CN118666904A - Antiviral compounds, compositions and uses thereof - Google Patents

Abstract

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

Description

Antiviral compounds and compositions and uses thereof

Field of the Invention

The present disclosure relates generally to compounds that exhibit activity in inhibiting RNA polymerase and pharmaceutical compositions comprising these compounds, as well as methods of treatment by administering these compounds or pharmaceutical compositions comprising the same.

Background Art

In the past two decades, a variety of viruses have been identified that can cause life-threatening diseases in humans and animals, 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. Coronaviruses are very prone to mutating into epidemic variants. Although multiple 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.

Coronaviruses are positive-strand RNA viruses that encode 16 nonstructural proteins (nsp1 to nsp16). Many of the nonstructural proteins combine to form a multiprotein replicase-transcriptase complex (RTC). The major replicase-transcriptase protein is the RNA-dependent RNA polymerase (RdRp), which is directly involved in RNA replication and transcription of the RNA strand. In addition, RdRp is highly conserved across variants and viruses, making it an ideal drug target for controlling various RNA virus infections.

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

Therefore, there is a need in the art to develop improved compounds that exhibit inhibitory activity against RNA polymerase, particularly RNA polymerase inhibitors that have good oral and pulmonary bioavailability and high conversion rates to their monophosphate and triphosphate salts.

Summary of the invention

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.

In one aspect, the present disclosure provides the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a viral infection:

in

Base is a naturally occurring or modified pyrimidine base or purine base;

Q is CH ₂ , CHD or CD ₂ ;

R ¹ is 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 ;

each of R ²¹ , R ²² , R ³¹ , R ³² and R ⁴ is independently selected from the group consisting of hydrogen, deuterium, 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 and -S(O) ₂ R ^a ;

Each R ⁵ is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ;

R ⁶ is -OX;

X is hydrogen or a pharmaceutically acceptable cation;

^R7 is

R ⁸ is selected from the group consisting of hydrogen, C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n -, and ^Re OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -, each of which is optionally substituted with one or more R ^b ;

R ⁹ is selected from the group consisting of C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n -, and Re ^OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -, each of which is optionally substituted with one or more R ^b ;

Each ^Ra is independently selected from hydrogen, halogen or alkyl;

Each R ^b is independently selected from halogen, hydroxy, cyano, amino, alkyl or alkoxy;

Each ^{Re is} independently selected from hydrogen or alkyl;

Each m, n or p is independently an integer from 0 to 20;

Provided that when X is hydrogen, then

a) R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl; or

b) R ⁸ is C _1-18 alkyl or C _2-18 alkenyl, and R ⁹ is selected from C _7-25 alkyl or C _7-25 alkenyl.

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

or a pharmaceutically acceptable salt thereof,

in

Base is a naturally occurring or modified pyrimidine base or purine base;

Q is CH ₂ , CHD or CD ₂ ;

R ¹ is 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 ;

each of R ²¹ , R ²² , R ³¹ , R ³² and R ⁴ is independently selected from the group consisting of hydrogen, deuterium, 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 and -S(O) ₂ R ^a ;

Each R ⁵ is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ;

R ⁶ is -OX;

X is hydrogen or a pharmaceutically acceptable cation;

^R7 is

R ⁸ is selected from the group consisting of hydrogen, C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n -, and ^Re OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -, each of which is optionally substituted with one or more R ^b ;

R ⁹ is selected from the group consisting of C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n - and Re ^OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -,

Each of them is optionally substituted with one or more R ^b ;

Each ^Ra is independently selected from hydrogen, halogen or alkyl;

Each R ^b is independently selected from halogen, hydroxy, cyano, amino, alkyl or alkoxy;

Each ^{Re is} independently selected from hydrogen or alkyl;

Each m, n or p is independently an integer from 0 to 20;

Provided that when X is hydrogen, then

a) R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl; or

b) R ⁸ is C _1-18 alkyl or C _2-18 alkenyl, and R ⁹ is selected from C _7-25 alkyl or C _7-25 alkenyl.

In a further aspect, there is provided a compound having formula (Ia):

or a pharmaceutically acceptable salt thereof.

In another aspect, a compound having a chemical formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

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.

In another aspect, the present disclosure provides a method for treating a viral infection in a patient in need thereof, comprising 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.

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

In another aspect, the present disclosure provides 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.

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 use in treating viral infection.

DETAILED DESCRIPTION

For details, please 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 enumerated embodiments, it should be understood that it is not intended that the present disclosure will be limited to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications or equivalents, which may be included within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize that many methods or materials that can implement the present disclosure are similar or equivalent to those methods or materials described herein. The present disclosure is in no way limited to the methods or materials described. In the event that one or more of the incorporated references and similar materials (including but not limited to defined terms, term usage, the technology, etc.) are different from or contradictory to 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.

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

definition

Definitions of specific functional groups and chemical terms are described in more detail below.For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry as well as 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.

In various places of 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 variable listed for that group is to be understood as a linking group. For example, if a structure requires a linking group and the Markush group definition of the variable lists "alkyl", it is to be understood that the "alkyl" represents a linking alkylene group.

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

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

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

As used herein, the term "C _ij " indicates a range of carbon number, wherein i and j are integers, and the range of carbon number includes the endpoints (i.e., i and j) and each integer point therebetween, and wherein 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.

As used herein, the term "alkyl" refers to a saturated straight or branched hydrocarbon group, whether used as part of another term or independently, which may be optionally substituted with one or more substituents described below. The term " _Cij 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 " _C1-10 alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of “C _1-6 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 group contains 9 to 30 carbon atoms. In some embodiments, the alkyl group contains 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms.

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

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

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

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

Whether used as part of another term or independently, as used herein, the term "alkenyl" refers to a straight or branched hydrocarbon group having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents as described herein, and includes groups having "cis" and "trans" conformations, or alternatively, "E" and "Z" conformations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In some embodiments, the alkenyl group contains 9 to 30 carbon atoms. In some embodiments, the alkenyl group contains 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-butene-1-yl, 5-hexenyl, and the like.

As used herein, the term "alkoxy" refers to an alkyl group (-O-alkyl) connected to oxygen, whether as part of another term or used independently. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms. In some embodiments, the alkoxy group contains 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

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

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

Whether used as part of another term or independently, as used herein, the term "aryl" 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, and the like, which may bear 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 a polycyclic ring system, only one ring is required to be aromatic (e.g., 2,3-dihydroindole), although all rings may be aromatic (e.g., quinoline). The second ring may also be spirocyclic, fused, or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. Aryl groups may be substituted at one or more ring positions with substituents as described above.

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

Whether used as part of another term or independently, as used herein, the term "cycloalkyl" refers to monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring systems, wherein 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. Cycloalkyl may be saturated or partially unsaturated. Cycloalkyl may be substituted. In some embodiments, the cycloalkyl may be a saturated cyclic alkyl. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group containing at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups 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 cycloalkyl groups 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.

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

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).

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

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

As used herein, the term "heteroaryl" refers to an aryl group having one or more heteroatoms in addition to carbon atoms. The heteroaryl group may be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, wherein the linking group or point of attachment is located on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and the like.

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, wherein one or more ring atoms may be optionally independently substituted by 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. "Heterocyclic group" also includes groups in which heterocyclic groups are fused to saturated, partially unsaturated or completely unsaturated (i.e., aromatic) carbocyclic or heterocyclic rings. Where possible, the heterocyclic group may be carbon-connected or nitrogen-connected. In some embodiments, the heterocycle is carbon-connected. In some embodiments, the heterocycle is nitrogen-connected. For example, a group derived from pyrrole may be pyrrole-1-yl (nitrogen-connected) or pyrrole-3-yl (carbon-connected). Furthermore, a group derived from imidazole may be imidazol-1-yl (nitrogen attached) or imidazol-3-yl (carbon attached).

In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxothietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, 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, hexamethylenetetraminyl, 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), and the like.

As used herein, the term "hydroxy" refers to -OH.

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

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

As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (ie, fully unsaturated) moieties.

As used herein, the term "protonated organic amine" refers to NHR ₃ ⁺ , wherein each R group independently refers to an organic group, such as an alkyl or aryl group.

As used herein, the term "purine base" or "pyrimidine base" includes, but is not limited to, adenine, ^N6 -alkylpurines, ^N6 -acylpurines (wherein the acyl group is C(O)(alkyl, aryl, alkylaryl or arylalkyl)), ^N6 -benzylpurine, ^N6 -halopurine, N6-vinylpurine, N6-acetylenic purine, ^N6 -acylpurine, ^N6 -hydroxyalkylpurine, ^N6 -allylaminopurine, ^N6 -thioallylpurine, ^N2 -alkylpurine, ^N2 -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), ^C5 -alkylpyrimidine, ^C5- -benzylpyrimidine, C ⁵ -halopyrimidine, C ⁵ -vinylpyrimidine, C ⁵ -acetylenic pyrimidine, 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-azacytidine, 5-azauracil, triazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. ^Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine. Purine and pyrimidine bases are linked to ribose or its analogs via the nitrogen atom of the base. As required or desired, oxygen and nitrogen functional groups on the base can 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 p-toluenesulfonyl.

As used herein, the term "substituted", whether or not preceded by the term "optionally", refers to one or more hydrogens of a specified portion being replaced by a suitable substituent. Typical substituents include, but are not limited to, functional groups as described herein, such as halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc., each of which may also be similarly substituted. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., such substitutions meet the allowed valence of the substituted atom, and the substitution produces a stable or chemically feasible compound, for example, the compound does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise indicated, when the term "substituted" is used in conjunction with a group having two or more parts capable of substitution, such as an alkylaryl, the substituent may be connected to the aryl portion, the alkyl portion, or both. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. It will be understood by those skilled in the art that the substituent itself may be substituted when appropriate. Unless specifically stated as "unsubstituted", reference to a chemical moiety herein should be understood to include substituted variants. For example, reference to an "aryl" or "aryl" moiety implicitly includes both substituted and unsubstituted variants.

Compound

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

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

or a pharmaceutically acceptable salt thereof,

in

Base is a naturally occurring or modified pyrimidine base or purine base;

Q is CH ₂ , CHD or CD ₂ ;

R ¹ is 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 ;

each of R ²¹ , R ²² , R ³¹ , R ³² and R ⁴ is independently selected from the group consisting of hydrogen, deuterium, 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 and -S(O) ₂ R ^a ;

Each R ⁵ is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ;

R ⁶ is -OX;

X is hydrogen or a pharmaceutically acceptable cation;

^R7 is

R ⁸ is selected from the group consisting of hydrogen, C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n -, and ^Re OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -, each of which is optionally substituted with one or more R ^b ;

R ⁹ is selected from the group consisting of C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n - and Re ^OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -,

Each of them is optionally substituted with one or more R ^b ;

Each ^Ra is independently selected from hydrogen, halogen or alkyl;

Each R ^b is independently selected from halogen, hydroxy, cyano, amino, alkyl or alkoxy;

Each ^{Re is} independently selected from hydrogen or alkyl;

Each m, n or p is independently an integer from 0 to 20;

Provided that X is hydrogen, then

a) R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl; or

b) R ⁸ is C _1-18 alkyl or C _2-18 alkenyl, and R ⁹ is selected from C _7-25 alkyl or C _7-25 alkenyl.

In another aspect, a compound having formula (Ia) is provided:

or a pharmaceutically acceptable salt thereof, wherein Q, R ¹ to R ⁷ and base are as defined above. In some embodiments, Base is selected from the group consisting of:

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

In some embodiments, R ¹ is selected from hydrogen, hydroxy, cyano, azido, alkyl, or haloalkyl.

In certain embodiments, R ¹ is cyano.

In some embodiments, each of R ²¹ , R ²² , R ³¹ , R ³² , and R ⁴ is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, azido, alkyl, haloalkyl, or -OC(O)R ^a .

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

In certain embodiments, ^Ra is alkyl. In certain embodiments, ^Ra is C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, or C _1-3 alkyl. In certain embodiments, ^Ra is methyl.

In some embodiments, R ⁴ is selected from hydrogen, deuterium, halogen, cyano, azido, or haloalkyl.

In some embodiments, Select from the following group:

In some embodiments, Base is and yes

In some embodiments, Base is and yes

In some embodiments, each R ⁵ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _6-12 aryl, 5- to 12-membered heteroaryl, (C _1-3 alkyl)(C _3-12 cycloalkyl), (C _1-3 alkyl)(3- to 12-membered heterocyclyl), (C _1-3 alkyl)(C _6-12 aryl), (C _1-3 alkyl)(5- to 12-membered heteroaryl), and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b .

