Ester Derivatives of N4-Hydroxycytidine and Their Uses

Abstract

This disclosure relates to N 4 -Hydroxycytidine (NHC) Ester Derivatives, Pharmaceutical Compositions Comprising Them, Methods for Their Preparation, and Use of NHC Ester Derivatives for Treating Viral Infections - Patent application 4 The present invention relates to uses and methods of ester derivatives of -hydroxycytidine.

Description

[Technical field]

[0001] This disclosure relates to N 4 -Hydroxycytidine (NHC) Ester Derivatives, Pharmaceutical Compositions Comprising Them, and NHC-Hydroxycytidine (NHC) Ester Derivatives for Treating Viral Infections - Patent application 4 The present invention relates to the use of ester derivatives of N-hydroxycytidine. 4 -Hydroxycytidine can be given orally. [Background technology]

[0002] Currently, SARS-CoV-2, the virus that causes COVID-19, has infected over 240 million people worldwide with around 5 million deaths with no signs of slowing down. The global economy and human activity have been significantly affected. Although vaccines have recently been introduced, treatment of infected individuals with oral medications remains highly desirable and can complement vaccine use. 4 -Hydroxycytidine (NHC) is a ribonucleoside analogue with broad-spectrum antiviral activity against a variety of unrelated RNA viruses, including influenza, Ebola, CoV, and Venezuelan equine encephalitis viruses (VEEV), and most importantly, the human SARS-CoV-2 virus. Although the exact molecular mechanism of action of NHC remains unclear, it has been proposed that viral error catalysis underlies its antiviral activity [“Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia”, Sci Transl Med. 2019 Oct 23; 11(515): eaax5866], which stems from the tautomerization properties of NHC. [ka]

[0003] The oxime-type NHC mimics uridine and pairs with adenosine (structure on the left below), while the other tautomer mimics cytidine and pairs with guanosine (structure on the right below). Such mismatches can lead to viral error catastrophes. [ka] N 4 -One prodrug of hydroxycytidine (NHC), molnupiravir / EIDD2801 / MK4486, has just completed clinical trials for the treatment of SARS-CoV-2, the virus that causes COVID-19. A Phase III clinical trial for treating early SARS-CoV-2 infection reported a 50% reduction in patients progressing to hospitalization when administered at 800 mg twice daily for 5 days. High doses and twice daily dosing are required to sustain effective concentrations of NHC that can cause viral error catastrophe in the human body. Thus, more and potentially better prodrugs (i.e., smaller pills, less frequent dosing, and higher efficacy) are still needed to treat viral infections, especially for the urgent response to the current global human calamity. Summary of the Invention

[0004] The inventors have demonstrated that NHCs can be delivered into the bloodstream of animals with improved bioavailability and prolonged exposure compared to the parent molecule NHC. 4 A series of ester derivatives of -hydroxycytidine (NHC) have been discovered.

[0005] The present disclosure relates to certain ester prodrugs of NHCs, combinations, pharmaceutical compositions, uses and methods related thereto.

[0006] The present disclosure provides a compound of formula (I): [ka] or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof [In the formula, R is Ra-(C=O)-; Here, Ra is C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-7 Alkyl, C 6-10 Aryl-C 1-7 Alkyl, 5-10 membered heteroaryl-C 1-7 Alkyl, and 3- to 12-membered heterocycloalkyl-C 1-7 each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl being selected from the group consisting of halogen, acyl, hydroxy, cyano, nitro, amino, -NH(C 1-7 alkyl), -N(C 1-7 alkyl)2, -CO-NH2, -CO-NH(C 1-7 alkyl), -CO-N(C 1-7 alkyl)2, -NH(acyl), -N(acyl)2, NH2-acyl, NHRy-acyl, N(Ry)2-acyl, C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-7 Alkoxy, aryloxy, heteroaryloxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, Halo-C 2-6 Alkenyl, Halo-C 2-6 Alkynyl, Hydroxy-C 1-7 Alkyl, C 1-7 Alkoxy-C 1-7 Alkyl, halo-C 1-7 Alkoxy-C 1-7 Alkyl, halo-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8optionally substituted with one or more substituents selected from cycloalkyloxy or 3- to 12-membered heterocycloalkyloxy; Ry is C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-7 Alkyl, C 6-10 Aryl-C 1-7 Alkyl, 5-10 membered heteroaryl-C 1-7 Alkyl, and 3- to 12-membered heterocycloalkyl-C 1-7 alkyl, independently selected from to provide.

[0007] In a preferred embodiment, Ra is C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocycloalkyl, each of which is selected from the following groups: halogen, acyl, hydroxy, cyano, nitro, amino, -NH(C 1-7 alkyl), -N(C 1-7 alkyl)2, -CO-NH2, -CO-NH(C 1-7 alkyl), -CO-N(C 1-7 alkyl)2, -NH(acyl), -N(acyl)2, NH2-acyl, NHRy-acyl, N(Ry)2-acyl, C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-7 Alkoxy, Halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, aryloxy, heteroaryloxy, halo-C 2-6 Alkenyl, Halo-C 2-6 Alkynyl, Hydroxy-C 1-7 Alkyl, C 1-7 Alkoxy-C 1-7 Alkyl, halo-C 1-7 Alkoxy-C 1-7 Alkyl, halo-C3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 optionally substituted with one or more substituents selected from cycloalkyloxy or 3- to 12-membered heterocycloalkyloxy; Here, Ry is C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-7 Alkyl, C 6-10 Aryl-C 1-7 Alkyl, 5-10 membered heteroaryl-C 1-7 Alkyl, and 3- to 12-membered heterocycloalkyl-C 1-7 alkyl.

[0008] In a further preferred embodiment, Ra is C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, halo-C 1-7 Alkyl, C 1-7 Alkyl-OC 1-7 Alkyl, C 1-7 Alkyl-O-aryl, C 1-7 Alkyl-O-heteroaryl, halo-C 3-8 Cycloalkyl, C 1-6 Alkyl-O-(CH2) n -, C 1-6 Alkyl-OC 1-6 Alkyl-O-(CH2) n -, Halo-C 1-6 Alkyl-O-(CH2) n -, C 3-6 Cycloalkyl-O-(CH2) n -, Halo-C 3-6 Cycloalkyl-O-(CH2) n -, 3-12 membered heterocycloalkyl-O-(CH2) n- and 3-12 membered haloheterocycloalkyl-O-(CH2) n - is selected from the group consisting of

[0009] The compounds described above as well as those disclosed hereinafter in this disclosure (including the compounds of formula (I) and the specific compounds, particularly the compounds of the Examples) or their tautomers, stereoisomers, enantiomers, diastereomers, racemates, geometric isomers, hydrates or solvates, or pharma- ceutically acceptable salts thereof, are collectively referred to as "compounds of the invention" or "compounds of the disclosure."

[0010] The present disclosure also provides compounds of the present invention for use as pharmaceuticals.

[0011] The disclosure also provides a compound of the invention for use in treating or preventing an RNA viral infection.

[0012] The present disclosure also provides pharmaceutical compositions comprising a compound of the invention and, optionally, a pharma- ceutically acceptable excipient.

[0013] The present disclosure also provides a kit for treating or preventing an RNA viral infection, comprising a pharmaceutical composition of the present disclosure and instructions for use.

[0014] The disclosure also provides the use of a compound of the invention in the manufacture of a medicament for treating or preventing an RNA viral infection.

[0015] The disclosure also provides the use of the compounds of the invention for treating or preventing an RNA viral infection.

[0016] The present disclosure also provides a method of treating or preventing an RNA viral infection in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0017] The present disclosure also provides a method for treating or preventing an RNA viral infection. 4The present invention provides a method for increasing the bioavailability of -hydroxycytidine, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0018] The disclosure also provides a pharmaceutical combination comprising a compound of the invention and at least one additional therapeutic agent.

[0019] The disclosure also provides methods for preparing the compounds of the invention and intermediates for the preparation of the compounds of the invention.

[0020] Additional advantages will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the aspects described hereinafter. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

[0021] The drawings described herein are for illustration purposes only and are not intended to limit the scope of the present disclosure. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the mean±SD plasma concentration-time data of Examples EX-2, molnupiravir and NHC following po administration of EX-2 and molnupiravir in beagle dogs (EX-2=CH2101, molnupiravir=CH2017, NHC=CH2018). [Diagram 2] FIG. 2 shows the inhibitory activity curves of test compounds against the SARS-CoV-2 Omicron B.1.1.529 mutant strain. [Diagram 3] FIG. 3 shows the changes in animal body weight in study p26262-15. [Figure 4] FIG. 4 shows the clinical scores in study P26262-15. [Diagram 5] FIG. 5 shows survival rates in study P26262-15. [Figure 6] FIG. 6 shows lung viral titers in study p26262-15. [Figure 7] FIG. 7 shows individual plasma concentration-time data for CH2101 following PO administration of 10 mg / kg CH2101 in beagle dogs. [Figure 8] FIG. 8 shows individual plasma concentration-time data of EX-1 / NHC / CH2018 following PO administration of 10 mg / kg CH2101 in beagle dogs. [Figure 9] FIG. 9 shows individual plasma concentration-time data for CH2101 following administration of 20 mg / kg CH2101 PO in beagle dogs. [Figure 10] FIG. 10 shows the individual plasma concentration-time data of EX-1 / NHC / CH2018 following administration of 20 mg / kg CH2101 PO in beagle dogs. [Figure 11] FIG. 11 shows individual plasma concentration-time data for CH2107 (molnupiravir) following PO administration of 22 mg / kg CH2107 (molnupiravir) in beagle dogs. [Figure 12] FIG. 12 shows individual plasma concentration-time data of EX-1 / NHC / CH2018 following PO administration of 22 mg / kg CH2107 (molnupiravir) in beagle dogs. Description of the Invention

[0023] Detailed Description of the Invention definition As used herein, these words, phrases and symbols generally have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0024] As used herein, the singular forms "a," "an," and "the" are intended to refer to the plural forms as well, unless the context clearly indicates otherwise.

[0025] The compounds of the invention can be identified by either their chemical structure and / or chemical name. In the event that the chemical structure and the chemical name conflict with each other, the chemical structure is determinative of the compound's identity.

[0026] symbol [ka] means herein that the relevant structure is a tautomer, which exists in equilibrium and is easily converted from one isomeric form to the other. The compounds of the present invention may exist in oxime and other forms. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the compounds shown, in particular tautomers of the oxime form and other tautomers. Regardless of the tautomer depicted, and regardless of the nature of the equilibrium between tautomers, the compounds of the present invention will be understood by those skilled in the art to encompass both the oxime and other forms.

[0027] "Bioavailability" refers to the rate and amount of drug that reaches the subject's systemic circulation after administration of the drug or its prodrug to the subject, and can be determined, for example, by evaluating the plasma or blood concentration-time profile of the drug.Parameters useful for characterizing the plasma or blood concentration-time curve include area under the curve (AUC), time to maximum concentration (Tmax), and maximum drug concentration (Cmax), where Cmax is the maximum concentration of drug in the subject's plasma or blood after administration of a dose of the drug or drug form to the subject, and Tmax is the time to maximum concentration (Cmax) of drug in the subject's plasma or blood after administration of a dose of the drug or drug form to the subject.

[0028] A prodrug is a derivative form of a drug that is converted or metabolized in vivo into the active parent drug after administration. Prodrugs are used to modify one or more aspects of the pharmacokinetics of a drug in a way that enhances the therapeutic effect of the parent drug. For example, prodrugs are often used to increase the oral bioavailability of a drug. To be therapeutically effective, a drug with low oral bioavailability may require frequent administration, high dosages, or administration by a route other than oral, such as intravenous administration. Examples of prodrugs that can be used to improve bioavailability include esters, optionally substituted esters, branched esters, and optionally substituted branched esters.

[0029] "Metabolic intermediate" refers to a compound formed in vivo by metabolism of a parent compound and undergoing further reactions in vivo to release an active agent. The compound of formula (I) is a protected ester prodrug that is metabolized in vivo to provide the corresponding metabolic intermediate, such as N4-hydroxycytidine (NHC). It is desirable that the reaction product or its metabolites are not toxic.

[0030] "Subject" refers to a mammal, e.g., a human.

