N4-hydroxycytidine and derivatives and related antiviral uses thereof

Abstract

The present invention relates to certain N4-hydroxycytidine derivatives, pharmaceutical compositions, and methods related thereto. In certain embodiments, the present invention relates to the treatment and prevention of human coronavirus 2019-nCoV.

Description

[0001] This application is a divisional application of a Chinese patent application with the application number "202180013336.X", the filing date "February 7, 2021", and the invention title "N4-Hydroxycytidine and Derivatives and Their Related Antiviral Uses".

[0002] Government Support

[0003] This invention was made with government support under Contract Nos. HDTRA1-13-C-0072 and HDTRA1-15-C-0075 awarded by the U.S. Department of Defense, and Contract Nos. HHSN272201500008C and 75N93019C00058 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0004] Cross - Reference to Related Patent Applications

[0005] This application claims the priority benefits of U.S. Provisional Application Nos. 62 / 971,559 filed on February 7, 2020, 62 / 988,133 filed on March 11, 2020, 62 / 994,604 filed on March 25, 2020, and 63 / 006,625 filed on April 7, 2020. Technical Field

[0006] The present invention relates to N4 - hydroxycytidine nucleosides and derivatives, as well as related compositions and methods. In certain embodiments, the present invention relates to the treatment or prevention of viral infections, particularly 2019 - nCoV. Background Art

[0007] Coronaviruses are enveloped, positive-sense RNA viruses that cause most human respiratory diseases. Two coronaviruses that have previously emerged and caused human disease are SARS and MERS. There were over 8,000 human cases of SARS, with 774 deaths. Since 2012, there have been over 2,500 cases of MERS, with 919 deaths. The novel coronavirus 2019-nCoV, now known as SARS-CoV-2, was discovered in recent years. Reports show that over 28,000 people have been infected with the novel coronavirus, with over 560 recorded deaths. In addition, records demonstrate that 2019-nCov can be transmitted from person to person. Single complete whole-genome sequence analysis indicates that 2019-nCov belongs to the genus Betacoronavirus, but is different from SARS and MERS. 2019-nCoV is a highly pathogenic human pathogen, and relatively little is known about it. The disease caused by SARS-CoV-2 / 2019-nCoV is called COVID-19. COVID-19 can include severe human respiratory diseases and also appears to cause neurological diseases, including dizziness, impaired consciousness, acute cerebrovascular diseases, epilepsy, hyposmia, hypopsia, and neuralgia (medRxiv, 2020, 1-26). After the virus is circulated in the systemic circulation or passes through the cribriform plate, viral interaction with the ACE2 receptor can facilitate the entry of SARS-CoV-2 into the CNS. Additional studies are needed to further characterize the virus and determine disease prevention and treatment methods.

[0008] Stuyver et al. reported the discovery of β-D-N(4)-hydroxycytidine (NHC) with antiviral and anti-hepatitis virus activities. Antimicrobial Agents and Chemotherapy, 2003, 47(1):244-54. Constantini et al. reported the evaluation of the efficacy of 2'-C-MeC, 2'-F-2'-C-MeC, and NHC against Norwalk virus. See also Purohit et al., Journal of Medicinal Chemistry, 2012, 55(22):9988-9997; Ivanov et al., Collection of Czechoslovak Chemical Communications, 2006, 71(7):1099-1106; and Fox et al., JACS, 1959, 81:178-87.

[0009] There is a need to develop new compounds and treatment methods for dealing with viral infections. The compounds and methods disclosed herein meet these needs. SUMMARY OF THE INVENTION

[0010] The present invention relates to certain N4-hydroxycytidines and derivatives, combinations, pharmaceutical compositions, and related methods. In certain embodiments, the present invention relates to a compound having the chemical formula I,

[0011]

[0012] Chemical formula I

[0013] or a pharmaceutically acceptable salt, derivative, or prodrug thereof (as defined herein).

[0014] In certain embodiments, the present invention contemplates derivatives of the compounds disclosed herein, such as derivatives of compounds comprising one or more identical or different substituents.

[0015] In certain embodiments, the present invention contemplates a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound disclosed herein. In certain embodiments, the pharmaceutical composition is a tablet, capsule, pill, or buffered aqueous solution, such as normal saline or phosphate buffer.

[0016] In certain embodiments, the disclosed pharmaceutical composition may comprise a compound disclosed herein and a propellant. In certain embodiments, the propellant is an aerosol propellant, such as compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkane (HFA), 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, or a combination thereof.

[0017] In certain embodiments, the present invention contemplates a pressurized or non-pressurized container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the container is a manual pump sprayer, inhaler, metered-dose inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic nebulizer.

[0018] In certain embodiments, the present invention relates to a method of treating or preventing a viral infection by enhancing bioavailability, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0019] In certain embodiments, the viral infection is a human coronavirus SARS, MERS, or 2019-nCoV infection.

[0020] In certain embodiments, the compound or pharmaceutical composition is administered orally, intravenously, or by the pulmonary route (i.e., pulmonary administration).

[0021] In certain embodiments, the present invention relates to the use of a compound described herein to produce an agent for treating or preventing a viral infection (such as a 2019-nCoV viral infection).

[0022] In certain embodiments, the present invention relates to a method for preparing a compound disclosed herein by mixing a starting material with a reagent disclosed herein under conditions that allow for the formation of the compound. The compounds prepared by the disclosed method can be used to treat or prevent COVID-19 caused by 2019-nCoV / SARS-CoV-2.

[0023] Other advantages will be set forth in the following description, some of which will be apparent from the description, or may be learned by practice of the aspects set forth below. The advantages set forth below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The drawings incorporated herein and constituting a part of this specification, illustrate several aspects set forth below.

[0025] Figure 1 Schematic illustration for the preparation of β-D-N-hydroxycytidine. The synthesis steps are as follows: a.) tert-butyldimethylchlorosilane, 4-dimethylaminopyridine, diisopropylethylamine, dichloromethane; b.) (2,4,6-iPr)PhSO2Cl, diisopropylethylamine, 4-dimethylaminopyridine, dichloromethane; c.) NH2OH-HCl, diisopropylethylamine, dichloromethane; d.) F source; and e.) aqueous NH2OH, AcOH (50 °C).

[0026] Figure 2 Shows certain exemplary compounds.

[0027] Figure 3 Shows certain exemplary compounds.

[0028] Figure 4 Shows the average plasma drug concentration and pharmacokinetic parameters of mice treated with an exemplary compound.

[0029] Figure 5 Shows the nucleoside accumulation in the organs of mice treated with an exemplary compound.

[0030] Figure 6 Shows the triphosphate accumulation in the organs of mice treated with an exemplary compound.

[0031] Figure 7 Shows the N4-hydroxycytidine nucleoside tissue concentration in cynomolgus monkeys orally administered EIDD-1931 (100 mg / kg).

[0032] Figure 8 Shows the N4-hydroxycytidine nucleoside tissue concentration in cynomolgus monkeys intravenously administered EIDD-1931 (10 mg / kg).

[0033] Figure 9 Shows the structure of the compound administered orally to cynomolgus monkeys.

[0034] Figure 10 Shows the average plasma concentration of N4-hydroxycytidine nucleoside in cynomolgus monkeys administered the oral ester derivative.

[0035] Figure 11 Shows the average maximum concentration of N4-hydroxycytidine nucleoside in the plasma of cynomolgus monkeys administered the oral ester derivative.

[0036] Figure 12 Shows the effect of prophylactic treatment with EIDD-2801 on the pulmonary virus titer in SARS-infected mice.

[0037] Figure 13 Shows the effect of the treatment time of EIDD-2801 on the pulmonary hemorrhage score in SARS-infected mice.

[0038] Figure 14 Shows the effect of the treatment time of EIDD-2801 on the pulmonary virus titer in SARS-infected mice.

[0039] Figure 15 Shows the effect of the treatment with EIDD-2801 on the pulmonary hemorrhage score in MERS-infected mice.

[0040] Figure 16 Shows the arithmetic mean plasma concentration of EIDD-1931 (50 - 1600 mg EIDD-2801, single escalating dose).

[0041] Figure 17 Shows the arithmetic mean plasma concentration of EIDD-1931 (50 - 800 mg EIDD-2801, twice daily, multiple escalating doses) on day 1 (upper panel) and day 6 (lower panel).

[0042] Figure 18 Shows the arithmetic mean plasma concentration of EIDD-1931 (food effect). Detailed implementation mode

[0043] Before describing the present invention in further detail, it should be understood that the present invention is not limited to the specific embodiments described, and of course, it may be different. It should also be understood that the terms used herein are only for describing specific embodiments and do not limit the scope of the present invention, because the scope of the present invention is only limited by the appended claims.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, only the preferred methods and materials are described herein.

[0045] All publications and patents cited in this specification are hereby incorporated by reference into the present invention, as if each individual publication or patent was specifically and individually indicated to be incorporated by reference into the present invention, and is intended to disclose and describe the methods and / or materials related to the cited publications. The purpose of citing any publication is to disclose it before the filing date, and it should not be regarded as an admission that the present invention is not entitled to be prior to such publication due to prior disclosure. In addition, the provided publication dates may be different from the actual publication dates and may require separate confirmation.

[0046] After reading the present invention, it will be apparent to those skilled in the art that the various embodiments described herein have discrete components and features, which can be easily separated or combined with the features of any other several embodiments without departing from the scope or spirit of the present invention. Any of the recited methods can be performed in the order of the recited events or in any other order that is logically feasible.

[0047] Unless otherwise stated, the embodiments of the present invention will utilize medical, organic chemistry, biochemistry, molecular biology, and pharmacological techniques within the skill of the art. Such techniques are fully explained in the literature.

[0048] In certain embodiments, an agent in the form of a salt or prodrug is administered by weight as specified in the methods disclosed herein. This refers to the weight of the recited compound. If a salt or prodrug form is used, the weight is the molar equivalent of the corresponding salt or prodrug.

[0049] It must be noted that, unless the context clearly indicates otherwise, in this specification and the appended claims, the singular forms "a", "an", and "the" also include plural referents.

[0050] "Subject" refers to any animal, preferably human subjects, domestic animals, and household pets

[0051] In this context, the terms "prevent" and "preventing" include preventing recurrence, spread, or onset, but the present invention is not limited to complete prevention. In certain embodiments, the onset is delayed or the severity of the disease is reduced.

[0052] As used herein, the terms "treat" and "treating" are not limited to situations where a subject (e.g., a patient) is cured and the disease is eradicated. Embodiments of the present invention also contemplate treatments that can only alleviate symptoms and / or delay disease progression.

[0053] As used herein, when describing the co - administration of other treatments, the term "in combination with" means that an agent or a combination thereof can be administered before, during, or after the other treatment.

[0054] As used herein, "alkyl" refers to a straight - chain or branched - chain saturated hydrocarbon moiety, such as a moiety containing 1 - 10 carbon atoms. "Higher alkyl" refers to a saturated hydrocarbon containing 11 or more carbon atoms. "C6 - C 16 " refers to an alkyl containing 6 - 16 carbon atoms. Similarly, "C6 - C 22 " refers to an alkyl containing 6 - 22 carbon atoms. Representative saturated straight - chain alkyls include methyl, ethyl, n - propyl, n - butyl, n - pentyl, n - hexyl, n - heptyl, n - octyl, n - nonyl, etc.; and saturated branched - chain alkyls include isopropyl, sec - butyl, isobutyl, tert - butyl, isopentyl, etc.

[0055] As used herein, the term "alkenyl" refers to an unsaturated straight - chain or branched - chain hydrocarbon moiety containing one double bond. Unless otherwise specified, it is contemplated to use C2 - C 24 (e.g., C2 - C 22 、C2 - C 20 、C2 - C 18 、C2 - C 16 、C2 - C 14 、C2 - C 12 、C2 - C 10, C2-C8, C2-C6 or C2-C4) alkenyl. The alkenyl may contain more than one unsaturated bond. Examples include vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl. The term "vinyl" refers to a group having a –CH=CH2 structure; 1-propenyl refers to a group having a –CH=CH-CH3 structure; and 2-propenyl refers to a group having a –CH2-CH=CH2 structure. (Z 1 Z 2 ), C=C(Z 3 Z 4Asymmetric structures such as ( ) are intended to include E and Z isomers. It can be assumed in the structural formulas herein, where there are asymmetric alkenes, or which can be clearly indicated by the chemical bond symbol C=C.

[0056] As used herein, the term "alkynyl" represents a straight-chain or branched-chain hydrocarbon moiety containing a triple bond. Unless otherwise specified, it is contemplated to use C2-C 24 (e.g., C2-C 24 , C2-C 20 , C2-C 18 , C2-C 16 , C2-C 14 , C2-C 12 , C2-C 10 , C2-C8, C2-C6 or C2-C4) alkynyl. The alkynyl may contain more than one unsaturated bond. Examples include C2-C6-alkynyl such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl.

[0057] Non-aromatic monocyclic alkyl or polycyclic alkyl are referred to herein as "carbocyclic" or "carbocyclic group". Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; while unsaturated carbocycles include cyclopentenyl, cyclohexenyl, etc.

[0058] "Heterocyclic carbon" or "heterocyclic carbon group" refers to a saturated or unsaturated (but not aromatic), monocyclic or polycyclic carbon ring containing 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, and sulfur), wherein oxidation of the nitrogen and sulfur heteroatoms is optional, and quaternization of the nitrogen heteroatom is optional. Heterocyclic carbons include morpholinyl, pyrrolidinyl nonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, etc.

[0059] The term "aryl" refers to a group containing an aromatic homocyclic ring (i.e., hydrocarbon), monocyclic, bicyclic, or tricyclic, preferably containing 6 to 12 members, such as phenyl, naphthyl, and biphenyl. Phenyl is the preferred aryl. The term "substituted aryl" refers to an aryl substituted by one or more groups, preferably selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocycle (optionally substituted), halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, carbamate, sulfonyl, etc., wherein one or more pairs of substituents together with the atoms to which they are bonded form a 3- to 7-membered ring.

[0060] As used herein, "heteroaryl" or "heteroaromatic" refers to an aromatic heterocyclic carbon containing 1 to 4 heteroatoms (selected from nitrogen, oxygen, and sulfur) and containing at least 1 carbon atom, including monocyclic or polycyclic ring systems. The polycyclic ring system may or may not contain one or more non-aromatic rings, provided that at least one ring is aromatic. Representative heteroaryls are furyl, benzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyridinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl" includes N-alkylated derivatives, such as 1-methylimidazol-5-yl substituents.

[0061] As used herein, "heterocycle" or "heterocyclic group" refers to a monocyclic or polycyclic ring system containing 1 to 4 heteroatoms (selected from nitrogen, oxygen, and sulfur) and containing at least 1 carbon atom. The monocyclic or polycyclic ring system may be an aromatic ring, a non-aromatic ring, or a mixture of aromatic and non-aromatic rings. Heterocycles include heterocyclic carbons, heteroaryls, etc.

[0062] "Alkylthio" refers to an alkyl as defined above, containing the indicated number of carbon atoms (connected by a sulfur bridge). An example of alkylthio is methylthio (i.e., -S-CH3).

[0063] "Alkoxy" means an alkyl group as defined above, containing the indicated number of carbon atoms (connected by an oxygen bridge). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and sec-pentyloxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy.

[0064] "Alkylamino" means an alkyl group as defined above, containing the indicated number of carbon atoms (connected by an amino bridge). An example of an alkylamino group is methylamino (i.e., -NH-CH3).

[0065] "Alkanoyl" means an alkyl group as defined above, containing the indicated number of carbon atoms (connected by a carbonyl bridge) (i.e., -(C=O)alkyl).

[0066] "Alkylsulfonyl" means an alkyl group as defined above, containing the indicated number of carbon atoms (connected by a sulfonyl bridge) (i.e., -S(=O)2alkyl), such as methylsulfonyl, etc., and "arylsulfonyl" means an aryl group connected by a sulfonyl bridge (i.e., -S(=O)2aryl).

[0067] "Alkylaminosulfonyl" means an alkyl group as defined above, containing the indicated number of carbon atoms (connected by an aminosulfonyl bridge) (i.e., -NHS(=O)2alkyl), and "arylaminosulfonyl" means an aryl group connected by an aminosulfonyl bridge (i.e., -NHS(=O)2aryl).

[0068] "Alkylsulfinyl" means an alkyl group as defined above, containing the indicated number of carbon atoms (connected by a sulfinyl bridge) (i.e., -S(=O)alkyl).

[0069] The terms "cycloalkyl" and "cycloalkenyl" mean monocyclic, bicyclic, or tricyclic carbocyclic rings containing 3 - 15 carbon atoms (fully saturated and partially unsaturated, respectively). The term "cycloalkenyl" includes bicyclic and tricyclic ring systems, but is not entirely aromatic as a whole, but contains aromatic moieties (e.g., fluorene, tetrahydronaphthalene, indan, etc.). The rings of polycyclic cycloalkyls can be fused, bridged, and / or connected by one or more spiro linkages. The terms "substituted cycloalkyl" and "substituted cycloalkenyl" mean cycloalkyl and cycloalkenyl groups substituted with one or more groups, preferably selected from alkyl, substituted alkyl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, carbamate, sulfonyl, etc.