In certain embodiments, one R ⁵ is hydrogen, and the other R ⁵ is selected from C _1-6 alkyl, C _6-12 aryl, (C _1-3 alkyl)(C _6-12 aryl), (C _1-3 alkyl)(5- to 12-membered heteroaryl), or a natural amino acid side chain, each of which is optionally substituted with one or more R ^b .

In certain embodiments, one R ⁵ is hydrogen and the other R ⁵ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

In certain embodiments, one R ⁵ is hydrogen, and another R ⁵ is phenyl optionally substituted with one or more R ^b . In certain embodiments, R ^b is halogen, hydroxy, or alkoxy.

In certain embodiments, one R ⁵ is hydrogen, and the other R ⁵ is (C _1-3 alkyl)(C _6-12 aryl) or (C _1-3 alkyl)(5- to 12-membered heteroaryl), each of which is optionally substituted with one or more R ^b . In some embodiments, R ^b is halogen, hydroxyl, or alkoxy.

In some embodiments, one R ⁵ is hydrogen, and the other R ⁵ is selected from the group consisting of:

In some embodiments, one R ⁵ is hydrogen, and the other R ⁵ is a natural amino acid side chain. In certain embodiments, one R ⁵ is hydrogen, and the other R ⁵ is selected from the group consisting of:

In some embodiments, each R ⁵ is independently C _1-6 alkyl.

In some embodiments, both R ⁵ are methyl.

In some embodiments, X is hydrogen.

In some embodiments, X is selected from a metal ion, -NH ₄ ^+, or a protonated organic amine. In certain embodiments, X is selected from K ⁺ , Ca ²⁺ , Na ^+, or NH ₄ ⁺ .

In some embodiments, R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl.

In certain embodiments, R ⁸ is hydrogen and R ⁹ is C _11-25 alkyl. In certain embodiments, R ⁸ is hydrogen and R ⁹ is C _11-21 alkyl. In certain embodiments, R ⁸ is hydrogen and R ⁹ is C _15-19 alkyl.

In certain embodiments, R ⁸ is hydrogen and R ⁹ is a C _11-25 alkenyl group including 1-6 double bonds. In certain embodiments, R ⁸ is hydrogen and R ⁹ is a C _11-25 alkenyl group including 1-6 double bonds, wherein each double bond is in the Z configuration.

In some embodiments, R ⁸ is C _1-14 alkyl or C _2-14 alkenyl, and R ⁹ is selected from C _7-25 alkyl or C _7-25 alkenyl.

In certain embodiments, R ⁸ is C _1-3 alkyl, and R ⁹ is C _13-25 alkyl. In certain embodiments, R ⁸ is methyl or ethyl, and R ⁹ is C _13-25 alkyl.

In certain embodiments, R ⁸ is C _6-14 alkyl and R ⁹ is C _7-18 alkyl. In certain embodiments, R ⁸ is C _6-11 alkyl and R ⁹ is C _7-11 alkyl.

In certain embodiments, R ⁸ is a C _2-14 alkenyl group including 1 to 6 double bonds. In certain embodiments, each double bond in R ⁸ is in the Z configuration.

In certain embodiments, R ⁸ is C _2-4 alkenyl, and R ⁹ is C _10-25 alkenyl.

In certain embodiments, R ⁸ is C _6-14 alkenyl, and R ⁹ is C _7-18 alkenyl.

In a further aspect, a compound having a chemical formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein R ¹ to R ⁴ and R ⁷ are as defined above.

In some embodiments, R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl.

In some embodiments, R ⁸ is hydrogen and R ⁹ is C _11-25 alkyl. In certain embodiments, R ⁸ is hydrogen and R ⁹ is C _15-19 alkyl.

In another aspect, the present disclosure provides a compound selected from the group consisting of:

The compounds provided herein are described with reference to general chemical formulae and specific compounds. In addition, the disclosed compounds may 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 crystalline forms or polymorphs.

Depending on the substituent selection, the disclosed compounds may include one or more asymmetric centers, and therefore may exist in various stereoisomeric forms, such as enantiomers and/or diastereomers. For example, the compounds provided herein may have an asymmetric carbon center, and therefore the compounds provided herein may have I or (S) stereo configuration at the carbon asymmetric center. Therefore, the disclosed compounds may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers.

As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity.

When a particular enantiomer is preferred, it may be provided in some embodiments as being substantially free of the opposite enantiomer, and may also be referred to as "optically enriched". As used herein, "optically enriched" means that the compound is composed of a significantly larger proportion of one enantiomer. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95%, 98% by weight, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be separated from the racemic mixture by any method known to those skilled in the art, such as by chromatography or crystallization, by synthesizing using stereochemically uniform starting materials, or by stereoselective synthesis. Optionally, derivatization may be performed before separating stereoisomers. The separation of a mixture of stereoisomers may be performed during the synthesis of the compounds provided herein at an intermediate step or it may be performed on the final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of a crystalline product or a crystalline intermediate, which may be derivatized with a reagent containing a stereocenter of a known configuration if necessary. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

In some embodiments, a mixture of diastereomers is provided, for example, a mixture of diastereomers enriched with 51% or more of one of the diastereomers, including, for example, 60% or more, 70% or more, 80% or more, or 90% or more of one of the diastereomers.

In some embodiments, unless otherwise indicated, the compounds provided herein may have one or more double bonds that exist as Z or E isomers. Additionally, the disclosure also encompasses 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).

The disclosed compounds can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be mutually converted via low energy barriers. For example, proton tautomers (also referred to as prototransfer tautomers) include mutual conversions via proton migration, such as keto-enols, amide-imidic acids, lactams-lactams, imine-enamine isomerizations and cyclic forms, wherein protons can occupy two or more positions of heterocyclic systems (e.g., 1H-imidazoles and 3H-imidazoles, 1H-1,2,4-triazoles, 2H-1,2,4-triazoles and 4H-1,2,4-triazoles, 1H-isoindoles and 2H-isoindoles and 1H-pyrazoles and 2H-pyrazoles). Valence tautomers include mutual conversions performed by rearrangement of some bonding electrons. Tautomers can be in equilibrium or spatially locked into a form by appropriate substitution. Unless otherwise specified, a compound of the disclosure identified by name or structure as a particular tautomeric form is intended to encompass the other tautomeric forms.

The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of atoms 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 disclosed compounds are also meant 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, ⁷⁹ Br, ⁸¹ Br, ¹²⁴ I, ¹²⁷ I and ¹³¹ I. Isotopically enriched compounds of formula (I) may be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein, using appropriate isotopically enriched reagents and/or intermediates.

In some embodiments, the present disclosure includes compounds of formula (I), (Ia), (IIa), (IIb), (IIc) or (IId), wherein one or more hydrogens attached to a carbon atom are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and thus, when administered to a subject, such as a mammal, particularly a human, can be used to increase the half-life of any compound of formula (I), (Ia), (IIa), (IIb), (IIc) or (IId). 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 to synthesize such compounds.

The in vivo metabolic products of the compounds described herein also fall within the scope of this document, to the extent such products are novel and not obvious over the prior art. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, novel and not obvious compounds are included that are produced by a method comprising contacting a compound with a mammal for a period of time sufficient to produce a metabolic product thereof.

The compounds of the present disclosure may be formulated as or in the form of pharmaceutically acceptable salts. Unless specified to the contrary, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

As used herein, the term "pharmaceutically acceptable" indicates that the substance or composition described is chemically and/or toxicologically compatible with the other ingredients making up the formulation and/or the individual being treated therewith.

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 specified compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salt forms contemplated include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, and the like. Pharmaceutically acceptable salts are nontoxic in the amounts and concentrations to which they are applied. The preparation of such salts can facilitate pharmacological use by changing the physical characteristics of the compound without preventing it from exerting its physiological effects. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of drugs.

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

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

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent (such as an aqueous solution or water-alcohol solution containing a suitable acid), and then separated by evaporating the solution. Therefore, if the specific compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. to treat the free base, 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 acid (such as glucuronic acid or galacturonic acid), alpha-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc. to treat the free base.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or 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, secondary and tertiary amines and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

It will also be understood that the compounds of the disclosure may exist in unsolvated forms, solvated forms (eg, hydrated forms), and solid forms (eg, crystalline or polymorphic forms), and that the disclosure is intended to encompass all such forms.

As used herein, the term "solvate" or "solvated form" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to entrap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. 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 molecules of a substance, wherein the 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.

As used herein, the terms "crystalline form", "crystalline form", "polymorphic form" and "polymorph" are used interchangeably and mean that a compound (or its salt or solvate) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors can make one crystal form dominant. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

Synthesis of compounds

The synthesis of the compound (including its pharmaceutically acceptable salt) provided herein is described in the synthesis scheme in the example. The compound provided herein can be prepared using any known organic synthesis technology and can be synthesized according to any of a variety of possible synthetic pathways, and therefore, these schemes are only illustrative and are not intended to limit other possible methods that can be used to prepare the compound provided herein. In addition, the steps in the scheme are to better illustrate and can be changed when appropriate. For the purpose of research and possible submission to the management agency, the embodiment of the compound in the example is synthesized.

The reaction for preparing the disclosed compounds can be carried out in a suitable solvent, which can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be at a temperature where the reaction is carried out, for example, at a temperature within the range of the freezing temperature of the solvent to the boiling temperature of the solvent, substantially not reacting with the starting material (reactant), intermediate or product. The specified reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the specific reaction step, the suitable solvent for the specific reaction step can be selected by a technician in the field.

The preparation of the disclosed compounds may involve the protection and deprotection of various chemical groups. The demand for protection and deprotection, and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found in, for example, T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley & Sons, Inc., New York (1999); P.Kocienski, "Protective Groups", Georg Thieme Verlag, 2003; and Peter G.M.Wuts, "Gre'ne's Protective Groups in Organic Synthesis", 5th edition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 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). Those skilled in the art can purify 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, "Journal of Combinatorial Chemistry (J. Combi. Chem.)", 2004, 6 (6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

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. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification.

Unless otherwise specified, the reactions of the present disclosure were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents with dried tubes, and the reaction flasks were usually equipped with rubber septa for the introduction of substrates and reagents via syringes. Glassware was oven-dried and/or heat-dried.

For illustrative purposes, the following examples partially show synthetic routes and key intermediates for preparing compounds of the present disclosure. It will be appreciated by those skilled in the art that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described, other starting materials and reagents can be easily replaced to provide a variety of derivatives and/or reaction conditions. In addition, many compounds prepared by the methods described below can be further adjusted according to the present disclosure using conventional chemical reactions known to those skilled in the art.

Uses of Compounds

In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which can inhibit RNA polymerase. Therefore, the compound of the present disclosure or a pharmaceutically acceptable salt thereof can be used as a medicine, and in particular can be used as a therapeutic agent or preventive agent active against various viruses. In some embodiments, the compound of the present disclosure is a therapeutic agent or preventive agent active against calicivirus, picornavirus and coronavirus.

As used herein, the term "therapy" is intended to have its ordinary meaning, i.e., to treat a disease so as to completely or partially relieve one, some or all of its symptoms, or to correct or counteract the underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, alleviation of the extent of the disease, stabilization of the disease state (i.e., no deterioration), delay or slowing of disease progression, improvement or alleviation of the disease condition, and relief (partial or complete relief), whether detectable or undetectable. "Therapy" may also mean an extension of survival compared to the expected survival without therapy. Situations requiring therapy include situations in which a condition or illness has been suffered from, as well as situations in which a condition or illness is prone to be suffered from, or in order to prevent a condition or illness. Unless there is a specific indication to the contrary, the term "therapy" also encompasses prevention. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

The term "treat" is used synonymously with "therapy." Similarly, the term "treatment" can be viewed as "administering therapy," where "therapy" is as defined herein.

As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention to prevent the development of disease and secondary prevention to temporarily or permanently protect a patient from exacerbation or worsening of the disease or development of new symptoms associated with the disease once the disease has developed.

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

In yet another aspect, the present disclosure provides 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 viral infection.

In some embodiments, the compounds of the present disclosure have good inhibitory effects on various coronaviruses. In some embodiments, the compounds of the present disclosure have good inhibitory effects on various coronaviruses and have low cytotoxicity.