[0031] "Pharmaceutically acceptable" means approved or approved by a regulatory agency of the Federal or state government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, or more particularly, in humans.

[0032] "Pharmaceutically acceptable salt" refers to a salt of a compound that retains the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids and one or more protic functional groups, such as hydroxylamine, in the parent compound. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts may be formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. "Pharmaceutically acceptable salts" also include base addition salts formed with compounds of the present invention which retain an acidic moiety and pharma-ceutically acceptable cations, such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0033] "Pharmaceutical combination" as used herein means a product resulting from the mixing or combination of multiple therapeutic agents, including both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents, such as the compound of the present invention and the at least one additional therapeutic agent, are administered simultaneously to a subject in the form of a single entity or dosage form. The term "non-fixed combination" means that the therapeutic agents, such as the compound of the present invention and the at least one additional therapeutic agent, are administered simultaneously, in parallel, or sequentially without any specific time limit, as separate entities, to a subject, such that administration provides a therapeutically effective level of the agent in the subject's body.

[0034] "Prevent" or "prevention" refers to reducing the risk of acquiring a disease or disorder, e.g., a viral infection (i.e., preventing at least one clinical symptom of a disease from developing in a subject who may be exposed to or predisposed to the disease, but who has not yet suffered or exhibited symptoms of the disease). In some embodiments, "prevent" or "prevention" refers to reducing the symptoms of a disease by taking a compound prophylactically. The application of a therapeutic agent for the prevention of a disease or disorder is known as prophylaxis. The compounds provided by the present disclosure may provide better prophylaxis because they have antiviral activity.

[0035] "Treating" or "treatment" of a disease or disorder, such as a viral infection, refers to arresting or improving at least one clinical symptom of the disease or disorder, reducing the risk of acquiring at least one clinical symptom of the disease or disorder, reducing the onset of at least one clinical symptom of the disease or disorder, or reducing the risk of developing at least one clinical symptom of the disease or disorder. "Treating" or "treatment" also refers to inhibiting the disease, either physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both, and inhibiting at least one physical parameter or pathology that may or may not be discernible in the subject. "Treating" or "treatment" also refers to delaying the onset of a disease, such as a viral infection, or at least one or more symptoms thereof, in a subject that may be exposed to or may be predisposed to a disease or disorder, even if the subject has not yet suffered or exhibited symptoms of the disease.

[0036] The term "effective amount" as used herein refers to an amount of the compound of the present invention that is effective to "treat" or "prevent" a viral infection in a subject, as defined above. An effective amount can cause any observable or measurable change in a subject, as described in the definition of "treat", "treatment", "prevent" or "prevention" above. An "effective amount" can vary, for example, depending on the compound, the disease and / or symptoms of the disease, the severity of the disease and / or symptoms of the disease or disorder, the age, weight, and / or health of the subject to be treated, and the judgment of the prescribing physician. The appropriate amount in any given instance can be ascertained by one of ordinary skill in the art or can be determined by routine experimentation.

[0037] As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon moiety, e.g., of 1 to 7 carbon atoms (C 1-7 ), preferably 1 to 6 carbon atoms (C 1-6 ), 1 to 4 carbon atoms (C 1-4 ) or 1 to 3 carbon atoms (C 1-3 For example, "C 1-7 "Alkyl" refers to an alkyl having 1 to 7 (including 1, 2, 3, 4, 5, 6, or 7) carbon atoms. Representative C 1-7 Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl and the like.

[0038] As used herein, "alkenyl" refers to a straight or branched chain saturated hydrocarbon moiety containing at least one double bond, e.g., 2 to 7 carbon atoms (C 2-7 ), 2 to 6 carbon atoms (C 2-6 ), 2 to 4 carbon atoms (C 2-4 ) or 2-3 carbon atoms (C 2-3 For example, "C 2-6 "Alkenyl" refers to an alkenyl having 2 to 6 (including 2, 3, 4, 5, or 6) carbon atoms. Representative C 2-6Alkenyl groups include ethenyl, propenyl, allyl, butenyl, pentenyl and the like.

[0039] As used herein, "alkynyl" refers to a straight or branched chain saturated hydrocarbon moiety containing at least one triple bond, e.g., 2 to 7 carbon atoms (C 2-7 ), 2 to 6 carbon atoms (C 2-6 ), 2 to 4 carbon atoms (C 2-4 ) or 2-3 carbon atoms (C 2-3 For example, "C 2-6 "Alkynyl" refers to an alkynyl having 2 to 6 (2, 3, 4, 5, or 6) carbon atoms. Representative C 2-6 Alkynyl groups include ethynyl, propynyl, propargyl, butynyl and the like.

[0040] As used herein, "alkoxy" refers to -O-alkyl, where the alkyl has 1 to 7 carbon atoms (C 1-7 ), 1 to 6 carbon atoms (C 1-6 ), 1 to 4 carbon atoms (C 1-4 ) or 1 to 3 carbon atoms (C 1-3 ) and the like, have the meanings as defined above. For example, "C 1-7 "Alkoxy" refers to an alkoxy having 1 to 7 (1, 2, 3, 4, 5, 6, or 7) carbon atoms. Representative C 1-7 Alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy and the like.

[0041] The term "cycloalkyl" as used herein refers to a cycloalkyl group having 3 to 8 ring carbon atoms (C 3-8 ), for example, 3 to 6 ring carbon atoms (C 3-6 ) or 5-6 ring carbon atoms (C 5-6) refers to a saturated cyclic hydrocarbon group having a cyclic ring structure. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or bicyclo systems including spiro and bridged rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[3.2.1]octyl. As used herein, the term "halo-cycloalkyl" refers to a cycloalkyl as defined above in which one or more, e.g., one, two, or three, hydrogen atoms are replaced with halogen atoms.

[0042] The term "heterocycloalkyl," as used herein, refers to a saturated ring having 3 to 12 ring atoms (3-12 members), 3 to 10 ring atoms (3-10 members), 3 to 6 ring atoms (3-6 members), 4 to 6 ring atoms (4-6 members), or 5 to 6 ring atoms (5-6 members), in which one or more, e.g., 1, 2, 3, or 4, preferably 1 or 2, of the ring atoms are heteroatoms independently selected from N, O, and S, preferably O, and the remaining ring atoms are carbon. Examples of heterocycloalkyls include, but are not limited to, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, 1,3-dioxolane moieties, and the like. Preferably, the heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl. For example, the heterocycloalkyl may be selected from the group: [ka] structures having one or more asymmetric centers should be understood to include racemic mixtures thereof and / or single enantiomers or mixtures thereof. For example, the structures: [ka] is the following: [ka] Includes:

[0043] As used herein, the term "heterocycloalkyl" also includes "heterocycloalkenyl," which refers to a "heterocycloalkyl" as described herein that contains at least one (e.g., 1, 2, or 3) double bond. Examples of heterocycloalkenyl groups include, but are not limited to, [ka] wherein each W is selected from CH2, NH, O and S, each Y is selected from NH, O, C(=O), SO2 and S, and each Z is selected from N and CH, with the proviso that each ring contains at least one heteroatom selected from N, O or S. For example, the heterocycloalkenyl is pyrrolinyl (e.g., 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4-pyrrolinyl or 5-pyrrolinyl), dihydrofuranyl (e.g., 1-, 2-, 3- or 4-dihydrofuran), dihydrothienyl (e.g., 1-, 2-, 3- or 4-dihydrothienyl), tetrahydropyridinyl (e.g., 1-, 2-, 3-, 4-, 5- or 6-tetrahydropyridinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl) or tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl).

[0044] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon derived by removing one hydrogen atom from a single carbon atom of an aromatic ring system. Aryl refers to a monocyclic or fused polycyclic aromatic ring structure having the specified number of ring atoms. Specifically, the term includes groups containing 6 to 14, e.g., 6 to 10, preferably 6, ring members. Representative aryl groups include phenyl and naphthyl, preferably phenyl. The term "aryl" also includes biaryls, e.g., biphenyl and binaphthyl.

[0045] As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S, and the specified number of ring atoms, or N-oxides thereof, or S-oxides or S-dioxides thereof. Specifically, the aromatic ring structure may have 5 to 10 ring members. In general, a heteroaryl ring contains up to 4 heteroatoms independently selected from O, N, and S, up to 3 heteroatoms, up to 2 heteroatoms, e.g., 1 heteroatom, where N and S may be in an oxidation state, such as S=O or S(O)2. For example, heteroaryl is a fused ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, such as benzofuran, benzothiophene, indole, benzimidazole, indazole, benzotriazole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrazolo[4,3-c]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[3,4-b]pyridine, isoindole, purine, indolizine, imidazo[1, 2-a]pyridine, imidazo[1,5-a]pyridine, 1H-pyrazolo[3,4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, quinoline, isoquinoline, cinnaline, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7-naphthyridine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrimido[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine and pyrimido[4,5-d]pyrimidine. For example, the heteroaryl can be a 5- to 6-membered heteroaryl containing one or two heteroatoms independently selected from N, O or S. Examples of 5-6 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazan, oxazolyl, oxadiazole, oxatriazolyl, isoxazole, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0046] The term "acyl" refers to the group Rx-(C=O)-, where Rx is C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-7 Alkyl, C 6-10 Aryl-C 1-7 Alkyl, 5-10 membered heteroaryl-C 1-7 Alkyl, and 3- to 12-membered heterocycloalkyl-C 1-7 each of the alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl may be selected from the following groups: halogen, hydroxy, cyano, nitro, amino, -NH(C 1-7 alkyl), -N(C 1-7 Alkyl)2, -NH(acyl), -N(acyl)2, Amino-acyl, C 1-7 Alkyl, C 1-6 Alkoxy, Halo-C 1-7 Alkyl or halo-C 1-7 It may be optionally substituted with one or more substituents selected from alkoxy.

[0047] "Halogen" and "halo" refer to fluorine, chlorine, bromo or iodo.

[0048] The term "halo-alkyl," as used herein, refers to an alkyl, as defined herein, in which one or more, e.g., 1, 2, 3, 4, 5, or all, hydrogen atoms have been replaced with halogen atoms.

[0049] The term "substituted" refers to a molecule in which at least one hydrogen atom has been replaced with a substituent. When substituted, one or more of those groups is a "substituent." A molecule may be multiply substituted.

[0050] The term "optionally" as used herein means that the subsequently described event or circumstance may be present or absent, and the description includes both the presence and absence of that event or circumstance.

[0051] "Lower aliphatic alcohol" refers to a C1-C4 alcohol, which refers to an aliphatic alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butyl alcohol, and the like.

[0052] All numerical ranges herein should be understood to disclose every numerical value within that range and every subset of numerical values ​​within that range, whether or not otherwise specifically disclosed. For example, when any numerical range is mentioned, it should be considered to refer to every numerical value within that numerical range, for example, every integer within that numerical range. The present disclosure includes all values ​​falling within these ranges, all lower ranges, and the upper or lower limits of the ranges.

[0053] All technical and scientific terms used herein and not specifically defined have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0054] Disclosed embodiments Embodiment 1 Formula (I): [ka] or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof [In the formula, R is Ra-(C=O)-; Here, Ra is C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8Cycloalkyl-C 1-7 Alkyl, C 6-10 Aryl-C 1-7 Alkyl, 5-10 membered heteroaryl-C 1-7 Alkyl, and 3- to 12-membered heterocycloalkyl-C 1-7 each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl being selected from the group consisting of halogen, acyl, hydroxy, cyano, nitro, amino, -NH(C 1-7 alkyl), -N(C 1-7 alkyl)2, -CO-NH2, -CO-NH(C 1-7 alkyl), -CO-N(C 1-7 alkyl)2, -NH(acyl), -N(acyl)2, NH2-acyl, NHRy-acyl, N(Ry)2-acyl, C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-7 Alkoxy, aryloxy, heteroaryloxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, Halo-C 2-6 Alkenyl, Halo-C 2-6 Alkynyl, Hydroxy-C 1-7 Alkyl, C 1-7 Alkoxy-C 1-7 Alkyl, halo-C 1-7 Alkoxy-C 1-7 Alkyl, halo-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 optionally substituted with one or more substituents selected from cycloalkyloxy or 3- to 12-membered heterocycloalkyloxy; Ry is C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-7 Alkyl, C6-10 Aryl-C 1-7 Alkyl, 5-10 membered heteroaryl-C 1-7 Alkyl, and 3- to 12-membered heterocycloalkyl-C 1-7 alkyl].