[0070] The terms "halogen" and "halo" mean fluorine, chlorine, bromine, and iodine.

[0071] The term "substituted" refers to a molecule in which at least one hydrogen atom is replaced by a substituent. When substituted, one or more groups are "substituents". The molecule may be poly-substituted. For an oxo substituent ("=O"), two hydrogen atoms are replaced. In this case, exemplary substituents may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclic, carbocycloalkyl, heterocarbocyclic, heterocarbocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -NR a R b 、 -NR a C(=O)R b 、 -NR a C(=O)NR a NR b 、 -NR a C(=O)OR b 、 -NR a SO2R b 、 -C(=O)R a 、 -C(=O)OR a 、 -C(=O)NR a R b 、 -OC(=O)NR a R b 、 -OR a 、 -SR a 、 -SOR a 、 -S(=O)2R a 、 -OS(=O)2R a and -S(=O)2OR a . In this case, R a and R b may be the same or different and may be hydrogen, halogen, hydroxy, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclic, carbocycloalkyl, heterocarbocyclic, heterocarbocycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.

[0072] As used herein, the term "optionally substituted" means that other groups may be optionally selected for substitution, so as to ensure that the specified atom is not substituted. Thus, by using the term "optionally substituted", the present invention includes examples in which the group is substituted and examples in which the group is not substituted.

[0073] Examples of prodrugs useful for enhancing bioavailability include esters, optionally substituted esters, branched esters, optionally substituted branched esters, carbonates, optionally substituted carbonates, carbamates, optionally substituted carbamates, thioesters, optionally substituted thioesters, branched thioesters, optionally substituted branched thioesters, thiocarbonates, optionally substituted thiocarbonates, oxothiocarbonates, optionally substituted oxothiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, S-thiocarbonates, optionally substituted S-thiocarbonates, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, o-methoxycarbonyls, optionally substituted o-methoxycarbonyls, o-methoxycarbonates, optionally substituted o-methoxycarbonates, o-methoxythiocarbonyls, optionally substituted o-methoxythiocarbonyls, o-methylcarbonyls, optionally substituted o-methylcarbonyls, o-methylthiocarbonyls, optionally substituted o-methylthiocarbonyls, o-methoxythiocarbonates, optionally substituted o-methoxythiocarbonates, L-amino acid esters, D-amino acid esters, o-methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, oxothio, optionally substituted oxothio, sulfinyl, sulfonyl, sulfites, sulfates, sulfonamides, iminoesters, optionally substituted iminoesters, hydrazonates, optionally substituted hydrazonates, oximino, optionally substituted oximino, imido, optionally substituted imido, imino, optionally substituted imino, acetalamines, optionally substituted acetalamines, hemiacetalamines, optionally substituted hemiacetalamines, acetals, optionally substituted acetals, hemiacetals, optionally substituted hemiacetals, carbonimidate esters, optionally substituted carbonimidate esters, thiocarbonimidate esters, optionally substituted thiocarbonimidate esters, carbonimidoyl, optionally substituted carbonimidoyl, aminoiminocarbonates, optionally substituted aminoiminocarbonates, aminoguanidinyl, optionally substituted aminoguanidinyl, thioacetals, optionally substituted thioacetals, S-acyl-2-thioethyls, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, bis-(acyloxybenzyl) esters, optionally substituted bis-(acyloxybenzyl) esters, (acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters.

[0074] As used herein, the term "subject" (or "patient" or "participant", such as a clinical trial participant) refers to a mammal that is the object of treatment, observation, or experiment. The mammal can be male or female. The mammal can be one or more selected from a group including the following: humans, bovines (e.g., cows), porcines (e.g., domestic pigs), ovines (e.g., sheep), caprines (e.g., goats), equines (e.g., horses), canines (e.g., domestic dogs), felines (e.g., domestic cats), lagomorphs (domestic rabbits), rodents (e.g., rats or mice), procyons (e.g., North American raccoons). In certain embodiments, the subject is a human.

[0075] As used herein, the term "subject in need" (or "patient in need") refers to a subject diagnosed or suspected of being infected with a virus (such as SARS-CoV-2 infection (symptomatic or asymptomatic)); a subject at risk of viral infection (such as at risk of viral infection such as SARS-CoV-2 infection) (e.g., healthcare workers may be at risk of exposure to SARS-CoV-2); a subject exposed to a viral infection (such as SARS-CoV-2 infection) environment (such as a household contact of a COVID-19 patient or an asymptomatic patient infected with SARS-CoV-2) (as defined herein).

[0076] For clarity, the terms "2019-nCoV", "SARS-CoV-2", "SARS-CoV-2 / 2019-nCoV" and "2019-nCoV / SARS-CoV-2" are used interchangeably, singularly and collectively, to refer to the novel coronavirus and its variants discovered in recent years, including but not limited to the more virulent strains that have emerged recently in Brazil (referred to as "P.1"), the United Kingdom (referred to as 20I / 501Y.V1, VOC 202012 / 01 or B.1.1.7), and South Africa (referred to as 20H / 501Y.V2 or B.1.351), as well as variants and lineages derived therefrom. In the following references, certain variants are described in more detail, and the said references are hereby incorporated by reference in their entirety into the present invention (due to their viral variant teachings): Horby P, Huntley C, Davies N et al., Severity Memorandum for B.1.1.7 of NERVTAG. SAGE meeting report. January 21, 2021; Wu K, Werner AP, Moliva JI et al. Neutralizing antibodies against SARS-CoV-2 variant spike mutants induced by mRNA-1273 vaccine. bioRxiv, published on January 25, 2021; Xie X, Zou J, Fontes-Garfias CR et al. Serum induced by BNT162b2 vaccine neutralizes N501Y mutant SARS-CoV-2. bioRxiv, published on January 7, 2021. Greaney AJ, Loes AN, Crawford KHD et al. Comprehensive mapping of SARS-CoV-2 receptor-binding domain mutations that affect recognition by human serum polyclonal antibodies. bioRxiv, published on January 4, 2021; Weisblum Y, Schmidt F, Zhang F et al. Escape of SARS-CoV-2 spike protein variants from neutralizing antibodies; eLife, 2020;9:e61312; Resende PC, Bezerra JF, de Vasconcelos RHT et al. Spike E484K mutation in the first confirmed case of SARS-CoV-2 reinfection in Brazil in 2020. January 10, 2021.

[0077] The term "COVID-19" refers to the disease caused by infection with the SARS-CoV-2 / 2019-nCoV virus.

[0078] Those skilled in the art will recognize that certain compounds, particularly those containing certain heteroatoms and double or triple bonds, may be tautomers, structural isomers, which are readily interconvertible. Thus, tautomeric compounds may be obtained by many different equivalent methods. Non-limiting examples of such tautomers include the following exemplary tautomers.

[0079]

[0080] Compound

[0081] In certain embodiments, the present invention relates to a compound of formula I,

[0082]

[0083] Chemical formula I

[0084] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein

[0085] X is CH2, CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0086] Y is N or CR';

[0087] Z is N or CR";

[0088] R' is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl or carbonyl, wherein R' can be replaced by one or more identical or different R 10 replace;

[0089] R" is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl or carbonyl, wherein R" can be optionally replaced by one or more identical or different R 10 replace;

[0090] R 1 , R 2 , R 3 and R 5 Independently selected from H,

[0091] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or R 1 , R 2 , R 3 , and R 5With the oxygen to which it is attached, it forms an optionally substituted ester, an optionally substituted branched ester, an optionally substituted carbonate, an optionally substituted carbamate, an optionally substituted thioester, an optionally substituted branched thioester, an optionally substituted thiocarbonate, an oxythiothiocarbonate, an optionally substituted oxythiothiocarbonate, a 2-hydroxypropionate, an optionally substituted 2-hydroxypropionate, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonate, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxythiocarbonyl, an optionally substituted oxymethylcarbonyl, an optionally substituted oxymethylthiocarbonyl, an oxymethoxythiocarbonate, an optionally substituted oxymethoxythiocarbonate, an L-amino acid ester, a D-amino acid ester, an oxymethoxyamino ester, an N-substituted L-amino acid ester, an N,N-disubstituted L- Amino acid ester, N-substituted D-amino acid ester, N,N-disubstituted D-amino acid ester, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazine, optionally substituted oxime, optionally substituted imido, optionally substituted imino, optionally substituted aminal, optionally substituted hemiaminal, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carboimido ester, optionally substituted thiocarboimido ester, optionally substituted carboimido, optionally substituted aminoimidate, optionally substituted carbamidyl, optionally substituted thioacetal, optionally substituted S-acyl-2-thioethyl, (acyloxybenzyl) ether, (acyloxybenzyl) ester, PEG ester, PEG carbonate, optionally substituted bis-(acyloxybenzyl) ester, optionally substituted (acyloxybenzyl) ester or BAB ester, wherein R 1 , R 2 , R 3 and R 5 Optionally, one or more identical or different R 10 replace;

[0092] Y 1 O or S;

[0093] Y 3 OH or BH3 - M + , where M is Li, Na, K, NH4, (CH3CH2)3NH, (CH3CH2CH2CH2)4N;

[0094] R 6is hydrogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, cyano or lipid, wherein, R 6 is optionally substituted by one or more identical or different R 10 substituents;

[0095] R 7 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or or carbonyl, wherein, R 7 is optionally substituted by one or more identical or different R 10 substituents;

[0096] R 8 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or or carbonyl, wherein, R 8 is optionally substituted by one or more identical or different R 10 substituents;

[0097] R 9is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 9 is optionally substituted by one or more identical or different R 10 substituents;

[0098] R 7 and R 8 and R 9 may form a ring with the α-carbon to which they are attached and the amino group attached to the α-carbon;

[0099] R 8 and R 9 may form a ring with the α-carbon to which they are attached;

[0100] R 10 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0101] R 11 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl;

[0102] R 12 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic epoxy, heterocarbocyclic epoxy, aryloxy, heteroaryloxy, heterocyclic epoxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 12 is optionally substituted by one or more identical or different R 16 substituents;

[0103] R 13 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic epoxy, heterocarbocyclic epoxy, aryloxy, heteroaryloxy, heterocyclic epoxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 13 is optionally substituted by one or more identical or different R 16 substituents;

[0104] R 14 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic epoxy, heterocarbocyclic epoxy, aryloxy, heteroaryloxy, heterocyclic epoxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 14 is optionally substituted by one or more identical or different R 16 substituents;

[0105] R 15is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 15 is optionally substituted by one or more identical or different R 16 ;

[0106] R 16 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 16 is optionally substituted by one or more identical or different R 17 ;

[0107] R 17 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0108] lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or lipid as described herein.

[0109] In certain embodiments, the lipid is a fatty alcohol, fatty amine, or fatty thiol (derived from essential and / or non-essential fatty acids).

[0110] In certain embodiments, the lipid is an unsaturated, polyunsaturated, ω-unsaturated, or ω-polyunsaturated fatty alcohol, fatty amine, or fatty thiol (derived from essential and / or non-essential fatty acids).

[0111] In certain embodiments, the lipid is a fatty alcohol, fatty amine, or fatty thiol (derived from essential and non-essential fatty acids), wherein one or more carbon units are replaced by oxygen, nitrogen, or sulfur.

[0112] In certain embodiments, the lipid is an unsaturated, polyunsaturated, ω-unsaturated, or ω-polyunsaturated fatty alcohol, fatty amine, or fatty thiol (derived from essential and / or non-essential fatty acids), wherein one or more carbon units are replaced by oxygen, nitrogen, or sulfur.

[0113] In certain embodiments, the lipid is an optionally substituted fatty alcohol, fatty amine, or fatty thiol (derived from essential and / or non-essential fatty acids).

[0114] In certain embodiments, the lipid is an optionally substituted unsaturated, polyunsaturated, ω-unsaturated, or ω-polyunsaturated fatty alcohol, fatty amine, or fatty thiol (derived from essential and / or non-essential fatty acids).

[0115] In certain embodiments, the lipid is an optionally substituted fatty alcohol, fatty amine, or fatty thiol (derived from essential and / or non-essential fatty acids), wherein one or more carbon units are replaced by oxygen, nitrogen, or sulfur.

[0116] In certain embodiments, the lipid is an optionally substituted unsaturated, polyunsaturated, ω-unsaturated, or ω-polyunsaturated fatty alcohol, fatty amine, or fatty thiol (derived from essential and / or non-essential fatty acids), wherein one or more carbon units are replaced by oxygen, nitrogen, or sulfur.

[0117] In certain embodiments, the lipid is hexadecyloxypropyl.

[0118] In certain embodiments, the lipid is 2-hexadecyloxypropylamine.

[0119] In certain embodiments, the lipid is 2-eicosanolamine.

[0120] In certain embodiments, the lipid is 2-benzyloxyhexadecyloxypropyl.

[0121] In certain embodiments, the lipid is lauryl, myristyl, palmyl, stearyl, eicosanyl, behenyl, or lignoceryl.

[0122] In certain embodiments, the lipid is a sphingolipid having the following chemical formula:

[0123]

[0124] wherein,

[0125] R 20 of the sphingolipid is hydrogen, alkyl, C(=O)R 21 C(=O)OR 21 or C(=O)NHR 21 ;

[0126] R 19 of the sphingolipid is hydrogen, fluorine, OR 21 OC(=O)R 21 OC(=O)OR 21 or OC(=O)NHR 21 ;

[0127] R 18 of the sphingolipid is a saturated or unsaturated alkyl chain containing more than 6 and less than 22 carbons, optionally substituted by one or more halogens, hydroxyl groups or a structure having the following chemical formula:

[0128] , , , or ;

[0129] wherein, n is 8 - 14, or less than or equal to 8 to less than or equal to 14, o is 9 - 15, or less than or equal to 9 to less than or equal to 15, the sum of m and n is 8 - 14, or less than or equal to 8 to less than or equal to 14, and the sum of m and o is 9 - 15, or less than or equal to 9 to less than or equal to 15; or

[0130] , , , , or ;

[0131] wherein, n is 4 - 10, or less than or equal to 4 to less than or equal to 10, o is 5 - 11, or less than or equal to 5 to less than or equal to 11, the sum of m and n is 4 - 10, or less than or equal to 4 to less than or equal to 10, and the sum of m and o is 5 - 11, or less than or equal to 5 to less than or equal to 11; or

[0132] , , or ;

[0133] Wherein, n is 6 - 12, or n is less than or equal to 6 to less than or equal to 12, and the sum of m and n is 6 - 12, or n is less than or equal to 6 to less than or equal to 12;

[0134] R of the sphingolipid 22 is OR 21 、OC(=O)R 21 、OC(=O)OR 21 or OC(=O)NHR 21 ;

[0135] R of the sphingolipid 21 is hydrogen, cyano, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene or lipid, wherein, R 21 is optionally substituted by one or more identical or different R 23 ; and

[0136] R of the sphingolipid 23 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl.

[0137] In certain embodiments, R of the sphingolipid 20 is H, methyl, ethyl, propyl, n - butyl, isopropyl, 2 - butyl, 1 - ethylpropyl, 1 - propylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl or phenyl.

[0138] In certain embodiments, the sphingolipid is a sphingolipid having the following chemical formula:

[0139]

[0140] Wherein,

[0141] R of the sphingolipid 20 is hydrogen, hydroxyl, fluorine, OR21 、 OC(=O)R 21 、 OC(=O)OR 21 or OC(=O)NHR 21 ;

[0142] The R of the sphingolipid 19 is hydrogen, hydroxy, fluoro, OR 21 、 OC(=O)R 21 、 OC(=O)OR 21 or OC(=O)NHR 21 ;

[0143] The R of the sphingolipid 18 is a saturated or unsaturated alkyl chain containing more than 6 and less than 22 carbons, optionally substituted by one or more halogens or a structure having the following chemical formula:

[0144] or ,

[0145] wherein, n is 8 - 14, or less than or equal to 8 to less than or equal to 14, and the sum of m and n is 8 - 14, or less than or equal to 8 to less than or equal to 14;

[0146] The R of the sphingolipid 21 is hydrogen, cyano, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group or lipid, wherein, R 21 is optionally substituted by one or more identical or different R 23 substituents; and

[0147] The R of the sphingolipid 23 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro group, ester group, formyl group, carboxyl group, carbamoyl group, amide group or acyl group.

[0148] In certain embodiments, the R of the sphingolipid 21 is H, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl.

[0149] Suitable sphingolipids include but are not limited to sphingosine, ceramide or sphingomyelin and 2-aminoalkyl optionally substituted by one or more substituents.