In some embodiments, the compounds of the present disclosure have good inhibitory effects on various pneumonia viruses. In some embodiments, the compounds of the present disclosure have good inhibitory effects on various pneumonia viruses and have low cytotoxicity.

In some embodiments, the compounds of the present disclosure can be converted to triphosphorylated products and maintain high concentrations of the triphosphorylated products in target tissues and cells such as lung cells and respiratory epithelial cells.

Therefore, the present disclosure provides the use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating coronavirus or pneumonia virus infection.

In another aspect, the present disclosure provides 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 coronavirus infection.

In another aspect, the present disclosure provides 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 pneumonia virus infection.

Pharmaceutical composition

For administration purposes, in some embodiments, the compounds provided herein are administered as the raw chemical substance or formulated into a pharmaceutical composition.

Thus, in another aspect, provided are pharmaceutical compositions comprising one or more compounds of the present disclosure, or pharmaceutically acceptable salts thereof.

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

As used herein, the term "pharmaceutical composition" refers to a formulation containing a molecule or compound of the disclosure in a form suitable for administration to a subject.

In some embodiments, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of one or more compounds of Formula (I) to (VII) or a pharmaceutically acceptable salt thereof.

As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents an identified disease or condition, or shows a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, stature, and health; 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 experiments within the skill and judgment of the clinician.

In another aspect, provided are pharmaceutical compositions comprising one or more molecules or compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient suitable for preparing a pharmaceutical composition that is generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for veterinary use 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 carriers" and "pharmaceutically acceptable diluents".

The specific excipient used will depend on the means and purpose for which the disclosed compounds are to be administered. The solvent is generally selected based on a solvent recognized as safe by those skilled in the art to be administered to a mammal (including a human). In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc. and mixtures thereof.

In some embodiments, suitable excipients may include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; chloride); phenol, butyl alcohol, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, 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 ^™ , PLURONICS ^™ , or polyethylene glycol (PEG).

In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, slip agents, processing aids, colorants, sweeteners, aromatics, flavoring agents and other known additives to provide the best presentation of drugs (i.e., compounds disclosed herein or their pharmaceutical compositions) or to help manufacture pharmaceutical products (i.e., medicaments). Active pharmaceutical ingredients may also be coated 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 (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in coarse emulsions, respectively. Such technology is disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A., ed. (1980). "Liposomes" are vesicles comprising various types of lipids, phospholipids and/or surfactants, which are suitable for delivering drugs (compounds disclosed herein and optional chemotherapeutic agents) to mammals (including humans). The components of liposomes are typically arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

The pharmaceutical compositions provided herein may be in any form that permits administration of the composition to an individual, including but not limited to humans, and is formulated to be compatible with the intended route of administration.

A variety of approaches are considered for the pharmaceutical compositions provided herein, and therefore the pharmaceutical compositions provided herein can be supplied in bulk or unit dosage forms depending on the expected route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, lozenges, pills, capsules, soft capsules and caplets are acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions and solutions are acceptable as liquid dosage forms. For injection administration, emulsions and suspensions are acceptable as liquid dosage forms, and powders suitable for reconstitution with suitable solutions are acceptable as solid dosage forms. For inhalation administration, solutions, sprays, dry powders and aerosols can be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches can be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams and sprays can be acceptable dosage forms. For nasal or pulmonary administration, aqueous or oily solutions can be acceptable dosage forms.

The amount of active ingredient in the unit dosage form of the composition is a therapeutically effective amount and varies according to the specific treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, improves, or prevents an identified disease or condition or shows a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, stature, and health; 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 experiments within the skill and judgment of the clinician.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oral administration formulations.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated with coatings to regulate their disintegration and subsequent absorption of active ingredients in the gastrointestinal tract, or to improve their stability and/or appearance, in either case, conventional coating agents and procedures well known in the art are used.

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

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 fine powder form and one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic; a dispersant or wetting agent, such as lecithin, or a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxyhexadecanoic acid), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitan monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives (for example, ethyl or propyl p-hydroxybenzoate), antioxidants (for example, ascorbic acid), coloring agents, flavoring agents and/or sweetening agents (for example, sucrose, saccharin or aspartame).

In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of an oily suspension, which generally contains a suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspension can also contain a thickener, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners (such as those stated above) and flavoring agents can be added to provide a palatable oral formulation. These compositions can be preserved by adding an antioxidant (such as ascorbic acid).

In certain embodiments, the pharmaceutical composition 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 emulsifiers may be, for example, naturally occurring gums, such as gum arabic or gum tragacanth; naturally occurring phospholipids, such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of the partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners, flavorings, and preservatives.

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

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for injectable administration.

In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. The acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be used conventionally as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injectables.

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

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

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

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

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which can 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, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

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

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 therefore included in the present disclosure. Such excipients and carriers are described, for example, in "Remington's Pharmaceutical Sciences" Mark Publishing Company, New Jersey (191), "Remington: The Science and Practice of Pharmacy", University of the Sciences in Philadelphia, 21st edition, LWW (2005), which are incorporated herein by reference.

In certain embodiments, the pharmaceutical composition of the present disclosure can be formulated into a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for use in human individuals and other mammals in a single dose, each unit containing a predetermined amount of active substance calculated to be combined with a suitable pharmaceutical excipient to produce a desired therapeutic effect. The amount of the compound provided herein in a unit dosage form will vary according to the condition to be treated, the individual to be treated (e.g., age, body weight, and response of the individual), a specific route of administration, the actual compound administered, and its relative activity and the severity of individual symptoms.

In some embodiments, the dosage of the pharmaceutical composition of the present disclosure can be 0.001-1000 mg/kg body weight/day, for example, 0.001-1000 mg/kg body weight/day, 0.001-900 mg/kg body weight/day, 0.001-800 mg/kg body weight/day, 0.001-700 mg/kg body weight/day, 0.001-600 mg/kg body weight/day, 0.001-500 mg/kg body weight/day. day, 0.001-400 mg/kg body weight/day, 0.001-300 mg/kg body weight/day, 0.001-200 mg/kg body weight/day, 0.001-100 mg/kg body weight/day, 0.001-50 mg/kg body weight/day, 0.001-40 mg/kg body weight/day, 0.001-30 mg/kg body weight/day, 0.001-20 mg/kg body weight/day, 0.001-10 mg /kg body weight/day, 0.001-5 mg/kg body weight/day, 0.001-1 mg/kg body weight/day, 0.001-0.5 mg/kg body weight/day, 0.001-0.4 mg/kg body weight/day, 0.001-0.3 mg/kg body weight/day, 0.001-0.2 mg/kg body weight/day, 0.001-0.1 mg/kg body weight/day, 0.005-0.1 mg/kg body weight/day, 0.01 In some cases, the dosage amount below the lower limit of the aforementioned range may be more than enough, and in other cases, a larger dose can be used without causing any harmful side effects, provided that the larger dose is first divided into several small doses for use throughout the day. For additional information on routes of administration and dosing regimens, 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.

In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration. In some embodiments, the unit dose for oral administration contains one or more compounds provided herein in the following amounts: about 1 mg to about 1000 mg, for example, 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 about 1000 mg. In some embodiments, the dosage unit may be administered to an individual 1 to 6 times daily, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, etc. In some embodiments, the dosage unit may be administered to an individual 1 to 6 times daily, depending on the severity of the individual's symptoms.

In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration in treatments of 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.

In some embodiments, pharmaceutical compositions of the present disclosure are formulated for parenteral administration, such as via intravenous, subcutaneous or intramuscular injection. In some embodiments, the unit dose for parenteral administration contains one or more compounds provided herein in an amount of about 0.1 mg to about 500 mg of one or more 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 about 0.5 mg to about 100 mg, about 150 mg to about 200 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 500 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, etc.

In some embodiments, pharmaceutical compositions intended for administration by injection may be prepared by combining one or more compounds of the present disclosure with sterile distilled water, sesame oil, peanut oil, or propylene glycol aqueous solution to form a solution. In some embodiments, the pharmaceutical composition may include a surfactant or other dissolving excipient, which is added to facilitate the formation of a homogeneous solution or suspension. In some embodiments, the pharmaceutical composition may further include one or more additional agents selected from the group consisting of a wetting agent, a suspending agent, a preservative, a buffer, and an isotonic agent.

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

In another aspect, a veterinary composition is also provided, comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. A veterinary carrier is a substance suitable for the purpose of administering the composition, and may 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.

Pharmaceutical compositions or veterinary compositions can be packaged in a variety of ways depending on the method for administering the drug. For example, the article for distribution may include a container in which a composition of 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 may also include an anti-disassembly assembly to prevent easy access to the contents of the package. In addition, a label describing the contents of the container is attached to the container. The label may also include appropriate warnings. The composition may be packaged in unit dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored under a freeze-drying (lyophilized) condition, requiring only the addition of a sterile liquid carrier (e.g., water) for injection immediately before use. Ready-to-use injection solutions and suspensions are prepared by sterile powders, granules, and lozenges of the types described previously.

Treatment

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.

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 other embodiments, the RNA virus is a positive-sense RNA virus or a negative-sense RNA virus or a double-sense RNA virus.

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 Deltavirus.

In certain embodiments, the viral infection is from a virus selected from the group consisting of lymphocytic choriomeningitis virus, coronavirus, HIV, SARS, poliovirus, rhinovirus 16, hepatitis A, Norwalk virus, yellow fever virus, West Nile virus, hepatitis C virus, dengue 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, Hanta virus, Crimean-Congo hemorrhagic fever virus, influenza, hepatitis D virus, enterovirus 71, coxsackievirus, and norovirus.

In certain embodiments, the viral infection is a coronavirus infection.

In another embodiment, 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).

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

In some embodiments, the viral infection is a pneumovirus infection.

In certain embodiments, the pneumonia virus is human respiratory syncytial virus.

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 other embodiments, the DNA virus is a positive-sense DNA virus or a negative-sense DNA virus or an ambisense DNA virus.

In certain embodiments, the virus is Myoviridae, Brachyviridae, Dolichoviridae, Heteroherpesviridae, Herpesviridae (including human herpes virus and varicella zoster virus), Maloherpesviridae, Lipoviridae, Parvoviridae, Adenoviridae, Bottleviridae, Vesciviridae, Afriswine fever virus (including African swine fever virus), Baculoviridae, Sikandaviridae, Rhabdoviridae, Coverbacteriophage, Microspindle phage, Spheroviridae, Titvoviridae, Viridae, Hypersagittaviridae, Iridoviridae, Marseilleviridae, Mimiviridae, Nudiviridae, Clonotiridae, Pandoraviridae, Papillomaviridae, Phycodnaviridae, Blastophage, Polydnaviruses, Polyomaviridae (including simian virus 40, JC virus, BK virus), Poxviridae (including vaccinia and smallpox), Globuloviridae, Multilaminaviridae, Tuliviridae, Denodnaviruses, Haloterminal protein viruses or Razeviruses.

In some embodiments, the methods described herein can inhibit viral replication, propagation, replication, assembly or release, or minimize the expression of viral proteins. In one embodiment, described herein are methods of inhibiting viral propagation, methods of inhibiting viral replication, methods of minimizing the expression of viral proteins, or methods of inhibiting viral release, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a patient infected with the virus, and/or contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof with a cell infected with the virus.

In additional aspects, the present disclosure provides a method for inhibiting RNA polymerase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

Combination therapy

The compounds of the present disclosure may also be used in combination with one or more additional therapeutic agents or preventive agents. As such, a method for treating a viral infection in a subject in need thereof is also provided herein, the method comprising administering to the subject a compound disclosed herein as a first active ingredient, and a therapeutically effective amount of one or more additional therapeutic agents or preventive agents as a second active ingredient. Therefore, a pharmaceutical composition is also provided, the pharmaceutical composition comprising one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof as a first active ingredient, and further comprising a second active ingredient.

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 a different class or group.

In some embodiments, the second active ingredient has complementary activities to the compounds provided herein such that they do not adversely affect each other. The ingredients are preferably present in combination in amounts effective for the intended purpose.

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

In some embodiments, the second active ingredient is an antibiotic. In some embodiments, the antibiotic can 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, cefdroxil, cefazolin, cephalothin, cefaclor, cefmandole, 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, ceftibuten, ceftizoxime, ceftriaxone, cefoxotin, and streptomycin. In some embodiments, the antibiotic is azithromycin.