[0055] Preferably, Ra is C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocycloalkyl, each of which is selected from the group consisting of halogen, acyl, hydroxy, cyano, nitro, amino, -NH(C 1-7 alkyl), -N(C 1-7 alkyl)2, -CO-NH2, -CO-NH(C 1-7 alkyl), -CO-N(C 1-7 alkyl)2, -NH(acyl), -N(acyl)2, NH2-acyl, NHRy-acyl, N(Ry)2-acyl, C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-7 Alkoxy, Halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, aryloxy, heteroaryloxy, halo-C 2-6 Alkenyl, Halo-C 2-6 Alkynyl, Hydroxy-C 1-7 Alkyl, C 1-7 Alkoxy-C 1-7 Alkyl, halo-C 1-7 Alkoxy-C 1-7 Alkyl, halo-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 optionally substituted with one or more substituents selected from cycloalkyloxy or 3- to 12-membered heterocycloalkyloxy; Here, Ry is C 1-7 Alkyl, C 3-8 Cycloalkyl, C6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-7 Alkyl, C 6-10 Aryl-C 1-7 Alkyl, 5-10 membered heteroaryl-C 1-7 Alkyl, and 3- to 12-membered heterocycloalkyl-C 1-7 alkyl.

[0056] Embodiment 2 R is selected from the group: [ka] [ka] or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof, according to embodiment 1.

[0057] Embodiment 3 R is Ra-(C=O)-; Ra is methyl substituted with Ra1, Ra2 and Ra3; Ra1, Ra2 and Ra3 are H, C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkyl-O-(CH2) n -, C 1-7 Alkyl-O-aryl, C 1-7 Alkyl-O-heteroaryl, C 1-6 Alkyl-OC 1-6 Alkyl-O-(CH2) n -, C 1-6 Haloalkyl-O-(CH2) n -, C 3-6 Cycloalkyl-O-(CH2) n - and 3-6 membered heterocycloalkyl-O-(CH2) n-, wherein each of the alkyl, cycloalkyl and heterocycloalkyl is independently selected from the group consisting of: halogen, acyl, hydroxy, cyano, nitro, amino, -NH(C 1-7 alkyl), -N(C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-6 Alkoxy, Halo-C 1-7 Alkyl or halo-C 1-7 Optionally substituted with one or more substituents selected from alkoxy; and n is 0 or 1; A compound according to embodiment 1 or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0058] Embodiment 4 R is Ra-(C=O)-; Ra-(C=O)- is as follows: [ka] is selected from the group consisting of Raa is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OC 1-6 Alkyl-, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl; preferably C 1-6 selected from the group consisting of alkyl, A compound according to any one of embodiments 1 to 3, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0059] Embodiment 5 Ra-(C=O)- is: [ka] (where Raa is defined as above) or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0060] Embodiment 6 Ra-(C=O)- is: [ka] (where Raa is defined as above) or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0061] Embodiment 7 Ra-(C=O)- is: [ka] (where Raa is defined as above) or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0062] Embodiment 8 Ra-(C=O)- is: [ka] (where Raa is defined as above) or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0063] Embodiment 9 Raa is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl-OC 1-4 Alkyl-, C 3-5 The compound according to any one of embodiments 1 to 8, wherein the compound is selected from the group consisting of cycloalkyl and 4-6 membered heterocycloalkyl, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0064] Embodiment 10 A compound according to any one of embodiments 1 to 9, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof, wherein Ra is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, 2-methoxyethyl, fluoro-substituted ethyl, fluoro-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydro-2-furanyl, tetrahydro-3-furanyl or tetrahydro-2H-pyran-4-yl; preferably, methyl, ethyl, propyl, isopropyl, oxetanyl and tetrahydro-2H-pyran-4-yl.

[0065] Embodiment 11. The compound of any one of embodiments 1 to 10, or a tautomer, stereoisomer, or racemate thereof, or a pharma- ceutically acceptable salt thereof, wherein Ra is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, and sec-butyl.

[0066] Embodiment 12 Ra1 and Ra3 are H, C 1-6 Alkyl, C 1-6 Alkyl-O- and C 1-6 independently selected from the group consisting of alkyl-O-CH2-; Ra2 is C 1-6 Alkyl, C 1-6 Alkyl-O- and C 1-6 alkyl-O-CH2-; or Ra2 and Ra3, together with the carbon to which they are attached, form C 3-6 cycloalkyl, or O, forming a 5-6 membered haloheterocycloalkyl, A compound according to any one of embodiments 1 to 3, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0067] Embodiment 13 Ra1 is C 1-6 Alkyl, C 1-6 Alkyl-O- and C 1-613. The compound according to any one of embodiments 1 to 12, selected from the group consisting of alkyl-O-CH2-, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0068] Embodiment 14 Ra3 is C 1-6 Alkyl, C 1-6 Alkyl-O- and C 1-6 14. The compound according to any one of embodiments 1 to 13, selected from the group consisting of alkyl-O-CH2-, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0069] Embodiment 15 Ra1 is C 1-6 Alkyl-O- or C 1-6 alkyl-O-CH2-, Ra2 is C 1-6 Alkyl, C 1-6 Alkyl-O- and C 1-6 alkyl-O-CH2-; and Ra3 is H, C 1-6 Alkyl, C 1-6 Alkyl-O- and C 1-6 alkyl-O-CH2-; A compound according to any one of embodiments 1 to 3, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0070] Embodiment 16 Ra1 is C 1-6 alkyl-O-; Ra2 is C 1-6 is alkyl, and Ra3 is H or C 1-6 is alkyl, A compound according to any one of embodiments 1 to 3, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0071] Embodiment 17 Ra1 is C 1-6 alkyl-O-CH2-, and Each of Ra2 and Ra3 is C1-6 is alkyl, A compound according to any one of embodiments 1 to 3, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0072] Embodiment 18 Ra1 is C 1-6 Alkyl-O- or C 1-6 alkyl-O-CH2-, and Each of Ra2 and Ra3 is C 1-6 alkyl-O-CH2-; A compound according to any one of embodiments 1 to 17, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0073] Embodiment 19: Ra1 is C 1-6 alkyl-O-CH2, and One of Ra2 and Ra3 is C 1-6 alkyl and the other is C 1-6 alkyl-O-CH2; A compound according to any one of embodiments 1 to 18, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0074] Embodiment 20 Ra1 is C 1-6 alkyl-O-; and Ra2 and Ra3 are independently C 1-3 alkyl, preferably, Ra2 and Ra3 are the same; A compound according to any one of embodiments 1 to 19, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0075] Embodiment 21 Ra1 is C 1-6 Alkyl-O- or C 1-6 alkyl-O-CH2-, and Ra2 and Ra3, together with the carbon to which they are attached, form C 3-6 forming a cycloalkyl, A compound according to any one of embodiments 1 to 20, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0076] Embodiment 22 Ra1 is H, C 1-6 Alkyl, C 1-6 Alkyl-O- and C 1-6 alkyl-O-CH2-; and Ra2 and Ra3 together with the carbons to which they are attached form a 5-6 membered haloheterocycloalkyl comprising one ring heteroatom selected from O; Preferably, Ra1 is C 1-6 Alkyl, C 1-6 Alkyl-O- and C 1-6 alkyl-O-CH2-; 22. A compound according to any one of embodiments 1 to 21, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0077] Embodiment 23 R 1 is RaC=O, and R 2 and R 3 each of which is H, A compound according to any one of embodiments 1 to 22, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0078] Embodiment 24 R 1 , R 2 and R 3 Each of the following is RaC=O:

[0079] Embodiment 25 Ra1 is C 1-6 25. The compound according to any one of embodiments 1 to 24, wherein R is alkyl-O-, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0080] Embodiment 26 Ra-(C=O)- is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] 26. The compound according to any one of embodiments 1 to 25, selected from the group consisting of:

[0081] Embodiment 27. The compound of claim 2, wherein the compound is: [Table 1-1] [Table 1-2]

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

[0082] Embodiment 28 A method for preparing a compound of formula I as described in any one of embodiments 1 to 27, comprising the steps of: Reacting the NHC with an acid anhydride of formula II to obtain a compound of formula I. [ka] (wherein Ra is defined in any one of embodiments 1 to 27). The method comprising:

[0083] Embodiment 29. The method according to embodiment 28, wherein the reaction is carried out in water or a mixture of water and an organic solvent, preferably the reaction solvent is selected from pure water, methanol, ethanol, propanol, isopropanol, other lower aliphatic alcohols or mixtures of aliphatic alcohols, DMF, DMSO, NMP, water-methanol mixtures, water-ethanol mixtures, water-propanol mixtures, water-isopropanol mixtures, water-n-butanol mixtures, water-sec-butanol mixtures, water-isobutanol mixtures, water-THF mixtures, water-ACN mixtures, water-DMF mixtures, water-DMSO mixtures, water / 2-methylTHF mixtures, or any mixture of water and an organic solvent capable of dissolving the NHC completely or partially; more preferably water, a lower aliphatic alcohol, a water-lower aliphatic alcohol mixture, a water-THF mixture, a water / 2-methylTHF mixture, a water / ACN mixture.

[0084] Embodiment 30 The reaction is carried out in the presence of an inorganic or organic base (or catalyst), such as an alkali metal hydroxide, carbonate, bicarbonate, alkoxide or hydride, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, or sodium hydride, or an organic tertiary amine, such as tri-C1-4 30. The method of embodiment 28 or 29, performed without the addition of an alkylamine, such as TEA, diisopropylethylamine, tripropylamine, tributylamine, or a heterocyclic base, such as pyridine, picoline, lutidine, DMAP, DBU, and the like.

[0085] Embodiment 31 The reaction is carried out in the presence of an inorganic or organic base (or catalyst), such as an alkali metal hydroxide, carbonate, bicarbonate, alkoxide or hydride, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, or sodium hydride, or an organic tertiary amine, such as tri-C 1-4 30. The method of embodiment 28 or 29, wherein the method is carried out in the presence of an alkylamine, such as TEA, diisopropylethylamine, tripropylamine, tributylamine, or a heterocyclic base, such as pyridine, picoline, lutidine, DMAP, DBU, and the like.

[0086] Embodiment 32. The method of any one of embodiments 28 to 31, wherein the product is obtained in solid crystalline form by cooling the reaction mixture without adding an anti-solvent.

[0087] Embodiment 33. The method of any one of embodiments 28 to 32, wherein the product is obtained in solid crystalline form without undergoing chromatographic purification.

[0088] Embodiment 34. The method of any one of embodiments 28 to 33, wherein the purity of the product produced in the reaction solution is about 90% to 98%.

[0089] Embodiment 35. The method of any one of embodiments 28-33, wherein the purity of the product produced in the reaction solution is greater than 98%.

[0090] Embodiment 36. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 27, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable excipient.

[0091] Embodiment 37. Use of a compound of any one of embodiments 1 to 27, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing an RNA viral infection.

[0092] EMBODIMENT 38 Use according to embodiment 29, wherein the RNA virus is a coronavirus, such as a human coronavirus, a SARS-coronavirus or a MERS-coronavirus, an alphavirus, such as an Eastern Equine Encephalitis Virus, a Western Equine Encephalitis Virus, a Venezuelan Equine Encephalitis Virus, a Chikungunya Virus, a Ross River Virus or a Barmah Forest Virus, a Filoviridae virus, such as an Ebola virus, an Orthomyxoviridae virus, such as an Influenza virus, Influenza A virus or Influenza B virus, a Paramyxoviridae virus, such as a Respiratory Syncytial Virus (RSV), a Flavivirus, such as a Zika virus or a Powassan virus; preferably a SARS-CoV-2 / COVID-19 virus, a SARS-CoV-2 / COVID-19 virus alpha mutant, a SARS-CoV-2 / COVID-19 virus beta mutant, a SARS-CoV-2 / COVID-19 virus gamma mutant, a SARS-CoV-2 / COVID-19 virus delta mutant, or any other mutant of the SARS-CoV-2 / COVID-19 virus.

