Diester derivative of N4-hydroxycytidine and application thereof

Abstract

The present disclosure relates to diester derivatives of N4-hydroxycytidine (NHC), to pharmaceutical compositions comprising the same, and to the use and methods of the diester derivatives of N4-hydroxycytidine for the treatment of viral infections.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to international application PCT / CN2022 / 139636 filed on December 16, 2022; the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to N 4 - Diester derivatives of hydroxycytidine (NHC), pharmaceutical compositions containing the same, and N 4 The diester derivatives of -hydroxycytidine are used to treat viral infections. These compounds can be administered orally to provide N 4 -Hydroxycytidine. Background Art

[0004] Currently, SARS-CoV-2, the virus that causes COVID-19, has infected more than 240 million people worldwide and caused approximately 5 million deaths, with no signs of slowing down. The world economy and human activities have been significantly negatively impacted. Although vaccines are being introduced recently, oral medications to treat infected patients are still very much needed and can complement the use of vaccines. 4 β-Hydroxycytidine (NHC) is a ribonucleoside analog with broad-spectrum antiviral activity against a variety of unrelated RNA viruses, including influenza, Ebola, CoV, and Venezuelan equine encephalitis virus (VEEV), and most importantly, the human SARS-CoV-2 virus. Although the exact molecular mechanism of action of NHC remains undetermined, it has been proposed that viral error catastrophe is the basis of 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 comes from the tautomerization property of NHC:

[0005]

[0006] The oxime form of NHC mimics uridine and matches adenosine (left structure below), while the other tautomer mimics cytidine and matches guanosine (right structure below). This mismatch can lead to viral errors and disasters.

[0007]

[0008] N 4A prodrug of hydroxycytidine (NHC), monoclavir / EIDD2801 / MK4486, has just completed clinical trials for the treatment of SARS-CoV-2 (the virus that causes COVID-19). According to reports, a Phase III clinical trial for the treatment of patients with early SARS-CoV-2 infection, at a dose of 800 mg twice a day for 5 days, showed a 50% reduction in the number of patients who progressed to hospitalization. Both high doses and BID dosing are required for sustained and effective concentrations of NHC in the human body to induce viral error disasters. Therefore, there is still a need for more and potentially better prodrugs (i.e., smaller tablets, lower dosing frequency, and higher efficacy) to treat viral infections, especially for the urgent treatment of the current human disaster around the world. SUMMARY OF THE INVENTION

[0010] The inventors have discovered a series of N 4 Diester derivatives of -hydroxycytidine (NHC) can deliver NHC in the bloodstream of animals with improved bioavailability and prolonged exposure compared to the parent molecule NHC.

[0011] The present disclosure relates to certain diester prodrugs of NHC, combinations, pharmaceutical compositions, uses and methods related thereto.

[0012] The present disclosure provides compounds of formula (I):

[0013]

[0014] or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are the same or different and are independently selected from C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-7 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, 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 heterocyclyl-C 1-7 Alkyl, wherein the alkyl is optionally substituted with one or more substituents 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 1-7alkyl)2, -NH(acyl), -N(acyl)2, NH2-acyl, NHRy-acyl, N(Ry)2-acyl, C 1-7 Alkoxy, halo-C 1-7 Alkoxy, halo-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy; wherein each of the cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more substituents 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, 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 heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy;

[0015] wherein the acyl group is Rx-(C=O)-; and

[0016] Rx and Ry are independently selected from C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, C 3-8 Cycloalkyl-C 1-7 Alkyl, C 6-10Aryl-C 1-7 alkyl, 5- to 10-membered heteroaryl-C 1-7 alkyl and 3 to 12 membered heterocyclyl-C 1-7 alkyl.

[0017] The above-mentioned compounds and the compounds disclosed below (including compounds of formula (I) and specific compounds, especially example compounds) or their tautomers, stereoisomers, enantiomers, diastereomers, racemates, geometric isomers, hydrates or solvates or pharmaceutically acceptable salts thereof are collectively referred to as "compounds of the present invention" or "compounds of the present disclosure."

[0018] The present disclosure also provides compounds of the present disclosure for use as medicaments.

[0019] The present disclosure also provides the compounds of the present disclosure for use in treating or preventing RNA virus infection.

[0020] The present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure, and optionally comprising a pharmaceutically acceptable excipient.

[0021] The present disclosure also provides a kit for treating or preventing RNA virus infection, comprising the pharmaceutical composition of the present disclosure and instructions for use.

[0022] The present disclosure also provides use of the compound of the present disclosure in preparing a medicament for treating or preventing RNA virus infection.

[0023] The present disclosure also provides use of the compounds of the present disclosure for treating or preventing RNA virus infection.

[0024] The present disclosure also provides a method of treating or preventing an RNA viral infection in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of the present disclosure.

[0025] The present disclosure also provides a method for increasing the bioavailability of N4-hydroxycytidine isobutyl ester to treat or prevent RNA virus infection, comprising administering an effective amount of a compound of the present disclosure to a subject in need thereof.

[0026] The present disclosure also provides pharmaceutical combinations comprising a compound of the present disclosure and at least one additional therapeutic agent.

[0027] The present disclosure also provides methods for preparing compounds of the present disclosure, and intermediates for preparing compounds of the present disclosure. The present inventors have discovered that the methods of the present disclosure, in which the acylation reaction is carried out using a carboxylic anhydride as an acylating agent, are advantageous for industrial production, particularly when compared to those carried out using an acyl chloride. The method can be carried out in the absence of a catalyst, such as an inorganic or organic base. It is easy to operate, environmentally friendly, and efficiently produces a high-purity product.

[0028] Additional advantages will be set forth in part in the description that follows and in part will be obvious from the description or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Detailed Description of the Invention

[0030] definition

[0031] As used herein, words, phrases and symbols are generally intended to have the meanings set forth below unless the context of their use indicates otherwise.

[0032] As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0033] The compounds of the present disclosure can be identified by their chemical structure and / or chemical name. When the chemical structure and chemical name conflict, the identity of the compound is determined by the chemical structure.

[0034] In this document, the symbol "=" or Refers to related structures are tautomers, they exist under equilibrium and are easy to convert from one isomeric form to another. Compounds of the present disclosure can exist in oxime form and other forms. Therefore, chemical structures as herein described include all possible tautomeric forms of the compounds shown, particularly tautomers of the oxime form and tautomers of other forms. No matter which tautomer is shown, and no matter how the balanced properties between the tautomers are, it will be understood by those skilled in the art that compounds of the present disclosure include oxime form and other forms.

[0035] "Bioavailability" refers to the rate and amount of a drug that reaches the systemic circulation of a subject following administration of a drug or a prodrug thereof to a subject, and can be determined, for example, by evaluating the drug's plasma or blood concentration-time profile. Parameters that can be used to characterize a plasma or blood concentration-time profile include the area under the curve (AUC), the time to maximum concentration (Tmax), and the maximum drug concentration (Cmax), where Cmax is the maximum concentration of the drug in the subject's plasma or blood following administration of a dose of the drug or drug form to the subject, and Tmax is the time to maximum concentration (Cmax) of the drug in the subject's plasma or blood following administration of a dose of the drug or drug form to the subject.

[0036] Prodrugs are derivative forms of drugs that are converted or metabolized into the active form of the parent drug in the body after administration. Prodrugs are used to modify one or more aspects of the pharmacokinetics of a drug to improve the therapeutic effect of the parent drug. For example, prodrugs are generally used to improve the oral bioavailability of a drug. In order to achieve therapeutic effects, drugs with poor oral bioavailability may require frequent administration, large doses, or may need to be administered by routes other than oral administration, 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.

[0037] "Metabolic intermediates" refer to compounds that are formed in vivo through the metabolism of the parent compound and further react in vivo to release the active agent. The compound of formula (I) is a protected diester prodrug that is metabolized in vivo to provide the corresponding metabolic intermediate, such as N4-hydroxycytidine isobutyl ester (NHC). It is desirable that the reaction product or its metabolite is non-toxic.

[0038] "Subject" refers to a mammal, such as a human.

[0039] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0040] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids and one or more protonatable functional groups in the parent compound, such as hydroxylamine. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts can 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, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc. "Pharmaceutically acceptable salts" also include base addition salts formed by compounds of the present disclosure carrying an acidic moiety with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0041] As used herein, "pharmaceutical combination" refers to a product that is a mixture or combination of more than one therapeutic agent, and includes fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" refers to a therapeutic agent (e.g., a compound of the present disclosure) and at least one additional therapeutic agent, administered to an individual simultaneously as a single entity or dosage. The term "non-fixed combination" refers to a therapeutic agent (e.g., a compound of the present disclosure) and at least one additional therapeutic agent, each administered to an individual as a separate entity, simultaneously, concurrently, or sequentially, without specific time limits, wherein such administration provides therapeutically effective levels of the active agents in the individual.

[0042] "Prevention" refers to reducing the risk of acquiring a disease or disorder, such as a viral infection, (even if an individual who may be exposed to the disease or is predisposed to the disease but has not yet experienced or displayed symptoms of the disease does not develop at least one clinical symptom of the disease). In some embodiments, "prevention" refers to reducing the symptoms of the disease by taking a compound in a preventive manner. Therapeutic applications for preventing a disease or disorder are called prophylaxis. The compounds provided by the present disclosure can provide excellent prophylactic effects due to their antiviral activity.