In some embodiments, the second active ingredient can be a protease inhibitor. In some embodiments, the protease inhibitor can be selected from nafamostat, camostat, gabexate, ε-aminocaproic acid, aprotinin, amprenavir, indinavir, nelfinavir, namatevir, ensetvir, EDP-235, PBI-0451, senotevir, leretevir, atetevir, ritonavir and saquinavir.

In some embodiments, the second active ingredient can be an antiviral agent. In some embodiments, the antiviral agent can be selected from ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbavir, ledipasvir, glecaprevir, sofosbuvir, bicagvir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, parivrevir, simeprevir , daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, alaviroc, anti-goat antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methylthiazone, MK-2048, nelfinavir, nevirapine, nitazoxanide, ritonavir (norvir), plerixafor, PRO 140, raltegravir, pyramididine, saquinavir, telbivudine, TNX-355, valacyclovir, remidevir, ZX-7101A, baloxavir, zirisovir, monoupravir, GS-5806, VIR-576, and zalcitabine.

In some embodiments, the second active ingredient can be an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent can be selected from antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium cromoglycate, 5-lipoxygenase inhibitors (zyflo), DPI antagonists, DP2 antagonists, PI3Kδ inhibitors, GGK inhibitors, LP (lysophospholipid) inhibitors Preparations or FLAP (5-lipoxygenase activating protein) inhibitors, bronchodilators (e.g., muscarinic antagonists, beta-2 agonists), methotrexate and similar agents; monoclonal antibody therapy, such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapy, such as etanercept and similar agents; antigen non-specific immunotherapy (e.g., interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents), suitable anti-infective agents (including antibiotics, antifungals, anthelmintics, antimalarials, antiprotozoals and anti-tuberculosis agents).

In some embodiments, the second active ingredient can be an immunomodulator. In some embodiments, the immunomodulator can 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 relalizumab, 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 R0 7009789), anti-CD47 therapeutics (including but not limited to Hu5F9-G4), anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists (including but not limited to ADU-S100, MK-1454, ASA404 or amide benzimidazole), anthracyclines (including but not limited to doxorubicin or mitoxantrone), demethylating agents (including but not limited to azacytidine or decitabine), other immunomodulatory therapeutics (including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone or dexamethasone). In some embodiments, the additional therapeutic agent is a p2-adrenergic receptor agonist, including but not limited to vilanterol, salmeterol, salbutamol, formoterol, salmethamine, fenoterol, carmoterol, etanterol, nalminterol, clenbuterol, pirbuterol, flubuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, such as the xinafoate (1-hydroxy-2-naphthoic acid) salt of salmeterol, the sulfate salt of salbutamol, or the fumarate salt of formoterol.

In some embodiments, the second active ingredient can be a kinase inhibitor. In some embodiments, the kinase inhibitor can 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.

The present disclosure also includes the following embodiments:

Item 1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating viral infection:

in

Base is a naturally occurring or modified pyrimidine base or purine base;

Q is CH ₂ , CHD or CD ₂ ;

R ¹ is 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 ;

each of R ²¹ , R ²² , R ³¹ , R ³² and R ⁴ is independently selected from the group consisting of hydrogen, deuterium, 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 and -S(O) ₂ R ^a ;

Each R ⁵ is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ;

R ⁶ is -OX;

X is hydrogen or a pharmaceutically acceptable cation;

^R7 is

R ⁸ is selected from the group consisting of hydrogen, C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n -, and ^Re OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -, each of which is optionally substituted with one or more R ^b ;

R ⁹ is selected from the group consisting of C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n -, and Re ^OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -, each of which is optionally substituted with one or more R ^b ;

Each ^Ra is independently selected from hydrogen, halogen or alkyl;

Each R ^b is independently selected from halogen, hydroxy, cyano, amino, alkyl or alkoxy;

Each ^{Re is} independently selected from hydrogen or alkyl;

Each m, n or p is independently an integer from 0 to 20;

Provided that when X is hydrogen, then

a) R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl; or

b) R ⁸ is C _1-18 alkyl or C _2-18 alkenyl, and R ⁹ is selected from C _7-25 alkyl or C _7-25 alkenyl.

Item 2. The use as described in Item 1, wherein:

^R1 is selected from hydrogen, hydroxy, cyano, azido, alkyl or haloalkyl; and/or

Each of R ²¹ , R ²² , R ³¹ , R ³² and R ⁴ is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, azido, alkyl, haloalkyl or -OC(O)R ^a ; and/or

^Ra is alkyl; and/or

^R4 is selected from hydrogen, deuterium, halogen, cyano, azido or haloalkyl; and/or

Each R ⁵ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _6-12 aryl, 5- to 12-membered heteroaryl, (C _1-3 alkyl)(C _3-12 cycloalkyl), (C _1-3 alkyl)(3- to 12-membered heterocyclyl), (C _1-3 alkyl)(C _6-12 aryl), (C _1-3 alkyl)(5- to 12-membered heteroaryl), and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ; and/or

X is selected from hydrogen, metal ions, -NH ₄ ⁺ or protonated organic amines; and/or

^R8 is hydrogen, _C1-14 alkyl or _C2-14 alkenyl, and ^R9 is selected from _C11-25 alkyl or _C11-25 alkenyl.

Item 3. The use as described in Item 2, wherein:

^R1 is cyano;

Each of R ²¹ , R ²² , R ³¹ , and R ³² is selected from hydrogen, deuterium, halogen, hydroxyl, alkyl, or —OC(O)R ^a ;

^Ra is a methyl group;

^R4 is hydrogen;

one R ⁵ is hydrogen, and the other R ⁵ is selected from C _1-6 alkyl, C _6-12 aryl, (C _1-3 alkyl)(C _6-12 aryl), (C _1-3 alkyl)(5- to 12-membered heteroaryl), or a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ;

X is selected from hydrogen, K ⁺ , Ca ²⁺ , Na ⁺ or NH ₄ ⁺ ;

^R8 is hydrogen or _C1-3 alkyl, and ^R9 is _C11-25 alkyl.

Item 4. The use as described in Item 3, wherein one R ⁵ is hydrogen and the other R ⁵ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl optionally substituted by one or more R ^b , (C _1-3 alkyl) (C _6-12 aryl) optionally substituted by one or more R ^b , (C _1-3 alkyl) (5-membered to 12-membered heteroaryl) optionally substituted by one or more R ^b , or a natural amino acid side chain, wherein R ^b is halogen, hydroxyl or alkoxy.

Item 5. The use as described in Item 4, wherein one R ⁵ is hydrogen, and the other R ⁵ is selected from the group consisting of:

Item 6. The use as described in Item 3, wherein R ⁸ is hydrogen and R ⁹ is C _13-25 alkyl.

Item 7. The use as described in Item 6, wherein R ⁸ is hydrogen and R ⁹ is C _15-19 alkyl.

Item 8. The use as described in Item 3, wherein R ⁸ is a C _1-3 alkyl group, and R ⁹ is a C _13-25 alkyl group.

Item 9. The use as described in Item 8, wherein R ⁸ is methyl or ethyl, and R ⁹ is C _13-25 alkyl.

Item 10. The use as described in Item 2, wherein both R ⁵ are methyl.

Item 11. The use as described in any one of Items 1 to 10 above, wherein the Base is and yes Item 12. The use as described in Item 11, wherein the Base is and yes

Item 13. The use according to Item 1, wherein the compound has a chemical formula selected from the group consisting of:

Item 14. The use as described in Item 13, wherein R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl.

Item 15. The use as described in Item 14, wherein R ⁸ is hydrogen and R ⁹ is C _15-19 alkyl.

Item 16. The use as described in Item 1, wherein the compound is selected from Table 1.

Item 17. The use as described in Item 1, wherein the virus is SARS-CoV-2 or respiratory syncytial virus.

Item 18. A pharmaceutical composition comprising the compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Item 19. The pharmaceutical composition as described in Item 17, which is formulated for oral administration, injection administration, nasal administration or pulmonary administration.

Item 20. A compound having formula (I):

or a pharmaceutically acceptable salt thereof,

in

Base is a naturally occurring or modified pyrimidine base or purine base;

Q is CH ₂ , CHD or CD ₂ ;

R ¹ is 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 ;

each of R ²¹ , R ²² , R ³¹ , R ³² and R ⁴ is independently selected from the group consisting of hydrogen, deuterium, 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 and -S(O) ₂ R ^a ;

Each R ⁵ is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ;

^R6 is -OX;

X is hydrogen or a pharmaceutically acceptable cation;

^R7 is

R ⁸ is selected from the group consisting of hydrogen, C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n -, and ^Re OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -, each of which is optionally substituted with one or more R ^b ;

R ⁹ is selected from the group consisting of C _1-26 alkyl, C _2-26 alkenyl, CH ₃ (CH ₂ ) _m O(CH ₂ ) _n -, and Re ^OCH ₂ (CH ₂ OCH ₂ ) _p CH ₂ -, each of which is optionally substituted with one or more R ^b ;

Each ^Ra is independently selected from hydrogen, halogen or alkyl;

Each R ^b is independently selected from halogen, hydroxy, cyano, amino, alkyl or alkoxy;

Each ^{Re is} independently selected from hydrogen or alkyl;

Each m, n or p is independently an integer from 0 to 20;

Provided that when X is hydrogen, then

a) R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl; or

b) R ⁸ is C _1-18 alkyl or C _2-18 alkenyl, and R ⁹ is selected from C _7-25 alkyl or C _7-25 alkenyl.

Item 21. The compound according to Item 20, or a pharmaceutically acceptable salt thereof, wherein:

^R1 is selected from hydrogen, hydroxy, cyano, azido, alkyl or haloalkyl; and/or

Each of R ²¹ , R ²² , R ³¹ , R ³² and R ⁴ is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, azido, alkyl, haloalkyl or -OC(O)R ^a ; and/or

^Ra is alkyl; and/or

^R4 is selected from hydrogen, deuterium, halogen, cyano, azido or haloalkyl; and/or

Each R ⁵ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _6-12 aryl, 5- to 12-membered heteroaryl, (C _1-3 alkyl)(C _3-12 cycloalkyl), (C _1-3 alkyl)(3- to 12-membered heterocyclyl), (C _1-3 alkyl)(C _6-12 aryl), (C _1-3 alkyl)(5- to 12-membered heteroaryl), and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ; and/or

X is selected from hydrogen, metal ions, -NH ₄ ⁺ or protonated organic amines; and/or

^R8 is hydrogen, _C1-14 alkyl or _C2-14 alkenyl, and ^R9 is selected from _C11-25 alkyl or _C11-25 alkenyl.

Item 22. The compound according to Item 21, or a pharmaceutically acceptable salt thereof, wherein:

^R1 is cyano;

Each of R ²¹ , R ²² , R ³¹ , and R ³² is selected from hydrogen, deuterium, halogen, hydroxyl, alkyl, or —OC(O)R ^a ;

^Ra is a methyl group;

^R4 is hydrogen;

one R ⁵ is hydrogen, and the other R ⁵ is selected from C _1-6 alkyl, C _6-12 aryl, (C _1-3 alkyl)(C _6-12 aryl), (C _1-3 alkyl)(5- to 12-membered heteroaryl), or a natural amino acid side chain, each of which is optionally substituted with one or more R ^b ;

X is selected from hydrogen, K ⁺ , Ca ²⁺ , Na ⁺ or NH ₄ ⁺ ;

^R8 is hydrogen or _C1-3 alkyl, and ^R9 is _C11-25 alkyl.

Item 23. A compound as described in Item 22, or a pharmaceutically acceptable salt thereof, wherein one R ⁵ is hydrogen and the other R ⁵ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl optionally substituted by one or more R ^b , (C _1-3 alkyl) (C _6-12 aryl) optionally substituted by one or more R ^b , (C _1-3 alkyl) (5-membered to 12-membered heteroaryl) optionally substituted by one or more R ^b , or a natural amino acid side chain, wherein R ^b is halogen, hydroxyl or alkoxy.

Item 24. The compound as described in Item 23, or a pharmaceutically acceptable salt thereof, wherein one R ⁵ is hydrogen, and the other R ⁵ is selected from the group consisting of:

Item 25. The compound as described in Item 22, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen and R ⁹ is C _13-25 alkyl.

Item 26. The compound as described in Item 25, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen and R ⁹ is C _15-19 alkyl.

Item 27. The compound as described in Item 22, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a C _1-3 alkyl group and R ⁹ is a C _13-25 alkyl group.

Item 28. The compound as described in Item 27, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is methyl or ethyl, and R ⁹ is C _13-25 alkyl.

