH 2 OCH 2 ) 2 CH 2 -, CH 3 OCH 2 (CH 2 OCH 2 ) 3 CH 2 -, CH 3 OCH 2 (CH 2 OCH 2 ) 4 CH 2 -, HOCH 2 (CH 2 OCH 2 ) 5 CH 2 -, CH 3 OCH 2 (CH 2 OCH 2 ) 5 CH 2 - and CH 3 CH 2 OCH 2 (CH 2 OCH 2 ) 5 CH 2 -.

[0130] In some embodiments, L 2 is

[0131] In some embodiments, R 7 is C 6-26 alkyl, C 6-26 alkenyl, C 6-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH2 -.

[0132] In certain embodiments, R 7 is a straight-chain C 6-26 alkyl or a straight-chain C 6-26 alkenyl.

[0133] In certain embodiments, R 7 is a straight-chain C 13-21 alkyl or a straight-chain C 13-21 alkenyl. In certain embodiments, R 7 is a straight-chain C 15-20 alkyl or a straight-chain C 15-20 alkenyl.

[0134] In certain embodiments, R 7 is a straight-chain C 13-21 alkenyl having 1-6 double bonds.

[0135] In certain embodiments, R 7 is a straight-chain C 13-21 alkenyl having 1-6 double bonds, and each double bond is in the Z configuration.

[0136] In certain embodiments, R 7 is selected from the group consisting of:

[0137]

[0138] In some embodiments, R 7 is CH 3 (CH 2 ) p O(CH 2 ) q -.

[0139] In certain embodiments, R 7 is CH 3 (CH 2 ) p O(CH 2 ) q -, where p is an integer from 3 to 20, and q is an integer from 1 to 6.

[0140] In certain embodiments, R 7 is selected from CH 3 (CH 2 ) 5 O(CH 2 ) 2 -, CH 3 (CH 2 ) 5 O(CH 2 ) 3 -, CH3 (CH 2 ) 5 O(CH 2 ) 4 -、CH 3 (CH 2 ) 5 O(CH 2 ) 5 -、CH 3 (CH 2 ) 6 O(CH 2 ) 3 -、CH 3 (CH 2 ) 7 O(CH 2 ) 3 -、CH 3 (CH 2 ) 8 O(CH 2 ) 3 -、CH 3 (CH 2 ) 9 O(CH 2 ) 3 -、CH 3 (CH 2 ) 10 O(CH 2 ) 3 -、CH 3 (CH 2 ) 11 O(CH 2 ) 3 -、CH 3 (CH 2 ) 12 O(CH 2 ) 3 -、CH 3 (CH 2 ) 13 O(CH 2 ) 3 -、CH 3 (CH 2 ) 14 O(CH 2 ) 3 -、CH 3 (CH 2 ) 15 O(CH 2 ) 3 -、CH 3 (CH 2 ) 16 O(CH 2 )3 -, CH 3 (CH 2 ) 17 O(CH 2 ) 3 -, CH 3 (CH 2 ) 18 O(CH 2 ) 3 - or CH 3 (CH 2 ) 19 O(CH 2 ) 3 -.

[0141] In some embodiments, R 7 is R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

[0142] In certain embodiments, R 7 is R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, where n is an integer from 1 to 6.

[0143] In certain embodiments, R 7 is R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, where R a is hydrogen, methyl or ethyl.

[0144] In certain embodiments, R 7 is selected from the group consisting of: CH 3 OCH 2 (CH 2 OCH 2 ) 2 CH 2 -, CH 3 OCH 2 (CH 2 OCH 2 ) 3 CH 2 -, CH 3 OCH 2 (CH 2OCH 2 ) 4 CH 2 -, HOCH 2 (CH 2 OCH 2 ) 5 CH 2 -, CH 3 OCH 2 (CH 2 OCH 2 ) 5 CH 2 - and CH 3 CH 2 OCH 2 (CH 2 OCH 2 ) 5 CH 2 -.

[0145] In some embodiments, R 8 is C 1-26 alkyl or C 2-26 alkenyl, and R 9 is hydrogen or C 1-26 alkyl.

[0146] In certain embodiments, R 8 is straight-chain C 1-26 alkyl or straight-chain C 8-26 alkenyl, and R 9 is hydrogen or straight-chain C 1-26 alkyl.

[0147] In certain embodiments, R 7 is straight-chain C 6-26 alkyl, R 8 is straight-chain C 2-26 alkyl, and R 9 is hydrogen.

[0148] In certain embodiments, R 7 is straight-chain C 7-26 alkyl, R 8 is methyl, and R 9 is hydrogen or methyl.

[0149] In some embodiments, L 2 is

[0150] In certain embodiments, R 7 is straight-chain C 6-26 alkyl, straight-chain C 6-26 alkenyl, straight-chain C 6-26 alkynyl, CH 3 (CH2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

[0151] In certain embodiments, R 7 is a straight-chain C 6-26 alkyl or a straight-chain C 6-26 alkenyl.

[0152] In certain embodiments, R 8 is a straight-chain C 1-26 alkyl, a straight-chain C 2-26 alkenyl, a straight-chain C 2-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, and R 9 is hydrogen or C 1-26 alkyl.

[0153] In certain embodiments, R 8 is a straight-chain C 1-26 alkyl or a straight-chain C 2-26 alkenyl, and R 9 is hydrogen or a straight-chain C 1-26 alkyl.

[0154] In certain embodiments, R 7 is a straight-chain C 6-26 alkyl, R 8 is a straight-chain C 1-26 alkyl, and R 9 is hydrogen.

[0155] In certain embodiments, R 7 and R 8 are described as follows:

[0156]

[0157]

[0158] In some embodiments, R 1Selected from hydrogen, hydroxyl, cyano, azido, alkyl or haloalkyl. In certain embodiments, R 1 is cyano.

[0159] In certain embodiments, R 1 is alkyl. In certain embodiments, R 1 is methyl.

[0160] In certain embodiments, R 1 is haloalkyl. In certain embodiments, R 1 is -CH 2 F.

[0161] In some embodiments, R 21 , R 22 , R 31 , R 32 and R 4 each independently is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, haloalkyl, -OC(O)R a .

[0162] In certain embodiments, R 21 , R 22 , R 31 , R 32 each is selected from hydrogen, deuterium, halogen, hydroxyl, alkyl or -OC(O)R a . In certain embodiments, R a is alkyl. In certain embodiments, R a is methyl.

[0163] In certain embodiments, R 4 is selected from hydrogen, deuterium, halogen, cyano, azido or haloalkyl.

[0164] In some embodiments, is selected from the group consisting of:

[0165]

[0166] In some embodiments, the base is and is

[0167]

[0168] In certain embodiments, the base is In yet another aspect, the present disclosure provides a compound having a chemical formula selected from the group consisting of:

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193] The compounds provided herein are described with reference to general chemical formulas and specific compounds. In addition, the disclosed compounds can exist in many different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvated forms, amorphous forms, different crystal forms or polymorphs.

[0194] Depending on the substituent selection, the disclosed compounds can contain one or more asymmetric centers and can thus exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds provided herein can have asymmetric carbon centers and can thus have an (R) or (S) configuration at the carbon asymmetric centers. Accordingly, the compounds of the present disclosure can be in the form of individual enantiomers, diastereomers or geometric isomers, or can be in the form of a mixture of stereoisomers.

[0195] As used herein, the term “enantiomer” refers to two stereoisomers of a compound that are non - superimposable mirror images of one another. The term “diastereomer” refers to a pair of optical isomers that are not mirror images of one another. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity.

[0196] When a particular enantiomer is preferred, in some embodiments it may be provided as being substantially free of the opposite enantiomer and may also be referred to as "optically enriched". As used herein, "optically enriched" means that a compound consists of a significantly greater proportion of one enantiomer. In certain embodiments, the compound consists of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound consists of at least about 95%, 98% or 99% by weight of the preferred enantiomer. The preferred enantiomer can be separated 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. Optionally, derivatization may be carried out prior to separation of the stereoisomers. Separation of a mixture of stereoisomers may be carried out at an intermediate step during the synthesis of the compounds provided herein or it may be carried out on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, which, if necessary, is derivatized with a reagent containing a stereocenter of known configuration. Alternatively, the absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, page 268 (ed. E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0197] In some embodiments, a mixture of diastereomers is provided, such as a mixture of diastereomers enriched in one of the diastereomers by 51% or more, including for example one of the diastereomers being 60% or more, 70% or more, 80% or more or 90% or more.

[0198] In some embodiments, unless otherwise indicated, the compounds provided herein may have one or more double bonds present as Z or E isomers. Additionally, the present disclosure also encompasses the compounds in the form of individual isomers that are substantially free of other isomers and, alternatively, in the form of mixtures of multiple isomers (e.g., racemic mixtures of enantiomers).

[0199] The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerization, and cyclic forms, where the proton can occupy two or more positions in a heterocyclic system (e.g., 1H-imidazole and 3H-imidazole, 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 the rearrangement of some bonding electrons. Tautomers may be in equilibrium or locked in one form by appropriate substitution. Unless otherwise specified, the compounds of the present disclosure identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms.

[0200] The present disclosure also intends to include all isotopes of the atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure also mean to include their isotopes, such as (but not limited to) 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79Br, 81 Br, 124 I, 127 I and 131 I. Isotopically enriched compounds of formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by methods similar to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0201] In some embodiments, the present disclosure includes compounds of formula (I) or (Ia) in which one or more hydrogens attached to carbon atoms are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and can therefore be used to increase the half-life of any compound of formula (I) or (Ia) when administered to a subject, such as a mammal, particularly a human. See, for example, Foster “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527(1984). In view of the present disclosure, such compounds are synthesized by methods known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0202] The in vivo metabolites of the compounds described herein also fall within the scope of the present disclosure to the extent that such products are novel and non-obvious with respect to the prior art. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic processes. Accordingly, there is provided a novel and non-obvious compound produced by a method comprising contacting a compound with a mammal for a period of time sufficient to produce its metabolite.

[0203] The compounds of the present disclosure can be formulated as pharmaceutically acceptable salts or in the form of pharmaceutically acceptable salts. Unless otherwise specified, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0204] As used herein, the term “pharmaceutically acceptable” indicates that the substance or composition is chemically and / or toxicologically compatible with the other components of the formulation and / or the individual being treated therewith.

[0205] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the designated compounds and are not otherwise undesirable biologically or otherwise. Pharmaceutically acceptable salt forms that are contemplated include, but are not limited to, mono-, di-, tri-, tetra-, etc. salts. Pharmaceutically acceptable salts are non-toxic at the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of the compound without preventing it from exerting its physiological action. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0206] Pharmaceutically acceptable salts include acid addition salts, such as those containing: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, esylate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. Pharmaceutically acceptable salts can be obtained from acids such as: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0207] When acidic functional groups (such as carboxylic acid or phenol) are present, pharmaceutically acceptable salts also include base addition salts, such as those containing: benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc. See, e.g., Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0208] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent (such as an aqueous solution containing a suitable acid or a water-alcohol solution), and then separated by evaporation of the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosyl 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.

[0209] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treating the free acid with an inorganic base or an organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids (such as L-glycine, L-lysine and L-arginine), ammonia, primary amines, secondary amines and tertiary amines, and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0210] It should also be understood that the compounds of the present disclosure can exist in unsolvated form, solvated form (such as hydrated form) and solid form (such as crystalline or polycrystalline form), and the present disclosure is intended to cover all such forms.

[0211] As used herein, the term "solvate" or "solvated form" refers to a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to form solvates by entrapping a fixed molar ratio of solvent molecules in the crystalline solid state. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with the molecules of a substance, where water retains its molecular state as H 2 O. Examples of solvents that form solvates include (but are not limited to) water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.

[0212] As used herein, the terms "crystalline form", "crystallized form", "polymorphic form", and "polymorph" are used interchangeably and mean the crystal structures in which a compound (or its salt or solvate) can crystallize in different crystal packing arrangements, all of which crystal structures have the same elemental composition. Different crystal forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stabilities, and solubilities. The recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystal form to predominate. The crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0213] Synthesis of compound

[0214] The syntheses of the compounds provided herein (including their pharmaceutically acceptable salts) are illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, and thus, these schemes are illustrative only and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. In addition, the steps in the schemes are for better illustration and can be changed as appropriate. Examples of synthesizing the compounds in the examples are for research and for possible submission to regulatory agencies.