[0043] "Treating" a disease or disorder, such as a viral infection, refers to arresting or ameliorating the disease or at least one clinical symptom of the disease or disorder, reducing the risk of acquiring the disease or at least one clinical symptom of the disease, reducing the development of the disease or at least one clinical symptom of the disease, or reducing the risk of developing the disease or at least one clinical symptom of the disease. "Treating" also refers to inhibiting the disease, which may be physical (e.g., stabilizing an identifiable symptom), physiological (e.g., stabilizing a physical parameter), or both, as well as inhibiting at least one physical parameter or manifestation, which may or may not be identifiable by the individual. "Treating" also refers to delaying the onset of a disease (e.g., a viral infection), or at least one or more symptoms thereof, in an individual who may be exposed to or predisposed to the disease or disorder, even if the subject does not yet experience or display symptoms of the disease.

[0044] As used herein, the term "effective amount" refers to an amount of a compound of the present disclosure that is effective for "treating" or "preventing" a viral infection in a subject as defined above. An effective amount can cause any observable or measurable change in the subject as described in the above definitions of "treating" or "preventing." An "effective amount" can vary depending on, for example, the compound, the disease and / or disease symptoms, the severity of the disease and / or disease or disorder symptoms, the age, weight, and / or health of the subject to be treated, and the judgment of the prescribing physician. In any given case, an appropriate amount can be determined by one skilled in the art or can be determined by routine experimentation.

[0045] As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon moiety, such as a (C) 1-7), preferably 1 to 6 carbon atoms (C 1-6 ), 1-4 carbon atoms (C 1-4 ) or 1-3 carbon atoms (C 1-3 For example, “C 1-7 "Alkyl" refers to an alkyl group having 1 to 7 (including 1, 2, 3, 4, 5, 6 or 7) carbon atoms. Representative C 1-7 The alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl and the like.

[0046] As used herein, "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon moiety containing at least one double bond, for example, a group containing 2 to 7 carbon atoms (C 2-7 ), 2-6 carbon atoms (C 2-6 ), 2-4 carbon atoms (C 2-4 ) or 2-3 carbon atoms (C 2-3 For example, “C 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 (including 2, 3, 4, 5 or 6) carbon atoms. Representative C 2-6 Alkenyl groups include ethenyl, propenyl, allyl, butenyl, pentenyl and the like.

[0047] As used herein, "alkynyl" refers to a straight or branched chain unsaturated hydrocarbon moiety containing at least one triple bond, for example, containing 2 to 7 carbon atoms (C 2-7 ), 2-6 carbon atoms (C 2-6 ), 2-4 carbon atoms (C 2-4 ) or 2-3 carbon atoms (C 2-3 For example, “C 2-6 "Alkynyl" refers to an alkynyl group having 2 to 6 (including 2, 3, 4, 5 or 6) carbon atoms. Representative C 2-6 Alkynyl groups include ethynyl, propynyl, propargyl, butynyl and the like.

[0048] As used herein, "alkoxy" refers to an -O-alkyl group, wherein the alkyl group has the meaning defined above, for example, a group containing 1 to 7 carbon atoms (C 1-7 ), 1 to 6 carbon atoms (C 1-6 ), 1-4 carbon atoms (C 1-4 ) or 1-3 carbon atoms (C 1-3 ) alkoxy. For example, "C 1-7 "Alkoxy" refers to an alkoxy group having 1 to 7 (including 1, 2, 3, 4, 5, 6 or 7) carbon atoms. Representative C 1-7Alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy and the like.

[0049] The term "cycloalkyl" as used herein refers to a group having 3 to 8 ring carbon atoms (C 3-8 ), such as 3-6 ring carbon atoms (C 3-6 ) or 5-6 ring carbon atoms (C 5-6 ) is a saturated cyclic hydrocarbon moiety. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or bicyclic ring 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. The term "halo-cycloalkyl" herein refers to a cycloalkyl group as defined above in which one or more, for example, 1, 2 or 3, hydrogen atoms are replaced by halogen atoms.

[0050] The term "heterocyclyl" as used herein refers to a saturated or partially unsaturated ring having 3-12 ring atoms (3-12 members), 3-10 ring atoms (3-10 members), 5-8 ring atoms (5-8 members), 3-6 ring atoms (3-6 members), 4-6 ring atoms (4-6 members), or 5-6 ring atoms (5-6 members), wherein one or more, for example 1, 2, 3 or 4, preferably 1 or 2 ring atoms are heteroatoms independently selected from N, O and S, preferably O, and the remaining ring atoms are carbon. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, pyrrolidonyl, pyrrolidinyl, piperidinyl, oxiranyl, oxiranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, 1,3-dioxolane moiety, etc. Preferably, the heterocyclyl group is tetrahydrofuranyl or tetrahydropyranyl. For example, the heterocyclic group may be selected from the following groups:

[0051] It is understood that structures having one or more asymmetric centers encompass racemic mixtures and / or single enantiomers or mixtures thereof. For example, the structure Covered and / or

[0052]

[0053] As used herein, the term "heterocyclyl" also includes "heterocycloalkenyl," which refers to a partially unsaturated "heterocyclyl" as defined herein that contains at least one (e.g., 1, 2, or 3) double bond. Examples of heterocycloalkenyl groups include, but are not limited to:

[0054]

[0055] wherein each W is selected from CH 2 , NH, O, and S, each Y is selected from NH, O, C(═O), SO 2 , and S, and each Z is selected from N and CH, provided that each ring contains at least one heteroatom selected from N, O, or S. For example, the heterocycloalkenyl group is pyrrolinyl (e.g., 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4-pyrrolinyl, or 5-pyrrolinyl), dihydrofuranyl (e.g., 1-, 2-, 3-, or 4-dihydrofuranyl), dihydrothiophenyl (e.g., 1-, 2-, 3-, or 4-dihydrothiophenyl), tetrahydropyridinyl (e.g., 1-, 2-, 3-, 4-, 5-, or 6-tetrahydropyridinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), or tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl).

[0056] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon group derived from a single carbon atom in an aromatic ring system by removing a hydrogen atom. Aryl refers to a monocyclic or fused polycyclic aromatic ring structure having a 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, with phenyl being preferred. The term "aryl" also includes biaryl groups, such as biphenyl and binaphthyl.

[0057] As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S and a specific number of ring atoms, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Specifically, the aromatic ring structure may have 5 to 10 ring members, 5 to 9 ring members, or 5 to 6 ring members. Typically, the heteroaryl ring comprises up to 4 heteroatoms independently selected from O, N, and S, up to 3 heteroatoms, up to 2 heteroatoms, such as one heteroatom, wherein N and S may be in an oxidized state, such as S=O or S(O)2. For example, the heteroaryl group can be 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, cinnoline, 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 group may be a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O or S. Examples of 5-6 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0058] 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- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, 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 heterocyclyl-C 1-7 Alkyl, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -NH(C 1-7 Alkyl), -N(C 1-7Alkyl)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 Alkoxy.

[0059] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine or iodine.

[0060] The term "halo-alkyl" herein refers to an alkyl group as defined herein wherein one or more, for example 1, 2, 3, 4, 5 or all, of the hydrogen atoms are replaced by halogen atoms.

[0061] The term "substituted" means that at least one hydrogen atom in a molecule is replaced by a substituent. When substituted, one or more groups are "substituents". Molecules can be multiply substituted.

[0062] The term "substituted" or "substituted by" refers to a molecule in which one or more (e.g., 1, 2, 3, or 4, such as 1, 2, or 3) hydrogen atoms are replaced by one or more (e.g., 1, 2, 3, or 4, such as 1, 2, or 3) substituents. The molecule may be multiply substituted.

[0063] As used herein, the term "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0064] The term "lower aliphatic alcohol" refers to C1-C4 alcohol, which represents an aliphatic alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like.

[0065] In general, the term "about" is used herein to modify a numerical value above or below the stated value by a variance of 20%, 10%, or 5%.

[0066] All numerical ranges herein should be understood to disclose each and all values within that range and each and all subsets of values within that range, whether or not they are specifically disclosed. For example, when any numerical range is mentioned, it should be considered to refer to each and all values within the index value range, for example, each and all integers within the numerical range. The present disclosure includes all values falling within these ranges, all smaller ranges, and upper or lower limits of the ranges.

[0067] Technical and scientific terms used herein, unless specifically defined, have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0068] Implementations of the Disclosure

[0069] Embodiment 1. Compound of formula (I):

[0070]

[0071] or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are the same or different and are independently selected from C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-7 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, 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 heterocyclyl-C 1-7 Alkyl, wherein the alkyl is optionally substituted with one or more substituents 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 Alkoxy, halo-C 1-7 Alkoxy, halo-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy; wherein each of the cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more substituents 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, C1-7 Alkoxy, 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 heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy;

[0072] wherein the acyl group is Rx-(C=O)-; and

[0073] Rx and Ry are independently selected from C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, 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 heterocyclyl-C 1-7 alkyl.