[0150] Other suitable sphingolipids include, but are not limited to, 2 - aminooctadecane - 3,5 - diol; (2S,3S,5S) - 2 - aminooctadecane - 3,5 - diol; (2S,3R,5S) - 2 - aminooctadecane - 3,5 - diol; 2 - (methylamino)octadecane - 3,5 - diol; (2S,3R,5S) - 2 - (methylamino)octadecane - 3,5 - diol; 2 - (dimethylamino)octadecane - 3,5 - diol; (2R,3S,5S) - 2 - (dimethylamino)octadecane - 3,5 - diol; 1 - (pyrrolidin - 2 - yl)hexadecane - 1,3 - diol; (1S,3S) - 1 - ((S) - pyrrolidin - 2 - yl)hexadecane - 1,3 - diol; 2 - amino - 11,11 - difluorooctadecane - 3,5 - diol; (2S,3S,5S) - 2 - amino - 11,11 - difluorooctadecane - 3,5 - diol; 11,11 - difluoro - 2 - (methylamino)octadecane - 3,5 - diol; (2S,3S,5S) - 11,11 - difluoro - 2 - (methylamino)octadecane - 3,5 - diol; N - ((2S,3S,5S) - 3,5 - dihydroxyoctadec - 2 - yl)acetamide; N - ((2S,3S,5S) - 3,5 - dihydroxyoctadec - 2 - yl)palmitamide; 1 - (1 - aminocyclopropyl)hexadecane - 1,3 - diol; (1S,3R) - 1 - (1 - aminocyclopropyl)hexadecane - 1,3 - diol; (1S,3S) - 1 - (1 - aminocyclopropyl)hexadecane - 1,3 - diol; 2 - amino - 2 - methyloctadecane - 3,5 - diol; (3S,5S) - 2 - amino - 2 - methyloctadecane - 3,5 - diol; (3S,5R) - 2 - amino - 2 - methyloctadecane - 3,5 - diol; (3S,5S) - 2 - methyl - 2 - (methylamino)octadecane - 3,5 - diol; 2 - amino - 5 - hydroxy - 2 - methyloctadecan - 3 - one; (Z) - 2 - amino - 5 - hydroxy - 2 - methyloctadecan - 3 - one oxime; (2S,3R,5R) - 2 - amino - 6,6 - difluorooctadecane - 3,5 - diol; (2S,3S,5R) - 2 - amino - 6,6 - difluorooctadecane - 3,5 - diol; (2S,3S,5S) - 2 - amino - 6,6 - difluorooctadecane - 3,5 - diol; (2S,3R,5S) - 2 - amino - 6,6 - difluorooctadecane - 3,5 - diol; and (2S,3S,5S) - 2 - amino - 18,18,18 - trifluorooctadecane - 3,5 - diol, optionally substituted with one or more substituents.

[0151] In an exemplary embodiment of Formula I, R 1 is hydrogen, , or .

[0152] In an exemplary embodiment of Formula I, R’ is methyl, fluorine, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, sulfomethyl, carboxylic acid, formyl, vinyl or ethynyl.

[0153] In an exemplary embodiment of Formula I, R” is methyl, fluorine, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, sulfomethyl, carboxylic acid, formyl, vinyl or ethynyl.

[0154] In an exemplary embodiment of Formula I, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0155] In an exemplary embodiment of Formula I, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0156] In an exemplary embodiment of Formula I, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0157] In an exemplary embodiment of Formula I, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0158] In certain embodiments, the present invention relates to a compound having Formula II,

[0159]

[0160] Chemical formula II

[0161] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0162] X is CH2, CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0163] Y is N or CR';

[0164] Z is N or CR";

[0165] R' is hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic group, heterocarbocyclic group, cycloalkyl, heterocyclic group or carbonyl, wherein, R' may be optionally substituted by one or more identical or different Rs 10 substituted;

[0166] R" is hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic group, heterocarbocyclic group, cycloalkyl, heterocyclic group or carbonyl, wherein, R" may be optionally substituted by one or more identical or different Rs 10 substituted;

[0167] R1, R 2 , R 3 and R 5 are independently selected from H,

[0168] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or R1, R 2 , R 3 and R 5 form, with the oxygen to which they are attached, optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted o-methoxycarbonyls, o-methoxycarbonates, optionally substituted o-methoxycarbonates, optionally substituted o-methoxythiocarbonyls, optionally substituted o-methylcarbonyls, optionally substituted o-methylthiocarbonyls, o-methoxythiocarbonates, optionally substituted o-methoxythiocarbonates, L-amino acid esters, D-amino acid esters, o-methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oximes, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted aminoiminocarbonates, optionally substituted aminocarbonimidoyl groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein R 1 , R 2 , R 3 and R 5Optionally substituted by one or more identical or different Rs 10 ;

[0169] with the proviso that R 1 , R 2 , R 3 and R 5 are not all H; and

[0170] R 6 -R 17 and lipids are as shown in Chemical Formula I.

[0171] In an exemplary embodiment of Chemical Formula II, R' is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, sulfomethyl, carboxylic acid, formyl, vinyl or ethynyl.

[0172] In an exemplary embodiment of Chemical Formula II, R" is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, sulfomethyl, carboxylic acid, formyl, vinyl or ethynyl.

[0173] In an exemplary embodiment of Chemical Formula II, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0174] In an exemplary embodiment of Chemical Formula II, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0175] In an exemplary embodiment of Chemical Formula II, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0176] In an exemplary embodiment of Formula II, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0177] In certain embodiments, the present invention relates to a compound having Formula III,

[0178]

[0179] Formula III

[0180] or a tautomer, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0181] X is CH2, CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0182] Z is N or CR”;

[0183] R” is hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic group, heterocarbocyclic group, cycloalkyl, heterocyclic group or carbonyl, wherein R” may be optionally substituted by one or more identical or different R 10 substituents;

[0184] R 1 -R 3 and R 5 are as shown in Formula II, provided that R 1 , R 2 , R 3 and R 5 are not all H; and

[0185] R 6 -R 17 and lipids are as shown in Formulas I and II.

[0186] In an exemplary embodiment of Formula III, R” is methyl, fluorine, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, sulfomethyl, carboxylic acid, formyl, vinyl or ethynyl.

[0187] In an exemplary embodiment of Formula III, R 6is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0188] In an exemplary embodiment of Chemical Formula III, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0189] In an exemplary embodiment of Chemical Formula III, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0190] In an exemplary embodiment of Chemical Formula III, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0191] In certain embodiments, the present invention relates to a compound having Chemical Formula IV,

[0192]

[0193] Chemical Formula IV

[0194] or a pharmaceutically acceptable salt or physiological salt thereof, wherein,

[0195] X is CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0196] R 1 -R 3 and R5 As shown in Chemical Formulas II and III, provided that R 1 , R 2 , R 3 and R 5 are not all H; and

[0197] R 6 -R 17 and lipids are as shown in Chemical Formulas I-III.

[0198] In an exemplary embodiment of Chemical Formula IV, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0199] In an exemplary embodiment of Chemical Formula IV, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0200] In an exemplary embodiment of Chemical Formula IV, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0201] In an exemplary embodiment of Chemical Formula IV, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0202] In certain embodiments, the present invention relates to a compound having Chemical Formula V

[0203]

[0204] Chemical formula V

[0205] or its tautomer, its medicinal salt or physiological salt,

[0206] R 1 -R 3 and R 5 as shown in Chemical formulas II-IV; and

[0207] R 6 -R 17 and lipids as shown in Chemical formulas I-IV.

[0208] In an exemplary embodiment of Chemical formula V, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0209] In an exemplary embodiment of Chemical formula V, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0210] In an exemplary embodiment of Chemical formula V, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0211] In an exemplary embodiment of Chemical formula V, R 9is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0212] In certain embodiments, the present invention relates to a compound having the chemical formula VI,

[0213]

[0214] Chemical formula VI

[0215] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0216] R 1 -R 3 as shown in Chemical formulas II-V; and

[0217] R 6 -R 17 and lipids as shown in Chemical formulas I-V.

[0218] In an exemplary embodiment of Chemical formula VI, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0219] In an exemplary embodiment of Chemical formula VI, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0220] In an exemplary embodiment of Chemical formula VI, R 8is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropyl alcohol, tert-butyl alcohol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0221] In an exemplary embodiment of Formula VI, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropyl alcohol, tert-butyl alcohol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0222] In certain embodiments, the present invention relates to a compound having Formula VIa-f,

[0223]

[0224]

[0225] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof,

[0226] wherein R 1 -R 3 As shown in Formulas II-VI, R 6 -R 17 and lipids are as shown in Formulas I-VI.

[0227] In an exemplary embodiment of Formula VIa-f, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropyl alcohol, tert-butyl alcohol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0228] In an exemplary embodiment of Formula VIa-f, R 7is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0229] In an exemplary embodiment of Formula VIa-f, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0230] In an exemplary embodiment of Formula VIa-f, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0231] In certain embodiments, the present invention relates to a compound having Formula VII,

[0232]

[0233] Formula VII

[0234] or a tautomer, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0235] wherein, R 1 , R 2 and R 5 are as shown in Formulas II-VI, R 6 -R 17 and the lipid are as shown in Formulas I-VI.

[0236] In an exemplary embodiment of Formula VII, R 6is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0237] In an exemplary embodiment of Formula VII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0238] In an exemplary embodiment of Formula VII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0239] In an exemplary embodiment of Formula VII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0240] In certain embodiments, the present invention relates to a compound having Formula VIII,

[0241]

[0242] Formula VIII

[0243] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0244] wherein, R 1 , R 3 and R 5 are as shown in Formulas II-VII, R 6-R 17 and lipids as shown in Chemical Formulas I-VII.

[0245] In an exemplary embodiment of Chemical Formula VIII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0246] In an exemplary embodiment of Chemical Formula VIII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0247] In an exemplary embodiment of Chemical Formula VIII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0248] In an exemplary embodiment of Chemical Formula VIII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0249] In certain embodiments, the present invention relates to a compound having Chemical Formula IX,

[0250]

[0251] Chemical Formula IX

[0252] or a tautomer, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0253] Among them, R 2 , R 3 and R 5 As shown in Chemical Formula II-VIII, R 6 -R 17 and lipids are as shown in Chemical Formula I-VIII.

[0254] In an exemplary embodiment of Chemical Formula IX, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0255] In an exemplary embodiment of Chemical Formula IX, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0256] In an exemplary embodiment of Chemical Formula IX, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0257] In an exemplary embodiment of Chemical Formula IX, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0258] In certain embodiments, the present invention relates to a compound having Chemical Formula X,

[0259]

[0260] Chemical formula X

[0261] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0262] wherein, R 1 and R 5 As shown in Chemical formulas II - IX, R 6 -R 17 and lipids are as shown in Chemical formulas I - IX.

[0263] In an exemplary embodiment of Chemical formula X, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0264] In an exemplary embodiment of Chemical formula X, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0265] In an exemplary embodiment of Chemical formula X, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0266] In an exemplary embodiment of Chemical formula X, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0267] In certain embodiments, the present invention relates to a compound having the chemical formula XI,

[0268]

[0269] Chemical formula XI

[0270] or a tautomer, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0271] wherein, R 1 and R 3 are as shown in Chemical Formulas II-X, R 6 -R 17 and lipids are as shown in Chemical Formulas I-X.

[0272] In an exemplary embodiment of Chemical Formula XI, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0273] In an exemplary embodiment of Chemical Formula XI, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0274] In an exemplary embodiment of Chemical Formula XI, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0275] In an exemplary embodiment of Chemical Formula XI, R 9is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0276] In certain embodiments, the present invention relates to a compound having the formula XII,

[0277]

[0278] Formula XII

[0279] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0280] wherein, R 1 and R 2 As shown in Formulas II - XII, R 6 -R 17 and lipids are as shown in Formulas I - XI.

[0281] In an exemplary embodiment of Formula XII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0282] In an exemplary embodiment of Formula XII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0283] In an exemplary embodiment of Formula XII, R 8is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0284] In an exemplary embodiment of Formula XII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0285] In certain embodiments, the present invention relates to a compound having Formula XIII,

[0286]

[0287] Formula XIII

[0288] or a tautomer, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0289] wherein, R 2 and R 5 As shown in Formulas II-XII, R 6 -R 17 and the lipid are as shown in Formulas I-XII.

[0290] In an exemplary embodiment of Formula XIII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0291] In an exemplary embodiment of Formula XIII, R 7is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropyl alcohol, tert-butyl alcohol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0292] In an exemplary embodiment of Formula XIII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropyl alcohol, tert-butyl alcohol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0293] In an exemplary embodiment of Formula XIII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropyl alcohol, tert-butyl alcohol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0294] In certain embodiments, the present invention relates to a compound having Formula XIV,

[0295]

[0296] Formula XIV

[0297] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0298] wherein, R 2 and R 3 as shown in Formulas II-XIII, R 6 -R 17 and lipids as shown in Formulas I-XIII.

[0299] In an exemplary embodiment of Formula XIV, R 6is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0300] In an exemplary embodiment of Formula XIV, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0301] In an exemplary embodiment of Formula XIV, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0302] In an exemplary embodiment of Formula XIV, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0303] In certain embodiments, the present invention relates to a compound having Formula XV,

[0304]

[0305] Formula XV

[0306] or a tautomer, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0307] wherein, R 3 and R 5 as shown in Formulas II - XIV, R 6 -R 17and lipids are shown in Chemical Formulas I - XIV.

[0308] In an exemplary embodiment of Chemical Formula XV, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0309] In an exemplary embodiment of Chemical Formula XV, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0310] In an exemplary embodiment of Chemical Formula XV, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0311] In an exemplary embodiment of Chemical Formula XV, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0312] In certain embodiments, the present invention relates to a compound having Chemical Formula XVI,

[0313]

[0314] Chemical Formula XVI

[0315] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0316] wherein, R2 As shown in Chemical Formulas II - XV, R 6 -R 17 and lipids as shown in Chemical Formulas I - XV.

[0317] In an exemplary embodiment of Chemical Formula XVI, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0318] In an exemplary embodiment of Chemical Formula XVI, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0319] In an exemplary embodiment of Chemical Formula XVI, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0320] In an exemplary embodiment of Chemical Formula XVI, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0321] In certain embodiments, the present invention relates to a compound having Chemical Formula XVII,

[0322]

[0323] Chemical Formula XVII

[0324] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0325] wherein, R 3 As shown in Chemical Formulas II-XVI, R 6 -R 17 and lipids as shown in Chemical Formulas I-XVI.

[0326] In an exemplary embodiment of Chemical Formula XVII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0327] In an exemplary embodiment of Chemical Formula XVII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0328] In an exemplary embodiment of Chemical Formula XVII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0329] In an exemplary embodiment of Chemical Formula XVII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0330] In certain embodiments, the present invention relates to a compound having Chemical Formula XVIII,

[0331]

[0332] Chemical formula XVIII

[0333] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0334] wherein, R 1 as shown in Chemical formulas II - XVII, R 6 -R 17 and lipids as shown in Chemical formulas I - XVII.

[0335] In an exemplary embodiment of Chemical formula XVIII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0336] In an exemplary embodiment of Chemical formula XVIII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0337] In an exemplary embodiment of Chemical formula XVIII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0338] In an exemplary embodiment of Chemical formula XVIII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0339] In certain embodiments, the present invention relates to a compound having the chemical formula XIX,

[0340]

[0341] Chemical formula XIX

[0342] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0343] wherein, R 5 As shown in Chemical formulas II - XVIII, R 6 -R 17 and lipids are as shown in Chemical formulas I - XVIII.

[0344] In an exemplary embodiment of Chemical formula XIX, R 6 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0345] In an exemplary embodiment of Chemical formula XIX, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0346] In an exemplary embodiment of Chemical formula XIX, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec - butyl, tert - butyl, pentyl, sec - pentyl, tert - pentyl, neopentyl, 3 - pentyl, hexyl, tert - hexyl, 4 - heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6 - dimethylphenyl, isopropanol, tert - butanol, N - propylamino, N - isopropylamino, N - tert - butylamino, N,N - dimethylamino, N,N - diethylamino or N,N - dipropylamino.

[0347] In an exemplary embodiment of Chemical formula XIX, R 9is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropyl alcohol, tert-butyl alcohol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0348] In certain embodiments, the present invention relates to a compound having the chemical formula XX,

[0349]

[0350] Chemical formula XX

[0351] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0352] X is CH2, CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0353] Y is N or CR';

[0354] Z is N or CR";

[0355] R' is hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic group, heterocarbocyclic group, cycloalkyl, heterocyclic group or carbonyl group, wherein R' may be optionally substituted by one or more identical or different R 10 substituted;

[0356] R" is hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic group, heterocarbocyclic group, cycloalkyl, heterocyclic group or carbonyl group, wherein R" may be optionally substituted by one or more identical or different R 10 substituted;

[0357] wherein, R 1 -R 3 and R 5 are as shown in Chemical formulas II - XIX;

[0358] Provided that R 1 , R 2 , R 3 and R 5 are not all H;

[0359] R 6 -R 17 and lipids are as shown in Chemical formulas I - XIX.