[0215] The reactions for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent can substantially not react with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, at a temperature within the range from the freezing temperature of the solvent to the boiling temperature of the solvent. The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, the suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0216] The preparation of the compounds of the present disclosure 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 chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, 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 Edition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0217] The reaction can be monitored according to any suitable method known in the art. For example, it can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy (IR), spectrophotometry (e.g., UV-visible light), mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC) to monitor product formation. Those skilled in the art can purify the compounds by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem., 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

[0218] The known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from commercial suppliers. Analytical grade solvents and commercially available reagents are used without further purification unless otherwise indicated.

[0219] Unless otherwise specified, the reactions of the present disclosure are carried out under a positive pressure of nitrogen or argon or in an anhydrous solvent using a dry tube, and the reaction flask is typically equipped with a rubber septum for introducing substrates and reagents via a syringe. The glassware is dried and / or heat-dried.

[0220] For illustrative purposes, the following Examples section shows synthetic routes for preparing the compounds of the present disclosure and key intermediates. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the invention. Although specific starting materials and reagents are depicted, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. Additionally, many of the compounds prepared by the methods described below can be further modified using conventional chemical reactions well known to those skilled in the art in accordance with the present disclosure.

[0221] Use of compound

[0222] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is capable of inhibiting RNA polymerase. Accordingly, the compounds of the present disclosure or pharmaceutically acceptable salts thereof can be used as drugs, particularly as therapeutic or prophylactic agents active against various viruses. In some embodiments, the compounds of the present disclosure are therapeutic or prophylactic agents active against caliciviruses, picornaviruses, and coronaviruses.

[0223] As used herein, the term "therapy" is intended to have its ordinary meaning, i.e., treating a disease so as to relieve, in whole or in part, 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 the present disclosure, beneficial or desired clinical outcomes include (but are not limited to): relief of symptoms, reduction in the degree of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease condition, and remission (partial or complete), whether detectable or not. "Therapy" can also mean an extension of the survival period compared to what would be expected in the absence of therapy. Conditions that require therapy include those in which a condition or disorder is already present, those that are predisposed to a condition or disorder, or those for the prevention of a condition or disorder. Unless specifically indicated to the contrary, the term "therapy" also encompasses prophylaxis. The terms "therapeutic" and "therapeutically" should be construed correspondingly.

[0224] The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" can be considered "administering therapy", where "therapy" is as defined herein.

[0225] As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention for preventing the development of a disease and secondary prevention for temporarily or permanently protecting a patient against disease exacerbation or deterioration or the development of new disease-related symptoms when the disease has already developed.

[0226] In yet another aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a viral infection.

[0227] In yet another aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating a viral infection.

[0228] In some embodiments, the compounds of the present disclosure have good inhibitory effects against various coronaviruses. In some embodiments, the compounds of the present disclosure have good inhibitory effects against various coronaviruses and have low cytotoxicity.

[0229] In some embodiments, the compounds of the present disclosure can be converted into triphosphorylated products and maintain a high concentration of the triphosphorylated products in target tissues and cells such as lung cells and respiratory epithelial cells.

[0230] Accordingly, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a coronavirus infection.

[0231] In a further aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a coronavirus infection.

[0232] In another aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a pneumovirus infection.

[0233] Pharmaceutical composition

[0234] For administration purposes, in some embodiments, the compounds provided herein are administered in their original chemical form or formulated into a pharmaceutical composition.

[0235] Accordingly, in another aspect, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0236] In some embodiments, the pharmaceutical composition of the present disclosure comprises a compound selected from any one of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure comprises a first compound selected from any one of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula, provided that the first compound and the additional compounds are not the same molecule.

[0237] As used herein, the term "pharmaceutical composition" refers to a formulation containing a molecule or compound of the present disclosure in a form suitable for administration to an individual.

[0238] In some embodiments, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0239] As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition containing the molecule or compound that treats, ameliorates, or prevents a identified disease or condition or exhibits a detectable therapeutic or inhibitory effect. The effectiveness can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's body weight, size, and health status; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of a clinician.

[0240] In another aspect, there is provided a pharmaceutical composition comprising one or more molecules or compounds of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0241] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient suitable for preparing pharmaceutical compositions that are generally safe, non-toxic, and otherwise desirable biologically, and includes excipients acceptable for veterinary as well as for human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent".

[0242] The particular excipient used will depend on the means and purpose of preparing the compound of the present disclosure for administration. Solvents are generally selected based on solvents recognized as 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), etc. and mixtures thereof.

[0243] In some embodiments, suitable excipients can include buffering agents such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoic acid 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, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, dextrin, or substituted dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (such as Zn-protein complexes); and / or nonionic surfactants such as TWEEN TM , PLURONICS TM or polyethylene glycol (PEG).

[0244] In some embodiments, suitable excipients can include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweetening agents, flavoring agents, and other known additives to provide optimal presentation of the drug (i.e., the compounds of the present disclosure or their pharmaceutical compositions) or to assist in the manufacture of a pharmaceutical product (i.e., a medicament). The active pharmaceutical ingredient can also be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in coarse emulsions, respectively. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th Edition, Osol, A. ed. (1980). "Liposomes" are small vesicles containing various types of lipids, phospholipids, and / or surfactants, which are suitable for delivering drugs (such as the compounds disclosed herein and optionally chemotherapeutic agents) to mammals including humans. The components of liposomes are generally arranged in a bilayer form similar to the lipid arrangement of biological membranes.

[0245] The pharmaceutical compositions provided herein can be in any form that permits the composition to be administered to an individual (including but not limited to humans) and is formulated to be compatible with the intended route of administration.

[0246] A variety of routes are considered for the pharmaceutical compositions provided herein, and thus the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage forms depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, lozenges, pills, capsules, softgels, and cachets are acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions are acceptable as liquid dosage forms. For parenteral administration, emulsions and suspensions are acceptable as liquid dosage forms, and powders suitable for reconstitution with a suitable solution are acceptable as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams, and sprays may be acceptable dosage forms. For nasal or pulmonary administration, aqueous or oily solutions may be acceptable dosage forms.

[0247] The amount of the active ingredient in a unit dosage form of the composition is a therapeutically effective amount and varies according to the particular treatment involved. As used herein, the term "therapeutically effective amount" means the amount of a molecule, compound, or composition comprising the molecule or compound that will treat, ameliorate, or prevent the identified disease or condition or exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for an individual will depend on the individual's weight, size, and health status; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0248] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oral administration formulation.

[0249] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a lozenge formulation. Pharmaceutically acceptable excipients suitable for lozenge formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. The lozenge formulation may be uncoated or coated to regulate its disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and / or appearance, in either case using conventional coating agents and procedures well known in the art.

[0250] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate or kaolin); or in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or an oil (such as peanut oil, liquid paraffin or olive oil).

[0251] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which generally contains the active ingredient in finely powdered form and one or more suspending agents, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents, such as lecithin, or condensation products of alkylene oxides and fatty acids (such as polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain aliphatic alcohols (such as heptadecaethyleneoxycetanol), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol (such as polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (such as polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (such as sucrose, saccharin or aspartame).

[0252] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oily suspension, which usually contains the suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil or coconut oil) or a mineral oil (such as liquid paraffin). The oily suspension may also contain thickening agents, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents (such as those described above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of antioxidants (such as ascorbic acid).

[0253] In certain embodiments, the pharmaceutical compositions of the present disclosure 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 a mixture of any of these oils. Suitable emulsifying agents may be, for example, naturally occurring gums, such as acacia or tragacanth; naturally occurring phospholipids, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (such as sorbitan monooleate) and condensation products of said partial esters with ethylene oxide (such as polyoxyethylene sorbitan monooleate). The emulsion may also contain sweetening agents, flavoring agents and preservatives.

[0254] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents, such as glycerol, propylene glycol, sorbitol, aspartame or sucrose; demulcents; preservatives; flavoring agents and / or coloring agents.

[0255] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for parenteral administration.

[0256] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. Such suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol or prepared as a dry powder for injection. Acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be used, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0257] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for nasal or pulmonary administration. In certain embodiments, the formulation is administered by rapid inhalation through the nasal passage or by oral inhalation to reach the alveolar sacs.

[0258] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for inhalational administration.

[0259] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non - aqueous (e.g., in a hydrofluorocarbon propellant) aerosols, which contain any suitable solvent and optionally other compounds, such as (but not limited to) stabilizers, antimicrobial agents, antioxidants, pH regulators, surfactants, bioavailability modifiers, and combinations thereof. The carrier and stabilizer vary with the requirements of the particular compound, but generally include non - ionic surfactants (Tweens, Pluronics, or polyethylene glycols), innocuous proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars, or sugar alcohols.

[0260] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for topical or transdermal administration.

[0261] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oleaginous solutions or suspensions, which may generally be obtained by formulating the active ingredient with conventional topically acceptable excipients, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0262] In certain embodiments, the pharmaceutical compositions provided herein can be formulated in the form of transdermal skin patches well known to those of ordinary skill in the art.

[0263] In addition to those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences", Mack Publishing Co., New Jersey (1991), "Remington: The Science and Practice of Pharmacy", edited by the University of the Sciences in Philadelphia, 21st Edition, LWW (2005), which are hereby incorporated by reference.

[0264] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable for single dosage administration to an individual human and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. The amount of the compounds provided herein in unit dosage form will vary depending on the condition to be treated, the individual to be treated (e.g., the age, weight, and response of the individual), the particular route of administration, the actual compound being administered and its relative activity, and the severity of the individual's symptoms.

[0265] In some embodiments, the dosage of the pharmaceutical composition of the present disclosure can be from 0.001 to 1000 milligrams per kilogram of body weight per day, for example, from 0.001 to 1000 milligrams per kilogram of body weight per day, from 0.001 to 900 milligrams per kilogram of body weight per day, from 0.001 to 800 milligrams per kilogram of body weight per day, from 0.001 to 700 milligrams per kilogram of body weight per day, from 0.001 to 600 milligrams per kilogram of body weight per day, from 0.001 to 500 milligrams per kilogram of body weight per day, from 0.001 to 400 milligrams per kilogram of body weight per day, from 0.001 to 300 milligrams per kilogram of body weight per day, from 0.001 to 200 milligrams per kilogram of body weight per day, from 0.001 to 100 milligrams per kilogram of body weight per day, from 0.001 to 50 milligrams per kilogram of body weight per day, from 0.001 to 40 milligrams per kilogram of body weight per day, from 0.001 to 30 milligrams per kilogram of body weight per day, from 0.001 to 20 milligrams per kilogram of body weight per day, from 0.001 to 10 milligrams per kilogram of body weight per day, from 0.001 to 5 milligrams per kilogram of body weight per day, from 0.001 to 1 milligrams per kilogram of body weight per day, from 0.001 to 0.5 milligrams per kilogram of body weight per day, from 0.001 to 0.4 milligrams per kilogram of body weight per day, from 0.001 to 0.3 milligrams per kilogram of body weight per day, from 0.001 to 0.2 milligrams per kilogram of body weight per day, from 0.001 to 0.1 milligrams per kilogram of body weight per day, from 0.005 to 0.1 milligrams per kilogram of body weight per day, from 0.01 to 0.1 milligrams per kilogram of body weight per day, from 0.02 to 0.1 milligrams per kilogram of body weight per day, from 0.03 to 0.1 milligrams per kilogram of body weight per day, from 0.04 to 0.1 milligrams per kilogram of body weight per day, from 0.05 to 0.1 milligrams per kilogram of body weight per day, from 0.06 to 0.1 milligrams per kilogram of body weight per day, from 0.07 to 0.1 milligrams per kilogram of body weight per day, from 0.08 to 0.1 milligrams per kilogram of body weight per day, or from 0.09 to 0.1 milligrams per kilogram of body weight per day. In some cases, a dosage below the lower limit of the foregoing range may be sufficient, while in other cases, larger doses can be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day. For other information regarding the route of administration and dosage regimen, see Volume 5, Chapter 25.3 in Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

[0266] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration. In some embodiments, a unit dose for oral administration contains one or more of the compounds provided herein in the following amounts: 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 1 mg to 500 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, etc. In some embodiments, depending on the severity of the individual's symptoms, the dosage unit may be administered to the individual 1 to 6 times per day.