[0074] Embodiment 2. Compound 1 of formula (I) according to the embodiment, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are the same or different and are independently selected from C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl, wherein the alkyl group is optionally substituted with one or more substituents 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 Alkoxy, halo-C 1-7 Alkoxy, halo-C3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5 to 10 membered heteroaryloxy and 3 to 12 membered heterocyclyloxy; and each of the cycloalkyl, aryl, heteroaryl and heterocyclyl groups is optionally substituted with one or more substituents 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, 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 heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy;

[0075] wherein the acyl group is Rx-(C=O)-; and

[0076] Rx and Ry are independently selected from C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, 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 heterocyclyl-C 1-7 alkyl.

[0077] Embodiment 3. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rx and Ry are independently C 1-7 alkyl.

[0078] Embodiment 4. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are the same or different and are independently selected from:

[0079] C 1-7 Alkyl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -NH(C 1-7 Alkyl), -N(C 1-7 Alkyl)2, C 1-7 Alkoxy, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy;

[0080] C 3-8 Cycloalkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -NH(C 1-7 Alkyl), -N(C 1-7 Alkyl)2, -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy and C 1-7 Alkoxy-C 1-7 alkyl;

[0081] C 6-10 Aryl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -NH(C 1-7 Alkyl), -N(C 1-7 Alkyl)2, -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and phenyl groups;

[0082] 5 to 10 membered heteroaryl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy and C 1-7 Alkoxy-C 1-7 alkyl; and

[0083] 3 to 12 membered heterocyclic group, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and -(C=O)-C 1-7 alkyl.

[0084] Embodiment 5. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are the same or different and are independently selected from:

[0085] C 1-7 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-7 Alkoxy, C 3-8 Cycloalkyloxy and C 6-10 aryloxy;

[0086] C 3-8 Cycloalkyl, optionally substituted with one or more substituents selected from: -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl and C 1-7 Alkoxy-C 1-7 alkyl;

[0087] C 6-10 Aryl, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C1-7 Alkyl, halo-C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and phenyl groups;

[0088] 5 to 10 membered heteroaryl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy and C 1-7 Alkoxy-C 1-7 alkyl; and

[0089] 5 to 8 membered heterocyclyl, which is optionally substituted by one or more substituents selected from: -C 1-7 Alkyl, C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and -(C=O)-C 1-7 alkyl.

[0090] Embodiment 6. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is selected from:

[0091] C 1-7 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-7 Alkoxy, C 3-8 Cycloalkyloxy and C 6-10 aryloxy;

[0092] C 3-8 Cycloalkyl, optionally substituted with one or more substituents selected from: -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl and C 1-7 Alkoxy-C 1-7 Alkyl; preferably, C 3-6 cycloalkyl; and

[0093] 5 to 8 membered heterocyclyl, which is optionally substituted by one or more substituents selected from: -C 1-7 Alkyl, C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and -(C=O)-C1-7 Alkyl; preferably, 5- to 6-membered heterocyclyl; preferably 5- to 6-membered heterocyclyl; more preferably tetrahydropyranyl.

[0094] Embodiment 7. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is selected from:

[0095] C 1-7 Alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-7 Alkoxy, C 3-8 Cycloalkyloxy and C 6-10 aryloxy;

[0096] C 3-8 Cycloalkyl, preferably C 3-6 cycloalkyl; and

[0097] 5- to 8-membered heterocyclic group, preferably 6-membered heterocyclic group, more preferably tetrahydropyranyl group.

[0098] Embodiment 8. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is C 1-7 Alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-7 Alkoxy and C 3-6 Cycloalkyloxy.

[0099] Embodiment 9. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is C 1-4 Alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-4 Alkoxy and C 3-6 Cycloalkyloxy.

[0100] Embodiment 10. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is C 1-4 Alkyl, which is optionally substituted by 1, 2 or 3 C 1-4 Alkoxy substituted; preferably Rb is C 1-4 alkyl.

[0101] Embodiment 11. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is C 1-3Alkyl, which is optionally replaced by 1 C 1-3 Alkoxy substituted; preferably Rb is C 1-3 alkyl.

[0102] Embodiment 12. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is isopropyl, which is optionally replaced by 1 C 1-3 Alkoxy substituted; preferably Rb is isopropyl or n-propyl.

[0103] Embodiment 13. A compound of formula (I) according to any one of embodiments 1 to 7, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is C 3-6 Cycloalkyl, such as cyclopropyl.

[0104] Embodiment 14. A compound of formula (I) according to any one of the preceding embodiments, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is independently selected from:

[0105] C 3-8 Cycloalkyl, optionally substituted with one or more substituents selected from: -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl and C 1-7 Alkoxy-C 1-7 alkyl;

[0106] C 6-10 Aryl, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and phenyl groups;

[0107] 5 to 10 membered heteroaryl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy and C1-7 Alkoxy-C 1-7 alkyl; and

[0108] 5 to 8 membered heterocyclyl, which is optionally substituted by one or more substituents selected from: -C 1-7 Alkyl, C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and -(C=O)-C 1-7 alkyl.

[0109] Embodiment 15. A compound of formula (I) according to any one of Embodiments 1-13, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is independently selected from:

[0110] C 1-4 Alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-4 Alkoxy, C 3-6 cycloalkyloxy and phenoxy groups;

[0111] C 3-6 Cycloalkyl, optionally substituted with 1, 2 or 3 substituents selected from: -NH(-(C=O)-C 1-3 alkyl), -N(-(C=O)-C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, halo-C 1-3 Alkyl and C 1-3 Alkoxy-C 1-3 alkyl;

[0112] C 6-10 Aryl, optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, nitro, -NH(-(C=O)-C 1-3 alkyl), -N(-(C=O)-C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, halo-C 1-3 Alkyl, halo-C 1-3 Alkoxy, C 1-3 Alkoxy-C 1-3 Alkyl and phenyl groups;

[0113] 5 to 8 membered heteroaryl, optionally substituted by 1, 2 or 3 substituents selected from halogen, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, halo-C 1-3 Alkyl, halo-C 1-3 Alkoxy and C1-3 Alkoxy-C 1-3 alkyl; and

[0114] 5 to 6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 substituents selected from: -C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy-C 1-3 Alkyl and -(C=O)-C 1-3 alkyl.

[0115] Embodiment 16. A compound of formula (I) according to any one of Embodiments 1-13, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is independently selected from:

[0116] C 3-6 Cycloalkyl, optionally substituted with 1, 2 or 3 substituents selected from: -NH(-(C=O)-C 1-3 alkyl), -N(-(C=O)-C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, halo-C 1-3 Alkyl and C 1-3 Alkoxy-C 1-3 alkyl;

[0117] C 6-10 Aryl, optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, nitro, -NH(-(C=O)-C 1-3 alkyl), -N(-(C=O)-C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, halo-C 1-3 Alkyl, halo-C 1-3 Alkoxy, C 1-3 Alkoxy-C 1-3 Alkyl and phenyl groups;

[0118] 5 to 8 membered heteroaryl, optionally substituted by 1, 2 or 3 substituents selected from halogen, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, halo-C 1-3 Alkyl, halo-C 1-3 Alkoxy and C 1-3 Alkoxy-C 1-3 alkyl; and

[0119] 5 to 6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 substituents selected from: -C 1-3 Alkyl, C1-3 Alkoxy, C 1-3 Alkoxy-C 1-3 Alkyl and -(C=O)-C 1-3 alkyl.

[0120] Embodiment 17. A compound of formula (I) according to any one of embodiments 1 to 13, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is C 1-7 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-7 Alkoxy and C 3-6 Cycloalkyloxy.

[0121] Embodiment 18. A compound of formula (I) according to any one of embodiments 1 to 13, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is C 1-4 Alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-4 Alkoxy and C 3-6 Cycloalkyloxy.

[0122] Embodiment 19. A compound of formula (I) according to Embodiments 1-13, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is C 1-4 Alkyl, which is optionally substituted by 1, 2 or 3 C 1-4 Alkoxy substituted; preferably Ra is C 1-4 alkyl.

[0123] Embodiment 20. A compound of formula (I) according to Embodiments 1-13, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is C 1-3 Alkyl, which is optionally substituted by 1, 2 or 3 C 1-3 Alkoxy substituted; preferably Ra is methyl, replaced by a C 1-3 Alkoxy-substituted methyl, ethyl, propyl or isopropyl.

[0124] Embodiment 21. A compound of formula (I) according to any one of Embodiments 1 to 5, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra-(C=O)- and Rb-(C=O)- are the same or different and are selected from:

[0125]

[0126]

[0127]

[0128] Embodiment 22. A compound according to any one of embodiments 1 to 5, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra-(C=O)- and Rb-(C=O)- are the same or different and are independently selected from:

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142] Embodiment 23. A compound according to any one of embodiments 1-5 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

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[0152]

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[0190]

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[0192]

[0193]

[0194]

[0195]

[0196]

[0197] Embodiment 24. A method for preparing a compound of formula (I) according to any one of Embodiments 1-23, comprising the following steps:

[0198] Reaction of the compound of formula (III) with the anhydride of formula (II) to obtain the compound of formula (I),

[0199]

[0200] wherein Ra and Rb are independently as defined in any one of embodiments 1-23; preferably Rb is isopropyl.