[0093] Embodiment 39. A method of treating or preventing an RNA viral infection in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-27, or a tautomer, stereoisomer, or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0094] Embodiment 40 The method of embodiment 31, wherein the RNA virus is a coronavirus, such as a human coronavirus, a SARS-coronavirus or a MERS-coronavirus, an alphavirus, such as an Eastern Equine Encephalitis Virus, a Western Equine Encephalitis Virus, a Venezuelan Equine Encephalitis Virus, a Chikungunya virus or a Ross River Virus, a Filoviridae virus, such as an Ebola virus, an Orthomyxoviridae virus, such as an Influenza virus, Influenza A virus or Influenza B virus, a Paramyxoviridae virus, such as a Respiratory Syncytial Virus (RSV), a Flavivirus, such as a Zika virus; preferably a SARS-CoV-2 / COVID-19 virus, a SARS-CoV-2 / COVID-19 virus alpha mutant, a SARS-CoV-2 / COVID-19 virus beta mutant, a SARS-CoV-2 / COVID-19 virus gamma mutant, a SARS-CoV-2 / COVID-19 virus delta mutant, or any other mutant of the SARS-CoV-2 / COVID-19 virus.

[0095] Embodiment 41 A compound of any one of embodiments 1 to 27 or a tautomer, stereoisomer or racemate thereof or a pharma- ceutically acceptable salt thereof for use as a medicament.

[0096] Embodiment 42. A compound of any one of embodiments 1 to 27, or a tautomer, stereoisomer or racemate thereof, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of an RNA viral infection.

[0097] Embodiment 43 The compound for use according to embodiment 34, wherein the RNA virus is a coronavirus, such as a human coronavirus, a SARS-coronavirus or a MERS-coronavirus, an alphavirus, such as an Eastern Equine Encephalitis Virus, a Western Equine Encephalitis Virus, a Venezuelan Equine Encephalitis Virus, a Chikungunya virus or a Ross River Virus, a Filoviridae virus, such as an Ebola virus, an Orthomyxoviridae virus, such as an Influenza virus, Influenza A virus or Influenza B virus, a Paramyxoviridae virus, such as a Respiratory Syncytial Virus (RSV), a Flavivirus, such as a Zika virus; preferably a SARS-CoV-2 / COVID-19 virus, a SARS-CoV-2 / COVID-19 virus alpha mutant, a SARS-CoV-2 / COVID-19 virus beta mutant, a SARS-CoV-2 / COVID-19 virus gamma mutant, a SARS-CoV-2 / COVID-19 virus delta mutant, or any other mutant of the SARS-CoV-2 / COVID-19 virus.

[0098] Embodiment 44: N is a compound used to treat or prevent an RNA viral infection. 4 28. A method for increasing the bioavailability of -hydroxycytidine, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-27, or a tautomer, stereoisomer, or racemate thereof, or a pharma- ceutically acceptable salt thereof.

[0099] Embodiment 45 A pharmaceutical combination comprising a compound of any one of embodiments 1 to 27 or a tautomer, stereoisomer or racemate thereof or a pharma- ceutically acceptable salt thereof and at least one further therapeutic agent.

[0100] Embodiment 46 The further therapeutic agent is selected from the group consisting of: [ka] The pharmaceutical combination according to embodiment 37, wherein the compound is selected from the group consisting of:

[0101] How to use According to the present disclosure, the RNA virus can be a coronavirus, such as a human coronavirus, a SARS coronavirus, or a MERS coronavirus; an alphavirus, such as an Eastern equine encephalitis virus, a Western equine encephalitis virus, a Venezuelan equine encephalitis virus, a Chikungunya virus, or a Ross River virus; a Filoviridae virus, such as an Ebola virus; an Orthomyxoviridae virus, such as an influenza virus, influenza A virus (including subtypes H1N1, H3N2, H7N9, or H5N1), influenza B virus, or influenza C virus; a Paramyxoviridae virus, , for example, respiratory syncytial virus (RSV), flaviviruses, for example, Zika virus, rotaviruses, for example, group A rotavirus, group B rotavirus, group C rotavirus, group D rotavirus, group E rotavirus; preferably, SARS-CoV-2 / COVID-19 virus, SARS-CoV-2 / COVID-19 virus alpha mutant, SARS-CoV-2 / COVID-19 virus beta mutant, SARS-CoV-2 / COVID-19 virus gamma mutant, SARS-CoV-2 / COVID-19 virus delta mutant, or any other mutant of SARS-CoV-2 / COVID-19 virus.

[0102] Preferably, according to the present disclosure, the RNA virus is a human coronavirus, a SARS coronavirus, a MERS coronavirus, an Eastern equine encephalitis virus, a Western equine encephalitis virus, a Venezuelan equine encephalitis virus, a Chikungunya virus, a Ross River virus, an Orthomyxoviridae virus, a Paramyxoviridae virus, a RSV virus, an Influenza A virus, an Influenza B virus, a Filoviridae virus, or an Ebola virus.

[0103] More preferably, according to the present disclosure, the RNA virus is a human coronavirus, a SARS-CoV-2 / COVID-19 virus, a SARS-CoV-2 / COVID-19 virus alpha mutant, a SARS-CoV-2 / COVID-19 virus beta mutant, a gamma mutant SARS-CoV-2 / COVID-19 virus, a delta mutant SARS-CoV-2 / COVID-19 virus, or any other mutant of a SARS-CoV-2 / COVID-19 virus.

[0104] According to the disclosure, the subject is a virus that is a human coronavirus, such as SARS-CoV-2 / COVID-19 virus, influenza A virus (including subtypes H1N1, H3N2, H7N9, or H5N1), influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus (HAdV-1 to 55), type 16, Human papillomavirus (HPV) types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, group A coxsackievirus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCMV), dengue virus, Zika virus, chikungunya, eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV), Virus (WEEV), Venezuelan equine encephalitis virus (VEEV), Ross River virus, Barmah Forest virus, yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, Ebola virus, Marburg virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus, In some embodiments, the subject is at risk for, has symptoms of, or has been diagnosed with, an EBV, a cytomegalovirus (CMV), a herpes lymphotropic virus, a roseolovirus, or a Kaposi's sarcoma-associated herpes virus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, or a human immunodeficiency virus (HIV), a human T-lymphotropic virus type I (HTLV-1), a Friend spleen-limited forming virus (SFFV), or a xenotropic MuLV-related virus (XMRV). In some embodiments, the subject is at risk for, has symptoms of, or has been diagnosed with, a Zika virus infection.

[0105] According to the present invention, the subject has been diagnosed with SARS-CoV-2 / COVID-19 virus, including a SARS-CoV-2 / COVID-19 virus alpha mutant, a SARS-CoV-2 / COVID-19 virus beta mutant, a SARS-CoV-2 / COVID-19 virus gamma mutant, a SARS-CoV-2 / COVID-19 virus delta mutant, or any mutant of the SARS-CoV-2 / COVID-19 virus treatable by a compound of formula (I) or a medicament containing a compound of formula (1).

[0106] According to the present invention, the subject is influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low pass type), and H5N1 (high pass type), influenza B, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus (HAdV-1 to 55), types 16, 18, 31, 33, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 101, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, Human papillomavirus (HPV) types 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, group A coxsackievirus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, and types 1 and 3 papillomavirus. Influenza virus, Rinderpest virus, Chikungunya, Eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), Western equine encephalitis virus (WEEV), California encephalitis virus, Japanese encephalitis virus, Rift Valley fever virus (RVFV), Hantavirus, Dengue virus serotypes 1, 2, 3 and 4, Zika virus, West Nile virus, Tacaribe virus, Junin virus, Rabies virus, Ebola virus, Marsh virus, The subject has been diagnosed with Rubruga virus, adenovirus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpes virus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV). In certain embodiments, the subject has been diagnosed with Zika virus infection.

[0107] According to the present invention, the subject has been diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fever, acquired immune deficiency syndrome or hepatitis.

[0108] Pharmaceutical Compositions and Administration The compounds of the invention (e.g., any of the compounds of the Examples herein), alone or in combination with one or more additional therapeutic agents, can be formulated as pharmaceutical compositions comprising (a) an effective amount of a compound of the invention; (b) a pharma- ceutical acceptable excipient (e.g., one or more pharma- ceutical acceptable carriers); and, optionally, (c) at least one additional therapeutic agent.

[0109] Pharmaceutically acceptable excipient refers to an excipient that is compatible with the active ingredient in the composition (in some embodiments, it can stabilize the active ingredient) and is not harmful to the subject being treated.Suitable pharmacopoeia acceptable excipients are disclosed in standard reference books in the field (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy), and include one or more of buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweeteners, aromas, flavoring agents, diluents and other known additives for providing delicate dosage form of drug (i.e., the compound of the present invention or its pharmaceutical composition) or for assisting in the manufacture of pharmaceutical preparations (i.e., medicaments).

[0110] The compounds of the present invention can be administered in a variety of known ways, such as orally, parenterally, by inhalation, or via the lungs, i.e., pulmonary, nasal, sublingual, lingual, buccal, rectal, intradermal, transdermal, conjunctival, auricular, or as an implant or stent. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion.

[0111] Oral or parenteral administration, particularly oral administration, is preferred.

[0112] The compounds of the present invention can be administered in any convenient form, such as, for example, tablets, powders, capsules, pills, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, saline or aqueous buffers such as phosphate buffers, etc. Such compositions may contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH modifiers, sweeteners, bulking agents, and additional active agents.

[0113] In general, to achieve effective results, it has been found to be advantageous to administer an amount of about 0.001-20 mg / kg, preferably about 0.01-10 mg / kg body weight for parenteral administration, whereas for oral administration, the dosage is about 0.01-100 mg / kg, preferably about 0.01-20 mg / kg, most preferably 0.1-15 mg / kg body weight.

[0114] Combination Therapy The compounds described herein can be administered with at least one additional therapeutic agent.

[0115] The additional therapeutic agent includes, but is not limited to, analgesics, anti-inflammatory agents, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinic drugs, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatic drugs, cardiovascular drugs, corticosteroids, dopaminergic drugs, electrolytes, gastrointestinal drugs, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, appetite suppressants, antihypnotics, and antiviral drugs.In certain embodiments, the antiviral drug is a non-CNS targeting antiviral compound.As used herein, "adjunctive administration" means that the compound can be administered in the same dosage form as one or more other active agents or in a different dosage form.The additional therapeutic agent can be formulated for immediate release, controlled release, or a combination thereof.

[0116] The compounds and pharmaceutical compositions of the invention may be administered in combination with at least one further therapeutic agent, e.g., an antiviral agent, such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, valapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, GS-5734, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lavir, Mivudine, Lediparvir, Lopinavir, Loviride, Maraviroc, Moroxydine, Methisazone, Nelfinavir, Nevirapine, Nexavir, NITD008, Ombitasvir, Oseltamivir, Paritaprevir, Peginterferon alfa-2a, Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Raltegravir, Ribavirin, Rimantadine, Ritonavir, Pyramidine, Saquinavir, Simeprevir , sovosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, molnupiravir or zidovudine and combinations thereof.

[0117] The compounds of the invention and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in WO 2012 / 119559 for the treatment of SARS-CoV-2 / COVID-19 infection.

[0118] The compounds of the invention and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in WO 2012 / 119559 for the prevention of SARS-CoV-2 / COVID-19 infection.

[0119] The compounds of the present invention and the pharmaceutical compositions disclosed herein are useful in the treatment of SARS-CoV-2 / COVID-19 infections, including proxalutamide [ka] It can be administered in combination with

[0120] The compounds of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with proxalutamide for the prevention of SARS-CoV-2 / COVID-19 infection.

[0121] The compounds of the present invention and the pharmaceutical compositions disclosed herein are useful as compounds of Compound-X for the treatment of SARS-CoV-2 / COVID-19 infection. [ka] It can be administered in combination with

[0122] The compounds of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with Compound-X for the prevention of SARS-CoV-2 / COVID-19 infection.

[0123] The compounds of the present invention and the pharmaceutical compositions disclosed herein are useful in the treatment of SARS-CoV-2 / COVID-19 infection, including, but not limited to, PF-07321332 [ka] It can be administered in combination with

[0124] The compounds of the present invention and pharmaceutical compositions disclosed herein can be administered in combination with PF-07321332 for the prevention of SARS-CoV-2 / COVID-19 infection.