[0360] In an exemplary embodiment of Chemical formula XX, R 6is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0361] In an exemplary embodiment of Chemical Formula XX, R 7 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0362] In an exemplary embodiment of Chemical Formula XX, R 8 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0363] In an exemplary embodiment of Chemical Formula XX, R 9 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, neopentyl, 3-pentyl, hexyl, tert-hexyl, 4-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropanol, tert-butanol, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino or N,N-dipropylamino.

[0364] In certain embodiments, the compound having Chemical Formula XX does not have any of the following structures:

[0365] .

[0366] In an exemplary embodiment, the compound is selected from:

[0367] .

[0368] In an exemplary embodiment, the compound is selected from:

[0369] .

[0370] In an exemplary embodiment, the compound is selected from:

[0371] .

[0372] In an exemplary embodiment, the compound is selected from:

[0373] .

[0374] In an exemplary embodiment, the compound is selected from:

[0375] .

[0376] In an exemplary embodiment, the compound is selected from:

[0377] .

[0378] In an exemplary embodiment, the compound is selected from:

[0379] .

[0380] In certain examples, the present invention relates to a compound having the chemical formula XXI,

[0381]

[0382] Chemical formula XXI

[0383] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein R 1 is H, , , or , and R 6 is alkyl or carbocyclic group. In certain cases, R 6 is selected from: C3-C6 cycloalkyl, C3-C7 normal alkyl and C3-C7 branched alkyl. In a more specific case, R 6 is isopropyl.

[0384] Method of use

[0385] In certain embodiments, the present invention relates to a method for treating or preventing a viral infection, comprising administering to a subject in need an effective amount of a compound or a pharmaceutical composition disclosed herein.

[0386] In certain embodiments, the present invention relates to methods of treating or preventing viral infections of the central nervous system (CNS), comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0387] In certain embodiments, the present invention relates to methods of treating or preventing CNS coronavirus infections, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0388] In certain embodiments, the present invention relates to methods of treating or preventing CNS SARS-CoV-2 infections, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0389] In certain embodiments, the present invention relates to methods of treating or preventing viral infections of the CNS, comprising administering to a subject in need thereof an effective amount of EIDD-1931.

[0390] In certain embodiments, the present invention relates to methods of treating or preventing CNS coronavirus infections, comprising administering to a subject in need thereof an effective amount of EIDD-1931.

[0391] In certain embodiments, the present invention relates to methods of treating or preventing CNS SARS-CoV-2 infections, comprising administering to a subject in need thereof an effective amount of EIDD-1931.

[0392] In certain embodiments, the present invention relates to methods of treating or preventing viral infections of the CNS, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0393] In certain embodiments, the present invention relates to methods of treating or preventing CNS coronavirus infections, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0394] In certain embodiments, the present invention relates to methods of treating or preventing CNS SARS-CoV-2 infections, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0395] In certain embodiments, the present invention relates to methods of treating or preventing viral infections of the CNS, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0396] In certain embodiments, the present invention relates to methods of treating or preventing CNS coronavirus infections, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0397] In certain embodiments, the present invention relates to methods of treating or preventing CNS SARS-CoV-2 infection, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0398] In certain embodiments, the present invention relates to methods of treating or preventing CNS viral infection, comprising administering to a subject in need thereof an effective amount of EIDD-2898.

[0399] In certain embodiments, the present invention relates to methods of treating or preventing CNS coronavirus infection, comprising administering to a subject in need thereof an effective amount of EIDD-2898.

[0400] In certain embodiments, the present invention relates to methods of treating or preventing CNS SARS-CoV-2 infection, comprising administering to a subject in need thereof an effective amount of EIDD-2898.

[0401] In certain embodiments, the present invention relates to methods of treating or preventing signs of neurological diseases caused by treating or preventing CNS viral infection, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0402] In certain embodiments, the present invention relates to methods of treating or preventing signs of neurological diseases caused by CNS coronavirus infection, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0403] In certain embodiments, the present invention relates to methods of treating or preventing signs of neurological diseases caused by treating or preventing CNS SARS-CoV-2 infection, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0404] In certain embodiments, the present invention relates to methods of treating or preventing signs of neurological diseases caused by CNS viral infection, comprising administering to a subject in need thereof an effective amount of EIDD-1931.

[0405] In certain embodiments, the present invention relates to methods of treating or preventing signs of neurological diseases caused by CNS coronavirus infection, comprising administering to a subject in need thereof an effective amount of EIDD-1931.

[0406] In certain embodiments, the present invention relates to methods of treating or preventing signs of neurological diseases caused by treating or preventing CNS SARS-CoV-2 infection, comprising administering to a subject in need thereof an effective amount of EIDD-1931.

[0407] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS viral infection, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0408] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS coronavirus infection, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0409] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS SARS-CoV-2 infection, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0410] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS viral infection, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0411] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS coronavirus infection, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0412] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS SARS-CoV-2 infection, comprising administering to a subject in need thereof an effective amount of EIDD-2801.

[0413] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS viral infection, comprising administering to a subject in need thereof an effective amount of EIDD-2898.

[0414] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS coronavirus infection, comprising administering to a subject in need thereof an effective amount of EIDD-2898.

[0415] In certain embodiments, the present invention relates to a method of treating or preventing signs of a neurological disorder caused by a CNS SARS-CoV-2 infection, comprising administering to a subject in need thereof an effective amount of EIDD-2898.

[0416] In certain embodiments, the compound is administered by pulmonary inhalation.

[0417] In certain embodiments, the subject is at risk of developing symptoms of human coronavirus, SARS coronavirus, MERS coronavirus, or 2019 - nCoV, or has been diagnosed with an infection of human coronavirus, SARS coronavirus, MERS coronavirus, or 2019 - nCoV.

[0418] In certain embodiments, the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post - viral fatigue syndrome, viral hemorrhagic fever, acquired immunodeficiency syndrome, or hepatitis B.

[0419] Preparation

[0420] In an exemplary embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier) and an exemplary compound as described herein.

[0421] In certain exemplary embodiments, the pharmaceutical composition comprises or employs a pharmaceutically acceptable salt (generally as described below). Some non - limiting examples of suitable pharmaceutically acceptable organic and / or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, and citric acid, as well as other pharmaceutically acceptable acids known per se (refer to the references below).

[0422] When the exemplary compound contains an acid group and a base group, the compound can form an internal salt, and such internal salts can also be used in the compositions and methods described herein. When the exemplary compound contains a hydrogen - donating heteroatom (e.g., NH), it is expected that the salt will cover isomers (formed by transferring the hydrogen atom to a base or atom within the molecule).

[0423] Pharmaceutically acceptable salts of the exemplary compounds include their acid addition salts and base salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hippurate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / monohydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and cinchoninate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfates and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), which is hereby incorporated by reference into the present invention and made part of the present invention.

[0424] Physiologically acceptable salts of the exemplary compounds are salts that form in a subject to which the compound has been administered for the treatment or prevention of a disease. Suitable salts include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, manganese salts, bile salts.

[0425] The exemplary compounds can be administered in the form of prodrugs. A prodrug can include a covalently bonded carrier that releases the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying the functional groups present in the compound such that the modifying moiety cleaves from the parent compound either during conventional operations or in vivo. Prodrugs include compounds in which a hydroxyl group is bonded to any group that cleaves to form a free hydroxyl group upon administration to a subject. Examples of prodrugs include, but are not limited to, esters, optionally substituted esters, branched esters, optionally substituted branched esters, carbonates, optionally substituted carbonates, carbamates, optionally substituted carbamates, thioesters, optionally substituted thioesters, branched thioesters, optionally substituted branched thioesters, thiocarbonates, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, S-thiocarbonates, optionally substituted S-thiocarbonates, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, o-methoxycarbonyls, optionally substituted o-methoxycarbonyls, o-methoxycarbonates, optionally substituted o-methoxycarbonates, o-methoxythiocarbonyls, optionally substituted o-methoxythiocarbonyls, o-methylcarbonyls, optionally substituted o-methylcarbonyls, o-methylthiocarbonyls, optionally substituted o-methylthiocarbonyls, o-methoxythiocarbonates, optionally substituted o-methoxythiocarbonates, L-amino acid esters, D-amino acid esters, o-methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, oxythio groups, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, imino acid esters, optionally substituted imino acid esters, hydrazinates, optionally substituted hydrazinates, oximino groups, optionally substituted oximino groups, imido groups, optionally substituted imido groups, imino groups, optionally substituted imino groups, acetalamines, optionally substituted acetalamines, hemiacetalamines, optionally substituted hemiacetalamines, acetals, optionally substituted acetals, hemiacetals, optionally substituted hemiacetals, carbodiimide esters, optionally substituted carbodiimide esters, thiocarbodiimide esters, optionally substituted thiocarbodiimide esters, carbodiimide groups, optionally substituted carbodiimide groups, aminoimino acid esters, optionally substituted aminoimino acid esters, aminoguanidino groups, optionally substituted aminoguanidino groups, thioacetals, optionally substituted thioacetals, S-acyl-2-thioethyls, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, bis-(acyloxybenzyl) esters, optionally substituted bis-(acyloxybenzyl) esters, (acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, acetate, formate, and benzoate derivatives of the alcohol functional group in the compound. Methods for constructing prodrugs of the compounds can be found in the book Hydrolysis in Drug and Prodrug Metabolism by Testa and Mayer (Wiley (2006)).Typical prodrugs form active metabolites through prodrug conversion by hydrolytic enzymes, amide, lactam, peptide, carboxylic acid ester, epoxide hydrolysis, or cleavage of esters of inorganic acids.

[0426] In an exemplary embodiment, the pharmaceutical composition comprises an effective amount of an exemplary compound and a pharmaceutically acceptable carrier. Generally, for pharmaceutical use, the compound can be formulated into a pharmaceutical preparation comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent, or excipient and / or adjuvant, optionally comprising one or more other pharmaceutically active compounds. The preparation can be made by methods known per se, typically comprising mixing at least one compound according to the present invention with one or more pharmaceutically acceptable carriers, optionally in combination with other pharmaceutically active compounds, and, if necessary, under aseptic conditions. Also refer to U.S. Patent No. 6,372,778, U.S. Patent No. 6,369,086, U.S. Patent No. 6,369,087, and U.S. Patent No. 6,372,733, as well as the other references and standard manuals mentioned above, such as the latest edition of Remington's Pharmaceutical Sciences. The disclosed pharmaceutical composition can be in unit dosage form or in other suitable packaging, such as boxes, blisters, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose container (correctly labeled); optionally accompanied by one or more inserts containing product information and / or instructions for use. Generally, such unit doses contain 1 - 1000 mg, typically containing 5 - 500 mg of at least one compound according to the present invention, for example, about 10, 25, 50, 100, 200, 300, 400, 800 mg per unit dose.

[0427] The compounds can be administered by various routes, including oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, depending primarily on the particular formulation employed. The compounds are generally administered in an "effective amount", i.e., any amount of the compound that, when appropriately administered, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to whom the compound is administered. Such effective amounts generally range from 0.01 - 1000 mg / kg of patient body weight per day, more typically from 0.1 - 500 mg, such as 1 - 250 mg, e.g., about 5, 10, 20, 50, 100, 150, 200, or 250 mg / kg of patient body weight per day, and can be administered once daily, or divided into single or multiple doses per day. The amount, route of administration, and further treatment regimen can be determined by the treating clinician, depending on the age, sex, and general condition of the patient, as well as the nature and severity of the disease / symptoms to be treated. Reference is also made to U.S. Patent Nos. 6,372,778, 6,369,086, 6,369,087, and 6,372,733, as well as the other references and standard manuals noted above, such as the latest edition of Remington's Pharmaceutical Sciences.

[0428] Depending on the mode of introduction, the compounds described herein can be formulated in a variety of ways. Preparations containing one or more compounds can be prepared in a variety of dosage forms, such as granules, tablets, capsules, suppositories, powders, controlled-release formulations, suspensions, emulsions, creams, gels, ointments, pastes, lotions, or aerosols, among others. In certain embodiments, preparations using solid dosage forms (suitable for simple administration of precise dosages, preferably orally) are used. Oral solid dosage forms include, but are not limited to, tablets, soft gelatin, hard gelatin, or non-gelatin capsules, and cachets. However, liquid dosage forms such as solutions, syrups, suspensions, and elixirs can also be used. In another embodiment, the preparation is administered topically. Suitable topical administration preparations include, but are not limited to, lotions, ointments, creams, and gels. In one embodiment, the topical preparation is a gel. In another embodiment, the preparation is administered intranasally.

[0429] Preparations containing one or more of the compounds described herein can be prepared using pharmaceutically acceptable carriers, which consist of substances that are safe, effective, and do not cause adverse biological side effects or unfavorable interactions when administered to an individual. The carrier is all components of the pharmaceutical preparation other than the active ingredient. As used herein, "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, pH adjusters, preservatives, antioxidants, solubilizing agents, and coating compositions.

[0430] The carrier also includes all components of the coating composition, and may include plasticizers, pigments, colorants, stabilizers, and glidants. Sustained-release, extended-release, and / or pulsatile-release formulations can be prepared according to the instructions in the following standard references: "Pharmaceutical Dosage Forms - Tablets", edited by Liberman et al. (New York, Marcel Dekker, Inc., 1989); "Remington: The Science and Practice of Pharmacy", 20th Edition, Lippincott Williams & Wilkins (Baltimore, Maryland), 2000; and "Pharmaceutical Dosage Forms and Drug Delivery Systems", 6th Edition, Ansel et al. (Media, Pennsylvania: Williams & Wilkins, 1995). These references provide information on carriers, materials, equipment, and processes for preparing tablets and capsules, as well as sustained-release dosage forms of tablets, capsules, and granules.

[0431] Examples of suitable coating materials include, but are not limited to, cellulose polymers (such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, and hydroxypropyl methyl cellulose acetate succinate); polyvinyl acetate phthalate, acrylic polymers and copolymers, methacrylic acid resins commercially available under the trade name EUDRAGIT TM (available from Roth Pharma (Wetterstadt, Germany)), zein, shellac, and polysaccharides.

[0432] In addition, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilizers, pore formers, and surfactants.

[0433] Optional pharmaceutically acceptable excipients present in the medicated tablets, microspheres, granules, or microparticles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also known as "fillers", are generally used to increase the volume of solid dosage forms, thereby providing the actual size required for compression tablets or for forming microspheres and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silica, titanium oxide, magnesium aluminum silicate, and powdered sugar.

[0434] Binders are used to impart cohesiveness to solid dosage forms, thereby ensuring that tablets, beads, or granules remain intact after formation of the dosage form. Suitable binder materials include, but are not limited to, starches, pregelatinized starches, gelatin, sugars (including sucrose, glucose, lactose, and sorbitol), polyethylene glycols, waxes, natural and synthetic gums (such as gum arabic, tragacanth), sodium alginate, celluloses (including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose), and magnesium aluminum silicate, as well as synthetic polymers (such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone).

[0435] Lubricants are used to improve tablet production efficiency. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, polyethylene glycol, talc, and mineral oil.

[0436] Disintegrants are used to promote the disintegration or "breakdown" of the dosage form after administration and generally include, but are not limited to, starches, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropylcellulose, pregelatinized starch, clays, celluloses, algins, gums, and crosslinked polymers such as crosslinked PVP (Polyplasdone XL from GAF Chemicals).

[0437] Stabilizers are used to inhibit or retard drug decomposition reactions, including oxidation reactions and the like.

[0438] Surfactants can be anionic surfactants, cationic surfactants, amphoteric surfactants, or nonionic surfactants. Suitable anionic surfactants include, but are not limited to, anionic surfactants containing carboxylate ions, sulfonate ions, and sulfate ions. Examples of anionic surfactants include long-chain alkyl sulfonates and alkylaryl sulfonates (such as sodium dodecylbenzenesulfonate); dialkyl sulfosuccinates (such as sodium dodecylbenzenesulfonate); dialkyl sulfosuccinates (such as bis-(2-ethylhexyl)-sulfosuccinate sodium); and sodium, potassium, and ammonium alkyl sulfates (such as sodium lauryl sulfate). Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and cocoamine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glycerol monostearate, glyceryl stearate, polyglycerol-4 oleate, sorbitan acylates, sucrose acylates, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMER TM401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alaninate, sodium N-lauryl-β-imino dipropionate, myristoyl amphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0439] If desired, the tablets, microbeads, granules or microparticles may also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifiers, dyes, pH buffers or preservatives.

[0440] The concentration of pharmaceutically acceptable carriers, excipients and / or other substances in the exemplary compounds may be from about 0.5 to about 100 wt.% (weight percentage). When used orally, the pharmaceutical composition typically may contain from about 5 to about 100% of the active substance (by weight). For other uses, the pharmaceutical composition typically may contain from about 0.5 to about 50 wt.% of the active substance.

[0441] The compositions described herein can be formulated for sustained release or controlled release purposes. Examples of controlled release dosage forms include sustained release dosage forms, delayed release dosage forms, pulsatile release formulations, and combinations thereof.