Item 29. The compound as described in Item 21, or a pharmaceutically acceptable salt thereof, wherein both R ⁵ are methyl.

Item 30. The compound as described in any one of Items 20 to 29 above, or a pharmaceutically acceptable salt thereof, wherein the Base is and yes Item 31. The compound as described in Item 30, or a pharmaceutically acceptable salt thereof, wherein the Base is and yes Item 32. The compound according to Item 20, or a pharmaceutically acceptable salt thereof, wherein the compound has a chemical formula selected from the group consisting of:

Item 33. The compound as described in Item 32, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl.

Item 34. The compound as described in Item 33, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen and R ⁹ is C _15-19 alkyl.

Item 35. The compound as described in Item 20, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1.

Item 36. A pharmaceutical composition comprising the compound according to any one of Items 20 to 35 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Item 37. The pharmaceutical composition as described in Item 36, which is formulated for oral administration, injection administration, nasal administration or pulmonary administration.

Item 38. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 35 or a pharmaceutical composition according to any one of claims 36-37 in the manufacture of a medicament for treating viral infection.

Item 39. The use as described in claim 38, wherein the virus is SARS-CoV-2 or respiratory syncytial virus.

Example

The following examples are included for illustrative purposes. However, it should be understood that these examples do not limit the present disclosure and are intended only to propose methods for implementing the present disclosure. Those skilled in the art will recognize that the chemical reactions described can be easily adapted to prepare many other compounds of the present disclosure, and alternative methods for preparing 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 utilizing other suitable reagents and building blocks known in the art in addition to those described, and/or by making conventional modifications to reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to be applicable to the preparation of other compounds of the present disclosure.

Example 1. Synthesis of intermediates

1.1 Synthesis of intermediate 1a:

Under _N2 atmosphere, a solution of compound s-1 (50 g, 0.1718 mol, 1 eq.) in TMP (400 mL) was stirred at 0°C for 15 min. _POCl3 (86.18 g, 0.5670 mol, 3.3 eq.) was added dropwise to the above mixture at 0°C over 30 min. The resulting mixture was stirred at 25°C for 1.5 h under _N2 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 give 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.

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

¹ H NMR (400MHz, D ₂ O) δ8.07 (s, 1H), 7.35-7.33 (m, 1H), 7.12-7.11 (m, 1H), 4.91-4.90 (m, 1H), 4.50 (d, J＝4.6Hz,1H),4.41-4.39(m,1H),4.14-4.10(m,2H).

1.2 Synthesis of intermediate 1b:

Step 1: Synthesis of compound 1b-2

To a solution of compound 1b-1 (20.0 g, 96.5 mmol, 1.0 equiv) in ACN (200 mL) was added DBDMH (15.2 g, 53.1 mmol, 0.55 equiv) under _N2 at -30°C, and the mixture was stirred at -20°C for 2 hours. 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 Na2SO4} , filtered and evaporated in vacuo to give a crude product. The crude product was purified by FCC (1% to 15% EtOAc in PE) to give compound 1b-2 (27.1 g, 98%) as a light yellow oil.

LCMS: m/z (M+H) ⁺ = 286.0

¹ H NMR (400MHz, 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).

Step 2: Synthesis of compound 1b-3

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

LCMS: m/z = 186.0

¹ H NMR (400MHz, DMSO-d ₆ ): δppm=7.24 (d, J=2.0Hz, 1H), 6.92 (d, J=2.0Hz, 1H).

Step 3: Synthesis of compound 1b-4

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) under N ₂ at 25°C, and the mixture was stirred at 78°C for 16 hours. The reaction mixture was filtered, and the filter cake was washed with EtOH (100 mL×2), and the filtrate was evaporated in vacuo to give a 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 light yellow solid.

LCMS: m/z = 213.0

¹ H NMR (400MHz, DMSO-d ₆ ): δppm=7.84(br,2H),7.82(s,1H),7.81(d,J=1.6Hz,1H),6.97(d,J=1.6Hz,1H ).

Step 4: Synthesis of compound 1b-5

D ₂ O (10 mL) was added to a solution of compound 1b-4 (21.1 g, 99.0 mmol) in THF (200 mL), which was then concentrated to dryness three times. Afterwards, THF (200 mL) and D ₂ O (10 mL) were added to the residue under N ₂ , and then Pd (dppf) Cl ₂ (7.2 g, 9.9 mmol) and TMEDA (2.3 g, 19.8 mmol) were added to the solution at 25° C. The reaction was stirred at 25° C. for 0.5 hours. Afterwards, the solution was cooled to 0° C., NaBD ₄ (8.3 g, 198.0 mmol) was added to the solution, and the reaction was stirred at 25° C. for 17 hours. TLC (PE: EA = 1: 1) showed that compound 1b-4 was completely consumed, and a new spot was 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 Na2SO4} and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc in PE 10%-50%) to give compound 1b-5 (7.5 g, 56.3%) as a yellow solid.

LCMS: m/z = 136.2

¹ H NMR (400MHz, DMSO-d ₆ ): δ: 7.80 (s, 1H), 7.70 (s, 2H), 7.61 (d, J = 1.6Hz, 1H), 6.86 (d, J = 1.6Hz, 1H ).

Step 5: Synthesis of compound 1b-6

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. NIS (6.7 g, 29.5 mmol, 1.0 equiv) was added to the above reaction under _N2 atmosphere. The reaction was stirred at -5°C to 5°C for 2 hours. TLC showed that the reaction was complete. The reaction mixture was poured into a NaOH aqueous solution (400 mL, 1 M) and stirred for another 30 minutes. The crushed solid was filtered out, and the solid was washed with _H2O (50 mL), PE (60 mL), and dried in vacuo to give compound 1b-6 as a solid (6 g, 77%).

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

Step 6: Synthesis of Compound 1b-7

Under _N2 atmosphere, TMSCl (2.4g, 21.7mmol, 2.2 equivalents) was added to a solution of compound 1b-6 (2.6g, 9.9mmol, 1.0 equivalents) in THF (40mL), and the reaction was stirred at room temperature for 40 minutes. The reaction mixture was cooled to -5°C to 5°C, PhMgCl (11.8mL, 2M, 23.6mmol) was added to the above reaction mixture, and the temperature was kept at -5°C to 5°C for another 1.5 hours. Then i-PrMgCl.LiCl (9.9mL, 12.9mmol, 1.3 equivalents) was added to the above reaction mixture, and stirred for another 15 minutes after addition. At -20°C to -15°C, a solution of compound A (4.1g, 9.9mmol, 1.0 equivalents) in THF (40mL) 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, and 1M HCl was added to the reaction to adjust pH＝2-3. EtOAc was added, the two phases were separated, and the organic phase was washed twice with HCl (1M). The organic phase was then washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was purified by column (PE:EA＝2:1) to give compound 1b-7 (2.0 g) as a solid.

Step 7: Synthesis of Compound 1b-8

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. TMSCN (1.4 g, 14.4 mmol, 4.0 equiv) was then added. After 10 minutes, TLC (PE: EA = 1: 1) showed that the reaction was complete. TEA was then added to quench the reaction, followed by 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 SO ₄ , filtered and concentrated in vacuo to give a crude product, which was purified by column to give compound 1b-8 (1.4 g, 69%) as a solid.

Step 8: Synthesis of Compound 1b-9

To a solution of compound 1b-8 (1.6 g, 2.8 mmol, 1.0 equiv.) in DCM (23 mL) was added BCl ₃ (11.1 mL, 11.1 M) at -78°C. The reaction mixture was stirred at -40°C for 2 hours. MeOH (10 mL) was added to quench the reaction, and then TEA was added to pH 8-9. The solution was concentrated. Water (100 mL) was then added, the aqueous phase was washed with DCM, and the aqueous phase was concentrated to 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.

¹ H NMR (400MHz, DMSO-d ₆ )δ:7.9-787(m,3H),6.86(s,1H),6.07(s,1H),5.15(s,1H),4.90-4.87(m,1H ),4.62-4.59(m,1H),4.03-4.01(m,1H),3.94-3.90(m,1H),3.63-3.46(m,2H).

Step 9: Synthesis of compound 1b:

Under _N2 atmosphere, a solution of compound 1b-9 (50.0 g, 0.1718 mol, 1 eq.) in TMP (400 mL) was stirred at 0°C for 15 min. _POCl3 (86.2 g, 56.7 mmol, 3.3 eq.) was added dropwise to the above mixture at 0°C over 30 min. The resulting mixture was stirred at 25°C for 1.5 h under _N2 atmosphere. The reaction was quenched with ice water at 0°C. The resulting mixture was concentrated under vacuum. The crude product was precipitated by adding acetonitrile (3 L). The precipitated solid was collected by filtration to give intermediate 1b (50.0 g, 134.8 mmol, 78%) as a light yellow solid.

LCMS: m/z = 373

Example 2. Synthesis of compounds

2.1 Synthesis of compound 1

Step 1: Synthesis of compound 1-3:

Compound 1-2 (478 mg, 5.38 mmol, 1 eq.) and PTSA (1.11 g, 6.45 mmol, 1.2 eq.) were added to a mixture of compound 1-1 (1 g, 5.38 mmol, 1 eq.) in toluene (20 mL), and the mixture was stirred at 130 ° C for 16 hours. The reaction mixture was quenched with saturated NaHCO ₃ and extracted with EA (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 1-3 (0.98 g, 71%) as a white solid.

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

¹ H NMR (400MHz, CDCl3) δ4.10-4.06(m,2H),3.52-3.50(m,1H),1.63-1.57(m,2H),1.34-1.24(m,21H),0.86(t, J＝6.7Hz,3H).

Step 2: Synthesis of compound 1:

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

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

¹ H NMR (400MHz, CD ₃ OD) δ7.85(s,1H),6.99-6.86(m,2H),4.81-4.80(m,1H),4.33-4.26(m,1H),4.21-4.19( m,1H),4.09-3.85(m,4H),3.75-3.72(m,1H),1.57-1.55(m,2H),1.25-1,18(m,21H),0.87(t,J＝6.7 Hz,3H).

The following compounds were synthesized according to the same procedure as compound 1, except that different starting materials or intermediates were used:

Compound 2:

LCMS: m/z＝667.4[M+1] ⁺ ; m/z＝665.4[M-1] ^-

¹ H NMR (400MHz, CD ₃ OD) δ7.85 (s, 1H), 6.95 (d, J = 4.8Hz, 1H), 6.87 (d, J = 4.8Hz, 1H), 4.81-4.78 (m, 1H ),4.30-4.29(s,1H),4.22-4.19(m,1H),4.03-3.94(m,4H),3.74-3.72(m,1H),1.57-1.55(m,2H),1.29-1.24 (m,26H),1.19(d,J＝6.7Hz,3H),0.88(t,J＝6.7Hz,3H).

Compound 3:

LCMS: m/z＝695.50[M+1] ⁺ ; m/z＝693.30[M-1] ^-

¹ H NMR (400MHz, CD ₃ OD) δ7.85 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.87 (d, J = 4.6Hz, 1H), 4.83-4.81 (m, 1H ),4.30(t,J＝4.3Hz,1H),4.20(t,J＝5.2Hz,1H),4.05-3.93(m,4H),3.78-3.70(m,1H),1.60-1.53(m, 2H),1.35-1.25(m,30H),1.19(d,J＝7.1Hz,3H),0.87(t,J＝6.8Hz,3H).

Compound 4:

LCMS: m/z＝751.50[M+1] ⁺ ; m/z＝749.25[M-1] ^-

¹ HNMR (400MHz, CD ₃ OD) δ7.85 (s, 1H), 6.96 (d, J = 4.5Hz, 1H), 6.88 (d, J = 4.5Hz, 1H), 4.82-4.81 (m, 1H) ,4.30(d,J＝4.6Hz,1H),4.20(t,J＝5.1Hz,1H),4.07-3.89(m,4H),3.75-3.71(m,1H),1.58-1.56(m,2H ),1.26-1.25(m,38H),1.18(d,J＝6.7Hz,3H),0.88(t,J＝6.7Hz,3H).

Compound 5:

LCMS:[MS+1]=709.45,[MS-1]=707.15.