[0125] Thus, the present disclosure also provides a pharmaceutical combination comprising a compound of the present invention and at least one additional therapeutic agent, examples of which include, but are not limited to, those mentioned above, preferably proxalutamide, compound-X and PF-07321332.

[0126] The percentages in the following tests and examples are percentages by weight and parts by weight unless otherwise indicated. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are in all cases based on volume.

[0127] It should be understood that each embodiment and technical solution described in the present disclosure, as well as the features in each embodiment and technical solution, can be combined with each other in any manner, and those technical solutions obtained by such combinations are all included in the scope of the present disclosure as if each and every technical solution obtained by such combination was specifically and individually described, unless the context clearly indicates otherwise.

[0128] All patents, patent applications, publications, and other references cited or referred to herein are hereby incorporated by reference in their entirety to the extent permitted by law. The discussion of these references is intended merely to summarize the assertions made therein. It is not an admission that such patents, patent applications, publications, or references, or any portion thereof, are relevant material or prior art. The right to challenge the accuracy and validity of assertions that such patents, patent applications, publications, and other references are relevant material or prior art is specifically reserved. EXAMPLES

[0129] Examples are provided below to illustrate compositions, methods, and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but are intended to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention that are obvious to those skilled in the art.

[0130] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some error and variation should be accounted for. Parts are parts by weight unless otherwise indicated. Numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions, can be used to optimize the purity and yield of the products obtained from the methods described. Only reasonable and routine experimentation is required to optimize such methods and conditions.

[0131] All reagents and starting materials used in the present invention are either commercially available or prepared according to conventional techniques, unless otherwise indicated.

[0132] 1 H NMR spectra were recorded on a Bruker 400 MHz instrument and chemical shifts were measured relative to the appropriate solvent peaks: CDCl3 (δ 7.27), DMSO-d6 (δ 2.50), CD3OD (δ 3.31), DO (δ 4.79). The following abbreviations were used to describe couplings: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, br = broad line. 13 C NMR spectra were measured on a Bruker instrument at 100 MHz as chemical shifts relative to the appropriate solvent peaks: CDCl3 (δ 77.0), DMSOd6 (δ 39.5), CD3OD (δ 49.0).

[0133] Abbreviations and Acronyms aq. aqueous solution calc. theoretical value br s broad line singlet (NMR) DCI Direct Chemical Ionization (MS) dec. decomposition point DMF Dimethylformamide DMSO Dimethyl sulfoxide DSC Dynamic Differential Calorimetry eq. equivalent amount ESI electrospray ionization (MS) Et Ethyl fnd. Measurements h time HPLC High Pressure High Performance Liquid Chromatography HRMS high resolution mass spectrometry conc. LC-MS Liquid Chromatography-Mass Spectrometry LiHMDS Lithium hexamethyldisilazide Me Methyl min MS mass spectrometry NMR nuclear magnetic resonance spectroscopy Pd2 dba3 Tris(dibenzylideneacetone)dipalladium Ph Phenyl PLM Polarizing Microscope RT room temperature Rt retention time (HPLC) TGA thermogravimetric analysis THF Tetrahydrofuran UV ultraviolet spectroscopy v / v volume / volume ratio (of a solution)

[0134] Preparation of Starting Materials and Intermediates Method 1 :Synthesis of alkoxy-substituted propionic acids and anhydrides. [ka] Procedure for the synthesis of (R)-2-methoxypropanoic acid (I-3) and anhydride (I-4): (S)-2-Chloropropanoic acid (80.0 g, 738 mmol, 1 equiv, 98%) was added to a two-neck round bottom flask under nitrogen. Sodium methoxide 25 wt% in methanol (506 mL, 2.212 mol, 3 equiv) was added slowly. The reaction was heated to 60° C. for 16 h and the conversion was monitored until less than 2% starting material remained. When sufficient conversion was achieved, the reaction vessel was cooled to room temperature and the pH was adjusted with 4 M HCl in dioxane (200 mL, 99%) to the point where the pH just changed from >12 to 7, indicating neutralization of excess sodium methoxide without protonating the sodium salt of the carboxylate. The reaction mixture was filtered to remove the salt and the salt mass was washed twice with 5 mL of methanol. The filtrate was concentrated, redissolved in water, acidified to pH=~2 with 6 M HCl, and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated to give compound (I-3) as a liquid (73 g, 95%), which was pure enough to be used without purification. 1 H NMR (CD3OD) δ 3.67 (q, 1H), 3.33 (s, 3H), and 1.33 ppm (d, 3H).

[0135] A 2-liter, four-necked glass reactor equipped with a thermometer and stirrer was charged with 500 g of methylene chloride, 104.1 g (1.0 mol) of (R)-2-methoxypropanoic acid (3) and 57.3 g (0.5 mol) of methanesulfonyl chloride under a nitrogen atmosphere. The mixture was cooled to 5°C.

[0136] Next, 101.3 g (1.0 mol, 1 equivalent relative to the acid generated from methanesulfonyl chloride) of triethylamine was added dropwise over 2 hours while controlling the temperature of the reaction mixture below 30° C. After the addition was completed, stirring was maintained at the same temperature for 1 hour. Analysis of the reaction mixture by gas chromatography (GC) showed that the conversion of (R)-2-methoxypropanoic acid (3) was >95%.

[0137] After the reaction was completed, 200 g of water was added to the reaction mixture to wash the reaction mixture. The reaction mixture was further washed with 200 g of water each time, and then distillation was carried out to remove methylene chloride. 85.6 g of (R)-2-methoxypropanoic anhydride (I-4) was obtained as a yellow liquid, which was used in the acylation step without further purification.

[0138] The following 2-alkoxyl substituted propionic anhydrides were prepared similarly to that described in Preparation 1: [ka]

[0139] Method 2 :Synthesis of alkoxy-substituted isobutyric acids and anhydrides. Procedure for the synthesis of 2-ethoxyisobutyric acid / 2-ethoxy-2-methylpropanoic acid (I-21) and anhydride (I-22): [ka] 2-Ethoxyisobutyric acid was prepared according to the references (Ragan, John A.; Ide, Nathan D.; Cai, Weiling; Cawley, James J.; Colon-Cruz, Roberto; Kumar, Rajesh; Peng, Zhihui; Vanderplas, Brian C. [Organic process research and development, 2010, vol. 14, # 6, p. 1402 - 1406]): In a 500 mL three-neck round bottom flask, 2-bromo-2-methylpropanoic acid (I-20) (40 g, 239.5 mmol) was dissolved in ethanol (320 mL) and cooled to 0-5 °C. Then, DIPEA (87.4 mL, 502.9 mmol) was added dropwise at 0-5 °C and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was warmed to 40 °C for 16 h. After 16 h, the reaction mixture was cooled to room temperature and the ethanol was removed in vacuo leaving a thick white slurry. To this slurry was added diethyl ether and water and cooled to 0° C. The mixture was acidified with 10% HC1 (50 mL) and the organic layer was separated and washed with brine. To the organic phase was added 10% aqueous NaHSO3 and the mixture was stirred at room temperature for 6 h. The biphasic mixture was acidified to pH 1.0±0.5 with 10% HC1 (50 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to give 30 g of 2-ethoxy-2-methylpropanoic acid (I-21). The product 2-ethoxy-2-methylpropanoic acid (I-21) was carried on to the next step without further purification.

[0140] A 2-liter four-neck glass reactor equipped with a thermometer and stirrer was charged under a nitrogen atmosphere with 300 g of methylene chloride, 66.1 g (0.5 mol) of 2-ethoxy-2-methylpropanoic acid (I-21) and 28.65 g (0.25 mol) of methanesulfonyl chloride. The mixture was cooled to 5°C.

[0141] Next, 50.65 g (0.5 mol, 1 equivalent relative to the acid generated from methanesulfonyl chloride) of triethylamine was added dropwise over 2 hours while controlling the temperature of the reaction mixture below 30° C. After the addition was completed, the mixture was stirred for 1 hour while maintaining the same temperature. Analysis of the reaction mixture by gas chromatography (GC) showed that the conversion of 2-ethoxy-2-methylpropanoic acid (I-21) was >95%.

[0142] After the reaction was completed, 100 g of water was added to the reaction mixture to wash the reaction mixture. The reaction mixture was further washed with 100 g of water each time, and then distillation was carried out to remove methylene chloride. 51 g of 2-ethoxy-2-methylpropanoic anhydride (I-22) was obtained as a yellow liquid, which was used in the acylation step without further purification.

[0143] The following 2-alkoxyl-substituted 2-methylpropionic acid / 2-alkoxyl-substituted isobutyric anhydrides were prepared similarly to that described in Preparation 1. [ka]

[0144] Method 3 Synthesis of 4-alkoxytetrahydro-2H-pyran-4-carboxylic acids and anhydrides Procedure for the synthesis of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid (I-36) and anhydride (I-37): Commercially available methyl tetrahydro-2H-pyran-4-carboxylate was brominated according to the method described in Organic Letters, 2020, vol. 22, # 10, p. 3922-3925. The ester was then hydrolyzed to the corresponding α-bromo acid (I-35). The α-bromo acid (I-35) was then converted to the corresponding acid (I-36) and anhydride (I-37) according to the method of Preparation 2. [ka]

[0145] The following 4-alkoxytetrahydro-2H-pyran-4-carboxylic acids and anhydrides were similarly prepared: [ka]

[0146] Method 4 Synthesis of 4-alkyltetrahydro-2H-pyran-4-carboxylic acids and anhydrides Procedure for the synthesis of 4-methyltetrahydro-2H-pyran-4-carboxylic acid (I-46) and anhydride (I-47): [ka] Commercially available tetrahydro-2H-pyran-4-carboxylic acid methyl ester (I-33) was methylated similarly as described in Example 64.1A of US Pat. No. 9,434,690. The methyl ester was hydrolyzed with aqueous NaOH and acidified with HCl to give 4-methyltetrahydro-2H-pyran-4-carboxylic acid (I-46) as an off-white solid.

[0147] 4-Methyltetrahydro-2H-pyran-4-carboxylic anhydride (I-47) was prepared as a yellowish oil following the method of Preparation 2.

[0148] The following 4-alkyltetrahydro-2H-pyran-4-carboxylic acid anhydrides were prepared similarly: [ka]

[0149] Recipe 5 Synthesis of 2-ethyl-2-alkoxy-butyric acids and anhydrides Procedure for the synthesis of 2-ethyl-2-methoxyl-butyric acid (I-62) and anhydride (I-63): [ka] 2-Ethyl-2-bromo-butyric acid (I-61) is commercially available or can be prepared according to the procedure described by Doran; Shonle in Journal of Organic Chemistry, 1938, vol. 3, p. 195.

[0150] As described in Preparation 2, 2-ethyl-2-bromo-butyric acid (I-61) was first converted to ethyl-2-methoxy-butyric acid (I-62) and then to ethyl-2-methoxy-butyric anhydride (I-63) as a pale yellow oil.

[0151] The following s and anhydrides were prepared similarly: [ka]

[0152] Recipe 6 Synthesis of 2-methyl-2-alkoxy-butyric acids and anhydrides Procedure for the synthesis of 2-methyl-2-methoxyl-butyric acid (I-72) and anhydride (I-73): Commercially available (R,S)-2-hydroxy-2-methylbutyric acid (I-70) was resolved into enantiomerically pure R and S isomers (I-71) and then esterified to the methyl ester (I-72) as described in Method 74 of U.S. Patent Application Publication No. 2008 / 114005. [ka]

[0153] Alternatively, commercially available 2-bromo-2-methylbutanoic acid was converted to (R,S)-2-methoxy-2-methylbutyric acid (I-78) according to the method disclosed in Preparation 2, and (I-78) was resolved into the enantiomers (I-80) and (I-77) according to the method described in Preparation 74 of U.S. Patent Application Publication No. 2008 / 114005. The chiral acid (I-75) was then converted to the anhydride (I-76) as an oil, as described in Preparation 2. [ka]

[0154] The following and the anhydrides were prepared similarly: [ka]

[0155] Recipe 7 Synthesis of 2-alkyltetrahydrofuran-2-carboxylic acids and anhydrides Procedure for the synthesis of 2-methyltetrahydrofuran-2-carboxylic acid (I-112), (I-114) and anhydrides (I-113), (I-115): Enantiomerically pure 2-methyltetrahydrofuran-2-carboxylic acids (I-112) and (I-114) were prepared according to the method described by Pohl; Wollweber in European Journal of Medicinal Chemistry, 1976, vol. 11, p. 163, 168, 169. These acids were then converted into the corresponding anhydrides (I-113) and (I-115) in a manner similar to that described in Preparation 2. [ka]

[0156] The following 2-alkyltetrahydrofuran-2-carboxylic acids and anhydrides were similarly prepared: [ka]

[0157] Recipe 8 Synthesis of 2-methyl-2-alkoxymethylpropionic acids and anhydrides Synthesis of 2-methyl-2-methoxymethylpropionic acid (I-130) and anhydride (I-131): [ka] Using the methods described in Examples 55 and 56 of WO 2009 / 77608 (2009), commercially available 2-methyl-2-hydroxymethylpropionic acid methyl ester (I-128) was first methylated and the ester was then hydrolyzed to give 2-methyl-2-methoxymethylpropionic acid (I-130).