[0267] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration in a treatment having a duration greater than 1 week, greater than 2 weeks, greater than 3 weeks, greater than 1 month, greater than 2 months, greater than 3 months, greater than 4 months, greater than 5 months, greater than 6 months, greater than 7 months, greater than 8 months, greater than 9 months, greater than 10 months, greater than 11 months, greater than 1 year or even longer.

[0268] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for parenteral administration, such as by intravenous, subcutaneous, or intramuscular injection. In some embodiments, a unit dose for parenteral administration contains one or more of the compounds provided herein in an amount of about 0.1 mg to about 500 mg of one or more of the compounds provided herein, 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 90 mg, about 0.5 mg to 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.

[0269] In some embodiments, pharmaceutical compositions intended to be administered by injection can be prepared by combining one or more of the compounds of the present disclosure with sterile distilled water, sesame oil, peanut oil, or an aqueous propylene glycol solution to form a solution. In some embodiments, the pharmaceutical composition can contain a surfactant or other solubilizing excipients, which are added to facilitate the formation of a homogeneous solution or suspension. In some embodiments, the pharmaceutical composition can further contain one or more additional reagents selected from the group consisting of wetting agents, suspending agents, preservatives, buffering agents, and isotonic agents.

[0270] In some embodiments, pharmaceutical compositions intended to be administered by injection can be administered using 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.

[0271] In another aspect, there is also provided a veterinary composition comprising one or more of the molecules or compounds of the present disclosure or a pharmaceutically acceptable salt thereof and a veterinary carrier. The veterinary carrier is a substance suitable for the purpose of administering the composition and can be a solid, liquid or gaseous substance that is originally inert or acceptable in the veterinary field and is compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally or by any other desired route.

[0272] The pharmaceutical composition or veterinary composition can be packaged in a variety of ways depending on the method used to administer the drug. For example, an article for dispensing can include a container in which a composition in a suitable form is deposited. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container can also include a tamper-proof assembly to prevent easy access to the contents of the package. Additionally, a label describing the contents of the container is attached to the container. The label can also include appropriate warnings. The composition can be packaged in unit dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored under a lyophilized (freeze-dried) condition, requiring only the immediate addition of a sterile liquid carrier (e.g., water) for injection prior to use. Ready-to-use injection solutions and suspensions are prepared from sterile powders, granules and lozenges of the types previously described.

[0273] Therapeutic method

[0274] In another aspect, the present disclosure provides a method for treating a viral infection in a patient in need thereof, the method comprising administering an effective amount of any of the compounds described herein.

[0275] In some embodiments, the viral infection is from an RNA virus. In certain embodiments, the RNA virus is a single-stranded or double-stranded RNA virus. In further embodiments, the RNA virus is a positive-sense RNA virus or a negative-sense RNA virus or an ambisense RNA virus.

[0276] In certain embodiments, the viral infection is from a virus selected from the group consisting of Retroviridae, Lentiviridae, Coronaviridae, Picornaviridae, Caliciviridae, Flaviviridae, Togaviridae, Bornaviridae, Filoviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae, Arenaviridae, Bunyaviridae, Orthomyxoviridae, and Delta virus.

[0277] In certain embodiments, the viral infection is from a virus selected from the group consisting of lymphocytic choriomeningitis virus, coronavirus, HIV, SARS, poliovirus, rhinovirus, hepatitis A, norovirus, yellow fever virus, West Nile virus, hepatitis C virus, dengue virus, Zika virus, rubella virus, Ross River virus, Sindbis virus, chikungunya virus, Borna disease virus, Ebola virus, Marburg virus, measles virus, mumps virus, Nipah virus, Hendra virus, Newcastle disease virus, human respiratory syncytial virus, rabies virus, Lassa virus, hantavirus, Crimean-Congo hemorrhagic fever virus, influenza, hepatitis D virus.

[0278] In certain embodiments, the viral infection is a coronavirus infection.

[0279] In additional embodiments, the coronavirus is selected from the group consisting of 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).

[0280] In certain embodiments, the coronavirus is SARS-CoV-2.

[0281] In some embodiments, the viral infection is from a DNA virus. In certain embodiments, the DNA virus is a single-stranded or double-stranded DNA virus. In additional embodiments, the DNA virus is a sense DNA virus or an antisense DNA virus or a bidirectional DNA virus.

[0282] In certain embodiments, the virus is Myoviridae, Podoviridae, Siphoviridae, Alloherpesviridae, Herpesviridae (including human herpesvirus and varicella-zoster virus), Malacoherpesviridae, Lipothrixviridae, Rudiviridae, Adenoviridae, Ampullaviridae, Guttaviridae, Asfarviridae (including African swine fever virus), Baculoviridae, Sipunviridae, Clavaviridae, Tectiviridae, Microviridae, Corticoviridae, Plasmaviridae, Iridoviridae, Marseilleviridae, Mimiviridae, Nucleocytoviricota, Phycodnaviridae, Inoviridae, Polydnaviridae, Polyomaviridae (including simian virus 40, JC virus, BK virus), Poxviridae (including vaccinia and smallpox), Globuloviridae, Fuselloviridae, Turriviridae, Dinodnavirus, Salterprovirus or Reoviridae.

[0283] In some embodiments, the methods described herein can inhibit viral replication spread, replication, assembly, or release, or minimize the expression of viral proteins. In one embodiment, a method of inhibiting viral spread, a method of inhibiting viral replication, a method of minimizing the expression of viral proteins, or a method of inhibiting viral release is described herein, including administering to a patient infected with the virus a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof with virus-infected cells.

[0284] In another aspect, the present disclosure provides a method for inhibiting RNA polymerase in a subject in need thereof, the method including administering to the subject an effective amount of a compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0285] Combination therapy

[0286] The compounds of the present disclosure can also be used in combination with one or more additional therapeutic or prophylactic agents. Accordingly, the present disclosure also provides a method for treating a viral infection in a subject in need thereof, the method including administering a compound disclosed herein as a first active ingredient to the subject, and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents as a second active ingredient. Thus, a pharmaceutical composition is also provided, the pharmaceutical composition including one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof as a first active ingredient, and further including a second active ingredient.

[0287] In some embodiments, the second active ingredient includes one or more additional therapeutic agents from the same class or group and / or one or more additional therapeutic agents from different classes or groups.

[0288] In some embodiments, the second active ingredient has an activity complementary to that of the compounds provided herein such that they do not have an adverse effect on each other. The ingredients should be present in combination in amounts effective for the intended purpose.

[0289] In some embodiments, the second active ingredient can be an antibiotic, protease inhibitor, antiviral agent, anti-inflammatory agent, immunomodulator, kinase inhibitor, antimetabolite, lysosomotropic agent, M2 proton channel blocker, polymerase inhibitor (e.g., EIDD-2801), neuraminidase inhibitor, reverse transcriptase inhibitor, viral entry inhibitor, integrase inhibitor, interferon (e.g., type I, type II, and type III), or nucleoside analog.

[0290] In some embodiments, the second active ingredient is an antibiotic. In some embodiments, the antibiotic may be selected from penicillin antibiotics, quinolone antibiotics, tetracycline antibiotics, macrolide antibiotics, lincosamide antibiotics, cephalosporin antibiotics, or RNA synthetase inhibitors. In some embodiments, the antibiotic is selected from azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cefalotin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin, moxifloxacin, norfloxacin, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem / cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, cefibuten, cefozopime, ceftriaxone, cefoxotin, and streptomycin. In some embodiments, the antibiotic is azithromycin.

[0291] In some embodiments, the second active ingredient may be a protease inhibitor. In some embodiments, the protease inhibitor may be selected from nafamostat, camostat, gabexate, ε-aminocaproic acid, aprotinin, amprenavir, indinavir, nelfinavir, nirmatrelvir, ensitrelvir, EDP-235, PBI-0451, xiannuanotvir, leretavir, atetovir, ritonavir, and saquinavir.

[0292] In some embodiments, the second active ingredient may be an antiviral agent. In some embodiments, the antiviral agent may be selected from ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, obitrovir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pelitinib, adefovir, amprenavir, amprenavir proximate, alavero, anti-goat antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, metiazinic acid, MK-2048, nelfinavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, remdesivir, ZX-7101A, baloxavir, ziritovir, molnupiravir, GS-5806, VIR-576, and zalcitabine.

[0293] In some embodiments, the second active ingredient may be an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent may be selected from antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene regulators (e.g., montelukast, zafirlukast, pranlukast), tryptase 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 activating protein) inhibitors, bronchodilators (e.g., muscarinic antagonists, β-2 agonists), methotrexate and similar agents; monoclonal antibody therapies such as anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies such as etanercept and similar agents; antigen non-specific immunotherapies (e.g., interferons or other cytokines / chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists and similar reagents), suitable anti-infective agents (including antibacterial agents, antifungal agents, anthelmintics, antimalarials, antiprotozoals and antituberculosis agents).

[0294] In some embodiments, the second active ingredient may be an immunomodulator. In some embodiments, the immunomodulator may be selected from anti-PD-1 or anti-PDL-1 therapeutic agents, including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559 or avelumab, anti-TIM3 (anti-HAVcr2) therapeutic agents (including but not limited to TSR-022 or MBG453), anti-LAG3 therapeutic agents (including but not limited to relatlimab, LAG525 or TSR-033), anti-4-1BB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutic agents (including but not limited to SGN-40, CP-870,893 or R07009789), anti-CD47 therapeutic agents (including but not limited to Hu5F9-G4), anti-CD20 therapeutic agents, anti-CD38 therapeutic agents, STING agonists (including but not limited to ADU-S100, MK-1454, ASA404 or amide benzimidazole), anthracyclines (including but not limited to doxorubicin or mitoxantrone), demethylating agents (including but not limited to azacitidine or decitabine), other immunomodulatory therapeutic 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 therapeutic agent is a β2-adrenergic receptor agonist, including but not limited to vilanterol, salmeterol, albuterol, formoterol, carmoterol, fenoterol, cimaterol, indacaterol, naminterol, clenbuterol, pirbuterol, flubuterol, reproterol, bambuterol, indacaterol, terbutaline and its salts, such as the xinafoate (1-hydroxy-2-naphthoate) salt of salmeterol, the sulfate salt of albuterol or the fumarate salt of formoterol.

[0295] In some embodiments, the second active ingredient may be a kinase inhibitor. In some embodiments, the kinase inhibitor may be selected from erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatinib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, sirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib, Loxo 292, larotrectinib and quizartinib.

[0296] Embodiment

[0297] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present disclosure and are only intended to present methods of implementing the present disclosure. Those skilled in the art will recognize that the chemical reactions can be readily adapted to prepare many other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-illustrative compounds according to the present disclosure can be successfully carried out by modifications that are obvious to those skilled in the art, such as by appropriately protecting interfering groups, by using other suitable reagents and structural units known in the art in addition to those described, and / or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered applicable to the preparation of other compounds of the present disclosure.

[0298] Example 1. Synthesis of Intermediate

[0299] 1.1 Synthesis of intermediate 1a:

[0300]

[0301] Under a N 2 atmosphere, a solution of compound s-1 (50 g, 0.1718 mol, 1 equivalent) in TMP (400 mL) was stirred at 0 °C for 15 minutes. At 0 °C, POCl 3 (86.18 g, 0.5670 mol, 3.3 equivalents) was added dropwise to the above mixture over 30 minutes. The resulting mixture was stirred at 25 °C for 1.5 hours under a N 2 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 filtered to obtain Intermediate 1a (50 g, 0.1348 mol, 78%) as a light yellow solid. The product was used directly in the next step without further purification.

[0302] LCMS: Rt = 0.396 min; m / z = 372 [M+1] + ; m / z = 370 [M-1] -

[0303] 1 H NMR (400 MHz, D 2 O) 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).

[0304] 1.2 Synthesis of intermediate 1b:

[0305]

[0306] Step 1: Synthesis of Compound 1b-2

[0307]

[0308] Under N 2 At -30 °C, DBDMH (15.2 g, 53.1 mmol, 0.55 equiv) was added to a solution of Compound 1b-1 (20.0 g, 96.5 mmol, 1.0 equiv) in ACN (200 mL). The mixture was stirred at -20 °C for 2 h. Then, the reaction mixture was poured into water (200 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with brine (200 mL), dried over Na 2 SO 4 , filtered, and evaporated in vacuo to give the 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.