[0442] As described in "Remington: The Science and Practice of Pharmacy" (20th Edition, Lippincott Williams & Wilkins, Baltimore, MD, 2000), sustained release formulations are typically prepared in the form of diffusion or osmotic systems. Diffusion systems generally include two types, reservoir type and matrix type, which are well known and described in the art. The matrix type is typically prepared by compressing the drug into tablets using a slowly dissolving polymeric carrier. The three main materials used in preparing the matrix type are insoluble plastics, hydrophilic polymers, and aliphatic compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, cellulose polymers (such as methyl and ethyl cellulose), hydroxyalkyl celluloses (such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose), sodium carboxymethyl cellulose, and CARBOPOL TM 934, polyoxyethylene, and mixtures thereof. Aliphatic compounds include, but are not limited to, various waxes (such as carnauba wax and tristearin) and wax-like substances (including hydrogenated castor oil and hydrogenated vegetable oils) or mixtures thereof.

[0443] In certain preferred embodiments, the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to copolymers of acrylic acid and methacrylic acid, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl cyanoacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymers poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymers.

[0444] In certain preferred embodiments, the acrylic polymer consists of one or more aminoalkyl methacrylate copolymers. Aminoalkyl methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylates and methacrylates with a low quaternary ammonium content.

[0445] In a preferred embodiment, the acrylic polymer is an acrylic resin paint, such as the acrylic resin paint sold under the trade name EUDRAGIT TM (available from Rohm Pharma). In other preferred embodiments, the acrylic polymer comprises a mixture of two acrylic resin paints (trade names EUDRAGIT TM RL30D and EUDRAGIT TM RS30D (available from Rohm Pharma)). EUDRAGIT TM RL30D and EUDRAGIT TM RS30D are copolymers of acrylates and methacrylates with a low quaternary ammonium content. In EUDRAGIT TM RL30D and EUDRAGIT TM RS30D, the molar ratios of ammonium groups to the remaining neutral (meth)acrylate are 1:20 and 1:40, respectively. The average molecular weight is approximately 150,000. EUDRAGIT TM S-100 and EUDRAGIT TM L-100 are also preferably used. The code names RL (high permeability) and RS (low permeability) refer to the permeability of these agents. EUDRAGIT TM RL / RS mixtures are insoluble in water and digestive fluids. However, the resulting multi-particle systems (including the same components) are swellable and permeable in aqueous solutions and digestive fluids.

[0446] The above polymers (such as EUDRAGIT TMare mixed together with RL / RS to finally obtain a sustained-release preparation with an ideal dissolution curve. For example, it can be obtained from 100% EUDRAGIT TM RL, 50% EUDRAGIT TM RL and 50% EUDRAGIT TM RS, and 10% EUDRAGIT TM RL and 90% EUDRAGIT TM RS to obtain an ideal sustained-release multi-particle system. Those skilled in the art should recognize that other acrylic polymers such as EUDRAGIT TM L can also be used.

[0447] Alternatively, a sustained-release preparation can be prepared using an osmotic system or a semi-permeable coating on the dosage form. In the latter case, low-permeability and high-permeability coating materials can be combined in appropriate proportions to obtain the desired drug release curve.

[0448] Diffusion systems with the above different drug release mechanisms can be combined and used in the final dosage form (including single-unit or multi-unit). Examples of multi-units include but are not limited to multi-layer tablets and capsules (including tablets, microbeads or granules, etc.). Coating or compression processes can be used, or in a multi-unit system (such as a capsule containing sustained-release microbeads and immediate-release microbeads), the immediate-release layer can be coated on top of the sustained-release core, and the immediate-release part can be added to the sustained-release system.

[0449] Sustained-release tablets containing hydrophilic polymers are prepared using techniques well known in the art, such as direct compression, wet granulation or dry granulation processes. Their formulations usually contain polymers, diluents, binders and lubricants as well as active pharmaceutical ingredients. Commonly used diluents include inert powdery substances (such as starch, powdered cellulose, especially crystalline cellulose and microcrystalline cellulose), sugars (such as fructose, mannitol and sucrose), cereal flours and similar edible powders. For example, typical diluents include various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride) and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars (such as lactose, fructose and glucose). Natural and synthetic gums (including gum arabic), alginates, methyl cellulose and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethyl cellulose and waxes can also be used as binders. In tablet formulation, lubricants are needed to prevent the tablets and punches from sticking in the die. Lubricants are selected from smooth solids such as talc, magnesium stearate, calcium stearate, stearic acid and hydrogenated vegetable oil.

[0450] Sustained-release tablets containing wax materials are usually prepared using methods known in the art, such as direct mixing, solidification, and aqueous dispersion methods. In the solidification method, the drug is mixed with the wax material and subjected to spray solidification or solidification, screening, and processing.

[0451] A solid dosage form is coated with a polymer film to obtain a delayed-release preparation, and the polymer film is insoluble in the acidic environment of the stomach but soluble in the neutral environment of the small intestine.

[0452] For example, a delayed-release dosage unit can be prepared by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition can be a tablet enclosed in a capsule, a tablet used as the core of a "coated core" dosage form, or multiple drug-containing microbeads, microparticles, or granules enclosed in tablets or capsules. Preferred coating materials include bioerodible polymers, gradually hydrolyzable polymers, gradually water-soluble polymers, and / or enzymatically degradable polymers, and can be conventional "enteric" polymers. As understood by those skilled in the art, enteric polymers are soluble in the high pH environment of the lower gastrointestinal tract or erode slowly as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes in the lower gastrointestinal tract (especially the colon). Suitable coating materials that affect delayed release include, but are not limited to, cellulose polymers (such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose); acrylic polymers and copolymers, preferably composed of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and other methacrylic resins with the trade name EUDRAGIT TM (available from Roth Pharma (Wertheim, Germany)), including EUDRAGIT TM L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT TM L-100 (soluble at pH 6.0 and above), EUDRAGIT TM S (soluble at pH 7.0 and above due to a higher degree of esterification), and EUDRAGIT TM NE, RL, and RS (water-insoluble polymers with different degrees of permeability and swellability); vinyl polymers and copolymers (such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer) enzymatically degradable polymers (such as azo polymers, pectin, chitosan, amylose, and guar gum); zein; and shellac. Combinations of different coating materials can also be used. Multilayer coatings using different polymers can also be applied.

[0453] Those skilled in the art can easily determine the preferred coating weight of a specific coating material by evaluating the individual release curves of tablets, microbeads, and granules prepared with different amounts of various coating materials. Combining the materials, methods, and application forms results in the desired release characteristics, which can only be determined from clinical studies.

[0454] The coating composition may include conventional additives such as plasticizers, pigments, colorants, stabilizers, glidants, etc. Plasticizers generally reduce the brittleness of the coating and are usually about 10 wt.% - 50 wt.% of the dry weight of the polymer. Typical examples of plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetylcitrate, castor oil, and acetylated monoglyceride. Stabilizers are preferably used to stabilize the fine particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Glidants are recommended to reduce the sticking effect during film formation and drying, and the glidants are usually about 25 wt.% - 100 wt.% of the polymer weight in the coating solution. Talc is an effective glidant. Other glidants such as magnesium stearate and glycerol monostearate can also be used. Pigments such as titanium dioxide can also be used. A small amount of defoaming agents such as silicone (e.g., simethicone) can also be added to the coating composition.

[0455] The formulation can achieve pulsed delivery of one or more compounds. The so-called "pulse" means releasing multiple drug doses at certain time intervals. Generally, after ingestion of the dosage form, the initial dose is released substantially immediately, that is, the first drug release "pulse" occurs within about 1 hour after ingestion. After the initial pulse, there is a first time interval (lag time) during which the dosage form releases very little or no drug, and then a second dose is released. Similarly, a second time interval with little or no drug release can be designed between the second and third drug release pulses. The duration of the time interval with little or no drug release will vary depending on the dosage form design (e.g., administered twice a day, administered three times a day, etc.). For a dosage form administered twice a day, the duration of the time interval with little or no drug release between the first and second doses is about 3 hours - 14 hours. For a dosage form administered three times a day, the duration of the time interval with little or no drug release between the three doses is about 2 hours - 8 hours.

[0456] In one embodiment, a closed and preferably sealed capsule dosage form (comprising at least two medicated "dose units") produces a pulsed release profile, wherein each dose unit within the capsule provides a different drug release profile. The delayed release dose units can be controlled by coating the dose units with a controlled release polymer or incorporating the active agent in a controlled release polymer matrix. Each dose unit can comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different drug release profile. For a twice-daily mimetic dosage form, the first tablet releases the drug substantially immediately after ingestion of the dosage form, while the second tablet releases the drug within about 3 to 14 hours after ingestion of the dosage form. For a thrice-daily mimetic dosage form, the first tablet releases the drug substantially immediately after ingestion of the dosage form, the second tablet releases the drug within about 3 to 10 hours after ingestion of the dosage form, and the third tablet releases the drug at least 5 hours to about 18 hours after ingestion of the dosage form. The dosage form can comprise more than three tablets of the drug. Although the dosage form generally does not comprise more than three tablets of the drug, dosage forms comprising more than three tablets can also be used.

[0457] Alternatively, each dose unit within the capsule can comprise a plurality of medicated microspheres, granules or microparticles. In the art, it is well known that a medicated "microsphere" refers to a microsphere made using a drug and one or more excipients or polymers. Medicated microspheres can be produced by coating a drug on an inert support (e.g., an inert sugar bead coated with the drug) or by preparing a "core" comprising the drug and one or more excipients. In the art, it is well known that medicated "granules" and "microparticles" include drug microparticles that may or may not contain one or more additional excipients or polymers. Granules and microparticles do not comprise an inert support as compared to medicated microspheres. Granules generally comprise drug microparticles and require further processing. Generally, microparticles are smaller than granules and do not require further processing. Although microspheres, granules and microparticles can be formulated for immediate release purposes, microspheres and granules are generally used for delayed release purposes.

[0458] In one embodiment, the composition is formulated for topical administration. Suitable topical dosage forms include lotions, ointments, creams and gels. A "gel" is a semi-solid system that comprises a dispersion of an active agent (i.e., a compound) in a liquid carrier that is rendered semi-solid by the action of a thickening or polymeric material dissolved or suspended therein. The liquid can comprise a lipophilic component and / or an aqueous component. Some emulsions can be gels or can comprise a gel component. However, some gels are not emulsions because they do not comprise a homogeneous mixture of immiscible components. The methods for preparing lotions, ointments, creams and gels are well known in the art.

[0459] Combination therapy

[0460] The compounds described herein can be co-administered with other active compounds. These compounds include, but are not limited to, analgesics, anti-inflammatory agents, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine agents, antimuscarinics, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatics, cardiovascular agents, corticosteroids, dopaminergic agents, electrolytes, gastrointestinal agents, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcolepsy agents, and antiviral agents. In a particular embodiment, the antiviral agent is a non-CNS-targeted antiviral compound. As used herein, "co-administered" means that one or more other active agents can be administered with the compound in the same dosage form or in different dosage forms. The other active agents can be formulated for immediate release, controlled release purposes, or a combination thereof.

[0461] Specific examples of compounds for adjunctive administration of the said compound include, but are not limited to, aceclofenac, paracetamol, adoxetane, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amlodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bromfenac, betamethasone, bisifadin, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carfilzomib, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazene, clozapine, chlorthiazide, chloroxazolone, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, desipramine, desipramine, desomorphine, dexamethasone, dexamethasone, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, diphenylhydantoin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproex acid, eletriptan, dolasetron, donepezil, doxepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamate, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, ginkgo biloba extract, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indalpine, indomethacin, indoprofen, iprindole, ixabepilone, ketanserin, ketoprofen, ketorolac, lexitropan, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol, mefenamic acid, melatonin, meclofenamic acid, memantine, meperidine, meprobamate, mefenamic acid, metapramine, methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methyl salicylate, methysergide, metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (a drug for narcolepsy), morinidone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, gabapentin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprozin, nordazepam, hydroxytryptophan, oxycodone, oxymorphone, pancreatic lipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phentermine, phenylpropanolamine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirazepine, piroxicam, pizotifen, pizotifen, polygonum cuspidatum, pramipexole, prednisolone, prednisone, pregabalin, propranolol, propizepine, propoxyphene, protriptyline, quazepam,Quinupramine, reboxetine, reserpine, risperidone, ritanserin, galantamine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenazine, thiazides, thioridazine, mesoridazine, tiapride, tiospirone, tiamenidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone and its isomers, salts and combinations.

[0462] In certain embodiments, the exemplary compounds and pharmaceutical compositions can be co-administered with another antiviral agent, such as abacavir, acyclovir, adefovir, amantadine, amprenavir, amprinavir, arbidol, AT-527, atazanavir, atripla, boceprevir, BCX4430 / galsevir, cobicistat, cidofovir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonoacetic acid, ganciclovir, GS-5734 / remdesivir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamividine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, metisazone, nelfinavir, nevirapine, nesacavir, NITD008, obitrovir, oseltamivir, paritaprevir, peginterferon alpha-2a, penciclovir, peramivir, prulifloxacin, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyrimidine, saquinavir, simiprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, truvada, valacyclovir, valganciclovir, verubecestat, vidarabine, veramidine, zalcitabine, zanamivir or zidovudine and combinations thereof.

[0463] In certain embodiments, the exemplary compounds and pharmaceutical compositions may be administered in combination with another agent, such as chloroquine, chloroquine phosphate, hydroxychloroquine, hydroxychloroquine sulfate, amprenavir, APN01, GLS4, IFX-1, BXT-25, CYNK-001, tocilizumab, lerizumab, Ii-key, COVID-19 S-Trimer, camrelizumab, thymosin, brilacidin, INO-4800, puzeli, cobicistat, mRNA-1273, arbidol, umifenovir, REGN3048, REGN3051, TNX-1800, fingolimod, methylprednisolone, nitazoxanide, purpurin B, C-467929, C-473872, NSC-306711, N-65828, C-21, CGP-42112A, L-163491, angelol or bevacizumab and combinations thereof.

[0464] In certain embodiments, the exemplary compounds and pharmaceutical compositions disclosed herein may be administered in combination with any compound disclosed in the following references:

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[0466] EIDD-1931 and its prodrugs (e.g., EIDD-2801) can be co-administered with or formulated with another antiviral agent, such as:

[0467] · Nucleoside reverse transcriptase inhibitors (NRTIs)

[0468] · Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[0469] · Protease inhibitors (PIs)

[0470] · Integrase inhibitors (INSTIs)

[0471] · Fusion inhibitors (FIs)

[0472] · Chemokine receptor antagonists

[0473] · Entry inhibitors.

[0474] Specific examples of pharmaceutical agents include abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, AT-527, atazanavir, atropine, balaprevir, BCX4430 / galicivir, boceprevir, cidofovir, compavir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxuridine, efavirenz, emtricitabine, enfuvirtide, Entecavir, famciclovir, favipiravir, fomivir, fosamprenavir, foscarnet, fosanoacetic acid, ganciclovir, GS-5734 / remdesivir, ibacitabine, imonovir, iodine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon, lamivudine, ledipasvir, lopinavir, loviramide, maraviroc, morpholino, methylthiazone, CD24Fc, nelfinavir, nevir Lapine, Nexavir, NITD008, Obitasvir, Oseltamivir, Paritaprevir, Peginterferon α-2a, Penciclovir, Peramivir, Pracona, Podophyllotoxin, Raltegravir, Ribavirin, Amantadine, Ritonavir, Pyrimidine, Saquinavir, Simeprevir, Sofosbuvir, Stavudine, Telaprevir, Telbivudine, Tenofovir, Tenofovir Disoproxil, Tenofovir Exalidex, Tipranavir, trifluridine, trimethoprim, tromantine, Truvada, valacyclovir, valganciclovir, viraviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine or chloroquine, chloroquine phosphate, hydroxychloroquine, hydroxychloroquine sulfate, Ampligen, APN01, Ganovo, IFX-1, BXT-25, CYNK-001, tocilizumab, lelizumab, Ii-key, COVID-19 S-Trimer, carrelizumab, thymosin, brinixin, INO-4800, prazidene, cobicistat, mRNA-1273, arbidol, umifenovir, REGN3048, REGN3051, TNX-1800, fingolimod, methylprednisolone, nitazoxanide, fenazolidinone B, C-467929, C-473872, NSC-306711, N-65828, C-21, CGP-42112A, L-163491, flavonoids, bevacizumab, patient-derived polyclonal antibodies and monoclonal antibodies (including antibodies from COVID-19 patients or monoclonal or polyclonal antibodies that bind to SARS-CoV-2), and combinations thereof.In addition, the compounds of the present invention can be combined with compounds that are beneficial for preventing COVID-19-related lung injury, including anti-IL-6 and TNF inhibitors, specifically including tocilizumab (Actemra), siltuximab (Sylvant), tocilizumab, fully humanized interleukin 6 receptor monoclonal antibody, olokizumab (CDP6038), elsilimomab, BMS-945429 (ALD518), sirukumab (CNTO 136), levilimomab (BCD-089), CPSI-2364 and ALX-0061, ARGX-109, FE301, FM10, infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia) and golimumab (Simponi), etanercept (Enbrel), CD24Fc, thalidomide (Immunoprin) and its derivatives lenalidomide (Revlimid) and pomalidomide (Pomalyst, Imnovid), xanthine derivatives (e.g., pentoxifylline) and bupropion as well as 5-HT agonist hallucinogens, including (R)-DOI, TCB-2, LSD and LA-SS-Az.