[0158] 2-Methyl-2-methoxymethylpropionic acid (I-130) was then converted to the anhydride (I-131) following the method of Preparation 2, which was obtained as an oil.

[0159] The following 2-methyl-2-alkoxymethylpropionic anhydrides were similarly prepared: [ka]

[0160] Recipe 9 1-Alkyl, 2,2-dialkoxy-isobutyric acids and their synthetic derivatives Procedure for the synthesis of 1-methyl-2,2-dimethoxy-isobutyric acid (I-142) and anhydride (I-143): [ka] 1-Methyl-2,2-dimethoxy-isobutyric acid (I-142) was prepared according to the procedure described in Reference Example 14 of US Patent Application Publication No. 2004 / 248941. [ka]

[0161] Alternatively, 1-methyl-2,2-dimethoxy-isobutyric acid (I-142) was prepared from commercially available 2,2-bis(hydroxymethyl)propanoic acid according to reference example 14 of EP 1 437 352.

[0162] 1-Methyl-2,2-dimethoxy-isobutyric acid (I-142) was then converted to the anhydride (I-143) following the method of Preparation 2, which was obtained as an oil.

[0163] The following 1-alkyl-2,2-dialkoxy-isobutyric acids and anhydrides were similarly prepared: [ka] [ka] [ka] [ka]

[0164] Recipe 10 Synthesis of 1-(alkoxymethyl)cyclopropane-1-carboxylic acids and anhydrides Procedure for the synthesis of 1-(methoxymethyl)cyclopropane-1-carboxylic acid (I-225) and anhydride (I-226) [ka] 1-(hydroxymethyl)cyclopropane-1-carboxylic acid methyl ester (I-223) was prepared according to the procedure described in US Pat. No. 9,546,155, Reference Example 22-1. The hydroxy group was then alkylated with methyl iodide using a method similar to that described by Shen, Peng-Xiang; et al. in Journal of the American Chemical Society, 2018, vol. 140, # 21, p. 6545-6549. The ester was then hydrolyzed to obtain 1-(methoxymethyl)cyclopropane-1-carboxylic acid (I-225).

[0165] 1-(Methoxymethyl)cyclopropane-1-carboxylic acid (I-225) was then converted to the anhydride (I-226) following the method of Preparation 2 to give (I-226) as an oil.

[0166] The following 1-(alkoxymethyl)cyclopropane-1-carboxylic acids and anhydrides were similarly prepared: [ka]

[0167] Recipe 11 Synthesis of 1-(alkoxymethyl)cyclobutane-1-carboxylic acids and anhydrides Procedure for the synthesis of 1-(methoxymethyl)cyclobutane-1-carboxylic acid (I-238) and anhydride (I-239): [ka] 1-(hydroxymethyl)cyclobutane-1-carboxylic acid methyl ester (I-236) was prepared according to the procedure described in Reference Example 22-4 of US Patent 9,546,155. The hydroxy group was then alkylated with methyl iodide, followed by hydrolysis of the ester, to give 1-(methoxymethyl)cyclobutane-1-carboxylic acid (I-238), using a method similar to that described in Reference Example K-19 of US Patent 1,004,0791.

[0168] 1-(Methoxymethyl)cyclobutane-1-carboxylic acid (I-238) was then converted to the anhydride (I-239) following the method of Preparation 2, which was obtained as an oil.

[0169] The following 1-(alkoxymethyl)cyclobutane-1-carboxylic acids and anhydrides were similarly prepared: [ka]

[0170] Recipe 12 Synthesis of 1,2,2-trialkoxy-isobutyric acids and anhydrides. Procedure for the synthesis of 1-methoxy-2,2-diethoxy-isobutyric acid (223) and anhydride (224): [ka] 1-Hydroxy-2,2-diethoxy-isobutyric acid ethyl ester (I-249) was prepared according to the procedure described by Bernardon, C. et al. in Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1968, vol. 266, p. 1502-1505. The hydroxy group was then alkylated with methyl iodide, followed by hydrolysis of the ester to give 1-methoxy-2,2-diethoxy-isobutyric acid (I-251), using a method similar to that described in Reference Example K-19 of US Patent No. 10040791.

[0171] 1-Methoxy-2,2-diethoxy-isobutyric acid (I-251) was then converted to the anhydride (I-252) following the method of Preparation 2, which was obtained as an oil.

[0172] The following 1-alkoxy-2,2-dialkoxy-isobutyric acids and anhydrides were similarly prepared: [ka] [ka]

[0173] Recipe 13 :Synthesis of 1-alkoxycyclobutanecarboxylic acids and anhydrides Procedure for the synthesis of 1-methoxycyclopropane carboxylic acid (I-291) and anhydride (I-292): In a manner similar to that described in Example 26 3A of US Patent No. 1,046,4914, commercially available methyl 2-methoxylacetate (I-289) was alkylated with dibromoethane to give methyl 1-methoxycyclopropanecarboxylate, which was then hydrolyzed under basic conditions to give the corresponding acid (I-291). The acid (I-291) was then converted to the corresponding anhydride (I-292) according to the method of Preparation 2, which was obtained as an oil. [ka]

[0174] The following 1-methoxycyclopropane carboxylic acids and anhydrides and 1-alkoxycyclobutane carboxylic acids and anhydrides can be prepared similarly to those described in the above preparations. [ka] Example 1: Synthesis of N4-hydroxycytidine (NHC) or 1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(hydroxyamino)pyrimidin-2-one

[0175] [ka] A mixture of cytidine (20.0 g, 82.24 mmol, 1.0 equiv.) and NH2OH.AcOH (23 g, 246.7 mmol, 3.0 equiv.) in HO (350 mL) was stirred at 40° C. for 48 h. The reaction was monitored by HPLC and after completion of the reaction, water was evaporated under vacuum on a rotavapor to obtain a viscous syrup, which was then suspended in 100 mL of water and placed in a refrigerator for 24 h for crystallization. The solid thus crystallized was filtered, washed with cold HO (approximately 15.0 mL) and dried under vacuum to obtain the desired N4-hydroxycytidine (NHC / EX-1) as a white solid (8.48 g, 40% yield). 1H NMR (400MHz, DMSO) δ 9.97 (br. s, 1H), 9.45 (bs, 1H), 7.04 (d, 1H), 5.74 (d, 1H), 5.57 (d, 1H), 5.52 (m, 2H),4.98-5.03 (m,2H) 3.91-4.00 (m, 2H), 3.78 (dd, 1H), 3.56 (m 2H); Purity: 98% (assessed by HPLC).

[0176] Example 2: Preparation of compound (EX-2) [ka] In a 250 mL round bottom flask equipped with magnetic stirring, N4-hydroxycytidine (20 g, 72.2 mmol) was added in 30 mL water under stirring and heated to 40 °C, then acetic anhydride (8.1 g, 0.794 mmol) was added dropwise. The reaction was stirred at this temperature for 2 h until HPLC showed the reaction was complete. The reaction mixture was slowly cooled to 0 °C, and the resulting solid was filtered and washed with methanol to give EX-2-1 as a white solid. 1H NMR (400 MHz, DMSO), two sets of peaks were observed in NMR due to tautomerization of NH=CNHO bond. δ 10.9 (br. s, 1H), 7.4(d, 1H), 5.7 (m, 2H), 5.3 (br.s, 1H), 5.0 (s, 2H), 4.0(m, 2H), 3.8 (s, 1H), 3.6 (m, 2H), 2.10 (s, 3H); Purity: 99% (assessed by HPLC).

[0177] The following example illustrates the present novel method for selective acylation with acetic anhydride. Single solvents or mixtures of solvents (such as binary, ternary or quaternary mixtures) can be used for the acylation in various ratios. The acylated product is generally produced in the reaction solution in >95% by HPLC.

[0178] [Table 2]

[0179] Below are examples that demonstrate the industrial feasibility of the novel process. In a 2-liter four-neck round bottom flask equipped with a stirrer and thermometer, 160 g of NHC / N4-hydroxycytidine was added followed by 1.52 kg of methanol. The reaction mixture was heated to 45-50°C and acetic anhydride (65 g) was added dropwise at this temperature, with the addition time being 10-15 min. Approximately 50% of the methanol was distilled off under vacuum at 40-45°C. The reaction mixture was cooled to 30°C and another 5 g of acetic anhydride was added dropwise. The reaction mixture was further cooled below 10°C and stirred at this temperature for 2 h. The resulting solid was filtered and washed with 100-150 g of methanol. The solid was dried to obtain 160 g of compound EX-2 as a white solid with a purity of 99.5%.

[0180] Example 3: Preparation of compound (EX-3) [ka] In a 100 mL round bottom flask equipped with magnetic stirring, N4-hydroxycytidine (20 g, 72. mmol) was added in 36 mL of water under stirring and heated to 45 °C, then isobutyric anhydride (12.5 g, 0.79 mmol) was added dropwise over 5-10 min. The reaction was stirred at this temperature for 1-2 h until HPLC showed the reaction was complete. After evaporating the water in the reaction flask to dryness, methanol (20 mL) was added. The reaction mixture was heated to 50-60 °C to completely dissolve the solid, which was then slowly cooled to 0 °C, and the resulting solid was filtered and washed with methanol to obtain EX-3-1 as a white solid (20.5 g) with a purity of 99.3% and a yield of 86%. 1H NMR (400 MHz, DMSO), two sets of peaks were observed in NMR due to tautomerization of the NH=CNHO bond. δ 10.9 (br. s, 1H), 7.4(d, 1H), 5.7 (m, 2H), 5.3 (br.s, 1H), 5.0 (s, 2H), 4.0(m, 2H), 3.8 (s, 1H), 3.6 (m, 2H), 2.8 (m, 1H), 1.1 (s, 6H).

[0181] The following example illustrates the present novel method for selective acylation with isobutyric anhydride. Single solvents or mixtures of solvents (such as binary, ternary or quaternary mixtures) can be used for the acylation in various ratios. The acylated product is generally produced in the reaction solution in >95% by HPLC.

[0182] [Table 3]

[0183] Example 4: Preparation of compound (EX-4) [ka] In a 100 mL round bottom flask equipped with magnetic stirring, N4-hydroxycytidine (20 g, 72.5 mmol) was added in 40 mL pyridine under stirring at room temperature, followed by dropwise addition of benzoyl chloride (11.1 g, 0.79 mmol) over 5-10 min. The reaction was stirred at 40-50 °C overnight until HPLC showed the reaction was complete. Excess pyridine was removed under vacuum, the reaction residue was dissolved in EtOAc, and the organic layer was washed with saturated sodium chloride solution. The organic layer was dried, concentrated, and purified on a silica gel column (DCM and MeOH, gradient) to give EX-4-1 as a white solid. 1H NMR (400 MHz, DMSO), two sets of peaks were observed in NMR due to tautomerization of the NH=CNHO bond. δ 11.14 (s, 1H), 8.22(d, 1H), 7.96 (dd, 1H),7.4-7.6 (m,5H), 5.80 (m , 1H), 5.3 (br.s, 1H), 5.0 (br.s, 2H), 3.83-4.03 (m,2H) ,3.8 (s, 1H), 3.5 (m, 2H).