[0309] LCMS: m / z (M+H) + = 286.0

[0310] 1 H NMR (400 MHz, CDCl 3 ): 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).

[0311] Step 2: Synthesis of Compound 1b-3

[0312]

[0313] Under N 2 At 0 °C, HCl / dioxane (104.8 mL, 4 M, 419.4 mmol) was added to a solution of Compound 1b-2 (20.0 g, 69.9 mmol) in dioxane (50 mL). The resulting mixture was stirred at 25 °C for 5 h. The mixture was filtered, and the filter cake was washed with MTBE (100 mL). Then, the filtrate was dried in vacuo 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.

[0314] LCMS: m / z = 186.0

[0315] 11H NMR (400 MHz, DMSO-d 6 ): δ ppm = 7.24 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H).

[0316] Step 3: Synthesis of Compound 1b-4

[0317]

[0318] Under N 2 , at 25 °C, to a solution of Compound 1b-3 (16.0 g, 71.9 mmol) in EtOH (200 mL) was added formamidine acetate (37.4 g, 359.6 mmol) and K 3 PO 4 (76.3 g, 359.6 mmol), and then the mixture was stirred at 78 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with EtOH (100 mL × 2), and then the filtrate was evaporated in vacuo to give the crude product. The crude product was triturated with THF:DCM (1:3) and filtered. The filter cake was dried in vacuo, and the filtrate was further purified by FCC (10%-26% THF in PE) to give Compound 1b-4 (9.5 g, 44.6 mmol, 62.0%), as a pale yellow solid.

[0319] LCMS: m / z = 213.0

[0320] 1 1H NMR (400 MHz, DMSO-d 6 ): 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).

[0321] Step 4: Synthesis of Compound 1b-5

[0322]

[0323] To a solution of Compound 1b-4 (21.1 g, 99.0 mmol) in THF (200 mL) was added D 2 O (10 mL), and then it was concentrated to dryness three times. Thereafter, under N 2 , THF (200 mL) and D 2 O (10 mL) were added to the residue, and then at 25 °C, to the solution was added Pd(dppf)Cl 2(7.2 g, 9.9 mmol) and TMEDA (2.3 g, 19.8 mmol). The reaction was stirred at 25 °C for 0.5 h. Then, the solution was cooled to 0 °C, and NaBD 4 (8.3 g, 198.0 mmol) was added to the solution, and the reaction was stirred at 25 °C for 17 h. TLC (PE:EA = 1:1) showed that compound 1b-4 was completely consumed and new spots were detected. The mixture was poured into saturated NH 4 Cl (200 mL). The reaction mixture was extracted with EA (100 mL × 3). The organic phase was washed with brine (100 mL), then dried over Na 2 SO 4 and concentrated to give a residue. The residue was purified by silica gel column chromatography (10%-50% EtOAc in PE) to give compound 1b-5 (7.5 g, 56.3%) as a yellow solid.

[0324] LCMS: m / z = 136.2

[0325] 1 1H NMR (400 MHz, DMSO-d 6 6): 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).

[0326] Step 5: Synthesis of compound 1b-6

[0327]

[0328] A solution of compound 1b-5 (4.0 g, 29.5 mmol, 1.0 equiv) in DMF (36 mL) was cooled to -5 °C to 5 °C. Under N 2 2 atmosphere, NIS (6.7 g, 29.5 mmol, 1.0 equiv) was added to the above reaction. The reaction was stirred at -5 °C to 5 °C for 2 h. TLC showed that the reaction was complete. The reaction mixture was poured into aqueous NaOH solution (400 mL, 1 M) and stirred for another 30 min. The crushed solid was filtered out and washed with H 2 2O (50 mL) and PE (60 mL), and dried in vacuo to give compound 1b-6 as a solid (6 g, 77%).

[0329] 1 1H NMR (400 MHz, DMSO-d 6 ) δ: 7.87 (s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H).

[0330] Step 6: Synthesis of Compound 1b-7

[0331]

[0332] Under N 2 atmosphere, TMSCl (2.4 g, 21.7 mmol, 2.2 equiv) was added to a solution of Compound 1b-6 (2.6 g, 9.9 mmol, 1.0 equiv) in THF (40 mL), and the reaction was stirred at room temperature for 40 minutes. The reaction mixture was cooled to -5 °C to 5 °C, and PhMgCl (11.8 mL, 2 M,

[0333] 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 hours. Then i-PrMgCl·LiCl (9.9 mL, 12.9 mmol, 1.3 equiv) was added to the above reaction mixture, and the mixture was stirred for 15 minutes after addition. At -20 °C to -15 °C, a solution of Compound A (4.1 g, 9.9 mmol, 1.0 equiv) in THF (40 mL) was added to the above reaction mixture. After addition, the reaction mixture was warmed to room temperature and stirred for another 1 hour. TLC (PE:EA = 1:1) showed that the reaction was complete. 1 M HCl was added to the reaction to adjust the pH to 2 - 3. EtOAc was added, the two phases were separated, and the organic phase was washed twice with HCl (1 M). Then the organic phase was washed with saturated NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (PE:EA = 2:1) to obtain Compound 1b-7 (2.0 g) as a solid.

[0334] Step 7: Synthesis of Compound 1b-8

[0335]

[0336] At -78 °C, TfOH (1.1 g, 7.2 mmol) was added to a solution of Compound 1b-7 (2.0 g, 3.6 mmol, 1.0 equiv) in DCM (24 mL). After 10 minutes, TMSOTf (1.7 g, 7.6 mmol, 2.1 equiv) was added to the above reaction and stirred for another 30 minutes. Then TMSCN (1.4 g, 14.4 mmol, 4.0 equiv) was added. After 10 minutes, TLC (PE:EA = 1:1) showed that the reaction was complete. Then TEA was added to quench the reaction, followed by adding NaHCO 3 to pH - 8. The two phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried over Na 2 SO4 It was dried, filtered and concentrated in vacuo to obtain the crude product, which was purified by column chromatography to give Compound 1b-8 (1.4 g, 69%), as a solid.

[0337] Step 8: Synthesis of Compound 1b-9

[0338]

[0339] At -78 °C, BCl 3 (11.1 mL, 11.1 M) was added to a solution of Compound 1b-8 (1.6 g, 2.8 mmol, 1.0 equiv) in DCM (23 mL). The reaction mixture was stirred at -40 °C for 2 h. MeOH (10 mL) was added to quench the reaction, and then TEA was added to pH 8 - 9. The solution was concentrated. Then water (100 mL) was added, the aqueous phase was washed with DCM, and the aqueous phase was concentrated to about 50 mL. Another 100 mL was added and the same procedure was repeated seven times. The solid formed was filtered and concentrated in vacuo to give Compound 1b-9 (0.4 g, 51%), as a solid.

[0340] 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.9 - 7.87 (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).

[0341] Step 9: Synthesis of Compound 1b:

[0342]

[0343] Under N 2 atmosphere, a solution of Compound 1b-9 (50.0 g, 0.1718 mol, 1 equiv) in TMP (400 mL) was stirred at 0 °C for 15 min. At 0 °C, POCl 3 (86.2 g, 56.7 mmol, 3.3 equiv) was added dropwise to the above mixture over 30 min. The resulting mixture was stirred at 25 °C for 1.5 h under N 2 atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was concentrated in vacuo. The crude product was precipitated by adding acetonitrile (3 L). The precipitated solid was collected by filtration to give Intermediate 1b (50.0 g, 134.8 mmol, 78%), as a light yellow solid.

[0344] LCMS: m / z = 373

[0345] Example 2. Synthesis of the compound

[0346]

[0347] Step 1: Synthesis of compound 51-2

[0348] To a mixture of compound 51-1 (8 g, 23.36 mmol, 1.0 eq) in cyclohexane (65 mL) was added Py (3.7 g, 46.72 mmol, 2.0 eq), followed by dropwise addition of compound s-2 (3.61 g, 28.03 mmol, 1.2 eq). Then the mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with NH 4 Cl (aqueous solution), and extracted with PE (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by FCC (n-hexane = 100%) to give compound 51-2 (6.6 g, white solid).

[0349] Step 2: Synthesis of compound 51

[0350] To a mixture of intermediate 1a (1 g, 0.0027 mol, 1.0 eq) in DMF (15 mL) was added compound 51-

[0351] 2 (1.36 g, 0.004 mol, 1.5 eq) and DIEA (2.09 g, 0.0162 mol, 6 eq). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was directly purified by preparative HPLC to give compound 51 (122 mg).

[0352] LCMS: Rt = 1.956 min; m / z = 670 [M+1] + ; m / z = 668 [M-1] -

[0353] 1 1H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 7.06 - 7.05 (m, 2H), 5.45–5.42 (m, 2H), 4.38 - 4,25 (m, 1H), 4.25 - 4.20 (m, 1H), 4.20 - 4.15 (m, 1H), 4.15 - 4.06 (m, 2H), 4.05 - 4.00 (m, 1H), 1.70 - 1.50 (m, 2H), 1.30 - 1.20 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H).

[0354] The following compounds were synthesized according to the same procedure as for compound 51, except that different starting materials or intermediates were used:

[0355] Compound 7:

[0356] LCMS: m / z = 671.30 [M+1] + ; m / z = 669.30 [M-1] -

[0357] 1 H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.06 (s, 1H), 5.45–5.40 (m, 2H), 4.83 - 4.80 (m, 1H), 4.33 - 4.28 (m, 1H), 4.23 (t, J = 5.3 Hz, 1H), 4.16–4.11 (m, 1H), 4.07–4.06 (m, 2H), 4.05–3.99 (m, 1H), 1.61–1.54 (m, 2H), 1.27 - 1.25 (m, 26H), 0.897 (t, J = 6.7 Hz, 3H).

[0358] Compound 8:

[0359] LCMS: m / z = 699.40 [M+1] + ; m / z = 697.35 [M-1] -

[0360] 1 H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.06 (s, 1H), 5.45–5.40 (m, 2H), 4.81–4.79 (m, 1H), 4.33–4.28 (m, 1H), 4.23 (t, J = 5.3 Hz, 1H), 4.16–4.11 (m, 1H), 4.07–3.99 (m, 3H), 1.61–1.54 (m, 2H), 1.27–1.25 (m, 30H), 0.87 (t, J = 6.7 Hz, 3H).

[0361] Compound 19:

[0362] LCMS: m / z = 572.40 [M+1] + ; m / z = 570.10 [M-1] -

[0363] 11H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.31–7.08 (m, 2H), 5.45–5.42 (m, 2H), 4.85–4.77 (m, 1H), 4.71–4.67 (m, 1H), 4.25–4.23 (m, 2H), 4.13–4.04 (m, 2H), 1.56–1.30 (m, 2H), 1.35–1.21 (m, 10H), 1.21–1.20 (m, 3H), 0.89 (t, J = 6.6 Hz, 3H).

[0364] Compound 23:

[0365] LCMS: m / z = 684.55 [M+1] + ; m / z = 682.25 [M−1] -

[0366] 1 1H NMR (400 MHz, CD 3 OD) δ 7.95 (s, 1H), 7.11–7.08 (m, 2H), 5.45–5.42 (m, 2H), 4.87–4.83 (m, 1H), 4.71–4.67 (m, 1H), 4.25–4.23 (m, 2H), 4.13–4.04 (m, 2H), 1.56–1.30 (m, 2H), 1.35 - 1.21 (m, 29H), 0.89 (t, J = 6.6 Hz, 3H).

[0367] Compound 53:

[0368] LCMS: m / z = 698.55 [M+1] + ; m / z = 696.30 [M−1] -

[0369] 1 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.05 (d, J = 4.7 Hz, 1H), 7.01 (d, J = 4.7 Hz, 1H), 5.46–5.38 (m, 2H), 4.81–4.79 (m, 1H), 4.33–4.30 (m, 1H), 4.23 (t, J = 5.2 Hz, 1H), 4.17–4.11 (m, 1H), 4.09–4.06 (m, 2H), 4.05–3.99 (m, 1H), 1.62–1.54 (m, 2H), 1.36–1.33 (m, 2H), 1.27 - 1.23 (m, 28H), 0.88 (t, J = 6.8 Hz, 3H).