[0475] In embodiments, the exemplary compounds and pharmaceutical compositions can be co-administered with and their derivatives and prodrugs.

[0476] In embodiments, and their derivatives and prodrugs can be co-administered with and their derivatives and prodrugs.

[0477] In embodiments, can be co-administered with and their derivatives and prodrugs.

[0478] In embodiments, can be co-administered with and their derivatives and prodrugs.

[0479] In embodiments, can be co-administered with and their derivatives and prodrugs.

[0480] Specific embodiments

[0481] In a specific embodiment, a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection is disclosed herein, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula XXI,

[0482]

[0483] Chemical formula XXI

[0484] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0485] R 1 is H,

[0486] , , or ,

[0487] In the formula, R 6 is alkyl or carbocyclic group. In some examples, the compound may have the following structure,

[0488] , or its tautomer, its pharmaceutically acceptable salt or physiological salt.

[0489] On the other hand, the present disclosure provides a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having Chemical formula I,

[0490]

[0491] Chemical formula I

[0492] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0493] X is CH2, CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0494] Y is N or CR';

[0495] Z is N or CR'';

[0496] R' is hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic group, heterocarbocyclic group, cycloalkyl, heterocyclic group or carbonyl, wherein, R' may be optionally substituted by one or more identical or different R 10 substituents;

[0497] R'' is hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic group, heterocarbocyclic group, cycloalkyl, heterocyclic group or carbonyl, wherein, R'' may be optionally substituted by one or more identical or different R 10 substituents;

[0498] R 1 、R 2 、R 3 and R 5independently selected from H, or with the oxygen to which it is attached, it forms an optionally substituted ester, an optionally substituted branched ester, an optionally substituted carbonate, an optionally substituted carbamate, an optionally substituted thioester, an optionally substituted branched thioester, an optionally substituted thiocarbonate, an oxythiothiocarbonate, an optionally substituted oxythiothiocarbonate, a 2-hydroxypropionate, an optionally substituted 2-hydroxypropionate, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonate, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxythiocarbonyl, an optionally substituted oxymethylcarbonyl, an optionally substituted oxymethylthiocarbonyl, an oxymethoxythiocarbonate, an optionally substituted oxymethoxythiocarbonate, an L-amino acid ester, a D-amino acid ester, an oxymethoxyamino ester, an N-substituted L-amino acid ester, an N,N-dithiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted dithiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxythiocarbonyl, an optionally substituted oxymethoxythiocarbonyl, an L-amino acid ester, a D-amino acid ester, an oxymethoxyamino ester, an N-substituted L-amino acid ester, an N,N-dithiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted dithiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl substituted L-amino acid ester, N-substituted D-amino acid ester, N,N-disubstituted D-amino acid ester, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazine, optionally substituted oxime, optionally substituted imido, optionally substituted imino, optionally substituted aminal, optionally substituted hemiaminal, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carboimido ester, optionally substituted thiocarboimido ester, optionally substituted carboimido, optionally substituted aminoimidate, optionally substituted carbamidyl, optionally substituted thioacetal, optionally substituted S-acyl-2-thioethyl, (acyloxybenzyl) ether, (acyloxybenzyl) ester, PEG ester, PEG carbonate, optionally substituted bis-(acyloxybenzyl) ester, optionally substituted (acyloxybenzyl) ester or BAB ester, wherein R 1 , R 2 , R 3 and R 5 Optionally, one or more identical or different R 10 replace;

[0499] R 10 is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyclyl, heterocarbocyclyl, aryloxy, heteroaryloxy, heterocyclyl, cycloalkyloxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclylamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 10 Optionally, one or more identical or different R 11 replace;

[0500] R 11is deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0501] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or lipid as described herein.

[0502] In certain examples, R 1 , R 2 , R 3 and R 5 can each independently be selected from H,

[0503] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0504] Y 1 is O or S;

[0505] Y 3 is OH or BH3 - M + , where M is Li, Na, K, NH4, (CH3CH2)3NH, (CH3CH2CH2CH2)4N;

[0506] R 6 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, cyano or lipid, where R 6 is optionally substituted by one or more identical or different R 10 substituents;

[0507] R 7 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, where R 7 is optionally substituted by one or more identical or different R 10 substituents;

[0508] R 8is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, where R 8 is optionally substituted by one or more identical or different R 10 ;

[0509] R 9 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, where R 9 is optionally substituted by one or more identical or different R 10 ;

[0510] R 7 、R 8 and R 9 may form a ring with the α-carbon to which they are attached and the amino group attached to the α-carbon; and

[0511] R 8 and R 9 may form a ring with the α-carbon to which they are attached.

[0512] In other examples, R 1 is hydrogen, 、 or .

[0513] In certain examples, R' is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, thiomethyl, carboxylic acid, formyl, vinyl or ethynyl. In certain examples, R'' is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, thiomethyl, carboxylic acid, formyl, vinyl or ethynyl. In certain examples, the compounds are selected from:

[0514] .

[0515] In some examples, the compound is selected from:

[0516] .

[0517] In some examples, the compound is selected from:

[0518] .

[0519] In some examples, the compound is selected from:

[0520] .

[0521] Also disclosed herein is a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, wherein the compound is a compound having a chemical formula II,

[0522]

[0523] Chemical formula II

[0524] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein

[0525] X is CH2, CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0526] Y is N or CR';

[0527] Z is N or CR";

[0528] R' is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl or carbonyl, wherein R' can be replaced by one or more identical or different R 10 replace;

[0529] R" is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl or carbonyl, wherein R" can be optionally replaced by one or more identical or different R 10 replace;

[0530] R 1 , R 2 , R 3 and R 5independently selected from H, or with the oxygen to which it is attached, it forms an optionally substituted ester, an optionally substituted branched ester, an optionally substituted carbonate, an optionally substituted carbamate, an optionally substituted thioester, an optionally substituted branched thioester, an optionally substituted thiocarbonate, an oxythiothiocarbonate, an optionally substituted oxythiothiocarbonate, a 2-hydroxypropionate, an optionally substituted 2-hydroxypropionate, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonate, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxythiocarbonyl, an optionally substituted oxymethylcarbonyl, an optionally substituted oxymethylthiocarbonyl, an oxymethoxythiocarbonate, an optionally substituted oxymethoxythiocarbonate, an L-amino acid ester, a D-amino acid ester, an oxymethoxyamino ester, an N-substituted L-amino acid ester, an N,N-dithiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted dithiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxythiocarbonyl, an optionally substituted oxymethoxythiocarbonyl, an L-amino acid ester, a D-amino acid ester, an oxymethoxyamino ester, an N-substituted L-amino acid ester, an N,N-dithiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted dithiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl substituted L-amino acid ester, N-substituted D-amino acid ester, N,N-disubstituted D-amino acid ester, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazine, optionally substituted oxime, optionally substituted imido, optionally substituted imino, optionally substituted aminal, optionally substituted hemiaminal, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carboimido ester, optionally substituted thiocarboimido ester, optionally substituted carboimido, optionally substituted aminoimidate, optionally substituted carbamidyl, optionally substituted thioacetal, optionally substituted S-acyl-2-thioethyl, (acyloxybenzyl) ether, (acyloxybenzyl) ester, PEG ester, PEG carbonate, optionally substituted bis-(acyloxybenzyl) ester, optionally substituted (acyloxybenzyl) ester or BAB ester, wherein R 1 , R 2 , R 3 and R 5 Optionally, one or more identical or different R 10 replace;

[0531] The condition is R 1 , R 2 , R 3 and R 5 Not all are H;

[0532] R 10is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituted;

[0533] R 11 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0534] the lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or the lipid described herein.

[0535] In certain examples, R' is methyl, fluorine, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, thiomethyl, carboxylic acid, formyl, vinyl or ethynyl. In other examples, R'' is methyl, fluorine, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, thiomethyl, carboxylic acid, formyl, vinyl or ethynyl.

[0536] The present disclosure also provides a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having Formula III,

[0537]

[0538] Formula III

[0539] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0540] X is CH2, CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0541] Z is N or CR”;

[0542] R” is hydrogen, deuterium, halogen, hydroxy, amino, mercapto, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic, heterocarbocyclic, cycloalkyl, heterocyclic or carbonyl, wherein R” may optionally be substituted by one or more identical or different R 10 substituents;

[0543] R 1 、R 2 、R 3 and R 5 are independently selected from H, or form with the oxygen to which they are attached an optionally substituted ester, optionally substituted branched ester, optionally substituted carbonate, optionally substituted carbamate, optionally substituted thioester, optionally substituted branched thioester, optionally substituted thiocarbonate, oxythiocarbonyl thiocarbonate, optionally substituted oxythiocarbonyl thiocarbonate, 2-hydroxypropionate, optionally substituted 2-hydroxypropionate, optionally substituted S-thiocarbonate, optionally substituted dithiocarbonate, optionally substituted thiocarbamate, optionally substituted o-methoxycarbonyl, o-methoxycarbonate, optionally substituted o-methoxycarbonate, optionally substituted o-methoxythiocarbonyl, optionally substituted o-methylcarbonyl, optionally substituted o-methylthiocarbonyl, o-methoxythiocarbonate, optionally substituted o-methoxythiocarbonate, L-amino acid ester, D-amino acid ester, o-methoxyamino ester, N-substituted L-amino acid ester, N,N-disubstituted L-amino acid ester, N-substituted D-amino acid ester, N,N-disubstituted D-amino acid ester, optionally substituted oxythio, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oxime, optionally substituted imide, optionally substituted imine, optionally substituted acetalamine, optionally substituted hemiacetalamine, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carbonimide ester, optionally substituted thiocarbonimide ester, optionally substituted carbonimide, optionally substituted aminoimidate, optionally substituted aminocarboximidate, optionally substituted thioacetal, optionally substituted S-acyl-2-thioethyl, (acyloxybenzyl) ether, (acyloxybenzyl) ester, PEG ester, PEG carbonate, optionally substituted bis-(acyloxybenzyl) ester, optionally substituted (acyloxybenzyl) ester or BAB ester, wherein R 1 、R 2 、R 3 and R 5 may optionally be substituted by one or more identical or different R 10 substituents;

[0544] Provided that R 1 、R 2 、R3 and R 5 are not all H;

[0545] R 10 is hydrogen, deuterium, hydroxyl, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, alleny, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0546] R 11 is hydrogen, deuterium, hydroxyl, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, alleny, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0547] lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or a lipid as described herein. In certain examples, R” is methyl, fluorine, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteriomethyl, thiomethyl, carboxylic acid, formyl, vinyl or ethynyl.

[0548] The present disclosure also provides a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having Formula IV,

[0549]

[0550] Formula IV

[0551] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0552] X is CHCH3, C(CH3)2, CHF, CF2 or CD2;

[0553] R 1 , R 2 , R 3 and R 5 independently selected from H, or with the oxygen to which it is attached, it forms an optionally substituted ester, an optionally substituted branched ester, an optionally substituted carbonate, an optionally substituted carbamate, an optionally substituted thioester, an optionally substituted branched thioester, an optionally substituted thiocarbonate, an oxythiothiocarbonate, an optionally substituted oxythiothiocarbonate, a 2-hydroxypropionate, an optionally substituted 2-hydroxypropionate, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonate, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxythiocarbonyl, an optionally substituted oxymethylcarbonyl, an optionally substituted oxymethylthiocarbonyl, an oxymethoxythiocarbonate, an optionally substituted oxymethoxythiocarbonate, an L-amino acid ester, a D-amino acid ester, an oxymethoxyamino ester, an N-substituted L-amino acid ester, an N,N-dithiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted dithiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxythiocarbonyl, an optionally substituted oxymethoxythiocarbonyl, an L-amino acid ester, a D-amino acid ester, an oxymethoxyamino ester, an N-substituted L-amino acid ester, an N,N-dithiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted dithiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl, an optionally substituted oxymethoxycarbonyl substituted L-amino acid ester, N-substituted D-amino acid ester, N,N-disubstituted D-amino acid ester, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazine, optionally substituted oxime, optionally substituted imido, optionally substituted imino, optionally substituted aminal, optionally substituted hemiaminal, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carboimido ester, optionally substituted thiocarboimido ester, optionally substituted carboimido, optionally substituted aminoimidate, optionally substituted carbamidyl, optionally substituted thioacetal, optionally substituted S-acyl-2-thioethyl, (acyloxybenzyl) ether, (acyloxybenzyl) ester, PEG ester, PEG carbonate, optionally substituted bis-(acyloxybenzyl) ester, optionally substituted (acyloxybenzyl) ester or BAB ester, wherein R 1 , R 2 , R 3 and R 5 Optionally, one or more identical or different R 10 replace;

[0554] The condition is R 1 , R 2 , R 3 and R 5 Not all are H;

[0555] R 10is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0556] R 11 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0557] the lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or the lipid described herein.

[0558] The present invention also discloses a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula V,

[0559]

[0560] Chemical formula V

[0561] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0562] R 1 、R 2 、R 3 and R 5and the oxygen to which it is attached is independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted methoxycarbonyls, methoxycarbonates, optionally substituted methoxycarbonates, optionally substituted methoxythiocarbonyls, optionally substituted methoxycarbonyls, optionally substituted methoxythiocarbonyls, methoxythiocarbonates, optionally substituted methoxythiocarbonates, L-amino acid esters, D-amino acid esters, methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oxime groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimide esters, optionally substituted thiocarbonimide esters, optionally substituted carbonimide groups, optionally substituted amino imino acid esters, optionally substituted aminoguanidino groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, where R 1 、R 2 、R 3 and R 5 are optionally substituted by one or more identical or different R 10 substituents;

[0563] R 10 is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro or carbonyl, where R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0564] R 11is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0565] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or lipid as described herein.

[0566] The present disclosure also provides a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having Formula VI,

[0567]

[0568] Formula VI

[0569] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0570] R 1 、R 2 and R 3and the oxygen to which it is attached is independently selected from: optionally substituted carbonate, optionally substituted carbamate, optionally substituted thioester, optionally substituted branched thioester, optionally substituted thiocarbonate, oxythiocarbonyl thiocarbonate, optionally substituted oxythiocarbonyl thiocarbonate, 2-hydroxypropionate, optionally substituted 2-hydroxypropionate, optionally substituted S-thiocarbonate, optionally substituted dithiocarbonate, optionally substituted thiocarbamate, optionally substituted methoxycarbonyl, methoxycarbonate, optionally substituted methoxycarbonate, optionally substituted methoxythiocarbonyl, optionally substituted methoxycarbonyl, optionally substituted methoxythiocarbonyl, methoxythiocarbonate, optionally substituted methoxythiocarbonate, L-amino acid ester, D-amino acid ester, N-substituted L-amino acid ester, N,N-disubstituted L-amino acid ester, N-substituted D-amino acid ester, N,N-disubstituted D-amino acid ester, methoxyaminoester, optionally substituted oxythio, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oxime, optionally substituted imide, optionally substituted imine, optionally substituted acetalamine, optionally substituted hemiacetalamine, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carbonimide ester, optionally substituted thiocarbonimide ester, optionally substituted carbonimide group, optionally substituted aminoimidate, optionally substituted aminoguanidino, optionally substituted thioacetal, optionally substituted S-acyl-2-thioethyl, (acyloxybenzyl) ether, (acyloxybenzyl) ester, PEG ester, PEG carbonate, optionally substituted bis-(acyloxybenzyl) ester, optionally substituted (acyloxybenzyl) ester or BAB ester, wherein, R 1 、R 2 and R 3 are optionally substituted by one or more identical or different R 10 ;

[0571] R 10 is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic epoxy group, heterocarbocyclic epoxy group, aryloxy, heteroaryloxy, heterocyclic epoxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 ;

[0572] R 11Hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic epoxy, heterocarbocyclic epoxy, aryloxy, heteroaryloxy, heterocyclic epoxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0573] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, an aryl substituted with an alkyl or a lipid as described herein. In certain examples, the compound has the chemical formula VIa-f,

[0574]

[0575] In other examples, the compound is selected from:

[0576] .

[0577] Also disclosed herein is a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula VII,

[0578]

[0579] Chemical formula VII

[0580] or a tautomer, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0581] R 1 、R 2 and R 5and the oxygen to which it is attached is independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted methoxycarbonyls, methoxycarbonates, optionally substituted methoxycarbonates, optionally substituted methoxythiocarbonyls, optionally substituted methoxycarbonyls, optionally substituted methoxythiocarbonyls, methoxythiocarbonates, optionally substituted methoxythiocarbonates, L-amino acid esters, D-amino acid esters, methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oximes, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted aminoiminocarbonates, optionally substituted aminocarboxamidines, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, where R 1 、R 2 and R 5 are optionally substituted by one or more identical or different R 10 substituents;

[0582] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allenes, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, where R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0583] R 11is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0584] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted with alkyl or a lipid as described herein.