[0184] The following exemplary compounds were also prepared using commercially available anhydrides or acyl chlorides as described in Examples 2, 3, or 4. In the case of carboxylic acid anhydrides and acyl chlorides that are not commercially available, they can be readily prepared by well-known standard procedures.

[0185] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0186] The following exemplary compounds can be prepared in a manner similar to that described in the examples above using commercially available anhydrides or acyl chlorides. In the case of carboxylic acid anhydrides and acyl chlorides that are not commercially available, they can be readily prepared by well-known standard procedures. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] [Table 5-14] [Table 5-15]

[0187] Example 170: Plasma Stability [Table 6]

[0188] Preparation of solutions: A stock solution (10 mM) of each test compound was prepared in DMSO. The stock solution of each compound was then diluted to 100 μM in acetonitrile.

[0189] Plasma incubation: Plasma incubations were performed in duplicate in 96-well plates at 37° C. After prewarming plasma for 5 min at 37° C. in a total volume of 198 μL, 2 μL of 100 μM test compound was added to the incubation wells containing plasma, mixed with a pipette to obtain a uniform suspension, and 20 μL of the incubation was immediately transferred to a well of the “quenching” plate as the 0 min sample, followed by the addition of 200 μL of acetonitrile containing metolazone as an internal standard (IS) and mixing with a pipette. At 2, 5, 60, and 90 min, the incubations were mixed with a pipette and 20 μL samples of the incubations from each time point were sequentially transferred to another well of the “quenching” plate, followed by the addition of 200 μL of acetonitrile containing metolazone as the IS and mixing with a pipette.

[0190] Sample Analysis:The 96-well plate was centrifuged at 6000 g for 10 min. The supernatant was injected into the LC-MS / MS system for analysis.

[0191] Example 171: Microsomal Stability [Table 7]

[0192] Preparation of solutions: A stock solution (10 mM) of each test compound was prepared in DMSO. The stock solution of each compound was then diluted to 100 μM in acetonitrile.

[0193] Microsome incubation: Incubation mixtures were prepared in a total volume of 200 μL with the following final component concentrations: 0.1 M PBS (pH 7.4), NADPH (2 mM) and liver microsomes (0.2 mg / mL) as well as test compounds (1 μM) or molnupiravir (1 μM) as a positive control, where NADPH was added after preincubation of all other components for 5 min at 37°C. The suspensions were mixed with a pipette to homogenize and 20 μL of the incubation was immediately transferred to a well of the "quenching" plate as a 0 min sample, followed by addition of 200 μL of acetonitrile with metolazone as IS and mixing with a pipette. At 2, 5, 10, and 45 min, the incubations were mixed with a pipette and 20 μL of the incubation samples from each time point were transferred sequentially to another well of the "quenching" plate, followed by addition of 200 μL of acetonitrile with metolazone as IS and mixing with a pipette.

[0194] Sample Analysis: The 96-well plate was centrifuged at 6000 g for 10 min. The supernatant was injected into the LC-MS / MS system for analysis.

[0195] Example 172: In vitro activity of exemplary compounds EX-2 (CH2101) and molnupiravir against the SARS-CoV-2 Omicron B.1.1.529 mutant strain This experiment was designed to test the antiviral activity of compounds of the invention against the SARS-CoV-2 Omicron B.1.1.529 mutant strain in VERO E6 cells.

[0196] [Table 8]

[0197] Vero E6 cells were transferred and inoculated into 96-well plates at a density of 10,000 cells / well. The plates were then incubated overnight at 37°C with 5% CO2. Diluted test compounds EX-2 (CH2101) and molnupiravir (3-fold serial dilutions, 8 concentrations, triplicate) and virus (MOI=0.1) were added, along with blank controls (Vero E6 cells without virus or test compound) and virus controls (Vero E6 cells with virus but without test compound). The 96-well plates were incubated at 37°C with 5% CO2 for 4 days. The cell viability of each cell was measured by Celltiter Glo. The cell viability was used to calculate the antiviral activity of the test compounds. If the cell activity of the wells treated with the test compounds was higher than that of the wells treated with the virus but not the test compounds, i.e., weaker CPE (weeker CPE), it means that the test compounds have inhibitory activity against the virus.

[0198] EC of test compound 50 Value and CC 50 Values ​​were calculated using GraphPad Prism (version 8) with the log(inhibitor) method--variable slope of response. EC 90 The formula for calculating the value is EC 90 =EC 50 ×9^(1 / gradient).

[0199] The experimental results are shown in Table 2 and FIG.

[0200] [Table 9]

[0201] Example 173: In vivo efficacy evaluation of test compound CH2101 (compound EX-2) against SARS-CoV-2 in a K18-hACE2 transgenic mouse infection model This study was designed to evaluate the in vivo efficacy of the test compound CH2101 (EX-2) against SARS-CoV-2 in a K18-hACE2 transgenic mouse infection model, with primary endpoints being body weight change, clinical symptom scores, mortality and lung viral titers.

[0202] 1.1 Male specific pathogen-free K18 hACE2 transgenic mice (B6.Cg-Tg(K18-ACE2)2Primn / J mice) were purchased from Jackson Laboratories. Mice were housed and maintained according to IACUC approved protocol #20003. Qualified mice were used for the study after a minimum of 3 days of acclimation.

[0203] 1.2 Virus: The SARS-CoV-2 Hong Kong strain was supplied by BEI Resources (NR-52282) and amplified in-house.

[0204] 1.3 Cells: Vero E6 were purchased from ATCC and propagated in-house.

[0205] The vehicle of EX-2 / CH2101 is 10% (v / v) PEG400 + 0.5% (w / v) CMC in purified water. Compound EX-2 / CH2101 was formulated to the desired concentration of 45 mg / mL in the above vehicle taking into account purity.

[0206] The vehicle for remdesivir was 5% DMSO + 10% solutol + 85% saline (0.9% sodium chloride) at the desired concentration of 2.5 mg / mL, taking into account purity.

[0207] Animal grouping: Qualified mice were randomly and uniformly divided into 6 groups according to the study design.

[0208] Viral inoculation: Mice were anesthetized and inoculated with SARS-CoV-2 virus via the intranasal route on day 0 at a volume of 5,000 pfu / mouse / 50 μL.

[0209] Compound / vehicle dosing: Mice were treated with vehicle, or remdesivir or test compound EX-2 / CH2101 by PO or SC route twice daily, 8-16 hours apart, on days 0-6 or 4 (groups 4-6). The first dose was administered 2 hours post-infection. See Table 3 for details.

[0210] Animal Follow-up: Animals were followed daily for body weight and mortality throughout the study. Clinical signs were observed and scored as 1 for ruffled fur, curled up, lethargy / hyperactivity and signs of respiratory distress.

[0211] Sample collection: Final sample collection: Mice from groups 4-6 were sacrificed on day 5 and lung samples were collected in a vial containing 1 mL of EMEM. The vials were weighed before and after lung sample collection to calculate net lung weight. Lung samples were frozen and stored for virus titration by plaque assay.

[0212] Termination of the in vivo study: On the final day, day 14, all surviving animals were sacrificed.

[0213] Human endpoints: Mice surviving ≥20% or / and with a score of 3 were euthanized and counted as a mortality.

[0214] Plan and Schedule: The detailed study plan for the in vivo portion is shown in Table 3.

[0215] [Table 10]

[0216] Measurement of viral titers: Lung viral titers were determined by plaque assay. Plaque assays were performed using VERO E6 cells. After the lung samples were homogenized with a tissue lyser, the supernatants of the lung homogenates were serially diluted 10-fold and 0.2 mL was pipetted into pre-seeded 6-well plates. After 3 days of incubation, the cells were fixed with 4% paraformaldehyde and stained with crystal violet solution. The plaques were visually counted, and the viral titers were calculated using the following formula: Viral titer / g lung tissue = Log10 (plaques / well / 0.2 * Dilution ratio / lung weight * 1000)

[0217] Results: The in vivo efficacy of test compounds was determined by body weight change, clinical symptom scores, survival rate and lung virus titers.

[0218] Protection on Mouse Body Weight: During the entire duration of the in vivo study, mice were followed daily for body weight and body weight change, normalized to day 0 body weight, described as follows and plotted in Figures 3 and 4.

[0219] Infected control group (vehicle): Weight loss was observed from day 5 onwards and continued to decline thereafter without signs of recovery, leading to death or euthanasia.

[0220] Remdesivir-25mpk group: Weight loss was observed from day 2 and continued to decline thereafter, reaching a -13.6% decrease on day 6, accompanied by death or euthanasia.

[0221] Test compound (EX-2 / CH2101-450mpk) group: All mice did not show any significant weight loss and maintained a stable weight.

[0222] Observation of clinical signs: Mice were followed daily for clinical signs throughout the entire in vivo study. Signs of ruffled fur, curled up, lethargy and respiratory distress were scored as 1. The total scores are described as follows and plotted in Figure 4.

[0223] Infected control group (vehicle): Mice began to show gross clinical symptoms from day 5, which progressed rapidly and reached a peak on day 6, with a maximum clinical symptom score of 2 (mean value, same below).

[0224] Remdesivir group (25mpk): Mice began to show gross clinical symptoms from day 6, with a maximum clinical symptom score of 2.

[0225] Test compound (CH2101-450mpk) group: Mice were in good health and no infection-related clinical symptoms were observed.

[0226] Survival Rate: Mice were followed daily for mortality throughout the entire in vivo study. Mice survival status is described below, plotted in Figure 5, and summarized in Table 4.

[0227] Infected control group (vehicle): Mortality was observed on days 5 and 7. The survival rate was 0% and the median survival time was 5 days.

[0228] Remdesivir group (25mpk): Deaths were observed on days 6 and 7. The survival rate was 0%, and the median survival time was 6 days.

[0229] Test compound (CH2101-450mpk) group: No deaths were observed throughout the entire study period, and all mice survived until the end of the study, ie, a survival rate of 100%.

[0230] [Table 11]

[0231] Lung viral titers: For groups 4-6, lung samples were taken on day 5 and lung viral titers were determined by plaque assay. The results are described as follows, plotted in Figure 6, and summarized in Table 5.

[0232] Infected control group (vehicle): The mean virus titer was 5.94 Log10 (plaques / g lung), which met the study design and inclusion criteria and was consistent with historical data.

[0233] Remdesivir group (25mpk): The mean viral titer was 5.11 Log, which was 0.83 Log lower than that of the vehicle group, with a significant difference (p>0.05), indicating good antiviral efficacy in vivo.

[0234] Test compound group (CH2101-450mpk): The mean viral titer was 2.64 Log, which was 3.31 Log lower than the vehicle group, the difference was statistically significant (p<0.01), of which two samples reached the lower limit of detection, indicating optimal antiviral efficacy.

[0235] Figure 6 shows lung virus titers in study p26262-15. Mice were treated as indicated and sacrificed on day 5 to determine lung virus titers by plaque assay. Data are presented as mean ± SEM and analyzed by T-test: * , p < 0.05; *** , p<0.001, compared with vehicle; and ### , p<0.001 compared with the remdesivir group. Data indicated with a star were below the LLOD.

[0236] [Table 12]

[0237] Conclusion: The data showed that mice in the vehicle group showed the expected infection symptoms, suffered weight loss, and eventually died from infection. Furthermore, the virus titer in the lung samples from the vehicle group was 5.94 Log, and remdesivir significantly reduced the lung virus titer by 0.83 Log. All these results indicated that we successfully established a SARS-COV-2 mouse infection model, providing a platform for evaluating the efficacy of test compounds in vivo.

[0238] The test compound EX-2 (CH2101) significantly inhibited viral replication in the lungs, prevented weight loss and clinical symptoms in infected mice, and increased survival rates, demonstrating optimal antiviral effects in this model under the established conditions in vivo.

[0239] Example 174: Pharmacokinetic study of EX-2 (CH2101), molnupiravir (CH2017) and its metabolite NHC (CH2018) following a single PO dose of EX-2 (CH2101) or molnupiravir (CH2017) in male and female beagle dogs Both test compounds were prepared in 1% methylcellulose (400 cps, SIGMA, SLCF9694) solution in purified water.

[0240] A total of six male and six female beagle dogs weighing approximately 7-13 kg were initially purchased from Marshall Biotechnology Co. Ltd. The animals were fasted overnight prior to dosing and were re-fed 4 hours after dosing.