[0370] Compound 62:

[0371] LCMS: [MS + 1] + = 656.45, [MS - 1] - = 654.15。

[0372] 1 H NMR(400MHz, CD 3 OD) δ8.02(s, 1H), 7.20(d, J = 4.3Hz, 1H), 7.14(d, J = 4.3Hz, 1H), 5.52 - 5.48(m, 2H), 4.80(d, J = 5.1Hz, 1H), 4.73–4.64(m, 1H), 4.39–4.30(m, 1H), 4.25(t, J = 5.3Hz, 1H), 4.23–4.15(m, 1H), 4.14–4.03(m, 1H), 1.66–1.46(m, 4H), 1.28 - 1.24(m, 20H), 0.96–0.79(m, 6H)。

[0373] Compound 127:

[0374] LCMS: m / z = 685.30 [M + 1] + ; m / z = 683.30 [M - 1] -

[0375] 1 H NMR(400MHz, CD 3 OD) δ7.86(s, 1H), 6.88(s, 1H), 5.44–5.40(m, 2H), 4.82(d, J = 5.1Hz, 1H), 4.69–4.68(m 1H), 4.32(d, J = 4.3Hz, 1H), 4.23(t, J = 5.1Hz, 1H), 4.15–4.09(m, 1H), 4.05–4.00(m, 1H), 1.57–1.51(m, 2H), 1.28–1.20(m, 26H), 1.19(d, J = 6.7Hz, 3H), 0.88(t, J = 6.7Hz, 3H)。

[0376] Compound 128:

[0377] LCMS: [MS + 1] + = 685.35, [MS - 1] - = 683.30

[0378] 1 H NMR(400MHz, CD 3OD) δ 7.91 (s, 1H), 6.97 (s, 1H), 5.45 (dd, J = 11.5, 2.3 Hz, 2H), 4.84 (d, J = 5.2 Hz, 1H), 4.74–4.69 (m, 1H), 4.36–4.33 (m, 1H), 4.26 (t, J = 5.2 Hz, 1H), 4.19–4.13 (m, 1H), 4.07–4.01 (m, 1H), 1.59–1.44 (m, 2H), 1.29–1.25 (m, 26H), 1.22 (d, J = 6.3 Hz, 3H), 0.90 (t, J = 6.8 Hz, 3H).

[0379] 2.2 Synthesis of compound 57:

[0380]

[0381] Step 1: Synthesis of Compound 57-2:

[0382] To a mixture of Compound 57-1 (1 g, 3.06 mmol, 1 equiv) in cyclohexane (20 mL) was added Compound s-2 (473 mg, 3.67 mmol, 1.2 equiv) and py (484 mg, 6.12 mmol, 2 equiv) ， The mixture was then stirred at room temperature for 4 h. The reaction mixture was quenched with NH 4 Cl (aqueous solution) and extracted with PE (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by FCC to give Compound 57-2 (0.98 g).

[0383] 1 H NMR (400 MHz, CDCl 3 ) δ 5.71 (s, 2H), 4.22 - 4.18 (m, 2H), 1.69 - 1.64 (m, 2H), 1.24 (br s, 38H), 0.86 (t, J = 6.6 Hz, 3H).

[0384] Step 2: Synthesis of Compound 57-3:

[0385] To a solution of Compound 57-2 (0.98 g, 2.34 mmol, 1.0 equiv) in acetone (10 mL) was added NaHCO 3 (0.59 g, 7.03 mmol, 3 equiv) and NaI (1.4 g, 9.38 mmol, 4 equiv). The mixture was stirred at 45 °C under N 2 for 4 h. The reaction mixture was quenched with H2 Quenched with O(aqueous solution) (30 mL), and extracted with PE (30 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over Na 2 SO 4 , filtered and concentrated to give Compound 57-3 (1.16 g).

[0386] Step 3: Synthesis of Compound 57:

[0387] To a mixture of Intermediate 1a (300 mg, 0.800 mmol, 1.0 equiv) in DMF (20 mL) was added DIEA (521 mg, 4.043 mmol, 5 equiv) and Compound 57-3 (1.237 g, 2.426 mmol, 3 equiv). The reaction mixture was stirred at 45 °C for 16 h. The reaction mixture was purified directly by column (DCM:MeOH = 5:1). The organic layer was concentrated under reduced pressure. The resulting residue was purified again by preparative TLC (DCM:MeOH = 5:1) to give Compound 57 (23.66 mg).

[0388] LCMS: Rt = 2.2 min; m / z = 754 [M+1] + ; m / z = 752 [M-1] -

[0389] 1 H NMR (400 MHz, CD 3 OD) δ 7.85 (s, 1H), 6.97 (d, J = 4.6 Hz, 1H), 6.86 (d, J = 4.6 Hz, 1H), 5.43 (d, J = 13.0 Hz, 2H), 4.85 - 4.81 (m, 1H), 4.32 - 4,31 (m, 1H), 4.24 - 4.23 (m, 1H), 4.12 - 4.00 (m, 3H), 1.59 - 1.57 (m, 2H), 1.38 - 1.35 (m, 8H), 1.26 (br s, 31H), 0.88 (t, J = 6.8 Hz, 3H).

[0390] 2.3 Synthesis of compound 85:

[0391]

[0392] Step 1: Synthesis of Compound 85-2:

[0393] To a mixture of Compound 85-1 (1 g, 2.94 mmol, 1 equiv) in DCM:H 2 O (20 mL 1:1) was added K 2 CO 3(1.54 g, 11.2 mmol, 3.8 equiv), (nBu 4 N) 2 SO 4 (170 mg, 0.29 mmol, 0.1 equiv) and compound s-3 (532 mg, 3.23 mmol, 1.1 equiv), and then the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with H 2 O and extracted with PE (50 mL × 3), the combined organic layers were washed with brine (50 mL × 2), dried over Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by FCC to give compound 85-2 (0.9 g).

[0394] Step 2: Synthesis of compound 85:

[0395] Then to a mixture of intermediate 1a (300 mg, 0.800 mmol, 1.0 equiv) in DMF (20 mL) was added DIEA (521 mg, 4.043 mmol, 5 equiv) and compound 85-2 (1.02 g, 2.426 mmol, 3 equiv). The reaction mixture was stirred at 45 °C for 16 h. The reaction mixture was purified by column (DCM:MeOH = 5:1). The organic layer was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH = 5:1) to give compound 85 (21.9 mg).

[0396] m / z = 724 [M+1] + ; m / z = 722 [M-1] -

[0397] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.00 - 7.75 (m, 2H), 6.85 (d, J = 4.5 Hz, 1H), 6.80 (d, J = 4.3 Hz, 1H), 6.12 (d, J = 5.9 Hz, 1H), 5.50 (s, 1H), 5.28 (d, J = 12.5 Hz, 2H), 4.55 (s, 1H), 4.06 (s, 1H), 3.85 (m, 2H), 3.70 (s, 1H), 3.56–3.48 (m, 1H), 3.06–3.00 (m, 1H), 2.22 - 2.18 (m, 2H), 1.42 (br s, 2H), 1.19 (br s, 36H), 0.81 (t, J = 6.8 Hz, 3H).

[0398] The following compounds were synthesized according to the same procedure as for compound 85, except that different starting materials or intermediates were used:

[0399] Compound 75:

[0400] LCMS: m / z = 584.40 [M+1] + ; m / z = 582.20 [M-1] -

[0401] 1 H NMR (400 MHz, CD 3 OD) δ 8.01 (s, 1H), 7.24 (d, J = 4.5 Hz, 1H), 7.15 (d, J = 4.7 Hz, 1H), 5.48–5.39 (m, 2H), 4.77–4.75 (m, 1H), 4.34–4.29 (m, 1H), 4.22 (t, J = 5.5 Hz, 1H), 4.18–4.12 (m, 1H), 4.08–4.00 (m, 1H), 2.30–2.25 (m, 2H), 1.54 (t, J = 7.5 Hz, 2H), 1.27–1.23 (m, 16H), 0.87 (t, J = 6.6 Hz, 3H).

[0402] Compound 79:

[0403] LCMS: m / z = 640.45 [M+1] + ; m / z = 638.20 [M-1] -

[0404] 1 H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.14 (d, J = 4.7 Hz, 1H), 7.08 (d, J = 5.9 Hz, 1H), 5.46–5.42 (m, 2H), 4.80–4.76 (m, 1H), 4.34–4.29 (m, 1H), 4.23–4.18 (m, 1H), 4.17–4.12 (m 1H), 4.06–4.01 (m, 1H), 2.31–2.22 (m, 2H), 1.57–1.53 (m, 2H), 1.26 (br s, 24H), 0.89 (t, J = 6.8 Hz, 3H).

[0405] Compound 81:

[0406] LCMS: [MS+1] + = 668.4, [MS-1] - = 666.15

[0407] 1 H NMR (400 MHz, CD 3OD) δ 8.00 (s, 1H), 7.15 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 5.49–5.47 (m, 2H), 4.79 - 4.77 (d, J = 5.5 Hz, 1H), 4.38–4.29 (m, 1H), 4.24–4.14 (m, 2H), 4.12–4.03 (m, 1H), 2.34–2.27 (m, 2H), 1.63–1.55 (m, 2H), 1.31–1.27 (m, 28H), 0.91 (t, J = 6.8 Hz, 3H).

[0408] Compound 83:

[0409] LCMS: [MS+1] + = 696.50, [MS-1] - = 694.25.

[0410] 1 H NMR (400 MHz, CD 3 OD) δ 7.87 (s, 1H), 6.97 (d, J = 4.6 Hz, 1H), 6.86 (d, J = 4.6 Hz, 1H), 5.44 (d, J = 12 Hz, 2H), 4.80 (d, J = 5.2 Hz, 1H), 4.32–4.22 (m, 2H), 4.16–3.99 (m, 2H), 2.27 (t, J = 7.5 Hz, 2H), 1.59–1.47 (m, 2H), 1.26 - 1.22 (m, 32H), 0.87 (t, J = 6.7 Hz, 3H).

[0411] 2.4 Synthesis of compound 66:

[0412]

[0413] Step 1: Synthesis of Compound 66-2:

[0414] To a mixture of Compound 66-1 (8 g, 17.75 mmol, 1 equiv) in THF (480 mL) at room temperature was added dropwise LiAlH 4 (2.5 M, 10.65 mL, 1.5 equiv), and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with sodium potassium tartrate (solution) and extracted with PE (150 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na 2 SO 4 and filtered and concentrated to give Compound 66-2 as a white solid, which was used directly in the next step.

[0415] 1¹H NMR (400 MHz, CDCl 3 ) δ 3.56 - 3.54 (m, 1H), 1.44 - 1.37 (m, 4H), 1.34 - 1.14 (m, 52H), 0.86 (t, J=6.6 Hz, 6H).

[0416] Step 2: Synthesis of Compound 66 - 4:

[0417] To a mixture of Compound 66 - 2 (12.64 g, 27.91 mmol, 1 equiv) in cyclohexane:DCM (120 mL:12 mL) at 0 °C was added Compound 66 - 3 (14.4 g, 111.65 mmol, 4.0 equiv) and pyridine (13.25 g, 167.49 mmol, 6.0 equiv) ， The mixture was then stirred at room temperature for 4 h. The reaction mixture was quenched with saturated NH 4 Cl and extracted with ethyl acetate (70 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by FCC (PE = 100%) to give Compound 66 - 4 (7.98 g, 52%) as a white solid.

[0418] 1 ¹H NMR (400 MHz, CDCl 3 ) δ 5.71 (s, 2H), 4.78–4.76 (m, 1H), 1.66–1.54 (m, 4H), 1.28–1.22 (m, 52H), 0.86 (t, J=6.8 Hz, 6H).

[0419] Synthesis of Compound 66 - 5:

[0420] To a mixture of Compound 66 - 4 (2.98 g, 5.46 mmol, 1.0 equiv) in acetone (30 mL) was added NaI (4.1 g, 27.32 mmol, 5.0 equiv) and NaHCO 3 (1.84 g, 21.86 mmol, 4.0 equiv). The mixture was then stirred at 45 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by FCC (PE = 100%) to give Compound 66 - 5 (2.2 g, 63%) as a yellow solid.

[0421] 1 ¹H NMR (400 MHz, CDCl 3)δ 5.93 (s, 2H), 4.77–4.74 (m, 1H), 1.58–1.53 (m, 4H), 1.28–1.22 (m, 52H), 0.86 (t, J = 6.6 Hz, 6H).