[0201] Embodiment 25. The method according to embodiment 24, 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 lower aliphatic alcohols, ACN, THF, DMF, DMSO, NMP (N-methylpyrrolidone), 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 that can completely or partially dissolve NHC; more preferably water, lower aliphatic alcohols, water-lower aliphatic alcohol mixtures, water-THF mixtures, water / 2-methylTHF mixtures, water / ACN mixtures.

[0202] Embodiment 26. The process according to embodiment 24 or 25, wherein the reaction is carried out without adding any 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 Alkylamines such as TEA, diisopropylethylamine, tripropylamine, tributylamine, or heterocyclic bases such as pyridine, picoline, lutidine, DMAP, DBU, and the like.

[0203] Embodiment 27. The process according to embodiment 24 or 25, wherein 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 Alkylamines such as TEA, diisopropylethylamine, tripropylamine, tributylamine, or heterocyclic bases such as pyridine, picoline, lutidine, DMAP, DBU, and the like.

[0204] Embodiment 28. The process according to any one of embodiments 24-27, wherein the product is obtained in solid crystalline form by cooling the reaction mixture without adding an antisolvent.

[0205] Embodiment 29. The method according to any one of embodiments 24-28, wherein the purity of the product produced in the reaction solution is about 90%-98%.

[0206] Embodiment 30. The method according to any one of embodiments 24-29, wherein the purity of the product produced in the reaction solution exceeds 98%.

[0207] Embodiment 31. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 23 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

[0208] Embodiment 32. Use of the compound according to any one of Embodiments 1 to 23 or its tautomer, stereoisomer or racemate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing RNA virus infection.

[0209] Embodiment 33. The use according to embodiment 32, wherein the RNA virus is a coronavirus, such as a human coronavirus, a SARS coronavirus, or a MERS coronavirus, an alpha virus, 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, an influenza A virus, or an 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, an alpha variant, a beta variant, a gamma variant, a delta variant, an o variant, or any other variant thereof.

[0210] Embodiment 34. A method of treating or preventing an RNA viral infection in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments 1-23 or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

[0211] Embodiment 35. The method according to embodiment 34, wherein the RNA virus is a coronavirus, such as a human coronavirus, a SARS coronavirus, or a MERS coronavirus, an alpha virus, 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, an influenza A virus, or an 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, an alpha variant, a beta variant, a gamma variant, a delta variant, an o variant, or any other variant thereof.

[0212] Embodiment 36. A compound according to any one of Embodiments 1 to 23 or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0213] Embodiment 37. A compound according to any one of Embodiments 1 to 23 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof for use in treating or preventing RNA viral infection.

[0214] Embodiment 38. The compound for use according to embodiment 37, wherein the RNA virus is a coronavirus, such as a human coronavirus, a SARS coronavirus or a MERS coronavirus, an alpha virus, 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, an influenza A virus or an 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, an alpha variant, a beta variant, a gamma variant, a delta variant, an o variant, or any other variant thereof.

[0215] Embodiment 39. A method for increasing the bioavailability of N4-hydroxycytidine for treating or preventing RNA viral infection, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments 1-23 or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

[0216] Embodiment 40. A pharmaceutical combination comprising a compound according to any one of embodiments 1 to 23 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent.

[0217] Embodiment 41. The pharmaceutical combination according to embodiment 40, wherein the additional therapeutic agent is selected from Enstevir Fumarate (S-217622), Nematevir (PF-07321332) or Pasirovir,

[0218]

[0219] Embodiment 42. A pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, comprising a pharmaceutically acceptable excipient and a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is as defined in any one of Embodiments 1-23.

[0220] How to use

[0221] According to the present disclosure, the RNA virus is a coronavirus, such as a human coronavirus, a SARS coronavirus or a MERS coronavirus, an alpha virus, 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, an influenza A virus (including H1N1, H3N2, H7N9 or H5N1 subtypes), an influenza B virus or an influenza C virus, a Paramyxoviridae virus, such as a respiratory syncytial virus (RSV), a Flavivirus, such as a Zika virus, a rotavirus, such as a rotavirus A, a rotavirus B, a rotavirus C, a rotavirus D, a rotavirus E; preferably a SARS-CoV-2 / COVID-19 virus, an alpha variant, a beta variant, a gamma variant, a delta variant, an o variant, or any other variant thereof.

[0222] 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, an RSV virus, an influenza A virus, an influenza B virus, a Filoviridae virus, or an Ebola virus.

[0223] More preferably, according to the present disclosure, the RNA virus is a human coronavirus, SARS-CoV-2 / COVID-19 virus, an α variant, a β variant, a γ variant, a δ variant, an ο variant or any other variant of the SARS-CoV-2 / COVID-19 virus.

[0224] According to the present disclosure, an individual is at risk for, displays symptoms of, or is diagnosed with the following viral infection: 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 types (HAdV-1 to 55), human papillomavirus (HPV) types 16, 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, coxsackie A virus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCMV), dengue virus, Zika virus, Kongunya virus, Eastern equine encephalitis virus (EEEV), Western equine encephalitis 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 (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseola virus, or Kaposi sarcoma-associated herpesvirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, or human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 (HTLV-1), splenic lesion-forming virus of Friend (SFFV), or xenotropic MuLV-related virus (XMRV). In some embodiments, the individual is at risk for, displays symptoms of, or is diagnosed with Zika virus infection.

[0225] According to the present disclosure, individuals are diagnosed with SARS-CoV-2 / COVID-19 viral infection, including α variant, β variant, γ variant, δ variant, ο variant or any variant of the SARS-CoV-2 / COVID-19 virus, and these viral infections can be treated by a compound of formula (I) or a drug containing a compound of formula (I).

[0226] According to the present disclosure, an individual is diagnosed with influenza A virus, including subtypes H1N1, H3N2, H7N9, H5N1 (low path) and H5N1 (high path), influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) types 16, 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, coxsackie A virus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus In some embodiments, the individual is diagnosed with Zika virus infection.

[0227] According to the present disclosure, the individual is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fever, acquired immunodeficiency syndrome, or hepatitis.

[0228] Pharmaceutical compositions and administration

[0229] The compounds of the present disclosure (e.g., any of the compounds described in the Examples herein) alone or in combination with one or more additional therapeutic agents can be formulated into pharmaceutical compositions. The pharmaceutical compositions comprise: (a) an effective amount of a compound of the present disclosure; (b) a pharmaceutically acceptable excipient (e.g., one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional therapeutic agent.

[0230] A pharmaceutically acceptable excipient is an excipient that is compatible with the active ingredient in the composition (in certain embodiments, can stabilize the active ingredient) and is not harmful to the individual being treated. Suitable pharmaceutically acceptable excipients are disclosed in standard reference books in this field (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy.), and include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide a perfect presentation of the drug (i.e., a disclosed compound or pharmaceutical composition thereof) or to aid in the preparation of a drug product (i.e., a drug).

[0231] 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 administration, nasal, sublingual, lingual, buccal, rectal, cutaneous, transdermal, conjunctival, otic routes, or as an implant or stent. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion.

[0232] Oral or parenteral administration is preferred, especially oral administration.

[0233] The compounds of the present invention can be administered in any convenient formulation, such as tablets, powders, capsules, pills, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, aqueous buffers, such as saline or phosphate buffers, etc. Such compositions may contain conventional components of pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers and additional active agents.

[0234] Generally, it has been found that in the case of parenteral administration, an amount of about 0.001 to 20 mg / kg body weight, preferably about 0.01 to 10 mg / kg body weight, is effective. In the case of oral administration, the dosage is about 0.01 to 100 mg / kg body weight, preferably about 0.01 to 20 mg / kg body weight, and most preferably 0.1 to 15 mg / kg body weight.

[0235] Combination therapy

[0236] The compounds described herein can be adjunctively administered with at least one additional therapeutic agent.

[0237] Additional therapeutic agents include, but are not limited to, analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, anti-migraine agents, antimuscarinics, antianxiety agents, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatics, cardiovascular drugs, corticosteroids, dopaminergic agents, electrolytes, gastrointestinal drugs, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, anorexia agents, anti-somnia agents, and antiviral agents. In a particular embodiment, the antiviral agent is a non-CNS targeted antiviral compound. "Adjunctive administration" as used herein means that the compound can be administered in the same dosage form or in a different dosage form with one or more other active agents. The additional therapeutic agent can be formulated as immediate release, controlled release, or a combination thereof.

[0238] The compounds and pharmaceutical compositions of the present disclosure can be administered in combination with at least one additional therapeutic agent, e.g., an antiviral agent, such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balapiravir, BCX4430, boceprevir, cidofovir, dipyridamole, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxuridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, sodium fosmoacetate, ganciclovir, GS-5734, ibacitabine, isoprenavir, idoxuridine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon lindane, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, morphine, methylphenidate, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, pariprevir, peginterferon α-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramivir dine, saquinavir, simiprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir Exalidex, tipranavir, trifluridine, triamterene, tromantine, Truvada, valacyclovir, valganciclovir, viraviroc, vidarabine, viramidine, zalcitabine, zanamivir, monoclavir or zidovudine, and combinations thereof.