[0585] Also disclosed herein is a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having Formula VIII,

[0586]

[0587] Formula VIII

[0588] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0589] R 1 、R 3 and R 5and the oxygen to which it is attached is independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted o-methoxycarbonyls, o-methoxycarbonates, optionally substituted o-methoxycarbonates, optionally substituted o-methoxythiocarbonyls, optionally substituted o-methylcarbonyls, optionally substituted o-methylthiocarbonyls, o-methoxythiocarbonates, optionally substituted o-methoxythiocarbonates, L-amino acid esters, D-amino acid esters, o-methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazinates, optionally substituted oxime groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimide esters, optionally substituted thiocarbonimide esters, optionally substituted carbonimide groups, optionally substituted amino imino acid esters, optionally substituted aminocarboximidoyl groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, where R 1 、R 3 and R 5 are optionally substituted by one or more identical or different R 10 substituents;

[0590] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro or carbonyl, where R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0591] R 11is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allenyloxy, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0592] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or lipid as described herein.

[0593] The present invention also discloses a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula IX,

[0594]

[0595] Chemical formula IX

[0596] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0597] R 2 、R 3 and R 5and the oxygen to which it is attached is independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted methoxycarbonyls, methoxycarbonates, optionally substituted methoxycarbonates, optionally substituted methoxythiocarbonyls, optionally substituted methoxycarbonyls, optionally substituted methoxythiocarbonyls, methoxythiocarbonates, optionally substituted methoxythiocarbonates, L-amino acid esters, D-amino acid esters, methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oxime groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted amino imino acid esters, optionally substituted aminocarboximidoyl groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 2 、R 3 and R 5 are optionally substituted by one or more identical or different R 10 substituents;

[0598] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allenylic, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0599] R 11is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0600] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or the lipid described herein.

[0601] The present disclosure also provides a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula X,

[0602]

[0603] Chemical formula X

[0604] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0605] -O-R 1 and -O-R 5Independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted oxycarbonyloxy, oxycarbonyloxy carbonates, optionally substituted oxycarbonyloxy carbonates, optionally substituted oxycarbonylthio, optionally substituted oxycarbonylmethyl, optionally substituted oxycarbonylmethylthio, oxycarbonylthio carbonates, optionally substituted oxycarbonylthio carbonates, L-amino acid esters, D-amino acid esters, oxycarbonylamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio, sulfinyl, sulfonyl, sulfites, sulfates, sulfonamides, optionally substituted iminoesters, optionally substituted hydrazonates, optionally substituted oximes, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetalamines, optionally substituted hemiacetalamines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted aminoiminocarboxylates, optionally substituted aminocarboximidamides, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 1 and R 5 is optionally substituted by one or more identical or different R 10 substituents;

[0606] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclicoxy, heterocarbocyclicoxy, aryloxy, heteroaryloxy, heterocyclicoxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclicamino, heterocarbocyclicamino, arylamino, heteroarylamino, heterocyclicamino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclicthio, heterocarbocyclicthio, arylthio, heteroarylthio, heterocyclicthio, cycloalkylthio, cycloalkenylthio, allenylic, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0607] R 11is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0608] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, an aryl substituted by alkyl or a lipid as described herein.

[0609] Also disclosed herein is a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the formula XI,

[0610]

[0611] Formula XI

[0612] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0613] -O-R 1 and -O-R 3Independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted methoxycarbonyls, methoxycarbonates, optionally substituted methoxycarbonates, optionally substituted methoxythiocarbonyls, optionally substituted methoxycarbonyls, optionally substituted methoxythiocarbonyls, methoxythiocarbonates, optionally substituted methoxythiocarbonates, L-amino acid esters, D-amino acid esters, methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazinates, optionally substituted oximes, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted amino imino acid esters, optionally substituted aminoguanidino groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 1 and R 3 is optionally substituted by one or more identical or different R 10 substituents;

[0614] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0615] R 11is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0616] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or lipid as described herein.

[0617] The present invention also discloses a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula XII,

[0618]

[0619] Chemical formula XII

[0620] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0621] -O-R 1 and -O-R 2Independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted oxy-methoxycarbonyls, oxy-methoxycarbonates, optionally substituted oxy-methoxycarbonates, optionally substituted oxy-methoxy-thiocarbonyls, optionally substituted oxy-methylcarbonyls, optionally substituted oxy-methylthiocarbonyls, oxy-methoxy-thiocarbonates, optionally substituted oxy-methoxy-thiocarbonates, L-amino acid esters, D-amino acid esters, oxy-methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oxime groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted amino imino acid esters, optionally substituted aminocarboximidoyl groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 1 and R 2 is optionally substituted by one or more identical or different R 10 substituents;

[0622] R 10 is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0623] R 11is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0624] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or the lipid described herein.

[0625] The present invention also discloses a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula XIII,

[0626]

[0627] Chemical formula XIII

[0628] or its tautomer, its medicinal salt or physiological salt, wherein,

[0629] -O-R 2 and -O-R 5Independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted oxy-methoxycarbonyls, oxy-methoxycarbonates, optionally substituted oxy-methoxycarbonates, optionally substituted oxy-methoxy-thiocarbonyls, optionally substituted oxy-methylcarbonyls, optionally substituted oxy-methylthiocarbonyls, oxy-methoxy-thiocarbonates, optionally substituted oxy-methoxy-thiocarbonates, L-amino acid esters, D-amino acid esters, oxy-methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oxime groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimide esters, optionally substituted thiocarbonimide esters, optionally substituted carbonimide groups, optionally substituted amino imino acid esters, optionally substituted aminomethyl groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 2 and R 5 are optionally substituted by one or more identical or different R 10 substituents;

[0630] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0631] R 11is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0632] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, an aryl substituted by an alkyl or a lipid as described herein.

[0633] The present disclosure also provides a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula XIV,

[0634]

[0635] Chemical formula XIV

[0636] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0637] -O-R 2 and -O-R 3Independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted o-methoxycarbonyls, o-methoxycarbonates, optionally substituted o-methoxycarbonates, optionally substituted o-methoxythiocarbonyls, optionally substituted o-methylcarbonyls, optionally substituted o-methylthiocarbonyls, o-methoxythiocarbonates, optionally substituted o-methoxythiocarbonates, L-amino acid esters, D-amino acid esters, o-methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imidate esters, optionally substituted hydrazonate salts, optionally substituted oxime groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted aminoimidate esters, optionally substituted aminoguanidine groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 2 and R 3 is optionally substituted by one or more identical or different R 10 substituents;

[0638] R 10 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, amidosulfonyl group, sulfonyl group, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0639] R 11is hydrogen, deuterium, hydroxyl, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allenyloxy, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0640] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, an aryl substituted by alkyl or a lipid as described herein.

[0641] The present invention also discloses a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula XV,

[0642]

[0643] Chemical formula XV

[0644] or its tautomer, its medicinal salt or physiological salt, wherein,

[0645] -O-R 3 and -O-R 5Independently selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted methoxycarbonyls, methoxycarbonates, optionally substituted methoxycarbonates, optionally substituted methoxythiocarbonyls, optionally substituted methoxycarbonyls, optionally substituted methoxythiocarbonyls, methoxythiocarbonates, optionally substituted methoxythiocarbonates, L-amino acid esters, D-amino acid esters, methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oxime groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted amino imino acid esters, optionally substituted aminocarboximidoyl groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 3 and R 5 is optionally substituted by one or more identical or different R 10 substituents;

[0646] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0647] R 11is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0648] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or a lipid as described herein.

[0649] Also disclosed herein is a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula XVI,

[0650]

[0651] Chemical formula XVI

[0652] or a tautomer thereof, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0653] -O-R 2Selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted methoxycarbonyls, methoxycarbonates, optionally substituted methoxycarbonates, optionally substituted methoxythiocarbonyls, optionally substituted methoxycarbonyls, optionally substituted methoxythiocarbonyls, methoxythiocarbonates, optionally substituted methoxythiocarbonates, L-amino acid esters, D-amino acid esters, methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imidate esters, optionally substituted hydrazinate salts, optionally substituted oxime groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted aminoimidate esters, optionally substituted aminocarboximidamide groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 2 is optionally substituted by one or more identical or different R 10 substituents;

[0654] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0655] R 11is hydrogen, deuterium, hydroxyl, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0656] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or a lipid as described herein.

[0657] The present invention also discloses a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula XVII,

[0658]

[0659] Chemical formula XVII

[0660] or a tautomer, a pharmaceutically acceptable salt or a physiological salt thereof, wherein,

[0661] -O-R 3Selected from: optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted o-methoxycarbonyls, o-methoxycarbonates, optionally substituted o-methoxycarbonates, optionally substituted o-methoxythiocarbonyls, optionally substituted o-methylcarbonyls, optionally substituted o-methylthiocarbonyls, o-methoxythiocarbonates, optionally substituted o-methoxythiocarbonates, L-amino acid esters, D-amino acid esters, o-methoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oximino groups, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted aminoiminocarbonates, optionally substituted aminocarbonimidoyl groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 3 is optionally substituted by one or more identical or different R 10 substituents;

[0662] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0663] R 11is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0664] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or lipid as described herein.

[0665] The present invention also discloses a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, which comprises a pharmaceutically acceptable excipient and a compound having the chemical formula XIX,

[0666]

[0667] Chemical formula XIX

[0668] or its tautomer, its pharmaceutically acceptable salt or physiological salt, wherein,

[0669] -O-R 5Selected from: optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, oxythiocarbonates, optionally substituted oxythiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, optionally substituted S-thiocarbonates, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted oxycarbonyloxys, oxycarbonyloxycarbonates, optionally substituted oxycarbonyloxycarbonates, optionally substituted oxycarbonylthiocarbonyls, optionally substituted oxycarbonylmethyls, optionally substituted oxycarbonylmethylthiocarbonyls, oxycarbonylthiocarbonates, optionally substituted oxycarbonylthiocarbonates, L-amino acid esters, D-amino acid esters, oxycarbonyloxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted oxythio groups, sulfinyl groups, sulfonyl groups, sulfites, sulfates, sulfonamides, optionally substituted imino acid esters, optionally substituted hydrazonates, optionally substituted oximes, optionally substituted imide groups, optionally substituted imine groups, optionally substituted acetal amines, optionally substituted hemiacetal amines, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbodiimide esters, optionally substituted thiocarbodiimide esters, optionally substituted carbodiimide groups, optionally substituted amino imino acid esters, optionally substituted aminocarbonimidoyl groups, optionally substituted thioacetals, optionally substituted S-acyl-2-thioethyls, (acyloxybenzyl) ethers, (acyloxybenzyl) esters, PEG esters, PEG carbonates, optionally substituted bis-(acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters or BAB esters, wherein, R 5 is optionally substituted by one or more identical or different R 10 substituents;

[0670] R 10 is hydrogen, deuterium, hydroxy, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro or carbonyl, wherein, R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0671] R 11is hydrogen, deuterium, hydroxyl, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0672] The lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, an aryl substituted with an alkyl or a lipid as described herein. In certain examples, R 5 is selected from:

[0673] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , ;

[0674] R 6 is hydrogen, C2-C7 normal alkyl, optionally substituted C8 normal alkyl, C9-C 22 normal alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl group, heteroaryl group, heterocyclic group, C3-C9 cycloalkyl group, C 11 -C 22 cycloalkyl group, optionally substituted C 10 cycloalkyl group, cycloalkoxy group, -O(C1-C6 normal alkyl), -O(optionally substituted C7 normal alkyl), -O(C8-C 21 normal alkyl), -O(branched alkyl), carbocyclic epoxy group, heterocarbocyclic epoxy group, aryloxy group, heteroaryloxy group, heterocyclic epoxy group, cycloalkoxy group, cycloalkenyloxy group, -N(C2-C 21 normal alkyl)2, -N(optionally substituted C1 alkyl)2, -NH(optionally substituted C1 alkyl), -NH(C2-C6 normal alkyl), -NH(optionally substituted C7 normal alkyl), -NH(C8-C 15 normal alkyl), -NH(optionally substituted C 16 normal alkyl), -NH(C 17 normal alkyl), -NH(optionally substituted C 18 normal alkyl), -NH(C 19 -C 21 normal alkyl), -NH(branched alkyl), -N(branched alkyl)2, carbocyclic amino group, heterocarbocyclic amino group, optionally substituted arylamino group, heteroarylamino group, heterocyclic amino group, cycloalkylamino group, cycloalkenylamino group, alkylthio group, carbocyclic thio group, heterocarbocyclic thio group, arylthio group, heteroarylthio group, heterocyclic thio group, cycloalkylthio group, cycloalkenylthio group, alleny group, cyano group or lipid, wherein, R 6 is optionally substituted by one or more identical or different R 10 substituents;

[0675] R 7 is hydrogen, deuterium, hydroxyl group, azide group, mercapto group, amino group, cyano group, halogen, alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocarbocyclic group, aryl group, heteroaryl group, heterocyclic group, cycloalkyl group, cycloalkenyl group, alkoxy group, carbocyclic epoxy group, heterocarbocyclic epoxy group, aryloxy group, heteroaryloxy group, heterocyclic epoxy group, cycloalkoxy group, cycloalkenyloxy group, alkylamino group, (alkyl)2amino group, carbocyclic amino group, heterocarbocyclic amino group, arylamino group, heteroarylamino group, heterocyclic amino group, cycloalkylamino group, cycloalkenylamino group, alkylthio group, carbocyclic thio group, heterocarbocyclic thio group, arylthio group, heteroarylthio group, heterocyclic thio group, cycloalkylthio group, cycloalkenylthio group, alleny group, sulfinyl group, sulfamoyl group, sulfonyl group, lipid, nitro group or or carbonyl group, wherein, R 7Optionally substituted by one or more identical or different R 10 ;

[0676] R 8 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 8 is optionally substituted by one or more identical or different R 10 ;

[0677] R 9 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 9 is optionally substituted by one or more identical or different R 10 ;

[0678] R 7 , R 8 and R 9 may form a ring with the α-carbon to which it is attached and the amino group attached to the α-carbon; and

[0679] R 8 and R 9 may form a ring with the α-carbon to which it is attached.

[0680] In certain examples of the compounds disclosed herein, R 1 , R 2 , R 3 and R 5 are independently selected from H,

[0681] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0682] Subject to the condition that R 1 , R 2 , R 3 and R 5 are not all H;

[0683] R 6 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, cyano or lipid, where R 6 is optionally substituted by one or more identical or different R 10 substituents;

[0684] R 7 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 7 is optionally substituted by one or more identical or different Rs 10 ;

[0685] R 8 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 8 is optionally substituted by one or more identical or different Rs 10 ;

[0686] R 9 is hydrogen, deuterium, hydroxyl, azide, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 9 is optionally substituted by one or more identical or different Rs 10 ;

[0687] R 7 、R 8 and R 9 may form a ring with the α-carbon to which they are attached and the amino group attached to the α-carbon;

[0688] R 8 and R 9 may form a ring with the α-carbon to which it is attached;

[0689] R 10 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, where R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0690] R 11 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0691] lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or a lipid as described herein.

[0692] In other examples of the compounds disclosed herein, R1, R 2 and R 3 are independently selected from:

[0693] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0694] R 6 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, optionally substituted phenyl, optionally substituted aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino group, heterocarbocyclic amino group, arylamino, heteroarylamino, heterocyclic amino group, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, cyano or lipid, wherein R 6 is optionally substituted by one or more identical or different R 10 substituents;

[0695] R 7is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, alleny, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 7 is optionally substituted by one or more identical or different R 10 substituents;

[0696] R 8 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, alleny, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 8 is optionally substituted by one or more identical or different R 10 substituents;

[0697] R 9 is hydrogen, deuterium, hydroxyl, azido, mercapto, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy, heterocarbocyclic oxy, aryloxy, heteroaryloxy, heterocyclic oxy, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio, heterocarbocyclic thio, arylthio, heteroarylthio, heterocyclic thio, cycloalkylthio, cycloalkenylthio, alleny, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein, R 9 is optionally substituted by one or more identical or different R 10 substituents;

[0698] R 7 R 8 and R 9 may form a ring with the α-carbon to which they are attached and the amino group attached to the α-carbon;

[0699] R8 and R 9 can form a ring with the α-carbon to which it is attached;

[0700] R 10 is hydrogen, deuterium, hydroxyl, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl, wherein R 10 is optionally substituted by one or more identical or different R 11 substituents;

[0701] R 11 is hydrogen, deuterium, hydroxyl, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic group, heterocarbocyclic group, aryl, heteroaryl, heterocyclic group, cycloalkyl, cycloalkenyl, alkoxy, carbocyclic oxy group, heterocarbocyclic oxy group, aryloxy, heteroaryloxy, heterocyclic oxy group, cycloalkoxy, cycloalkenyloxy, alkylamino, (alkyl)2amino, carbocyclic amino, heterocarbocyclic amino, arylamino, heteroarylamino, heterocyclic amino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclic thio group, heterocarbocyclic thio group, arylthio, heteroarylthio, heterocyclic thio group, cycloalkylthio, cycloalkenylthio, allene group, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro or carbonyl; and

[0702] lipid is C 11 -C 22 higher alkyl, C 11 -C 22 higher alkoxy, polyethylene glycol, aryl substituted by alkyl or lipid as described herein.