¹ H NMR (400MHz, CD ₃ OD) δ7.84 (s, 1H), 6.94 (d, J = 4.6Hz, 1H), 6.86 (d, J = 4.6Hz, 1H), 4.82 (d, J = 5.4 Hz,1H),4.31(q,J＝4.3Hz,1H),4.21(t,J＝5.2Hz,1H),4.07-3.98(m,3H),3.97-3.90(m,1H),1.63-1.55 (m,2H),1.36(s,3H),1.35(s,3H),1.29-1.23(m,30H),0.87(t,J＝6.8Hz,3H).

Compound 6:

LCMS:[MS+1]=723.55,[MS-1]=721.30.

¹ H NMR (400MHz, CD ₃ OD) δ7.88 (s, 1H), 6.99 (d, J = 4.7Hz, 1H), 6.95 (d, J = 4.8Hz, 1H), 4.85-4.81 (m, 1H ),4.22-4.20(m,1H),4.19-4.17(m,1H),4.05-4.00(m,4H),3.66-3.64(m,1H),1.58-1.56(m,2H),1.28-1.25 (m,34H),1.65-1.20(m,3H),0.88(t,J=6.6Hz,3H).

Compound 11:

LCMS:[MS+1]＝771.55,[MS-1]＝769.30

¹ H NMR (400MHz, CD3OD) δ7.84 (s, 1H), 7.20-7.14 (m, 2H), 7.14-7.07 (m, 3H), 6.97 (d, J = 4.7Hz, 1H), 6.92 (d ,J＝4.6Hz,1H),4.79(d,J＝5.2Hz,1H),4.30-4.24(m,1H),4.18(t,J＝ 5.3Hz,1H),4.02-3.90(m,3H),3.90-3.85(m,2H),2.94(dd,J＝11.1,5.4Hz,1H),2.81(dd,J＝11.4,7.8Hz,1H ),1.45-1.37(m,2H),1.29-1.18(m,30H),0.87(t,J=6.6Hz,3H).

Compound 12:

LCMS: [MS+1]=799.7, [MS-1]=797.4.

¹ H NMR (400MHz, methanol- _{d 4} ) δ7.84 (s, 1H), 7.19-7.15 (m, 2H), 7.13-7.08 (m, 3H), 6.98 (d, J = 4.6Hz, 1H), 6.93(d,J＝4.6Hz,1H),4.79(d,J＝5.3Hz,1H),4.27(d,J＝4.8Hz,1H),4.18(t,J＝5.2Hz,1H),4.00- 3.86(m,5H),2.96-2.91(m,1H),2.83-2.81(m,1H),1.41-1.37(m,2H),1.30-1.26(m,34H),0.88(t,J＝6.6 Hz,3H).

Compound 13:

LCMS: [MS-1] = 755.30.

¹ H NMR (400MHz, methanol-d ₄ ) δ7.91-7.85(m,1H),7.33-7.31(m,2H),7.28-7.14(m,3H),7.07-6.91(m,2H),4.85 -4.70(m,3H),4.20-3.90(m,5H),1.46(br s,2H),1.28-1.24(m,30H),0.88(t,J＝6.7Hz,3H).

Compound 14:

LCMS:[MS+1]=785.45,[MS-1]=783.35.

¹ H NMR (400MHz, methanol- _{d 4} ) δ7.88 (d, J = 4.9 Hz, 1H), 7.46-7.32 (m, 2H), 7.26-7.16 (m, 3H), 7.01-6.92 (m, 2H) ),4.79-4.68(m,3H),4.20(d,J＝5.0Hz,1H),4.10-4.01(m,2H),3.98-3.97(m,1H),3.88(br s,1H),1.47 (br s,2H),1.26(br s,34H),0.88(t,J＝6.6Hz,3H).

Compound 15:

LCMS:[MS+1]=751.40,[MS-1]=749.35.

¹ H NMR (400MHz, CD ₃ OD) δ7.89 (s, 1H), 7.00 (d, J = 4.6Hz, 1H), 6.96 (d, J = 4.7Hz, 1H), 4.80 (d, J = 5.3 Hz,1H),4.32-4.26(m,1H),4.18(t,J＝5.3Hz,1H),4.11-4.02(m,2H),4.01-3.95(m,2H),3.60-3.40(m, 1H),1.90-1.75(m,1H),1.60-1.52(m,2H),1.28-1.24(m,34H),0.90-0.84(m,9H).

Compound 16:

LCMS:[MS+1]＝737.45,[MS-1]＝735.35

¹ H NMR (400MHz, methanol- _{d 4} ) δ7.84 (s, 1H), 6.94 (d, J = 4.6Hz, 1H), 6.86 (d, J = 4.6Hz, 1H), 4.83-4.80 (m, 1H),4.31(t,J＝4.5Hz,1H),4.21(t,J＝5.2Hz,1H),4.07-4.01(m,3H),3.98-3.91(m,1H),1.61-1.55(m ,2H),1.36(s,3H),1.35(s,3H),1.26(br s,34H),0.90(t,J＝6.6Hz,3H)

Compound 17:

LCMS: [MS+1]=723.35, [MS-1]=721.40.

¹ H NMR (400MHz, CD ₃ OD) δ7.89 (s, 1H), 7.00 (d, J = 4.6Hz, 1H), 6.97 (d, J = 4.6Hz, 1H), 4.79 (d, J = 5.3 Hz,1H),4.32-4.27(m,1H),4.19(t,J＝5.3Hz,1H),4.12-4.04(m,2H),4.02-3.95(m,2H),3.58-3.47(m, 1H),1.96-1.86(m,1H),1.61-1.52(m,2H),1.28-1.23(m,30H),0.90-0.84(m,9H).

2.2 Synthesis of compound 10:

Step 1: Synthesis of compound 10-3:

A stirred solution of compound 10-1 (20 g, 0.075 mol, 1 eq.) in THF (150 mL) was cooled to 0 ° C, and methylmagnesium bromide (75 mL, 0.075 mol, 1 eq.) was slowly added in portions at 25 ° C. The resulting mixture was stirred at 0 ° C for 18 hours under N ₂ atmosphere. The reaction was then quenched with saturated NH ₄ Cl (50 mL). The two phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a residue, which was purified by silica gel column chromatography, eluted with PE: EtOAc (100: 0-90: 10) to give compound 10-3 (16.2 g, 76%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ4.25-4.24 (m, 1H), 3.51 (s, 1H), 1.25-1.20 (m, 32H), 0.98 (d, J = 6.1Hz, 3H), 0.82(t,J＝6.7Hz,3H).

Step 2: Synthesis of compound 10-5:

To a stirred solution of compound 10-3 (16.2 g, 0.057 mol, 1 eq.) and compound 10-4 (9.98 g, 0.057 mol, 1 eq.) in DCM (150 mL) at 25 °C, DCC (14.03 g, 0.0684 mol, 1.2 eq.) and DMAP (4.21 g, 0.0331 mol, 0.6 eq.) were added in portions. The resulting mixture was stirred at 25 °C for 18 h under _N2 atmosphere. The reactant was then washed with brine, the _organic phase was dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (100:0-90:10) to give compound 10-5 (12.2 g, 47%) as a white solid.

LCMS: [MS+1] = 456.4

Step 3: Synthesis of compound 10-6:

To a stirred solution of compound 10-5 (12.2 g, 26.8 mmol, 1 eq.) in ethyl acetate (30 mL) was added HCl in ethyl acetate (4 M, 100 mL) in portions at 0° C. The resulting mixture was stirred at 0° C. for 2 hours. The resulting mixture was concentrated under reduced pressure to give compound 10-6 (11.2 g, 95%) as a white solid, which was used directly in the next step without further purification.

LCMS: [MS+1] = 356.3

Step 4: Synthesis of compound 10:

To a stirred solution of compound 1a (1 g, 2.70 mmol, 1 eq.) and compound 10-6 (5.667 g, 13.50 mmol, 5 eq.) in t-BuOH (25 mL) and H ₂ O (5 mL) at 25° C., DCC (6.674 g, 32.40 mmol, 12 eq.) and TEA (6.817 g, 67.50 mmol, 25 eq.) were added portionwise. The resulting mixture was stirred at 95° C. for 18 h under N ₂ atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (90:10-80:20) to give a crude product, which was purified by preparative HPLC to give compound 10 (25.6 mg, 1.5%).

LCMS: [MS-1] = 707.30.

¹ H NMR (400MHz, methanol- _{d 4} ) δ7.86 (s, 1H), 6.97 (d, J = 4.6Hz, 1H), 6.91 (d, J = 4.7Hz, 1H), 4.83-4.80 (m, 2H),4.30(t,J＝4.6Hz,1H),4.20(t,J＝5.2Hz,1H),4.07 -3.96(m,2H),3.77-3.68(m,1H),1.75-1.30(m ,2H),1.26-1.20(m,30H),1.21-1.19(m,3H),1.15(d,J＝6.2Hz,3H),0.87(t,J＝6.6Hz,3H)

The following compounds were synthesized according to the same procedure as compound 10, except that different starting materials or intermediates were used:

Compound 7:

LCMS:[MS+1]＝723.55,[MS-1]＝721.30

¹ H NMR (400MHz, CD ₃ OD) δ7.90(s,1H),7.05-6.94(m,2H),4.83-4.80(m,2H),4.41-4.31(m,1H),4.26-4.19( m,1H),4.19-4.11(m,1H),4.11-3.98(m,1H),1.60-1.55(m,2H),1.50-1.38(m,6H),1.31-1.24(m,30H), 1.19(d,J＝6.2Hz,3H),0.90(t,J＝6.8Hz,3H).

Compound 8:

LCMS:[MS+1]＝653.5,[MS-1]＝651.2

¹ H NMR (400MHz, CD ₃ OD) δ7.85 (s, 1H), 6.96 (d, J = 4.6Hz, 1H), 6.87 (d, J = 4.6Hz, 1H), 4.81-4.76 (m, 2H ),4.35-4.25(m,1H),4.24-4.15(m,1H),4.05-3.98(m,1H),3.95-3.89(m,1H),3.81-3.73(m,1H),1.50-1.45 (m,4H),1.27-1.21(m,20H),1.19-1.18(m,3H),0.88-0.82(m,6H).

Compound 9:

LCMS:[MS+1]=933.85,[MS-1]=931.35.

¹ H NMR (400MHz, CD ₃ OD) δ7.85 (s, 1H), 6.95 (d, J = 4.6Hz, 1H), 6.87 (d, J = 4.6Hz, 1H), 4.80-4.78 (m, 1H ),4.58-4.56(m,1H),4.31-4.29(m,1H),4.22-4.20(m,1H),4.02-4.00(m,1H),3.96-3.89(m,1H),3.82-3.73 (m,1H),1.49-1.40(m,4H),1.26-1.20(m,63H),0.88(t,J=6.6Hz,6H).

Compound 18:

LCMS:[MS+1]＝737.55,[MS-1]＝735.40

¹ H NMR (400MHz, CD ₃ OD) δ7.89 (s, 1H), 6.98 (d, J = 4.6Hz, 1H), 6.96 (d, J = 4.6Hz, 1H), 4.83-4.81 (m, 1H ),4.30(t,J＝4.3Hz,1H),4.20(t,J＝5.2Hz,1H),4.07-4.00(m,3H),3.80-3.72(m,1H),1.52-1.49(m, 2H),1.27-1.21(m,37H),1.16(d,J＝7.1Hz,3H),0.87(t,J＝6.8Hz,3H).

Compound 19:

LCMS:[MS+1]=751.45,[MS-1]=749.45.

¹ H NMR (400MHz, CD ₃ OD) δ7.85(s,1H),6.94(d,J＝4.6Hz,1H),6.88(d,J＝4.6Hz,1H),4.83-4,81(m ,2H),4.34-4.29(m,1H),4.21(t,J＝5.3Hz,1H),4.09-4.01(m,1H),4.01-3.94(m,1H),1.60-1.48(m,2H ),1.39-1.33(m,6H),1.27-1.23(m,34H),1.16(d,J＝6.2Hz,3H),0.88(t,J＝6.8Hz,3H).

Compound 20:

LC/MS [M+H] ⁺ = 687.0.

¹ H NMR (400MHz, DMSO-d6) δ: 8.06-7.72 (m, 3H), 7.35-7.11 (m, 7H), 6.89 (d, J = 4.4Hz, 1H), 6.84 (d, J = 4.8Hz ,1H),6.23(d,J＝5.6Hz,1H),4.61(t,J＝4.8Hz,1H),4.11-3.95(m,1H),3.90-3.66(m,6H),2.88-2.78( m,2H),1.39-1.31(m,2H),1.28-1.00(m,18H),0.85(t,J＝6.4Hz,3H).