[0239] The compounds of the present disclosure and pharmaceutical compositions disclosed herein may be administered in combination with any compound disclosed in WO2012119559 for the treatment of SARS-CoV-2 / COVID-19 infection.

[0240] The compounds of the present disclosure and pharmaceutical compositions disclosed herein can be administered in combination with any compound disclosed in WO2012119559 for the prevention of SARS-CoV-2 / COVID-19 infection.

[0241] The compounds of the present disclosure and pharmaceutical compositions disclosed herein can be administered in combination with Enstevir fumarate (S-217622) for the treatment of SARS-CoV-2 / COVID-19 infection.

[0242]

[0243] The compounds of the present disclosure and pharmaceutical compositions disclosed herein can be used with nematevir (PF-07321332) or parovard to treat SARS-CoV-2 / COVID-19 infection.

[0244]

[0245] The compounds of the present disclosure and pharmaceutical compositions disclosed herein can be administered in combination with PF-07321332 for the prevention of SARS-CoV-2 / COVID-19 infection.

[0246] Therefore, the present disclosure also provides a pharmaceutical combination comprising a compound of the present invention and at least one additional therapeutic agent. Examples of additional therapeutic agents include, but are not limited to, those active agents mentioned above, preferably Enstevir Fumarate (S-217622), Nematevir (PF-07321332) or Parovide or other 3CL inhibitors.

[0247] Unless otherwise stated, the percentages in the tests and examples below are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid / liquid solutions are in each case based on volume.

[0248] Each embodiment and technical solution described in the present disclosure and the features in each embodiment and technical solution should be understood to be capable of being combined with each other in any way, and those technical solutions obtained by such combination are included in the scope of the present disclosure, just as each technical solution obtained by such combination is specifically and individually listed, unless the context clearly indicates otherwise.

[0249] To the extent permitted by law, all patents, patent applications, publications, and other references cited or mentioned herein are incorporated by reference in their entirety. The discussion of these references is intended solely to summarize the assertions made therein. No admission is made that any such patent, patent application, publication, or reference, or any portion thereof, is relevant material or prior art. The right to challenge the accuracy and pertinence of any assertion that these patents, patent applications, publications, and other references are relevant material or prior art is specifically reserved. Example

[0250] The examples listed below are to illustrate compositions, methods and results according to the disclosed subject matter. These examples are not intended to include all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions and results. These examples are not intended to exclude equivalents and variations of the disclosure, which will be apparent to those skilled in the art.

[0251] Efforts have been made to ensure the accuracy of numerical values (such as amounts, temperatures, etc.), but some errors and deviations should be taken into account. Unless otherwise stated, parts are parts by weight. There are many variations and combinations of reaction conditions, such as component concentrations, temperature, pressure and other reaction ranges and conditions, which can be used to optimize product purity and output obtained from the process. Only reasonable routine experiments need to be carried out to optimize such process conditions.

[0252] Unless otherwise stated, all reagents and starting materials used in the present invention are commercially available or prepared according to the prior art.

[0253] 1 H NMR spectra were measured on a Bruker 400 MHz instrument, and chemical shifts were determined relative to the corresponding solvent peaks: CDCl (δ 7.27), DMSO-d (δ 2.50), CD OD (δ 3.31), DO (δ 4.79). The following abbreviations are used to describe couplings: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, br = broad. 13 CNMR spectra were measured on a Bruker instrument at 100 MHz, and chemical shifts were determined relative to the corresponding solvent peaks: CDCl3 (δ 77.0), DMSOd6 (δ 39.5), CD3OD (δ 49.0).

[0254] Abbreviations and Acronyms:

[0255] aq. aqueous solution

[0256] calc.Calculated value

[0257] br s broad singlet (in NMR)

[0258] DCI direct chemical ionization (in MS)

[0259] dec.decomposition point

[0260] DMF dimethylformamide

[0261] DMSO dimethyl sulfoxide

[0262] DSC Differential Scanning Calorimetry

[0263] eq. equivalent

[0264] ESI Electrospray ionization (in MS).

[0265] Et Ethyl

[0266] fnd. measured value

[0267] h hour

[0268] HPLC high-pressure liquid chromatography

[0269] HRMS high-resolution mass spectrometry

[0270] Conc. Concentrated

[0271] LC-MS liquid chromatography-coupled mass spectrometry

[0272] LiHMDS lithium hexamethyldisilazide

[0273] Me methyl

[0274] Minutes

[0275] MS mass spectrometry

[0276] NMR nuclear magnetic resonance spectroscopy

[0277] Pd2 dba3 tris(dibenzylideneacetone)dipalladium

[0278] Ph Phenyl

[0279] PLM polarized light microscope

[0280] RT

[0281] Rt retention time (in HPLC)

[0282] TGA Thermogravimetric Analysis

[0283] THF Tetrahydrofuran

[0284] UV spectroscopy

[0285] v / v volume to volume ratio (solution)

[0286] Preparation of starting materials and intermediates

[0287] Preparation 1: Synthesis of alkoxy-substituted propionic acids and anhydrides

[0288]

[0289] Synthesis of (R)-2-methoxypropionic acid (I-3) and anhydride (I-4):

[0290] Under nitrogen, (S)-2-chloropropionic acid (80.0 g, 738 mmol, 1 equivalent, 98%) was added to a two-necked round-bottom flask. 25 wt% sodium methoxide (506 mL, 2.212 mol, 3 equivalents) was slowly added. The reaction was heated to 60 ° C for 16 hours, and the conversion was monitored until the remaining starting material was <2%. When sufficient conversion was reached, the reaction vessel was cooled to room temperature, and the pH was adjusted with 4 M hydrochloric acid (200 mL, 99%) in dioxane to a pH just below 7 from >12, indicating that excessive sodium methoxide was neutralized without protonating the sodium carboxylate. The reaction mixture was filtered to remove salt, and the salt cake 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) (73 g, 95%), which was a liquid with sufficient purity to be used without purification. 1 H NMR (CD3OD) δ 3.67 (q, 1H), 3.33 (s, 3H) and 1.33ppm (d, 3H).

[0291] In a 2-liter four-necked glass reactor equipped with a thermometer and a stirrer, 500 g of dichloromethane, 104.1 g (1.0 mol) of (R)-2-methoxypropionic acid (3), and 57.3 g (0.5 mol) of methanesulfonyl chloride were placed under a nitrogen atmosphere. The mixture was cooled to 5°C. Then, 101.3 g (1.0 mol, 1 equivalent relative to the acid generated from the methanesulfonyl chloride) of triethylamine was added dropwise over 2 hours, with the temperature of the reaction mixture being controlled at 30°C or lower. After the addition was complete, the mixture was stirred for 1 hour, maintaining the same temperature. The reaction mixture was analyzed by gas chromatography (GC), and the results showed that the conversion of (R)-2-methoxypropionic acid (3) was >95%.

[0292] After the reaction is complete, 200 g of water are added to the reaction mixture to wash the reaction mixture. The reaction mixture is further washed twice with 200 g of water each time and then distilled to remove dichloromethane. 85.6 g of (R)-2-methoxypropionic anhydride (I-4) are obtained as a yellow liquid and used in the acylation step without further purification.

[0293] In the same manner as described in Preparation 1, the following 2-alkoxy substituted propionic anhydride was prepared:

[0294]

[0295]

[0296] Preparation 2: Synthesis of alkoxy-substituted isobutyric acids and anhydrides

[0297] Synthesis of 2-ethoxyisobutyric acid / 2-ethoxy-2-methylpropionic acid (I-21) and anhydride (I-22):

[0298]

[0299] 2-Ethoxyisobutyric acid was prepared according to a reference (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, pp. 1402-1406]): 2-Bromo-2-methylpropanoic acid (I-20) (40 g, 239.5 mmole) was dissolved in ethanol (320 mL) in a 500 mL 3-necked round-bottom flask and cooled to 0 to 5° C. DIPEA (87.4 mL, 502.9 mmole) was then added dropwise at 0 to 5° C., and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was warmed to 40° C. for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature, and the ethanol was removed in vacuo to give a thick white slurry. Ether and water were added to the slurry and cooled to 0°C. The mixture was acidified with 10% HCl (50 mL), the organic layer was separated, and washed with brine. A 10% NaHSO3 aqueous solution was added to the organic phase, and the mixture was stirred at room temperature for 6 hours. The two-phase mixture was acidified with 10% HCl (50 mL) to a pH of 1.0 ± 0.5. The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to give 30 g of 2-ethoxy-2-methylpropionic acid (I-21). The product 2-ethoxy-2-methylpropionic acid (I-21) was used in the next step without further purification.

[0300] In a 2-liter four-necked glass reactor equipped with a thermometer and a stirrer, 300 g of dichloromethane, 66.1 g (0.5 mol) of 2-ethoxy-2-methylpropionic acid (I-21) and 28.65 g (0.25 mol) of methanesulfonyl chloride were placed under a nitrogen atmosphere and the mixture was cooled to 5°C.