[0422] Synthesis of Compound 66:

[0423] To a mixture of intermediate 1a (332 mg, 0.90 mmol, 1.0 equiv) in DMF (25 mL) was added DIEA (577 mg, 4.48 mmol, 5 equiv) and compound 66-5 (1.71 g, 2.7 mmol, 3 equiv). The reaction mixture was stirred at 45 °C for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column on silica gel (DCM:MeOH = 80:20) to give the crude product, which was purified by preparative TLC to give Compound 66 (29 mg, 4%).

[0424] 1 H NMR (400 MHz, CD 3 OD) δ 7.85 (s, 1H), 6.96 (d, J = 4.6 Hz, 1H), 6.87 (d, J = 4.6 Hz, 1H), 5.50 - 5.41 (m, 2H), 4.68 - 4.62 (m, 2H), 4.34 - 4.32 (m, 1H), 4.25 (t, J = 5.1 Hz, 1H), 4.16 - 4.10 (m, 1H), 4.04 - 3.99 (m, 1H), 1.59 - 1.48 (m, 4H), 1.37 - 1.12 (d, J = 10.7 Hz, 52H), 0.87 (t, J = 6.7 Hz, 6H).

[0425] LCMS: m / z = 880.55 [M+1] +

[0426] Compound 24 was synthesized according to a similar procedure as mentioned above.

[0427] Compound 24:

[0428] LCMS: [MS+1] + = 712.55, [MS-1] - = 710.25

[0429] 11H NMR (400 MHz, CD3OD) δ 7.85 (s, 1H), 6.96 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.5 Hz, 1H), 5.47 - 5.43 (m, 2H), 4.85 - 4.80 (m, 1H), 4.75 - 4.60 (m, 1H), 4.33 - 4.31 (m, 1H), 4.17 - 4.15 (m, 2H), 4.04 - 4.02 (m, 1H), 1.56 - 1.26 (m, 2H), 1.24 - 1.19 (m, 33H), 0.88 (t, J = 6.6 Hz, 3H).

[0430] 2.5 Synthesis of compound 125:

[0431]

[0432] Step 1: Synthesis of Compound 125 - 3:

[0433] To a solution of Mg (3.12 g, 1.4 equiv) in THF (250 mL) was added I 2 (228.8 mg, 0.01 equiv) and 1 - bromotetradecane (25 g, 90.16 mmol, 26.88 mL, 1 equiv) was slowly added at 50 °C under N 2 . The mixture was stirred at 50 °C for 5 h. The solution became turbid and grey. To the turbid grey solution of Compound 125 - 2 (above) at - 78 °C was slowly added Li 2 CuCl 4 (0.1 M, 18.60 mL) and (2R) - 2 - methyloxirane (3 g, 1 equiv). The reaction mixture was stirred at - 78 °C for 0.5 h and then at 25 °C for another 2 h. The mixture was quenched with aqueous NH 4 Cl solution (1 L) at 0 °C and extracted with EA (1 L * 3). The organic layer was washed with brine and dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 330 g Flash silica gel column, eluent with 0% - 10% ethyl acetate / petroleum ether gradient, at

[0434] 100 mL / min) to give Compound 125 - 3 as a white solid (14 g, 52.8% yield).

[0435] 1 1H NMR (400 MHz, CDCl 3) δ 3.85–3.80 (m, 1H), 1.45–1.41 (m, 2H), 1.29–1.25 (m, 26H), 1.21 (d, J = 6.2 Hz, 3H), 0.90 (t, J = 6.8 Hz, 3H).

[0436] Synthesis of Compound 125-5:

[0437] To a mixture of Compound 125-3 (2 g, 0.0078 mol, 1.0 equiv) in cyclohexane (50 mL) was added pyridine (1.24 g, 0.0156 mol, 2.0 equiv), and then Compound 125-4 (1.21 g, 0.0094 mol, 1.2 equiv) was added dropwise. ， Then the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (70 mL × 3), dried over Na 2 SO 4 dried, filtered, and concentrated to dryness. The residue was purified by FCC (n-hexane = 100%) to give Compound 125-5 (1.6 g, 60% yield) as a white solid.

[0438] 1 1H NMR (400 MHz, CDCl 3 ) δ 5.70 (s, 2H), 4.82–4.80 (m, 1H), 1.67–1.65 (m, 2H), 1.35–1.23 (m, 29H), 0.87 (t, J = 6.6 Hz, 3H).

[0439] Synthesis of Compound 125:

[0440] To a mixture of Intermediate 1a (500 mg, 1.38 mmol, 1.0 equiv) in DMF (8 mL) was added Compound 125-5 (940 mg, 2.7 mmol, 2 equiv) and DIEA (1.07 g, 8.28 mmol, 6 equiv). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was directly purified by preparative HPLC to give Compound 125 (44.3 mg, 4.7%).

[0441] LCMS: m / z = 684.35 [M+1] + ; m / z = 682.25 [M-1] -

[0442] 1 1H NMR (400 MHz, CD 3OD) δ 7.95 (s, 1H), 7.11–7.08 (m, 2H), 5.45–5.42 (m, 2H), 4.80–4.79 (m, 1H), 4.71–4.67 (m, 1H), 4.25–4.23 (m, 2H), 4.13–4.04 (m, 2H), 1.56–1.30 (m, 2H), 1.35–1.21 (m, 26H), 1.21–1.20 (m, 3H), 0.89 (t, J=6.6 Hz, 3H).

[0443] The following compounds were synthesized according to the same procedure as for Compound 125, except that different starting materials or intermediates were used:

[0444] Compound 126:

[0445] LCMS: m / z = 684.30 [M+1] + ; m / z = 682.30 [M-1] -

[0446] 1 1H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 7.07–7.04 (m, 2H), 5.46–5.40 (m, 2H), 4.80 (d, J = 5.1 Hz, 1H), 4.69 (q, J = 6.3 Hz, 1H), 4.32 (t, J = 4.2 Hz, 1H), 4.24 (t, J = 5.2 Hz, 1H), 4.17–4.11 (m, 1H), 4.06–4.00 (m, 1H), 1.62 - 1.40 (m, 2H), 1.32 - 1.23 (m, 26H), 1.20 (d, J = 6.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H).

[0447] Compound 129:

[0448] LCMS: m / z = 712.35 [M+1] + ; m / z = 710.25 [M-1] -

[0449] 1 1H NMR (400 MHz, CD 3OD) δ 7.93 (s, 1H), 7.05–7.04 (m, 2H), 5.48–5.40 (m, 2H), 4.80 (d, J = 5.2 Hz, 1H), 4.71–4.66 (m, 1H), 4.35–4.30 (m, 1H), 4.25 (t, J = 5.2 Hz, 1H), 4.14–4.12 (m, 1H), 4.04–4.03 (m, 1H), 1.65–1.41 (m, 2H), 1.29 - 1.23 (m, 30H), 1.21 (d, J = 6.2 Hz, 3H), 0.92–0.85 (t, J = 6.2 Hz, 3H).

[0450] Compound 130:

[0451] LCMS: m / z = 712.45 [M+1] + ; m / z = 710.40 [M - 1] -

[0452] 1 H NMR (400 MHz, CD 3 OD) δ 7.98 (s, 1H), 7.17 (d, J = 4.7 Hz, 1H), 7.12 (d, J = 4.7 Hz, 1H), 5.48–5.40 (m, 2H), 4.80 (d, J = 5.2 Hz, 1H), 4.71–4.66 (m, 1H), 4.35–4.30 (m, 1H), 4.25–4.12 (m, 2H), 4.06–4.01 (m, 1H), 1.65–1.41 (m, 2H), 1.29 - 1.23 (m, 30H), 1.21 (d, J = 6.2 Hz, 3H), 0.89 (t, J = 6.2 Hz, 3H).

[0453] 2.6 Synthesis of compound 117:

[0454]

[0455] Step 1: Synthesis of Compound 117 - 3

[0456] A solution of NaH (4.5 g, 113.5 mmol, 60% mineral oil solution), diisopropylamine (16.0 mL, 113.5 mmol) in THF (100 mL) was purged with N 2Degassing three times, then compound 117-1 (10.5 mL, 113.5 mmol) was added dropwise. After stirring at 70°C for 30 minutes, the mixture was cooled to 0°C. Then n-BuLi (45.4 mL, 2.5 M) was added dropwise, and the mixture was stirred at 0°C for 2 hours. Then compound 117-2 (35.8 mL, 113.5 mmol) was added dropwise, and the resulting mixture was stirred at 25°C for 16 hours. The mixture was heated with H 2 O (20 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with Na 2 SO 4 Drying, filtration and concentration gave a residue, which was purified by column to give compound 117-3 (35.0 g, 98% yield) as a white solid.

[0457] 1 H NMR (400MHz, CD 3 OD)δ:1.47–1.41(m,2H),1.34–1.24(m,28H),1.09(s,6H),0.90(t,J=6.8Hz,3H).

[0458] Step 2: Synthesis of compound 117-5

[0459] Compound 117-3 (0.5 g, 5.7 mmol), K 2 CO 3 (3.2 g, 23.0 mmol), compound 117-4 (195 mg, 0.6 mmol) in DCM (6 mL) and H 2 The solution in O (1.5 mL) was washed with N 2 Degassing three times. After stirring at 25°C for 20 minutes, a solution of compound 117-4 (947 mg, 5.7 mmol) in DCM (0.6 mL) was added dropwise, and the resulting mixture was stirred at 25°C for 16 hours. The mixture was extracted with DCM (50 mL×3). The combined organic layers were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration gave a residue, which was purified by flash column chromatography (0% to 3% EtOAc in PE) to give compound 117-5 (230 mg, 30% yield) as a colorless oil.

[0460] 1 H NMR (400 MHz, CDCl 3 )δppm 5.71(s,2H),1.55–1.46(m,2H),1.32–1.22(m,28H),1.19(s,6H),0.88(t,J=6.4Hz,3H).

[0461] Step 3: Synthesis of Compound 117

[0462] To a solution of intermediate 1a (360 mg, 1.0 mmol) and DIEA (1.0 mL, 6.0 mmol) in DMF (5 mL) was added compound 117-5 (350 mg, 1.0 mmol), and the mixture was stirred at 80 °C for 48 h. The mixture was concentrated to give a residue, which was purified by preparative HPLC (0.1% NH 4 HCO 3 ) to afford compound 117 (77.7 mg, 12% yield).

[0463] LCMS: m / z (M+H) + = 696.6; (M-H) - = 694.5

[0464] 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.03–7.71 (m, 3H), 6.92 (d, J = 4.6 Hz, 1H), 6.80 (d, J = 4.6 Hz, 1H), 6.23–6.11 (m, 1H), 5.37 (d, J = 12.4 Hz, 2H), 4.65–4.56 (m, 1H), 4.18–4.09 (m, 1H), 3.99–3.89 (m, 2H), 3.89–3.81 (m, 1H), 1.47–1.35 (m, 2H), 1.29–1.11 (m, 28H), 1.07 (s, 6H), 0.85 (t, J = 6.8 Hz, 3H).

[0465] Compound 131 was synthesized according to the same procedure as for compound 117, except that different starting materials or intermediates were used:

[0466] Compound 131:

[0467] LCMS: [MS+1] + = 724.35, [MS-1] - = 722.30

[0468] 1 H NMR (400 MHz, CD 3OD) δ 7.93 (s, 1H), 7.06 (d, J = 4.7 Hz, 1H), 7.03 (d, J = 4.7 Hz, 1H), 5.45 (d, J = 11.6 Hz, 2H), 4.82 (d, J = 5.2 Hz, 1H), 4.38–4.32 (m, 1H), 4.25 (t, J = 5.3 Hz, 1H), 4.20–4.14 (m, 1H), 4.11–4.04 (m, 1H), 1.53–1.46 (m, 2H), 1.31–1.22 (m, 32H), 1.13 (s, 6H), 0.90 (t, J = 5.3 Hz, 3H).

[0469] Example 3 Biochemical Assay

[0470] Assay 1: In Vitro Antiviral Activity Against OC43

[0471] The in vitro anti-OC43 activity and cytotoxicity were evaluated using Huh7 cells as described below.