Compound 21:

LC/MS [M+H] ⁺ = 743.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.97-7.75 (m, 3H), 7.24-7.08 (m, 7H), 6.88 (d, J = 5.2 Hz, 1H), 6.81 (d, J = 4.4 Hz,1H),6.16(d,J＝5.6Hz,1H),4.58(t,J＝5.2Hz,1H),4.10-4.05(m,1H),3.91-3.78(m,4H),3.73-3.63 (m,2H),2.89-2.75(m,2H),1.41-1.32(m,2H),1.27-1.09(m,26H),0.85(t,J＝6.8Hz,3H).

Compound 22:

LCMS: [M+H] ⁺ = 827.5

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.99-7.72(m,3H),7.28-7.04(m,7H),6.88(d,J＝4.4Hz,1H),6.81(d,J＝4.4 Hz,1H),6.21(d,J＝4.8Hz,1H),4.58(t,J＝4.4Hz,1H),4.10-4.04(m,1H),3.94-3.76(m,4H),3.74-3.61 (m,2H),2.89-2.73(m,2H),1.41-1.31(m,2H),1.29-1.03(m,38H),0.85(t,J＝6.8Hz,3H).

Compound 23:

LC/MS [M+H] ⁺ = 673.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.99-7.77(m,3H),7.45-7.20(m,7H),6.90(d,J＝4.8Hz,1H),6.79-6.76(m,1H ),6.17(d,J＝4.4Hz,1H),4.76(t,J＝9.2Hz,1H),4.57(t,J＝4.4Hz,1H),4.33-3.85(m,4H),3.79-3.64 (m,2H),1.45-1.42(m,2H),1.29-1.11(m,18H),0.85(t,J=6.4Hz,3H).

Compound 24:

LC/MS [M+H] ⁺ = 729.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.99-7.75 (m, 3H), 7.40-7.10 (m, 6H), 6.88 (d, J = 4.8Hz, 1H), 6.78-6.76 (m, 1H ),6.15(s,1H),4.76(t,J＝8.8Hz,1H),4.57(s,1H),4.30-3.69(m,6H),1.49-1.37(m,2H),1.29-1.04( m,26H),0.85(t,J=6.8Hz,3H).

Compound 25:

LC/MS [M+H] ⁺ = 813.6

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.98-7.76 (m, 3H), 7.39-7.31 (m, 2H), 7.28-7.18 (m, 5H), 6.89 (d, J = 4.4Hz, 1H ),6.77(d,J＝4.8Hz,1H),6.16(d,J＝4.8Hz,1H),4.76(t,J＝8.8Hz,1H),4.53(t,J＝5.2Hz,1H), 4.09-3.83(m,4H),3.71-3.64(m,2H),1.47-1.33(m,2H),1.28-1.04(m,38H),0.85(t,J＝6.8Hz,3H).

Compound 26:

LC/MS [M+H] ⁺ = 775.6.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.94-7.76(m,3H),7.41 -7.45(m,2H),7.26-7.11(brs,1H),7.11-7.05(m,2H),6.89 (d,J＝4.4Hz,1H),6.80-6.77(m,1H),6.18(d,J＝5.2Hz,1H),4.76(t,J＝6.0Hz,1H),4.60(t,J＝ 4.8Hz,1H),4.09-3.69(m,6H),1.44-1.39(m,2H),1.27-1.16(m,23H),1.14-1.02(m,7H),0.85(t,J＝7.2Hz ,3H).

Compound 27:

LC/MS [M+H] ⁺ = 787.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.94-7.79 (m, 3H), 7.38-7.11 (m, 4H), 6.90 (d, J = 4.4Hz, 1H), 6.82-6.80 (m, 3H) ),6.17(d,J＝5.6Hz,1H),4.69-4.58(m,2H),4.13-4.07(m,1H),4.01-3.86(m,3H),3.76-3.65(m,5H), 1.44-1.38(m,2H),1.29-1.18(m,21H),1.17-1.07(m,9H),0.85(t,J=7.2Hz,3H).

Compound 28:

LC/MS [M+H] ⁺ = 737.6.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.00-7.71 (m, 3H), 7.36-7.03 (br s, 2H), 6.88 (d, J＝4.4Hz, 1H), 6.88 (d, J＝ 4.8Hz,1H),6.20(d,J＝4.0Hz,1H),4.61(t,J＝4.4Hz,1H),4.16-4.08(m,1H),4.02-3.72(m,5H),3.64- 3.55(m,1H),1.71-1.58(m,3H),1.57-1.43(m,2H),1.28-1.16(m,30H),0.87-0.79(m,9H).

Compound 29:

LC/MS [M+H] ⁺ = 810.6.

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.82 (s, 1H), 7.96-7.77 (m, 3H), 7.44 (d, J = 8Hz, 1H), 7.28 (d, J = 8Hz, 1H) ,7.20(br s,2H),7.08(d,J＝6.4Hz,1H),7.01(t,J＝7.2Hz,1H),6.93-6.88(m,2H),6.82(dd,J＝4.4,1.6Hz,1H ),6.20(s,1H),4.60(s,1H),4.14-4.09(m,1H),3.95-3.69(m,6H),3.01-2.93(m,2H),1.32-0.94(m,32H ),0.85(t,J=6.8Hz,3H).

Compound 30:

LC-MS [M+1] ⁺ = 789.5

¹ H NMR (400MHz, DMSO-d6) δ7.98-7.76(m,3H),7.16-7.12(m,3H),7.03-6.99(m,2H),6.89(d,J＝4.4Hz,1H) ,6.84(d,J＝4.4Hz,1H),6.25(d,J＝5.2Hz,1H),4.62(t,J＝4.4Hz,1H),4.13-4.09(m,2H),3.91-3.68( m,5H),2.86-2.76(m,2H),1.37-1.26(m,2H),1.27-1.05(m,30H),0.85(t,J＝6.4Hz,3H).

Compound 31:

LC/MS [M+H] ⁺ = 801.6.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.96-7.77 (m, 3H), 7.24 (br s, 2H), 6.99 (d, J = 8.4Hz, 2H), 6.88 (d, J = 4.4Hz ,1H),6.84(d,J＝4.4Hz,1H),6.75(d,J＝8.8Hz,2H),6.25(d,J＝3.6Hz,1H),4.62(s,1H),4.13-4.08 (m,1H),3.93-3.62(m,9H),2.81-2.68(m,2H),1.42-1.32(m,2H),1.28-1.08(m,30H),0.85(t,J＝6.8Hz ,3H).

Compound 32:

LC/MS [M+H] ⁺ = 787.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.28 (s, 1H), 8.05-7.74 (m, 3H), 7.21 (br s, 2H), 6.93-6.86 (m, 3H), 6.82 (d, J＝4.8Hz,1H),6.61(d,J＝8.4Hz,2H),6.22(d,J＝5.2Hz,1H),4.60(t,J＝4.8Hz,1H),4.11-4.08(m, 1H),3.93-3.66(m,6H),2.77-2.65(m,2H),1.45-1.37(m,2H),1.29-1.00(m,30H),0.85(t,J＝6.8Hz,3H) .

Compound 33:

LC-MS [M+1] ⁺ = 821.6

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.94-7.72 (m, 6H), 7.61 (s, 1H), 7.46-7.36 (m, 2H), 7.30 (d, J = 9.2Hz, 1H), 7.19(br s,1H),6.89(d,J＝4.8Hz,1H),6.84(d,J＝4.4Hz,1H),6.23(d,J＝5.2Hz,1H),4.70-4.61(m,1H), 4.14-4.10(m,1H),4.02-3.66(m,6H),3.08-2.95(m,2H),1.28-1.10(m,30H),1.04-0.88(m,2H),0.85(t,J =6.8Hz,3H).

Compound 34:

LC-MS [M+1] ⁺ = 772.7

¹ H NMR (400MHz, DMSO-d6) δ8.37-8.35(m,2H),7.97-7.78(m,3H),7.59-7.57(m,1H),7.29-7.01(m,2H),6.89( d,J＝4.4Hz,1H),6.84(d,J＝4.8Hz,1H),6.25(brs,1H),4.71-4.45(m,1H),4.21-4.07(m,1H),3.97-3.79 (m,4H),3.78-3.67(m,2H),2.90-2.81(m,2H),1.45-1.33(m,2H),1.29-1.07(m,30H),0.84(t,J＝6.8Hz ,3H).

Compound 35:

LC-MS [M+1] ⁺ = 828.6.

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.96(s,1H),7.97-7.76(m,3H),7.30-7.26(m,1H),7.23-7.09(m,3H),6.89-6.82 (m,3H),6.20(s,1H),4.61(s,1H),4.18-4.10(m,1H),3.96-3.71(m,6H),3.00-2.88(m,2H),1.34-0.99 (m,32H),0.85(t,J＝6.0Hz,3H).

Compound 36:

LCMS: [M+1] ⁺ =761.7

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.40 (s, 1H), 7.99-7.77 (m, 3H), 7.14 (s, 1H), 6.87 (d, J = 4.4Hz, 1H), 6.81 ( d,J＝4.4Hz,1H),6.20(brs,1H),4.62(d,J＝4.4Hz,1H),4.16-4.11(m,1H),4.01-3.83(m,5H),3.79-3.71 (m,1H),3.07-3.02(m,1H),2.91-2.85(m,1H),1.52-1.43(m,2H),1.29-1.12(m,30H),0.85(t,J＝6.4Hz ,3H).

Compound 37:

LC/MS [M+H] ⁺ = 772.5

¹ H NMR (400MHz, DMSO-d6) δ8.01-7.74(m,3H),7.23-7.07(m,8H),6.89(s,1H),6.29(s,1H),4.61(s,1H) ,4.13-4.07(m,1H),3.96-3.92(m,1H),3.88-3.77(m,3H),3.74-3.61(m,2H),2.89-2.73(m,2H),1.38-1.30( m,2H),1.28-1.04(m,30H),0.85(t,J=6.4Hz,3H).

Compound 38:

LC/MS[MH] ^- ＝822.25

¹ H NMR (400MHz, CD ₃ OD) δ7.82 (s, 1H), 7.46 (d, J = 8.0Hz, 1H), 7.22 (d, J = 8.0Hz, 1H), 7.06 (t, J = 8.0 Hz,1H),6.95-6.93(m,2H),6.92-6.91(m,1H),6.82(t,J＝4.4Hz,1H),4.79(d,J＝5.2Hz,1H),4. 28-4.26(m,1H),4.20-4.17(m,1H),4.05-3.85(m,3H),3.73(t,J＝6.8Hz,2H),3.67(s,3H),3.13-3.06( m,1H),2.98-2.92(m,1H),1.26-1.22(m,32H),0.88(t,J=6.7Hz,3H).

Compound 39:

LC/MS [M+H] ⁺ = 852.8.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.99-7.74(m,3H),7.45(d,J＝7.6Hz,1H),7.38(d,J＝8.8Hz,1H),7.31-7.15( m,3H),7.06(t,J＝7.6Hz,1H),6.94(t,J＝7.6Hz,1H),6.89(d,J＝4.4Hz,1H),6.84(d,J＝4.4Hz, 1H),6 .19(d,J＝5.2Hz,1H),4.69-4.57(m,2H),4.15-4.08(m,1H),3.93-3.90(m,2H),3.82-3.70(m,4H),3.03 -2.88(m,2H),1.39-1.36(m,6H),1.37-0.89(m,32H),0.85(t,J＝7.2Hz,3H).

Example 3. Biochemical assay

Assay 1: In vitro antiviral activity of anti-229E

In vitro anti-229E activity and cytotoxicity were evaluated using MRC5 cells as described below.

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% CO _2. After incubation for 24 hours, the test compound and the positive control (Remdesivir) were diluted with assay medium and then added to the cells, 50 μl per well. Then 50 μl of virus diluted in assay medium was added to each well. The resulting cell culture was incubated for another 3 days until the virus infection in the virus control (virus-infected cells, no compound treatment) showed significant CPE. 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.

Inhibition % was calculated by the following equation: Inhibition (%) = (raw data CPD-average VC)/(average CC-average VC)×100.

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

Raw data CPD: value of sample treatment well

Mean VC: Mean value of virus control

Average CC: average value of cell control (cells without virus infection or compound treatment)

Mean MC: Mean of medium control (medium only) wells.

Assay 2: In vitro antiviral activity against SARS-CoV-2

In vitro anti-SARS-COV-2 activity and cytotoxicity were evaluated using Vero cells as described below.