[0301] Then, 50.65 g (0.5 mol, 1 equivalent relative to the acid generated from the methanesulfonyl chloride) of triethylamine was added dropwise over 2 hours, with the temperature of the reaction mixture maintained at 30°C or below. After the addition was complete, the mixture was stirred for 1 hour, maintaining the same temperature. Analysis of the reaction mixture by gas chromatography (GC) indicated a conversion of >95% to 2-ethoxy-2-methylpropionic acid (I-21).

[0302] After the reaction is complete, 100 g of water is added to the reaction mixture to wash the reaction mixture. The reaction mixture is further washed twice, each time with 100 g of water, and then distilled to remove dichloromethane. 51 g of 2-ethoxy-2-methylpropionic anhydride (I-22) is obtained as a yellow liquid, which is used in the acylation step without further purification.

[0303] In the same manner as described in Preparation 1, the following 2-alkoxy-substituted 2-methylpropionic acid / 2-alkoxy-substituted isobutyric anhydride was prepared:

[0304]

[0305]

[0306] Preparation 3 Synthesis of 4-alkoxytetrahydro-2H-pyran-4-carboxylic acid and anhydride

[0307] Synthesis of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid (I-36) and anhydride (I-37):

[0308] Commercially available tetrahydro-2H-pyran-4-carboxylic acid methyl ester was brominated according to the method described in Organic Letters, 2020, Vol. 22, #10, pp. 3922-3925. The ester was then hydrolyzed to the corresponding α-bromic acid (I-35). The α-bromic acid (I-35) was then converted into the corresponding acid (I-36) and anhydride (I-37) according to the method of Preparation 2.

[0309]

[0310] The following 4-alkoxytetrahydro-2H-pyran-4-carboxylic acids and anhydrides were prepared similarly.

[0311]

[0312] Preparation 4 Synthesis of 4-alkyltetrahydro-2H-pyran-4-carboxylic acids and anhydrides

[0313] Synthesis of 4-methyltetrahydro-2H-pyran-4-carboxylic acid (I-46) and anhydride (I-47):

[0314]

[0315] Commercially available methyl tetrahydro-2H-pyran-4-carboxylate (I-33) is methylated in the same manner as described in Example 64.1A of US9434690. The methyl ester is then hydrolyzed with aqueous NaOH and acidified with HCl to give 4-methyltetrahydro-2H-pyran-4-carboxylic acid (I-46) as an off-white solid.

[0316] 4-Methyltetrahydro-2H-pyran-4-carboxylic anhydride (I-47) was prepared according to the method of Preparation 2 as a light yellow oil.

[0317] The following 4-alkyltetrahydro-2H-pyran-4-carboxylic anhydrides were prepared in a similar manner.

[0318]

[0319]

[0320] Preparation 5 Synthesis of 2-ethyl-2-alkoxy-butyric acid and anhydride

[0321] Synthesis of 2-ethyl-2-methoxy-butyric acid (I-62) and anhydride (I-63):

[0322]

[0323] 2-Ethyl-2-bromo-butyric acid (I-61) is commercially available or can be prepared according to the method described by Doran; Shonle in Journal of Organic Chemistry, 1938, Vol. 3, p. 195.

[0324] 2-Ethyl-2-bromo-butyric acid (I-61) is first converted to ethyl-2-methoxy-butyric acid (I-62) and then to ethyl-2-methoxy-butyric anhydride (I-63) as a light yellow oil as described in Preparation 2.

[0325] The following acids and anhydrides were prepared in a similar manner.

[0326]

[0327] Preparation 6 Synthesis of 2-methyl-2-alkoxyl-butyric acid and anhydride

[0328] 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 separated into enantiomerically pure R and S isomers (I-71), and then esterified to the methyl ester (I-72) according to the method described in Preparation 74 of US2008114005.

[0329]

[0330]

[0331] Alternatively, commercially available 2-bromo-2-methylbutanoic acid is converted to (R, S)-2-methoxy-2-methylbutanoic acid (I-78) according to the method disclosed in Preparation 2, and (I-78) is resolved into enantiomers (I-80) and (I-77) according to the method described in Preparation 74 of US2008114005. Then, the chiral acid (I-75) is converted into anhydride (I-76) as described in Preparation 2, which is an oil.

[0332]

[0333] The following acids and anhydrides were prepared in a similar manner.

[0334]

[0335]

[0336] Preparation 7 Synthesis of 2-alkyltetrahydrofuran-2-carboxylic acids and anhydrides.

[0337] Synthesis of 2-methyltetrahydrofuran-2-carboxylic acid (I-112), (I-114) and anhydrides (I-113), (I-115): Enantiomerically pure 2-methyltetrahydrofuran-2-carboxylic acid (I-112) and (I-114) were prepared according to the method described by Pohl and Wollweber in European Journal of Medicinal Chemistry, 1976, Vol. 11, pp. 163, 168, 169. The acid was then converted to the corresponding anhydride (I-113) and (I-115) in a manner similar to that described in Preparation 2.

[0338]

[0339] The following 2-alkyltetrahydrofuran-2-carboxylic acids and anhydrides were prepared in a similar manner:

[0340]

[0341] Preparation 8 Synthesis of 2-methyl-2-alkoxymethylpropionic acid and anhydride.

[0342] Synthesis of 2-methyl-2-methoxymethylpropionic acid (I-130) and anhydride (I-131):

[0343]

[0344] Commercially available methyl 2-methyl-2-hydroxymethylpropanoate (I-128) was first methylated and then the ester was hydrolyzed using the method described in Examples 55 and 56 of WO 2009 / 77608, 2009 to give 2-methyl-2-methoxymethylpropionic acid (I-130).

[0345] 2-Methyl-2-methoxymethylpropionic acid (I-130) is then converted to the anhydride (I-131) according to the method of Preparation 2 and obtained as an oil.

[0346] The following 2-methyl-2-alkoxymethylpropionic anhydride was prepared in a similar manner.

[0347]

[0348] Preparation 9 Synthesis of 1-alkyl, 2,2-dialkoxy-isobutyric acid and anhydride

[0349] Synthesis of 1-methyl-2,2-dimethoxy-isobutyric acid (I-142) and anhydride (I-143):

[0350]

[0351] 1-Methyl-2,2-dimethoxy-isobutyric acid (I-142) was prepared according to the method described in Reference Example 14 of US2004248941.

[0352]

[0353] Alternatively, 1-methyl-2,2-dimethoxy-isobutyric acid (I-142) was prepared from commercially available 2,2-bis(hydroxymethyl)propionic acid according to Reference Example 14 of EP1437352.

[0354] 1-Methyl-2,2-dimethoxy-isobutyric acid (I-142) was then converted to the anhydride (I-143) according to the method of Preparation 2 and obtained as an oil.

[0355] The following 1-alkyl-2,2-dialkoxy-isobutyric acids and anhydrides were prepared in a similar manner.

[0356]

[0357]

[0358]

[0359]

[0360] Preparation 10 Synthesis of 1-(alkoxymethyl)cyclopropane-1-carboxylic acid and anhydride.

[0361] Synthesis of 1-(methoxymethyl)cyclopropane-1-carboxylic acid (I-225) and anhydride (I-226):

[0362]

[0363] 1-( Methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (I-223) was prepared according to the method described in Reference Example 22-1 of US9546155. The hydroxyl group was then alkylated with iodomethane using a similar method described in Shen, Peng-Xiang et al., Journal of the American Chemical Society, 2018, Vol. 140, #21, pp. 6545-6549. The ester was then hydrolyzed to give 1-(methoxymethyl)cyclopropane-1-carboxylic acid (I-225).

[0364] 1-(Methoxymethyl)cyclopropane-1-carboxylic acid (I-225) is then converted to the anhydride (I-226) according to the method of Preparation 2 to provide (I-226) as an oil.

[0365] The following 1-(alkoxymethyl)cyclopropane-1-carboxylic acids and anhydrides were prepared similarly.

[0366]

[0367] Preparation 11 Synthesis of 1-(alkoxymethyl)cyclobutane-1-carboxylic acid and anhydride.

[0368] Synthesis of 1-(methoxymethyl)cyclobutane-1-carboxylic acid (I-238) and anhydride (I-239):

[0369]

[0370] Methyl 1-(hydroxymethyl)cyclobutane-1-carboxylate (I-236) was prepared according to the method described in Reference Example 22-4 of US9546155. The hydroxyl group was then alkylated with iodomethane using a similar method as described in Reference Example K-19 of US10040791, followed by ester hydrolysis to give 1-(methoxymethyl)cyclobutane-1-carboxylic acid (I-238).

[0371] 1-(Methoxymethyl)cyclobutane-1-carboxylic acid (I-238) is then converted to the anhydride (I-239) according to the method of Preparation 2 to provide it as an oil.

[0372] The following 1-(alkoxymethyl)cyclobutane-1-carboxylic acids and anhydrides were prepared in a similar manner.

[0373]

[0374] Preparation 12 Synthesis of 1,2,2-Trialkoxy-isobutyric acid and anhydride

[0375] Synthesis of 1-methoxy-2,2-diethoxy-isobutyric acid (223) and anhydride (224):

[0376]

[0377] Ethyl 1-hydroxy-2,2-diethoxyisobutyrate (I-249) was prepared according to the method described by Bernardon, C. et al. in Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1968, Vol. 266, pp. 1502-1505. The hydroxyl group was then alkylated with iodomethane using a method similar to that described in Reference Example K-19 of US 10040791. The ester was then hydrolyzed to provide 1-methoxy-2,2-diethoxyisobutyric acid (I-251).