[0472] Antiviral activity assay : Huh7 cells were seeded in 96-well plates at a density of 8000 cells / well, with 100 μL of assay medium per well, and cultured at 37 °C and 5% CO2. After incubation for 24 hours, the test compound and reference compound were diluted with assay medium and then added to the cells, 50 μL per well. Then, 50 μL of virus diluted with assay medium was added to each well. The resulting cell cultures were incubated for an additional 7 days until significant CPE (cytopathic effect) was shown in the virus control (virus-infected cells without compound treatment). CPE was measured by CellTiter Glo according to the manufacturer's manual. The antiviral activity of the compound was calculated based on the protection of virus-induced CPE at each concentration normalized to the virus control.

[0473] The inhibition % was calculated by the following equation: Inhibition (%) = (Raw data CPD – Mean VC) / (Mean CC – Mean VC) × 100.

[0474] Cytotoxicity assay : The cytotoxicity of the compound was evaluated using the same method as the antiviral activity assay, but without the virus infection step. The viability of Huh7 cells was measured by Cell-Titer Glo according to the manufacturer's manual. The viability % was calculated by the following equation: Viability (%) = (Raw data CPD – Mean MC) / (Mean CC – Mean MC) × 100.

[0475] Raw data CPD: The value of the sample-treated well

[0476] Mean VC: The mean of the virus control

[0477] Average CC: the average value of cell controls (cells without virus infection or compound treatment)

[0478] Average MC: the average value of media control (media only) wells.

[0479] The EC50 and CC50 values were calculated using GraphPad Prism software with a non-linear regression model of log(inhibitor) vs. response - variable slope (four parameters).

[0480] Assay 2: In vitro antiviral activity against 229E

[0481] The in vitro anti-229E activity and cytotoxicity were evaluated using MRC5 cells as described below.

[0482] Antiviral activity assay : MRC5 cells were seeded in 96-well plates at a density of 20,000 cells / well, with 100 μL of assay medium per well, and cultured at 37 °C and 5% CO2. After incubation for 24 hours, the test compounds and reference compounds were diluted with assay medium and then added to the cells, 50 μL per well. Then 50 μL of virus diluted with assay medium was added to each well. The resulting cell cultures were incubated for another 3 days until significant CPE was shown in the virus control (cells infected with virus, without compound treatment). CPE was measured by CellTiter Glo according to the manufacturer's manual. The antiviral activity of the compounds was calculated based on the protection of virus-induced CPE at each concentration normalized to the virus control.

[0483] The percent inhibition was calculated by the following equation: Inhibition (%) = (Raw data CPD – Average VC) / (Average CC – Average VC) × 100.

[0484] Cytotoxicity assay : The cytotoxicity of the compounds was evaluated using the same method as the antiviral activity assay, but without the virus infection step. Cell viability was measured by Cell-Titer Glo according to the manufacturer's manual. The percent viability was calculated by the following equation: Viability (%) = (Raw data CPD – Average MC) / (Average CC – Average MC) × 100.

[0485] Raw data CPD: the value of the sample-treated well

[0486] Average VC: the average value of the virus control

[0487] Average CC: the average value of cell controls (cells without virus infection or compound treatment)

[0488] Average MC: the average value of media control (media only) wells.

[0489] The EC50 and CC50 values were calculated using the non - linear regression model of log(inhibitor) vs. response - variable slope (four - parameter) with GraphPad Prism software.

[0490] Assay 3: In vitro antiviral activity against SARS - CoV - 2

[0491] The in vitro anti - SARS - CoV - 2 activity and cytotoxicity were evaluated using Vero E6 / HAE / A549 cells as described below.

[0492] Antiviral activity assay : Vero E6 / HAE / A549 cells were seeded in 96 - well plates at a density of Vero E6 / HAE / A549 cells / well, 100 μL of assay medium per well, and cultured at 37 °C and 5% CO2. After incubation for 24 hours, the test compounds and reference compounds were diluted with assay medium and then added to the cells, 50 μL per well. Then 50 μL of virus diluted with assay medium was added to each well. The resulting cell cultures were incubated for another 3 days until significant CPE was shown in the virus control (virus - infected cells without compound treatment). CPE was measured by CellTiter Glo according to the manufacturer's manual. The antiviral activity of the compounds was calculated based on the protection of virus - induced CPE at each concentration normalized to the virus control.

[0493] The percent inhibition was calculated by the following equation: Inhibition (%)=(Raw data CPD - Mean VC) / (Mean CC - Mean VC)×100.

[0494] Cytotoxicity assay : The cytotoxicity of the compounds was evaluated in the same manner as the antiviral activity assay, but without the virus - infection step. Cell viability was measured by Cell - Titer Glo according to the manufacturer's manual. The percent viability was calculated by the following equation: Viability (%)=(Raw data CPD - Mean MC) / (Mean CC - Mean MC)×100.

[0495] Raw data CPD: The value of the sample - treated well

[0496] Mean VC: The mean of the virus control

[0497] Mean CC: The mean of the cell control (cells without virus infection or compound treatment)

[0498] Mean MC: The mean of the medium control (medium only) wells.

[0499] The EC50 and CC50 values were calculated using the log(inhibitor) vs. response - variable slope (four - parameter) non - linear regression model with GraphPad Prism software.

[0500] Assay 4: In vitro antiviral activity against SARS - CoV - 2 replicon

[0501] The compounds were serially diluted in DMSO and added to 384 - well plates, 0.3 μL per well (8 doses, 3 - fold, duplicate wells). The replicon RNA was generated in in vitro transcripts. Huh7 cells transfected with purified SARS - CoV - 2 replicon RNA were seeded at 4000 cells / well in 384 - well microplates containing the serially diluted compounds and then cultured at 37 °C and 5% CO2 for 1 day. The final volume of the cell culture was 60 μL / well, and the final concentration of DMSO in the test plates was 0.5%.

[0502] The fluorescence intensity was determined 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.

[0503] The antiviral activity and viability of the compounds were expressed as % inhibition and % viability, respectively, and calculated using the following equations:

[0504] Inhibition (%)=(Raw data CPD - Mean ZPE) / (Mean HPE - Mean ZPE)×100

[0505] Viability (%)=(Raw data CPD - Mean HPE) / (Mean ZPE - Mean HPE)×100

[0506] Raw data CPD: The value of the sample - treated well

[0507] Mean ZPE: The mean of the virus control

[0508] Mean HPE: The mean of the medium control (medium only) wells.

[0509] The EC50 and CC50 values were calculated using the log(inhibitor) vs. response - variable slope (four - parameter) non - linear regression model with GraphPad Prism software.

[0510] Assay 5: Determination of intracellular nucleoside triphosphates (NTPs) in HepG2 and A549:

[0511] The human hepatocellular carcinoma cell line HepG2 and the human lung adenocarcinoma cell line A549 were used to evaluate drug cellular uptake and intracellular nucleoside triphosphates. The cells were incubated in a 6-well plate at 37 °C in a 5% CO2 - 95% air atmosphere to allow cell attachment. The cell density of HepG2 was 2×10 6 / well, and the cell density of A549 was 1×10 6 / 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 media were removed, and 2.5 mL of fresh medium containing 1 μM of the test compound was added to each well and incubated at 37 °C in a 5% CO 2 -95% air atmosphere. At each specific time point (1 h, 2 h, 4 h, 6 h), the media were removed and the cells were washed twice with 3 mL of ice-cold PBS. After washing, the cells were lysed from the plate wells with 600 μL of ice-cold 70% methanol. The cell lysate was then centrifuged at 4 °C and 13,000 rpm for 5 min. An aliquot (200 μL) of the supernatant was transferred to a clean 96-well plate for LC-MS / MS (Shimazu 20A and API 4000 Qtrap) analysis to determine the concentration of intracellular nucleoside triphosphates.

[0512] Determination 6: Stability in human liver S9 fraction:

[0513] The stability was evaluated using human or rat liver S9. Briefly, the compound (1 μM) was incubated at 37 °C in 0.2 mL of 100 mM potassium phosphate buffer (PPB, pH 7.4) containing S9 (2.0 mg protein / mL) for 0 min, 5 min, 15 min, 30 min, 45 min, and 60 min. After incubation at each time point, the reaction was terminated by adding 600 μL of ice-cold acetonitrile. The samples were then centrifuged, and the supernatant was injected into UPLC-MS / MS for analysis. The half-life (t1 / 2) was determined from the elimination rate constant (k) using the following equation: in vitro t1 / 2 = 0.693 / k. The elimination rate constant (k) was determined as the gradient of the natural logarithm of the remaining percentage versus the incubation time curve by regression analysis, where the remaining percentage (%) was calculated as follows:

[0514]

[0515] Tables 1-4 show the results for Assays 1-6 of exemplary compounds of the present disclosure and reference compounds (remdesivir, remdesivir monophosphate (remdesivir-MP), GS-441524, and ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl (3-(hexadecyloxy)propyl) hydrogen phosphate (Reference Compound 1)). It shows that the compounds of the present disclosure have good inhibitory effects against various coronaviruses, have low cytotoxicity, show high stability in human liver, and produce more triphosphorylated products in lung cells.

[0516] Assay 7: In vitro antiviral activity against SARS-CoV-2 omicron BA.5

[0517] The in vitro anti-SARS-CoV-2 omicron BA.5 activity and cytotoxicity of the compounds in combination with 2 μM CP-100356 were tested in Vero E6 cells to obtain the in vitro antiviral activity against SARS-CoV-2 omicron BA.5. The test medium was MEM supplemented with 2% FBS and 50 μg / mL gentamicin.

[0518] CP-100356 in powder form was provided by the sponsor and dissolved in DMSO to prepare a 10 mM solution. The test compounds and reference compounds in powder form were also received from the sponsor and dissolved in DMSO to prepare 10 mM stock solutions. These compounds were serially diluted using an eight-fold semi-logarithmic dilution method in the test medium containing CP-100356 (final plate concentration of 2 μM in all dilutions) such that the starting (high) concentration of the test compounds was 1 μM. Each dilution was added to 5 wells of a 96-well plate containing 80%-100% confluent cells. Three wells of each dilution were infected with the virus, while two wells remained uninfected as toxicity controls. Six wells were infected and untreated as virus controls, and six wells were uninfected and untreated as cell controls. The virus was prepared to achieve an MOI of 0.003. Remdesivir was tested in parallel as a positive control. The plates were incubated at 37 °C ± 2 °C, 5% CO2.

[0519] On day 3 post-infection, when maximum CPE was reached in the untreated virus control wells, the plates were stained with neutral red dye for approximately 2 hours (±15 minutes). The supernatant dye was removed, and the wells were rinsed with PBS. The incorporated dye was extracted in 50:50 Sorensen citrate buffer / ethanol for >30 minutes and the optical density at 540 nm was read on a spectrophotometer. The optical density was converted to a percentage of the cell control and normalized relative to the virus control, and then the concentration of the test compound required to inhibit 50% CPE (EC50) was calculated by regression analysis. Similarly, the concentration of the compound that would cause 50% cell death in the absence of virus (CC50) was calculated. The selectivity index (SI) was EC50 divided by CC50. Table 5 shows the in vitro antiviral activity of exemplary compounds against SARS-CoV-2 Omicron BA.5.

[0520] Assay 8: Determination of Intracellular Nucleoside Triphosphates in HAE

[0521] Human airway epithelial cell (HAEC, HAE) lines were used to evaluate drug cellular uptake and intracellular nucleoside triphosphates. The cells were incubated overnight at 37 °C in a 5% CO 2 -95% air atmosphere in 6-well plates to allow cell attachment. The cell density of HAEC was 3×105 / well. The medium for HAEC was a specially designed medium (CM-H016) containing 2% fetal bovine serum (FBS). After cell attachment, the medium was removed, and 2.5 mL of fresh medium containing 5 μM of the test compound was added to each well and incubated at 37 °C in a 5% CO 2 -95% air atmosphere. At each specific time point (1 hour, 2 hours, 4 hours, 6 hours), the medium was removed and the cells were washed twice with 3 mL of ice-cold PBS. After washing, the cells were digested from the plate wells with 600 μL of ice-cold 70% methanol. The cell lysate was then centrifuged at 4 °C and 13,000 rpm for 5 minutes. An aliquot (200 μL) of the supernatant was transferred to a clean 96-well plate for LC-MS / MS (Waters and API 5500) analysis to determine the concentration of intracellular nucleoside triphosphates. Table 6 shows the concentration of intracellular nucleoside triphosphates of exemplary compounds.