Antiviral activity assay : Vero cells were seeded in 96-well plates at a density of Vero cells/well, with 100 μl of assay medium per well, and cultured at 37 ° C and 5% CO _2. After incubation for 24 hours, the test compound and the positive control (Remdesivir) were diluted with assay medium and then added to the cells, 50 μl per well. Then 50 μl of virus diluted in assay medium was added to each well. The resulting cell culture was incubated for another 3 days until the virus infection in the virus control (virus-infected cells without compound treatment) showed significant CPE. 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.

Inhibition % was calculated by the following equation: Inhibition (%) = (raw data CPD-average VC)/(average CC-average VC)×100.

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

Raw data CPD: value of sample treatment well

Mean VC: Mean value of virus control

Average CC: average value of cell control (cells without virus infection or compound treatment)

Mean MC: Mean of medium control (medium only) wells.

Assay 3: In vitro antiviral activity against SARS-CoV-2 replicons

Test compounds, positive control (Remdesivir) and reference compound 1 (octyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)-L-alaninate) were serially diluted in DMSO and added to 384-well plates at 0.3 μl/well (8 doses, 3 times, duplicate wells). Replicon RNA was produced in in vitro transcripts. Huh7 cells transfected with purified SARS-CoV-2 replicon RNA were seeded at 4000/well in 384 microplates containing serially diluted compounds and then cultured for 1 day at 37°C and 5% _CO2 . The final volume of the cell culture was 60 μl/well, and the final concentration of DMSO in the test plate was 0.5%.

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.

The antiviral activity and activity of the compounds were expressed as % inhibition and % activity, respectively, and were calculated using the following formula:

Inhibition (%) = (raw data CPD-average ZPE)/(average HPE-average ZPE) × 100

Vitality (%) = (original data CPD-average HPE)/(average ZPE-average HPE) × 100

Raw data CPD: value of sample treatment well

Average ZPE: average of virus control

Mean HPE: Mean of medium control (medium only) wells.

_EC50 and _CC50 values were calculated using GraphPad Prism software using a nonlinear regression model of log(inhibitor) vs. response - variable slope (four parameters).

Assay 4: Determination of intracellular nucleoside triphosphates:

The drug cell uptake and cytosolic nucleoside triphosphates were evaluated using the human liver cancer cell line HepG2 and the human lung adenocarcinoma cell line. The cells were incubated in a 6-well plate at 37°C in a 5% CO2-95% air atmosphere to allow the cells to attach. The cell density of HepG2 was 2×106/well, and the cell density of A549 was 1×106/well. The incubation medium for HepG2 and A549 was Eagle's Minimum Essential Medium (EMEM) and F-12K, respectively, both containing 2% fetal bovine serum (FBS). After cell attachment, the culture medium was removed, and 2.5 mL of fresh culture medium containing 1 μM of the test compound was added to each well and incubated at 37°C in a 5% _CO2-95 % air atmosphere. At each specific time point (1 hour, 2 hours, 4 hours, 6 hours), the culture medium was removed and the cells were washed twice with 3 mL of ice-cold PBS. After washing, the cells were digested from the plate wells with 600 μl of ice-cold 70% methanol. The cell lysate was then centrifuged at 13000 rpm for 5 minutes at 4° C. Aliquots (200 μL) of the supernatant were transferred to a clean 96-well plate and analyzed by LC-MS/MS (Shimazu 20A and API 4000Qtrap) to determine the concentration of intracellular nucleoside triphosphates.

Assay 5: In vitro antiviral activity against RSV

In vitro anti-RSV activity and cytotoxicity were evaluated using Hep-2 cells as described below.

Antiviral activity assay : Hep-2 cells were seeded in 96-well plates at a density of 6000 cells/well, with 100 μl of assay medium per well, and cultured at 37 ° C and 5% CO _2. After incubation for 24 hours, the test compound and the positive control (Remdesivir) were diluted with assay medium and then added to the cells, 50 μl per well. Then 50 μl of RSV A2 virus diluted in assay medium was added to each well. The final concentration of DMSO in the assay medium was 0.5%. The resulting cell culture was incubated for 5 days. The supernatant of the antiviral activity test plate was removed, and the intracellular viral protein expression was detected by anti-RSV F antibody ELISA assay. The antiviral activity of the test compound was calculated based on the viral replication inhibition rate of the test compound at different concentrations.

Inhibition % was calculated by the following equation: Inhibition (%) = (raw data CPD-average VC)/(average CC-average VC)×100.

Cytotoxicity assay : The cytotoxicity of the compounds was assessed following the same protocol as the antiviral activity assay, but without the viral infection step. Cell viability was measured using CCK8 following the manufacturer's manual.

Vitality % was calculated by the following equation: Vitality (%)=(raw data CPD-average MC)/(average CC-average MC)×100.

Raw data CPD: value of sample treatment well

Mean VC: Mean value of virus control

Average CC: average value of cell control (cells without virus infection or compound treatment)

Mean MC: Mean of medium control (medium only) wells.

_EC50 and _CC50 values were calculated using GraphPad Prism software using a nonlinear regression model of log(inhibitor) vs. response - variable slope (four parameters).

Tables 2 to 5 show the results of exemplary compounds of the present disclosure in assays 1 to 5. It shows that the compounds of the present disclosure have good inhibitory effects on various coronaviruses and respiratory syncytial viruses, have low cytotoxicity, show higher stability in human liver, and produce more triphosphorylated products in lung cells.

Table 2 - In vitro antiviral activity of exemplary compounds against 229E

Compound No. 229E EC ₅₀ ¹ (nM) MRC5 CC ₅₀ (nM) Remdesivir A >10000 3 A >10000 11 A >10000 13 A >10000

¹ A: <100nM, B: 100nM-1000nM, C: >1000nM.

Table 3 - In vitro antiviral activity of exemplary compounds against SARS-CoV-2 replicons

¹ A: <50nM, B: 50nM-100nM, C: 100nM-1000nM, D: >1000nM

Table 4 - Cytosine triphosphates of exemplary compounds

¹ A: >500nM, B: 200nM-500nM, C: <200nM.

Table 5 - In vitro antiviral activity of exemplary compounds against RSV A2

Compound No. RSV A2 EC ₅₀ ¹ (nM) Remdesivir A 3 B 5 A 6 B 11 A 12 B 13 A 14 A 20 A twenty one A twenty three A twenty four A 33 A 34 A 36 A 37 A 38 A

¹ A: <100nM, B: 100nM-1000nM, C: >1000nM

The above description is considered to be merely an illustration of the principles of the present disclosure. In addition, since many modifications and variations are apparent to those skilled in the art, it is not desirable to limit the present invention to the exact configuration and process as described above. Therefore, all suitable modifications and equivalents may be considered to fall within the scope of the present invention as defined by the appended claims.

Claims (19)

1. Use of a compound having the formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a viral infection:

Wherein the method comprises the steps of

Base is a naturally occurring or modified pyrimidine Base or purine Base;

Q is CH ₂, CHD, or CD ₂;

r ¹ is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl 、-OR^a、-NO₂、-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)₂R^a、-S(O)OR^a、-S(O)₂(OR^a), and-S (O) ₂N(R^a)₂;

Each of R ²¹、R²²、R³¹、R³² and R ⁴ is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, cyano, azido, alkyl, alkenyl, alkynyl, haloalkyl 、-OR^a、-NO₂、-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) ₂R^a;

Each R ⁵ is independently selected from the group consisting of: hydrogen, alkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b;

R ⁶ is-OX;

X is hydrogen or a pharmaceutically acceptable cation;

r ⁷ is

R ⁸ is selected from the group consisting of: hydrogen, C _1-26 alkyl, C _2-26 alkenyl, CH ₃(CH₂)_mO(CH₂)_n -, and R ^eOCH₂(CH₂OCH₂)_pCH₂ -, each of which is optionally substituted with one or more R ^b;

R ⁹ is selected from the group consisting of: c _1-26 alkyl, C _2-26 alkenyl, CH ₃(CH₂)_mO(CH₂)_n -, and R ^eOCH₂(CH₂OCH₂)_pCH₂ -, each of which is optionally substituted with one or more R ^b;

Each R ^a is independently selected from hydrogen, halogen, or alkyl;

each R ^b is independently selected from halogen, hydroxy, cyano, amino, alkyl, or alkoxy;

each R ^e is independently selected from hydrogen or alkyl;

Each m, n, or p is independently an integer from 0 to 20;

provided that when X is hydrogen then

A) R ⁸ is hydrogen and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl; or alternatively

B) R ⁸ is C _1-18 alkyl or C _2-18 alkenyl, and R ⁹ is selected from C _7-25 alkyl or C _7-25 alkenyl.

2. The use according to claim 1, wherein,

R ¹ is selected from hydrogen, hydroxy, cyano, azido, alkyl, or haloalkyl; and/or

Each of R ²¹、R²²、R³¹、R³² and R ⁴ is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, azido, alkyl, haloalkyl, or-OC (O) R ^a; and/or

R ^a is alkyl; and/or

R ⁴ is selected from hydrogen, deuterium, halogen, cyano, azido, or haloalkyl; and/or

Each R ⁵ is independently selected from the group consisting of: hydrogen, C _1-6 alkyl, C _6-12 aryl, 5-to 12-membered heteroaryl, (C _1-3 alkyl) (C _3-12 cycloalkyl), (C _1-3 alkyl) (3-to 12-membered heterocyclyl), (C _1-3 alkyl) (C _6-12 aryl), (C _1-3 alkyl) (5-to 12-membered heteroaryl), and a natural amino acid side chain, each of which is optionally substituted with one or more R ^b; and/or

X is selected from hydrogen, metal ions, -NH ₄ ⁺ or protonated organic amine; and/or

R ⁸ is hydrogen, C _1-14 alkyl or C _2-14 alkenyl, and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl.

3. The use according to claim 2, wherein,

R ¹ is cyano;

each of R ²¹、R²²、R³¹、R³² is selected from hydrogen, deuterium, halogen, hydroxy, alkyl, or-OC (O) R ^a;

r ^a is methyl;

r ⁴ is hydrogen;

One R ⁵ is hydrogen and the other R ⁵ is selected from C _1-6 alkyl, C _6-12 aryl, (C _1-3 alkyl) (C _6-12 aryl), (C _1-3 alkyl) (5-to 12-membered heteroaryl) or a natural amino acid side chain, each of which is optionally substituted with one or more R ^b;

X is selected from hydrogen, K ⁺、Ca²⁺、Na⁺ or NH ₄ ⁺;

R ⁸ is hydrogen or C _1-3 alkyl, and R ⁹ is C _11-25 alkyl.

4. The use of claim 3, wherein one R ⁵ is hydrogen and the other R ⁵ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl optionally substituted with one or more R ^b, (C _1-3 alkyl) (C _6-12 aryl) optionally substituted with one or more R ^b, (C _1-3 alkyl) (5-to 12-membered heteroaryl) optionally substituted with one or more R ^b, or a natural amino acid side chain, wherein R ^b is halogen, hydroxy or alkoxy.

5. The use of claim 4, wherein one R ⁵ is hydrogen and the other R ⁵ is selected from the group consisting of:

6. The use of claim 3, wherein R ⁸ is hydrogen and R ⁹ is C _13-25 alkyl.

7. The use of claim 6, wherein R ⁸ is hydrogen and R ⁹ is C _15-19 alkyl.

8. The use of claim 3, wherein R ⁸ is C _1-3 alkyl and R ⁹ is C _13-25 alkyl.

9. The use of claim 8, wherein R ⁸ is methyl or ethyl and R ⁹ is C _13-25 alkyl.

10. The use according to claim 2, wherein both R ⁵ are methyl.

11. The use according to any one of the preceding claims, wherein the Base isAndIs that

12. The use according to claim 11, wherein the Base isAndIs that

13. The use of claim 1, wherein the compound has a formula selected from the group consisting of:

14. The use of claim 13, wherein R ⁸ is hydrogen and R ⁹ is selected from C _11-25 alkyl or C _11-25 alkenyl.

15. The use of claim 14, wherein R ⁸ is hydrogen and R ⁹ is C _15-19 alkyl.

16. The use according to claim 1, wherein the compound is selected from the group consisting of:

17. The use according to claim 1, wherein the virus is SARS-CoV-2 or respiratory syncytial virus.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 17, formulated for oral administration, injection administration, nasal administration, or pulmonary administration.