[0241] [Table 13]

[0242] Animals were manually restrained and approximately 1 mL of blood was collected at each time point from the cephalic or saphenous vein into pre-chilled EDTA-K2 tubes. Blood samples were centrifuged (4000 rpm, 5 min) at 4°C and plasma was obtained within 30 min after sample collection. All samples were stored at approximately -80°C until analysis. Backup samples were discarded at the end of the 2-month in vivo experiment unless required.

[0243] The test results are shown in Tables 6 to 11 and Figures 7 to 12.

[0244] [Table 14]

[0245] [Table 15]

[0246] [Table 16]

[0247] [Table 17]

[0248] [Table 18]

[0249] [Table 19]

[0250] As can be seen from Tables 6-11 and Figures 7-12, the AUC values ​​of EX-1 / NHC / CH2018 after PO administration of CH2101 at 20 mg / kg in beagle dogs were very similar to the AUC values ​​of EX-1 / NHC / CH2018 after PO administration of CH2107 (molnupiravir) at 22 mg / kg in beagle dogs. Thus, a single dose of CH2101 (EX-2) has a pharmacokinetic profile comparable to a single dose of CH2107 (molnupiravir) in beagle dogs.

Claims

1. Formula (I): 【Chemical 1】 or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof [In the formula, R is Ra-(C═O)-; Here, Ra is C １－７ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocycloalkyl, C ３－８ Cycloalkyl-C １－７ Alkyl, C ６－１０ Aryl-C １－７ Alkyl, 5- to 10-membered heteroaryl-C １－７ alkyl, and 3- to 12-membered heterocycloalkyl-C １－７ alkyl, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl is selected from the group consisting of halogen, acyl, hydroxy, cyano, nitro, amino, —NH(C １－７ alkyl), -N(C １－７ alkyl) ２ , —CO—NH ２ , —CO—NH(C １－７ alkyl), —CO—N(C １－７ alkyl) ２ , -NH(acyl), -N(acyl) ２ , N.H. ２ -acyl, NHRy-acyl, N(Ry) ２ -Acyl, C １－７ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－７ Alkoxy, aryloxy, heteroaryloxy, halo-C １－７ Alkyl, halo-C １－７ Alkoxy, halo-C ２－６ Alkenyl, halo-C ２－６ Alkynyl, hydroxy-C １－７ Alkyl, C １－７ Alkoxy-C １－７ Alkyl, halo-C １－７ Alkoxy-C １－７ Alkyl, halo-C ３－８ Cycloalkyl, C ３－８ Cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocycloalkyl, C ３－８ optionally substituted with one or more substituents selected from cycloalkyloxy or 3- to 12-membered heterocycloalkyloxy; Ry is C １－７ Alkyl, C ３－８ Cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocycloalkyl, C ３－８ Cycloalkyl-C １－７ Alkyl, C ６－１０ Aryl-C １－７ Alkyl, 5- to 10-membered heteroaryl-C １－７ alkyl, and 3- to 12-membered heterocycloalkyl-C １－７ alkyl].

2. Ra is C １－７ Alkyl, C ３－８ Cycloalkyl, C ６－１０ and selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, acyl, hydroxy, cyano, nitro, amino, —NH(C １－７ alkyl), -N(C １－７ alkyl) ２ , —CO—NH ２ , —CO—NH(C １－７ alkyl), —CO—N(C １－７ alkyl) ２ , -NH(acyl), -N(acyl) ２ , N.H. ２ -acyl, NHRy-acyl, N(Ry) ２ -Acyl, C １－７ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－７ Alkoxy, halo-C １－７ Alkyl, halo-C １－７ Alkoxy, aryloxy, heteroaryloxy, halo-C ２－６ Alkenyl, halo-C ２－６ Alkynyl, hydroxy-C １－７ Alkyl, C １－７ Alkoxy-C １－７ Alkyl, halo-C １－７ Alkoxy-C １－７ Alkyl, halo-C ３－８ Cycloalkyl, C ３－８ Cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocycloalkyl, C ３－８ optionally substituted with one or more substituents selected from cycloalkyloxy or 3- to 12-membered heterocycloalkyloxy; Ry is C １－７ Alkyl, C ３－８ Cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocycloalkyl, C ３－８ Cycloalkyl-C １－７ Alkyl, C ６－１０ Aryl-C １－７ Alkyl, 5- to 10-membered heteroaryl-C １－７ alkyl, and 3- to 12-membered heterocycloalkyl-C １－７ independently selected from alkyl, 2. A compound according to claim 1, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

3. R is the following group: 【Chemistry 2-1】 【Chemistry 2-2】 2. The compound of claim 1 selected from: or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

4. R is Ra—(C═O)—, Ra is methyl substituted with Ra1, Ra2 and Ra3; Ra1, Ra2 and Ra3 are H, C １－６ Alkyl, C １－６ Alkyl-O-C １－６ Alkyl, C ３－６ cycloalkyl, 3- to 6-membered heterocycloalkyl, C １－６ Alkyl-O—(CH ２ ) ｎ -, C １－７ Alkyl-O-aryl, C １－７ Alkyl-O-heteroaryl, C １－６ Alkyl-O-C １－６ Alkyl-O—(CH ２ ) ｎ -, C １－６ Haloalkyl-O-(CH ２ ) ｎ -, C ３－６ Cycloalkyl-O—(CH ２ ) ｎ - and 3- to 6-membered heterocycloalkyl-O-(CH ２ ) ｎ -, wherein each of said alkyl, cycloalkyl and heterocycloalkyl is independently selected from the group consisting of: halogen, acyl, hydroxy, cyano, nitro, amino, -NH(C １－７ alkyl), -N(C １－７ alkyl) ２ , C １－７ Alkyl, C １－６ Alkoxy, halo-C １－７ Alkyl, or halo-C １－７ optionally substituted with one or more substituents selected from alkoxy; and n is 0 or 1; 2. A compound according to claim 1, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

5. R is Ra—(C═O)—, Ra—(C═O)— is the following: 【Chemistry 3】 is selected from the group consisting of Raa is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkyl-O-C １－６ Alkyl-, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl; preferably C １－６ selected from the group consisting of alkyl, 2. A compound of claim 1 or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

6. Ra—(C═O)— is the following: 【Chemistry 4】 6. The compound of claim 5, selected from the group consisting of: or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

7. RaC=O is: 【Chemistry 5】 7. The compound of claim 6, selected from the group consisting of: or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, 2-methoxyethyl, fluoro-substituted ethyl, fluoro-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydro-2-furanyl, tetrahydro-3-furanyl, or tetrahydro-2H-pyran-4-yl; preferably, methyl, ethyl, propyl, isopropyl, oxetanyl, and tetrahydro-2H-pyran-4-yl, or a tautomer, stereoisomer, or racemate thereof, or a pharmaceutically acceptable salt thereof.

9. 2. The compound of claim 1, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Raa is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and sec-butyl.

10. Ra1 and Ra3 are H, C １－６ Alkyl, C １－６ Alkyl-O— and C １－６ Alkyl-O-CH ２ - independently selected from the group consisting of; Ra2 is C １－６ Alkyl, C １－６ Alkyl-O— and C １－６ Alkyl-O-CH ２ - selected from the group consisting of; or Ra2 and Ra3, together with the carbons to which they are attached, form C ３－６ cycloalkyl, or a 5-6 membered haloheterocycloalkyl comprising one ring heteroatom selected from O; However, Ra3 is H or C １－６ When R is either alkyl, R is H or C １－６ Not alkyl, 5. The compound of claim 4, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

11. Ra1 is C １－６ alkyl-O—, and Ra2 and Ra3 are independently C １－３ alkyl, and preferably, Ra2 and Ra3 are the same; 2. A compound according to claim 1, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

12. R １ is RaC=O, and R ２ and R ３ is H, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

13. Ra1 is C １－６ 2. The compound of claim 1, which is alkyl-O-, or a tautomer, stereoisomer or racemate thereof, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

14. The compound is: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 2. The compound of claim 1, selected from the group consisting of: or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

16. A pharmaceutical composition described in claim 15 for treating or preventing an RNA virus infection.

17. 15. A compound according to any one of claims 1 to 14, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

18. The RNA virus may be a coronavirus, such as a human coronavirus, SARS coronavirus or MERS coronavirus, an alphavirus, such as an eastern equine encephalitis virus, a western equine encephalitis virus, a Venezuelan equine encephalitis virus, a chikungunya virus or a Ross River virus, a filoviridae virus, such as an Ebola virus, an orthomyxoviridae virus, such as an influenza virus, influenza A virus or influenza B virus, a paramyxoviridae virus, such as 17. The pharmaceutical composition of claim 16, wherein the virus is a respiratory syncytial virus (RSV), a flavivirus, such as Zika virus; preferably SARS-CoV-2 / COVID-19 virus, SARS-CoV-2 / COVID-19 virus alpha mutant, SARS-CoV-2 / COVID-19 virus beta mutant, SARS-CoV-2 / COVID-19 virus gamma mutant, SARS-CoV-2 / COVID-19 virus delta mutant, or any other mutant strain of SARS-CoV-2 / COVID-19 virus.

19. A pharmaceutical combination comprising the compound according to any one of claims 1 to 14, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent.

20. Further therapeutic agents include: 【Chemistry 6】 20. The pharmaceutical combination of claim 19, selected from the group consisting of:

21. 19. A pharmaceutical composition for the treatment of 2019_nCoV / SARS-CoV-2 infection, comprising a pharmaceutically acceptable excipient and a compound of formula I or a tautomer thereof or a pharmaceutically or physiologically acceptable salt thereof, wherein the compound of formula I is defined in any one of claims 1 to 14.

22. A process for preparing a compound of formula I according to any one of claims 1 to 14, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, comprising: reacting the NHC with an acid anhydride of formula II to obtain a compound of formula I; 【Chemistry 7】 (wherein Ra is defined as in any one of claims 1 to 14) The method comprising:

23. 23. The method of claim 22, wherein the reaction is carried out in water or a mixture of water and an organic solvent, preferably the reaction solvent is selected from pure water, methanol, ethanol, propanol, isopropanol, other lower aliphatic alcohols or mixtures of aliphatic alcohols, DMF, DMSO, NMP, a water-methanol mixture, a water-ethanol mixture, a water-propanol mixture, a water-isopropanol mixture, a water-n-butanol mixture, a water-sec-butanol mixture, a water-isobutanol mixture, a water-THF mixture, a water-ACN mixture, a water-DMF mixture, a water-DMSO mixture, a water / 2-methyl THF mixture, or any mixture of water and an organic solvent capable of completely or partially dissolving NHC; more preferably water, a lower aliphatic alcohol, a water-THF mixture, a water / 2-methyl THF mixture, a water / ACN mixture, or a water-lower aliphatic alcohol mixture.

24. The reaction may be carried out in the presence of an inorganic or organic base (or catalyst), such as an alkali metal hydroxide, carbonate, bicarbonate, alkoxide or hydride, e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, or sodium hydride, or an organic tertiary amine, e.g., tri-C １－４ 23. The method of claim 22, carried out without the addition of alkylamines such as TEA, diisopropylethylamine, tripropylamine, tributylamine, or heterocyclic bases such as pyridine, picoline, lutidine, DMAP, DBU, and the like.

25. The reaction may be carried out in the presence of an inorganic or organic base (or catalyst), such as an alkali metal hydroxide, carbonate, bicarbonate, alkoxide or hydride, e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, or sodium hydride, or an organic tertiary amine, e.g., tri-C １－４ 23. The process according to claim 22, carried out in the presence of an alkylamine, such as TEA, diisopropylethylamine, tripropylamine, tributylamine, or a heterocyclic base, such as pyridine, picoline, lutidine, DMAP, DBU, and the like.

26. 23. The process of claim 22, wherein the product is obtained in solid crystalline form by cooling the reaction mixture without adding an anti-solvent.

27. 23. The process of claim 22, wherein the product is obtained in solid crystalline form without undergoing chromatographic purification.

28. 23. The method of claim 22, wherein the purity of the resulting product is about 90% to 98%.

29. 23. The method of claim 22, wherein the purity of the resulting product is greater than 98%.

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