[0522] Table 1 - In Vitro Antiviral Activity of Exemplary Compounds Against 229E

[0523]

[0524] 1 For EC 50 , A: <100 nM, B: 100 nM - 1000 nM, C: >1000 nM.

[0525] Table 2 - In vitro antiviral activities of exemplary compounds against SARS-CoV-2 replicon

[0526] Compound number <![CDATA[Replicon EC 50 1 (nM)]]> <![CDATA[Huh7 CC 50 (nM) <!-- 69 -->]]> 19 B >10000 23 A >10000 24 A >10000 47 A >10000 51 A >10000 53 A >10000 57 A >10000 62 B >10000 75 B >10000 79 B >10000 81 A >10000 83 A >10000 85 A >10000 117 A >10000 125 A >1000 126 A >1000 131 A >1000 132 A >1000 133 A >1000 134 A >1000 Remdesivir A >10000 Remdesivir-MP C >10000 GS-441524 C >10000 Reference compound 1 B >10000

[0527] 1 For EC 50 , A: < 100 nM, B: 100 nM - 1000 nM, C: > 1000 nM.

[0528] Table 3 - Stability of exemplary compounds in human liver S9 fraction

[0529]

[0530] 1 For t 1 / 2 , A: > 60 minutes, B: 20 minutes - 60 minutes, C: < 20 minutes.

[0531] Table 4 - Intracellular nucleoside triphosphates of exemplary compounds

[0532]

[0533] 1 For Metapp concentration: A: > 500 nM, B: 200 nM - 500 nM, C: < 200 nM.

[0534] Table 5 - In vitro antiviral activities of exemplary compounds against SARS-CoV-2 Omicron BA.5

[0535]

[0536] 1 For EC 50 , A: < 50 nM, B: 50 nM - 500 nM, C: > 500 nM.

[0537] Table 6 - Intracellular nucleoside triphosphates of exemplary compounds

[0538]

[0539] 1 For MetaPpp concentration: A: > 400 nM, B: 200 nM - 400 nM, C: < 200 nM.

[0540] The foregoing description is to be considered merely illustrative of the principles of the disclosure. Further, since numerous modifications and changes will be apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and procedure described above. Accordingly, all suitable modifications and equivalents may be regarded as falling within the scope of the invention as defined by the appended claims.

Claims

1. A compound having the formula (I): or a pharmaceutically acceptable salt thereof, wherein the base is a naturally occurring or modified pyrimidine base or purine base; R 1 selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -OR a , -NO 2 , -N(R a ), 2 , -C(O)N(R a ), 2 , -C(O)R a , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a , -S(O)OR a , -S(O) 2 (OR a ) and -S(O) 2 N(R a ), 2 ; R 21 , R 22 , R 31 , R 32 and R 4 Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl, -OR a 、-NO 2 、-N(R a ) 2 、-C(O)N(R a ) 2 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-S(O)R a and -S(O) 2 R a ; Q is CH 2 , CHD or CD 2 ; Each M is independently selected from hydrogen, a metal ion, -NH 4 or a protonated organic amine; L is selected from hydrogen or -C(R 5 ) 2 -L 1 -L 2 ; Each R 5 is selected from hydrogen, deuterium or an alkyl group, wherein the alkyl group is optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, cycloalkyl, heterocyclic, aryl or heteroaryl; L 1 Selected from -OC(O)-*, -OC(O)O-*, -OC(O)N(R a )-*, -N(R a )C(O)-*, -N(R a )C(O)O-* or wherein the *-end of L 1 is connected to L 2 ; L 2 selected from hydrogen, R 6 , wherein L 2 the *-end of which is connected to L 1 ; R 6 selected from C 9-26 alkyl, C 9-26 alkenyl, C 9-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q -, R a OCH 2 (CH 2 OCH 2 ) n CH 2 (-), wherein the alkyl, alkenyl or alkynyl is optionally substituted by one or more R b substituents; R 7 selected from C 6-26 alkyl, C 6-26 alkenyl, C 6-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, each of which is optionally substituted with one or more R b substituents; R 8 and R 9 each independently selected from C 1-26 alkyl, C 2-26 alkenyl, C 2-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, each of which is optionally substituted with one or more R b ; Provided that when R 8 is methyl and R 9 is hydrogen, then R 7 is selected from C 7-26 alkyl, C 7-26 alkenyl, C 7-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -; Each R a is independently selected from hydrogen, halogen or alkyl; Each R b is independently selected from halogen, hydroxy, cyano, amino or alkyl; m is 0, 1, 2 or 3; and each n, p or q is independently an integer between 0 and 20.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula (Ia):

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

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

5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein, L is hydrogen.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein, m is 0, 1 or 3.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein, M is hydrogen.

8. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein, L is -C(R 5 ) 2 -L 1 -L 2 。 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, Two Rs 5 are both hydrogen or deuterium.

10. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, One R 5 is hydrogen and the other R 5 is alkyl optionally substituted by aryl.

11. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, One R 5 is hydrogen, and the other R 5 is methyl, ethyl, 12. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, L 1 selected from -OC(O)-*, -OC(O)O-*, -OC(O)NH-*, -OC(O)N(CH 3 )-*, -NHC(O)-*, -N(CH 3 )C(O)-*, -NHC(O)O-*, -N(CH 3 )C(O)O-* or 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein, L 1 is -OC(O)-*, -OC(O)O-* or 14. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, L 2 is R 6 .

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein, R 6 is a straight-chain C 9-26 alkyl group, a straight-chain C 9-26 alkenyl group, a straight-chain C 9-26 alkynyl group, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein, R 6 is a straight-chain C 14-22 alkyl group.

17. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein, R 6 is a straight-chain C 14-22 alkenyl group.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein, R 6 is a straight-chain C 14-22 alkenyl group having 1 to 6 double bonds.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein, each double bond is in the Z configuration.

20. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein, R 6 is CH 3 (CH 2 ) p O(CH 2 ) q -.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein, p is an integer from 3 to 20, and q is an integer from 1 to 6.

22. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein, R 6 is R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

23. The compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein, n is an integer from 1 to 6.

24. The compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein, R a is hydrogen, methyl or ethyl.

25. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, L 2 is 26. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein, R 7 is C 6-26 alkyl, C 6-26 alkenyl, C 6-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein, R 7 is a straight-chain C 6-26 alkyl or a straight-chain C 6-26 alkenyl.

28. The compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein, R 7 is a straight-chain C 13-21 alkyl or a straight-chain C 13-21 alkenyl.

29. The compound according to claim 28, or a pharmaceutically acceptable salt thereof, wherein, R 7 is a straight-chain C 13-21 alkenyl group having 1 to 6 double bonds.

30. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein, each double bond is in the Z configuration.

31. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein, R 7 is CH 3 (CH 2 ) p O(CH 2 ) q -.

32. The compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein, where p is an integer from 3 to 20, and q is an integer from 1 to 6.

33. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein, R 7 is R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

34. The compound according to claim 33, or a pharmaceutically acceptable salt thereof, wherein, n is an integer from 1 to 6.

35. The compound according to claim 33, or a pharmaceutically acceptable salt thereof, wherein, R a is hydrogen, methyl or ethyl.

36. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein, R 8 is C 1-26 alkyl or C 2-26 alkenyl, and R 9 is hydrogen or C 1-26 alkyl.

37. The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein, R 8 is a straight-chain C 1-26 alkyl or a straight-chain C 8-26 alkenyl, and R 9 is hydrogen or a straight-chain C 1-26 alkyl.

38. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein, R 7 is a straight-chain C 6-26 alkyl group, R 8 is a straight-chain C 2-26 alkyl group, and R 9 is hydrogen.

39. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein, R 7 is a straight-chain C 7-26 alkyl group, R 8 is methyl, and R 9 is hydrogen or methyl.

40. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, L 2 is 41. The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein, R 7 is a straight-chain C 6-26 alkyl, straight-chain C 6-26 alkenyl, straight-chain C 6-26 alkynyl, CH 3 (CH 2 ) p O(CH 2 ) q - or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -.

42. The compound according to claim 41, or a pharmaceutically acceptable salt thereof, wherein, R 7 is a straight-chain C 6-26 alkyl or a straight-chain C 6-26 alkenyl.

43. The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein, R 8 is a straight-chain C 1-26 alkyl group, a straight-chain C 2-26 alkenyl group, a straight-chain C 2-26 alkynyl group, CH 3 (CH 2 ) p O(CH 2 ) q -, or R a OCH 2 (CH 2 OCH 2 ) n CH 2 -, and R 9 is hydrogen or C 1-26 alkyl group.

44. The compound according to claim 43, or a pharmaceutically acceptable salt thereof, wherein, R 8 is a straight-chain C 1-26 alkyl or a straight-chain C 2-26 alkenyl, and R 9 is hydrogen or a straight-chain C 1-26 alkyl.

45. The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein, R 7 is a straight-chain C 6-26 alkyl group, R 8 is a straight-chain C 1-26 alkyl group, and R 9 is hydrogen.

46. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein, R 1 selected from hydrogen, hydroxyl, cyano, azido, alkyl or haloalkyl.

47. The compound according to claim 46, or a pharmaceutically acceptable salt thereof, wherein, R 1 is a cyano group.

48. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein, R 21 、R 22 、R 31 、R 32 and R 4 Each of R a is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, azido, alkyl, haloalkyl, -OC(O)R 49. The compound according to claim 48, or a pharmaceutically acceptable salt thereof, wherein, R 21 、R 22 、R 31 、R 32 Each of R, R, R, and R is independently selected from hydrogen, deuterium, halogen, hydroxyl, alkyl, or -OC(O)R a 。 50. The compound according to claim 49, or a pharmaceutically acceptable salt thereof, wherein, R a is an alkyl group.

51. The compound according to claim 50, or a pharmaceutically acceptable salt thereof, wherein, R a is methyl.

52. The compound according to claim 48, or a pharmaceutically acceptable salt thereof, wherein, R 4 selected from hydrogen, deuterium, halogen, cyano, azido or haloalkyl.

53. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein, Selected from the group consisting of:

54. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, The base is and is 55. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein, The base is 56. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein, the compound is selected from the following group:

57. A pharmaceutical composition comprising the compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

58. The pharmaceutical composition according to claim 57, which is formulated for oral administration, injection administration, nasal administration or pulmonary administration.

59. A method for treating a viral infection in a patient in need thereof, which comprises administering to the individual an effective amount of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 57 - 58.

60. The method according to claim 59, wherein the viral infection is an RNA virus.

61. The method according to claim 60, wherein the RNA virus is a single-stranded or double-stranded RNA virus.

62. The method according to claim 61, wherein the viral infection is from a virus selected from the group consisting of Retroviridae, Lentiviridae, Coronaviridae, Picornaviridae, Caliciviridae, Flaviviridae, Togaviridae, Bornaviridae, Filoviridae, Paramyxoviridae, Pneumoviridae, Rhabdoviridae, Arenaviridae, Bunyaviridae, Orthomyxoviridae and Delta virus.

63. The method according to claim 62, wherein the viral infection is from a virus selected from the group consisting of Lymphocytic choriomeningitis virus, Coronavirus, HIV, SARS, Poliovirus, Rhinovirus, Hepatitis A, Norwalk virus, Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue virus, Zika virus, Rubella virus, Ross River virus, Sindbis virus, Chikungunya virus, Borna disease virus, Ebola virus, Marburg virus, Measles virus, Mumps virus, Nipah virus, Hendra virus, Newcastle disease virus, Human respiratory syncytial virus, Rabies virus, Lassa virus, Hantavirus, Crimean-Congo hemorrhagic fever virus, Influenza, Hepatitis D virus.

64. The method according to claim 61, wherein, the viral infection is a coronavirus infection.

65. The method according to claim 64, wherein, the coronavirus is selected from the group consisting of 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV) and SARS-CoV-2 (COVID-19).

66. The method according to claim 65, wherein, the coronavirus is SARS-CoV-2.

67. A method for inhibiting RNA polymerase in an individual in need thereof, which comprises administering to the individual an effective amount of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 57 - 58.

68. Use of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 57 - 58 in the manufacture of a medicament for treating viral infections.

69. A compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 57 - 58, for use in the treatment of viral infections.

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