[0378] 1-Methoxy-2,2-diethoxy-isobutyric acid (I-251) is then converted to the anhydride (I-252) according to the method of Preparation 2 and obtained as an oil.

[0379] The following 1-alkoxy-2,2-dialkoxy-isobutyric acids and anhydrides were prepared in a similar manner.

[0380]

[0381]

[0382] Preparation 13: Synthesis of 1-alkoxycyclobutanecarboxylic acid and anhydride

[0383] Synthesis of 1-methoxycyclopropanecarboxylic acid (I-291) and anhydride (I-292):

[0384] In the same manner as described in Example 26 3A of US10464914, commercially available methyl 2-methoxyacetate (I-289) was alkylated with dibromoethane to give methyl 1-methoxycyclopropanecarboxylate, which was then hydrolyzed under alkaline 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 to give it as an oil.

[0385]

[0386] In the same manner as described above, the following 1-methoxycyclopropanecarboxylic acid and anhydride and 1-alkoxycyclobutanecarboxylic acid and anhydride can be prepared:

[0387]

[0388] Embodiment 1:

[0389] Synthesis of N4-hydroxycytidine isobutyl ester (monuprivir) or ((2R,3S,4R,5R)-isobutyric acid 3,4-dihydroxy-5-((E)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl ester.

[0390]

[0391] Monoupravir is prepared by various reported methods, such as those reported in Organic Process Research and Development, 2021, Vol. 25, #8, pp. 1822-1830 [also] or purchased from different commercial suppliers.

[0392] Example 2: Preparation of compound (EX-2)

[0393]

[0394] To a 250 mL round-bottom flask with magnetic stirring at room temperature was added N4-hydroxycytidine isobutyl ester (20 g, 60.79 mmol) in 200 mL of water, followed by the dropwise addition of acetic anhydride (7.44 g, 72.95 mmol). The reaction mixture was stirred at the same temperature for 3-4 hours until HPLC indicated the reaction was complete. The reaction mixture was slowly cooled to 10°C, and the resulting solid was filtered and washed with water to yield EX-2 as a white solid. 1H NMR (400 MHz, DMSO), due to the tautomerization of -N=C-NH-O- bond, two groups of peaks were observed in NMR, δ10.9 (br.s, 1H), 7.2 (d, 1H), 5.7 (m, 2H), 5.4 (s, 1H), 5.3 (s, 1H), 4.2 (m, 2H), 3.9-4.1 (m, 3H), 2.6 (m, 1H), 2.1 (s, 3H), 1.1 (s, 6H); purity: 99% (HPLC determination).

[0395] The following examples illustrate the novel process for selective acylation using acetic anhydride. A single solvent or solvent mixtures (binary, ternary, or quaternary, etc.) in varying proportions can be used for the acylation reaction. The acylated product formed in the reaction solution is typically greater than 95% pure as determined by HPLC.

[0396]

[0397] Example 3: Preparation of compound (EX-3)

[0398]

[0399] To a 250 mL round-bottom flask with magnetic stirring at room temperature was added N4-hydroxycytidine isobutyl ester (20 g, 60.79 mmol) in 200 mL of water, followed by the dropwise addition of isobutyric anhydride (11.53 g, 72.95 mmol) over 25-30 minutes. The reaction mixture was stirred at the same temperature for 3-4 hours until HPLC indicated completion of the reaction. The reaction mixture was then extracted with ethyl acetate (1 x 100 mL & 2 x 50 mL). The extract was washed with water (50 mL) and brine (50 mL), then dried over anhydrous Na2SO4 and concentrated in vacuo to afford EX-3 as a white solid (23.6 g) with a purity of 99.4% and a yield of 97.3%. 1H NMR (400 MHz, DMSO), due to the tautomerization of -N=C-NH-O- bond, two groups of peaks were observed in NMR δ10.9 (br.s, 1H), 7.2 (d, 1H), 5.7 (m, 2H), 5.4 (s, 1H), 5.3 (s, 1H), 4.2 (m, 2H), 3.9-4.1 (m, 3H), 2.8 (m, 1H), 2.5 (m, 1H), 1.1 (d, 12H).

[0400] The following examples illustrate the novel method for selective acylation using isobutyric anhydride. A single solvent or solvent mixtures (binary, ternary, or quaternary, etc.) in varying proportions can be used for the acylation reaction. The acylated product formed in the reaction solution is typically greater than 95% pure, as determined by HPLC.

[0401]

[0402] Example 4: Preparation of Compound (EX-4)

[0403]

[0404] To a 100 mL round-bottom flask with magnetic stirring at room temperature was added N4-hydroxycytidine isobutyl ester (20 g, 60.79 mmol) in 40 mL pyridine and 40 mL THF, followed by the dropwise addition of benzoyl chloride (10.25 g, 72.95 mmol) over 5-10 minutes. The reaction mixture was stirred at 40-50°C overnight until HPLC indicated completion of the reaction. Excess pyridine and THF were removed under vacuum, the reaction residue was dissolved in EtOAc, and the organic layer was washed with 5% HCl and then with saturated sodium chloride solution. The organic layer was dried over anhydrous Na2SO4, concentrated, and purified on a silica gel column (DCM and MeOH, gradient) to afford EX-4 as a white solid. 1H NMR (400 MHz, DMSO), due to the tautomerization of -N=C-NH-O- bond, two groups of peaks were observed in NMR δ11.16-11.37 (br.s, 1H), 8.04-8.23 (d, 2H), 7.67 (m, H), 7.55 (m, 2H), 7.25 (m, 1H), 5.84&6.25 (d, 1H), 5.76 (m, 1H), 5.46 (d, 1H), 5.27 (d, 1H), 4.15-4.25 (m, 2H), 4.0-4.1 (m, 1H), 3.9-4.0 (m, 2H), 2.56-2.63 (m, 1H), 1.1 (d, 6H).

[0405] Example 5: Preparation of Compound (EX-5)

[0406]

[0407] Under stirring at room temperature, a 250 mL round-bottom flask with magnetic stirring was added with monuprivir (20 g, 60.79 mmol) in 200 mL of water, followed by the dropwise addition of propionic anhydride (9.48 g, 72.95 mmol) for 25-30 minutes. The reaction mixture was stirred at this temperature for 3-4 hours until HPLC showed the reaction was complete. The reaction mixture was slowly cooled to 10 ° C and stirred at room temperature overnight. The solid formed was filtered and washed with cold water to obtain EX-5 as a white solid (21.1 g) with a purity of 98.8% and a yield of 90.0%. 1H NMR (400 MHz, DMSO), due to the tautomerization of -N=C-NH-O- bond, two groups of peaks were observed in NMR δ10.9 (br.s, 1H), 7.2 (d, 1H), 5.7 (m, 2H), 5.4 (br.s, 1H), 5.3 (s, 1H), 4.1-4.2 (m, 2H), 4.0 (m, 1H), 3.9 (m, 2H), 2.6 (m, 1H), 2.4-2.5 (m, 2H), 1.1 (m, 9H).

[0408] Example 6: Preparation of Compound (EX-39)

[0409]

[0410] To a 250 mL round-bottom flask with magnetic stirring at 10-15°C was added monuprivir (20 g, 60.79 mmol) in 200 mL of methanol, followed by the dropwise addition of methoxyacetic anhydride (11.82 g, 72.95 mmol) over 25-30 minutes. The reaction mixture was stirred at this temperature for 3-4 hours until HPLC indicated the reaction was complete. The methanol was removed under vacuum, and the reaction residue was dissolved in CH2Cl2. The organic layer was washed with saturated sodium chloride solution, then dried over anhydrous Na2SO4, and concentrated in vacuo to afford EX-39 as a white solid (21.6 g) with a purity of 97.7% and a yield of 88.5%. 1H NMR(400MHz,DMSO)δ10.9&11.2(br.s,1H),7.2(d,1H),5.7(m,2H),5.4(s,1H),5 .2(s,1H),4.1-4.2(m,4H),3.8-4.0(m,3H),3.3(m,3H),2.6(m,1H),1.1(d,6H).

[0411] Example 7: Preparation of Compound (EX-40)

[0412]

[0413] To a 250 mL round-bottom flask with magnetic stirring at 10-15°C was added monuprivir (20 g, 60.79 mmol) in 200 mL of methanol, followed by the dropwise addition of methoxyacetic anhydride (13.86 g, 72.95 mmol) over 25-30 minutes. The reaction mixture was stirred at this temperature for 3-4 hours until HPLC indicated the reaction was complete. The methanol was removed under vacuum, and the reaction residue was dissolved in CH2Cl2. The organic layer was washed with saturated sodium chloride solution, then dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford EX-40 as a white solid (22.8 g) with a purity of 99.3% and a yield of 90.5%. 1H NMR(400MHz,DMSO)δ10.9&11.2(br.s,1H),7.2(d,1H),5.7(m,2H),5.4(s,1H),5 .2(s,1H),4.1-4.2(m,4H),3.8-4.0(m,3H),3.5(m,2H),2.6(m,1H),1.1(m,9H).

[0414] The following exemplary compounds were prepared analogously to those described in Examples 2, 3 or 4, using commercially available anhydrides or acid chlorides. For those carboxylic anhydrides and acid chlorides that are not commercially available, they can be readily prepared by well-known standard methods.

[0415]

[0416]

[0417]

[0418] The following compounds can be prepared similarly

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435] Example 170: Plasma Stability

[0436] Solution preparation: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 with acetonitrile.

[0437] Plasma incubation: Plasma incubation was performed in duplicate at 37°C in a 96-well plate. Plasma was pre-warmed at 37°C for 5 minutes in a total volume of 198 μL, and then 2 μL of 100 μM test compound was added to the incubation well containing plasma, mixed with a pipette to obtain a uniform suspension, and immediately 20 μL of the incubation solution was transferred to the well of the "quench" plate as a 0 minute sample, followed by the addition of 200 μL of acetonitrile, metolazone as an internal standard (IS), and mixed with a pipette. At 2, 5, 60, and 90 minutes, the incubation solution was mixed with a pipette, and a 20 μL incubation solution sample series of each time point was transferred to the well of another "quench" plate, followed by the addition of 200 μL of acetonitrile, metolazone as an internal standard, and mixed with a pipette.

[0438] Sample analysis: The 96-well plate was centrifuged at 6000 g for 10 minutes and the supernatant was injected into the LC-MS / MS system for analysis.

[0439] Example 171: Microsomal Stability

[0440] Solution preparation: 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 with acetonitrile.

[0441] Microsomal incubation: The incubation mixture was 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 the test compound (1 μM) or monolavir (1 μM) as a positive control, where NADPH was added after preincubation of all other components at 37°C for 5 minutes. Mix with a pipette to obtain a homogenous suspension, and immediately transfer 20 μL of the incubation solution as a 0-minute sample to a well of a "quench" plate. Then, 200 μL of acetonitrile was added with trimethoprim as the IS and mixed with a pipette. At 2, 5, 10, and 45 minutes, the incubation solution was mixed with a pipette, and 20 μL of the incubation solution sample for each time point was continuously transferred to a well of a separate "quench" plate. Then, 200 μL of acetonitrile with metolazone as the IS was added and mixed with a pipette.

[0442] Sample analysis: The 96-well plate was centrifuged at 6000 g for 10 minutes and the supernatant was injected into the LC-MS / MS system for analysis.

Claims

1. Compound of formula (I): or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are the same or different and are independently selected from C 1-7 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-7 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, 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 heterocyclyl-C 1-7 Alkyl, wherein the alkyl is optionally substituted with one or more substituents 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 Alkoxy, halo-C 1-7 Alkoxy, halo-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy; wherein each of the cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more substituents 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, 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 heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy; wherein the acyl group is Rx-(C=O)-; and Rx and Ry are independently selected from C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, 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 heterocyclyl-C 1-7 alkyl.

2. A compound of formula (I) according to claim 1 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are the same or different and are independently selected from C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl, wherein the alkyl group is optionally substituted with one or more substituents 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 Alkoxy, halo-C 1-7 Alkoxy, halo-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5 to 10 membered heteroaryloxy and 3 to 12 membered heterocyclyloxy; and each of the cycloalkyl, aryl, heteroaryl and heterocyclyl groups is optionally substituted with one or more substituents 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, 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 heterocyclic group, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy; wherein the acyl group is Rx-(C=O)-; and Rx and Ry are independently selected from C 1-7 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, 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 heterocyclyl-C 1-7 alkyl.

3. A compound of formula (I) according to any one of the preceding claims, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are the same or different and are independently selected from: C 1-7 Alkyl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -NH(C 1-7 Alkyl), -N(C 1-7 Alkyl)2, C 1-7 Alkoxy, C 3-8 Cycloalkyloxy, C 6-10 aryloxy, 5- to 10-membered heteroaryloxy, and 3- to 12-membered heterocyclyloxy; C 3-8 Cycloalkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -NH(C 1-7 Alkyl), -N(C 1-7 Alkyl)2, -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy and C 1-7 Alkoxy-C 1-7 alkyl; C 6-10 Aryl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -NH(C 1-7 Alkyl), -N(C 1-7 Alkyl)2, -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and phenyl groups; 5 to 10 membered heteroaryl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy and C 1-7 Alkoxy-C 1-7 alkyl; and 3 to 12 membered heterocyclic group, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, -C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and -(C=O)-C 1-7 alkyl.

4. A compound of formula (I) according to any one of the preceding claims, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is selected from: C 1-7 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-7 Alkoxy, C 3-8 Cycloalkyloxy and C 6-10 aryloxy; C 3-8 Cycloalkyl, optionally substituted with one or more substituents selected from: -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl and C 1-7 Alkoxy-C 1-7 Alkyl; preferably C 3-6 cycloalkyl; and 5 to 8 membered heterocyclyl, which is optionally substituted by one or more substituents selected from: -C 1-7 Alkyl, C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and -(C=O)-C 1-7 Alkyl; preferably, 5- to 6-membered heterocyclyl; preferably 5- to 6-membered heterocyclyl; more preferably tetrahydropyranyl.

5. A compound of formula (I) according to any one of the preceding claims, wherein Rb is C or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof 1-7 Alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-7 Alkoxy and C 3-6 Cycloalkyloxy.

6. A compound of formula (I) according to any one of the preceding claims, wherein Rb is C or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof 1-4 Alkyl, which is optionally substituted by 1, 2 or 3 C 1-4 Alkoxy substituted; preferably Rb is C 1-4 alkyl.

7. A compound of formula (I) according to any one of the preceding claims, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is isopropyl, which is optionally replaced by 1 C 1-3 Alkoxy substituted; preferably Rb is isopropyl or n-propyl.

8. A compound of formula (I) according to any one of claims 1 to 4, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Rb is C 3-6 Cycloalkyl, such as cyclopropyl.

9. A compound of formula (I) according to any one of the preceding claims, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is independently selected from: C 3-8 Cycloalkyl, optionally substituted with one or more substituents selected from: -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl and C 1-7 Alkoxy-C 1-7 alkyl; C 6-10 Aryl, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, -NH(-(C=O)-C 1-7 alkyl), -N(-(C=O)-C 1-7 Alkyl)2, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and phenyl groups; 5 to 10 membered heteroaryl, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, C 1-7 Alkyl, C 1-7 Alkoxy, halo-C 1-7 Alkyl, halo-C 1-7 Alkoxy and C 1-7 Alkoxy-C 1-7 alkyl; and 5 to 8 membered heterocyclyl, which is optionally substituted by one or more substituents selected from: -C 1-7 Alkyl, C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl and -(C=O)-C 1-7 alkyl.

10. A compound of formula (I) according to any one of claims 1 to 8, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra is C 1-4 Alkyl, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-4 Alkoxy and C 3-6 Cycloalkyloxy.

11. The compound according to any one of claims 1 to 3, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, wherein Ra-(C=O)- and Rb-(C=O)- are the same or different and are independently selected from:

12. The compound according to claim 1 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

14. Use of the compound according to any one of claims 1 to 12 or its tautomer, stereoisomer or racemate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing RNA virus infection.

15. A method for treating or preventing an RNA viral infection in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 12, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof.

16. A compound according to any one of claims 1 to 12 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof for use as a medicament.

17. A compound according to any one of claims 1 to 12, or a tautomer, stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, for use in treating or preventing RNA virus infection.

18. The use according to claim 14, the method according to claim 15 or the compound for use according to any one of claims 16-17, wherein the RNA virus is a coronavirus, such as a human coronavirus, a SARS coronavirus or a MERS coronavirus, an alpha virus, 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, an influenza A virus or an 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, an alpha variant, a beta variant, a gamma variant, a delta variant, an o variant, or any other variant thereof.

19. A pharmaceutical combination comprising a compound according to any one of claims 1 to 12 or a tautomer, stereoisomer or racemate thereof or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, preferably an additional therapeutic agent selected from:

20. A pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, comprising a pharmaceutically acceptable excipient and a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is as defined in any one of claims 1 to 12.

21. A process for preparing a compound of formula (I) according to any one of claims 1 to 12, comprising the steps of: The compound of formula (III) is reacted with the anhydride of formula (II) to obtain the compound of formula (I), wherein Ra and Rb are independently as defined in any one of claims 1 to 12; preferably Rb is isopropyl.

22. The method according to claim 21, 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 lower aliphatic alcohols, ACN, THF, 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 that can completely or partially dissolve NHC; more preferably water, lower aliphatic alcohols, water-THF mixtures, water / 2-methylTHF mixtures, water / ACN mixtures or water-lower aliphatic alcohol mixtures.

23. The process according to claim 21 or 22, wherein the reaction is carried out without adding any 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 Alkylamines such as TEA, diisopropylethylamine, tripropylamine, tributylamine, or heterocyclic bases such as pyridine, picoline, lutidine, DMAP, DBU, and the like.

24. The process according to any one of claims 20 to 23, wherein the purity of the product obtained is about 90% to 98%, preferably more than 98%.

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