[0703] The present invention also discloses a pharmaceutical composition for treating COVID-19, comprising a pharmaceutically acceptable excipient and a compound having the following structure:

[0704] , or its tautomer, its pharmaceutically acceptable salt or physiological salt.

[0705] In addition, the present disclosure provides pharmaceutical compositions of the compounds disclosed herein, which further comprise a propellant. The propellant can be compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFAs), 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, or combinations thereof. The present disclosure also provides compressed containers containing the pharmaceutical compositions disclosed herein. The containers can be manual pump sprayers, inhalers, metered-dose inhalers, dry powder inhalers, nebulizers, vibrating mesh nebulizers, jet nebulizers, or ultrasonic nebulizers.

[0706] The present disclosure also provides a method for treating or preventing 2019nCoV / SARS-CoV-2 infection, which includes administering an effective amount of the compositions disclosed herein to a subject in need thereof. The method for treating or preventing 2019nCoV / SARS-CoV-2 infection may include administering an effective amount of a compound (having the following structure) to a patient:

[0707] , , , or its tautomer, its pharmaceutically acceptable salt or physiological salt.

[0708] The present disclosure also provides a method for preventing a patient in need from being infected with COVID, which includes administering an effective amount of a pharmaceutical composition (comprising a compound having the following structure) to the patient:

[0709] , , , or its tautomer, its pharmaceutically acceptable salt or physiological salt.

[0710] The present disclosure also provides a pharmaceutical composition (comprising a compound having the following structure):

[0711] , , , or its tautomer, its pharmaceutically acceptable salt or physiological salt; a pharmaceutically acceptable excipient or its tautomer, its pharmaceutically acceptable salt or physiological salt; further comprising one or more antiviral agents, such as abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balaprevir, BCX4430 / galicivir, boceprevir, cidofovir, compavir , daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxuridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosanoacetic acid, ganciclovir, GS-5734 / remdesivir, ibacitabine, imonovir, iodine, imiquimod, indinavir, inosine, type III stem cell Interferon, type II interferon, type I interferon, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, morphine, methylthiazone, nelfinavir, nevirapine, nesavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon α-2a, penciclovir, peramivir, praconavir, podophyllotoxin, raltegravir, ribavirin, rimantadine , ritonavir, pyrimidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir Exalidex, tipranavir, trifluridine, trimethoprim, tromantine, Truvada, valacyclovir, valganciclovir, viraviroc, adenosine, viramidine, zalcitabine, zanamivir or zidovudine and combinations thereof.

[0712] Also disclosed herein is a pharmaceutical composition for treating 2019nCoV / SARS-CoV-2 infection, comprising a pharmaceutically acceptable excipient and a compound having the following structure:

[0713] , , , or its tautomers, pharmaceutically acceptable salts or physiological salts thereof, and one or more antiviral agents selected from the following: abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atropine, balaprevir, galicivir, boceprevir, cidofovir, compivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosanoacetic acid, ganciclovir, remdesivir, ibacitabine, imonovir, iodine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon, lamivudine Vudine, Ledipasvir, Lopinavir, Loviramide, Maraviroc, Morphoguanidine, Methiazone, Nelfinavir, Nevirapine, Nexavir, NITD008, Obitasvir, Oseltamivir, Paritaprevir, Peginterferon alpha-2a, Penciclovir, Peramivir, Pracona, Podophyllotoxin, Raltegravir, Ribavirin, Amantadine, Ritonavir, Pyrimidine, Saquinavir, Simeprevir, Sofosbuvir, Stavudine, Telaprevir, Telbivudine, Tenofovir, Tenofovir Disoproxil, Tenofovir Exalidex, Tipranavir, Trifluridine, Trixievir, Tromantine, Truvada, Valacyclovir, Valganciclovir, Viraviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir and Zidovudine and combinations thereof.

[0714] Also disclosed herein is a compound for treating 2019nCoV / SARS-CoV-2 infection, wherein the compound is:

[0715] , , , or its tautomers, pharmaceutically acceptable salts or physiological salts thereof, and one or more antiviral agents selected from the following: abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atropine, balaprevir, galicivir, boceprevir, cidofovir, compivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosanoacetic acid, ganciclovir, remdesivir, ibacitabine, imonovir, iodine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon, lamivudine Vudine, Ledipasvir, Lopinavir, Loviramide, Maraviroc, Morphoguanidine, Methiazone, Nelfinavir, Nevirapine, Nexavir, NITD008, Obitasvir, Oseltamivir, Paritaprevir, Peginterferon alpha-2a, Penciclovir, Peramivir, Pracona, Podophyllotoxin, Raltegravir, Ribavirin, Amantadine, Ritonavir, Pyrimidine, Saquinavir, Simeprevir, Sofosbuvir, Stavudine, Telaprevir, Telbivudine, Tenofovir, Tenofovir Disoproxil, Tenofovir Exalidex, Tipranavir, Trifluridine, Trixievir, Tromantine, Truvada, Valacyclovir, Valganciclovir, Viraviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir and Zidovudine and combinations thereof.

[0716] Also disclosed herein is a pharmaceutical composition for treating COVID-19, comprising a pharmaceutically acceptable excipient and a compound having the following structure:

[0717] , , , or its tautomers, pharmaceutically acceptable salts or physiological salts thereof, and one or more antiviral agents selected from the following: abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atropine, balaprevir, galicivir, boceprevir, cidofovir, compivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosanoacetic acid, ganciclovir, remdesivir, ibacitabine, imonovir, iodine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon, lamivudine Vudine, Ledipasvir, Lopinavir, Loviramide, Maraviroc, Morphoguanidine, Methiazone, Nelfinavir, Nevirapine, Nexavir, NITD008, Obitasvir, Oseltamivir, Paritaprevir, Peginterferon alpha-2a, Penciclovir, Peramivir, Pracona, Podophyllotoxin, Raltegravir, Ribavirin, Amantadine, Ritonavir, Pyrimidine, Saquinavir, Simeprevir, Sofosbuvir, Stavudine, Telaprevir, Telbivudine, Tenofovir, Tenofovir Disoproxil, Tenofovir Exalidex, Tipranavir, Trifluridine, Trixievir, Tromantine, Truvada, Valacyclovir, Valganciclovir, Viraviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir and Zidovudine and combinations thereof.

[0718] This article also discloses a compound for treating COVID-19, wherein the compound is:

[0719] , , , or its tautomers, pharmaceutically acceptable salts or physiological salts thereof, and one or more antiviral agents selected from the following: abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atropine, balaprevir, galicivir, boceprevir, cidofovir, compivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosanoacetic acid, ganciclovir, remdesivir, ibacitabine, imonovir, iodine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon, lamivudine Vudine, Ledipasvir, Lopinavir, Loviramide, Maraviroc, Morphoguanidine, Methiazone, Nelfinavir, Nevirapine, Nexavir, NITD008, Obitasvir, Oseltamivir, Paritaprevir, Peginterferon alpha-2a, Penciclovir, Peramivir, Pracona, Podophyllotoxin, Raltegravir, Ribavirin, Amantadine, Ritonavir, Pyrimidine, Saquinavir, Simeprevir, Sofosbuvir, Stavudine, Telaprevir, Telbivudine, Tenofovir, Tenofovir Disoproxil, Tenofovir Exalidex, Tipranavir, Trifluridine, Trixievir, Tromantine, Truvada, Valacyclovir, Valganciclovir, Viraviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir and Zidovudine and combinations thereof.

[0720] Also disclosed herein is a method for treating 2019nCoV / SARS-CoV-2 infection, comprising administering an effective amount of a compound (having the following structure):

[0721] , , , or its tautomers, pharmaceutically acceptable salts or physiological salts thereof, and one or more antiviral agents selected from the following: abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atropine, balaprevir, galicivir, boceprevir, cidofovir, compivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edouridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosanoacetic acid, ganciclovir, remdesivir, ibacitabine, imonovir, iodine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon, lamivudine Vudine, Ledipasvir, Lopinavir, Loviramide, Maraviroc, Morphoguanidine, Methiazone, Nelfinavir, Nevirapine, Nexavir, NITD008, Obitasvir, Oseltamivir, Paritaprevir, Peginterferon alpha-2a, Penciclovir, Peramivir, Pracona, Podophyllotoxin, Raltegravir, Ribavirin, Amantadine, Ritonavir, Pyrimidine, Saquinavir, Simeprevir, Sofosbuvir, Stavudine, Telaprevir, Telbivudine, Tenofovir, Tenofovir Disoproxil, Tenofovir Exalidex, Tipranavir, Trifluridine, Trixievir, Tromantine, Truvada, Valacyclovir, Valganciclovir, Viraviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir and Zidovudine and combinations thereof.

[0722] Also disclosed herein is a method for treating COVID-19, comprising administering an effective amount of a compound (having the following structure):

[0723] , , , or its tautomer, its pharmaceutically acceptable salt or physiological salt, and one or more antiviral agents selected from the following: abacavir, acyclovir, adefovir, amantadine, amprenavir, amprenavir proximate, arbidol, atazanavir, atripla, boceprevir, galidesivir, boceprevir, cidofovir, corbavir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxuridine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonoacetic acid, ganciclovir, remdesivir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, lobivudine, maraviroc, moroxydine, metisazone, nelfinavir, nevirapine, nesacavir, NITD008, obitrovir, oseltamivir, paritaprevir, peginterferon alpha-2a, penciclovir, peramivir, placonaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyrimidine, saquinavir, simiprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir Exalidex, tipranavir, trifluridine, truvada, valacyclovir, valganciclovir, velivero, vidarabine, veramidine, zalcitabine, zanamivir, and zidovudine and combinations thereof.

[0724] Also disclosed herein is a method of treating or preventing an infection caused by 2019-nCoV / SARS-CoV-2, comprising administering to a host in need thereof an effective amount of a compound or composition disclosed herein. In certain examples, the compound can be

[0725] , or its tautomer, its pharmaceutically acceptable salt or physiological salt.

[0726] Also disclosed herein is a method of treating a patient with a CNS viral infection, comprising administering to a patient with a CNS viral infection an effective amount of a composition or compound disclosed herein. The viral CNS infection can be 2019-nCoV / SARS-CoV-2.

[0727] Examples

[0728] The following examples are intended to illustrate the compositions, methods, and results in accordance with the disclosed subject matter. These examples are not intended to cover all aspects of the disclosed subject matter, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the invention, which will be apparent to those skilled in the art.

[0729] The maximum effort has been made to ensure the accuracy of numbers (e.g., quantity, temperature, etc.), however, some errors and deviations should be considered. Unless otherwise specified, the parts are by weight. There are many variations and combinations of reaction conditions, e.g., component concentrations, temperature, pressure, and other reaction ranges and conditions that can be used to optimize the purity and yield of the products obtained from the process. Reasonable and routine experiments can be freely carried out to optimize such process conditions.

[0730] Unless otherwise specified, all chemical reactions are carried out in dried glassware under a nitrogen atmosphere. Unless otherwise specified, the chemicals and solvents are reagent-grade chemicals and solvents, which can be purchased from commercial suppliers (usually Aldrich, Fisher, Acros, Carbosynth Limited, and Oakwood Chemical Company) and used directly. In particular, EIDD-1910, EIDD-1993, and EIDD-2003 are purchased from Carbosynth Limited. In all cases, the solvents used for the reactions (tetrahydrofuran, methanol, acetonitrile, dichloromethane, toluene, pyridine, dimethylformamide) are ≥99.9% anhydrous solvents. Unless otherwise specified, all reactions are monitored by thin-layer chromatography until the reaction is complete. Thin-layer chromatography analysis is carried out on silica gel using ultraviolet light (254 nm) illumination or staining with KMnO4 and heating. The RediSep R with a particle size of 40 - 60 μm (pore size: 60 Å) f Silica gel (purchased from Teledyne Isco) is used as the stationary phase for performing manual flash column chromatography. Automated gradient flash column chromatography is carried out on the Teledyne Isco CombiFlash Companion; the pre-packed RediSep R f Silica gel is used as the stationary phase for normal-phase separation, and the pre-packed RediSep R f C 18 Gold high-performance stationary phase is used for reverse-phase separation. DEAE (diethylaminoethyl) Sephadex A-25 is used as the stationary phase, and aqueous TEAB (triethylammonium bicarbonate) is used as the mobile phase for purifying triphosphate by ion-exchange chromatography.

[0731] Measured on a Varian 400 MHz instrument 11H NMR spectra were recorded and processed using MestReNova software version 9.0.1. Chemical shifts were measured relative to the appropriate solvent peaks: CDCl3 (δ 7.27), dimethyl sulfoxide-d6 (δ 2.50), CD3OD (δ 3.31), D2O (δ 4.79). The following abbreviations were used to describe coupling: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, br = broad peak. Measurements were made on a Varian instrument at a frequency of 100 MHz. 13 13C NMR spectra were recorded, and chemical shifts were measured relative to the appropriate solvent peaks: CDCl3 (δ 77.0), dimethyl sulfoxide-d6 (δ 39.5), CD3OD (δ 49.0). Measurements were made on a Varian instrument at a frequency of 376 MHz. 19 19F spectra were recorded on a Varian instrument at a frequency of 162 MHz. 31 31P spectra. Using the absolute reference function of the corresponding 1 1H NMR spectrum in the same solvent, calibration was performed using MestReNova software. 19 19F spectra, 31 31P spectra, and 13 13C spectra (only in D2O) were calibrated for chemical shifts.

[0732] Nominal (low-resolution) liquid chromatography / mass spectrometry was performed using an Agilent 1200 series LC (254 nm UV absorbance detector) and a Zorbax Eclipse XDB C 18 4.6 × 50 mm, 3.5 μm column, with elution using a methanol / water mixture (typically 95 / 5 isocratic) and an Agilent 6120 liquid chromatography / mass spectrometry quadrupole instrument. High-resolution mass spectrometry was performed by the Mass Spectrometry Center at Emory University using a Thermo LTQ-FTMS (using APCI or ESI).

[0733] Example 1: Synthesis of N4-hydroxycytidine or 1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(hydroxyamino)pyrimidin-2-one (EIDD-1931)

[0734] Uridine was protected by complete silylation, and then the 4-position of the nucleobase was activated with a hindered arylsulfonyl group (see Figure 1 ). Displacement of this group with hydroxylamine introduced an N-4-hydroxy group. Global deprotection using any available fluorine source yielded the desired product.

[0735] Heat in an adjustable pH hydroxylamine solution and prepare the compound in one step using cytidine. Although short, this route often gives low yields and requires purification by reverse-phase flash column chromatography, so it is only used for small-scale production.

[0736] Another synthetic route is shown below.

[0737]

[0738] Add uridine (25 g, 102 mmol) and 1 L of dichloromethane to a 2 L three-necked flask equipped with an overhead stirrer and a nitrogen inlet. Cool the resulting solution to 0 °C and sequentially add 4-dimethylaminopyridine (1.251 g, 10.24 mmol) and imidazole (27.9 g, 409 mmol). Add tert-butyldimethylchlorosilane (61.7 g, 409 mmol) over more than 10 minutes, heat the resulting mixture to ambient temperature, and stir for 18 hours. Add water (300 mL) to the reaction mixture, stir at room temperature for 2 hours, separate the layers, and extract the aqueous layer with additional dichloromethane. Wash the combined organic layers with brine (1 × 300 mL), dry over sodium sulfate, then filter and concentrate under reduced pressure to give 75 g of a colorless clear oil. Purify by flash chromatography (ethyl acetate in hexane gradient 5 - 20%) to give a colorless clear oil S1 (45 g, 75%) that solidifies upon drying in vacuo: 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 8.02 (d, J = 8.2Hz, 1H), 5.87 (d, J = 3.6 Hz, 1H), 5.67 (dd, J = 8.1, 2.2 Hz, 1H), 4.07 (q, J= 3.8, 3.3 Hz, 1H), 3.98 (dd, J = 11.7, 1.7 Hz, 1H), 3.75 (dd, J = 11.7, 1.1Hz, 1H), 0.94 (s, 9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.13 (s, 3H), 0.12 (s,3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H).

[0739] Add S1 (28 g, 47.7 mmol) and dichloromethane (700 mL) to a 1 L round-bottom flask. Cool the solution to 0 °C using an ice bath; sequentially add 4-dimethylaminopyridine (0.583 g, 4.77 mmol) and N,N-diisopropylethylamine (41.7 mL, 239 mmol). Slowly add 2,4,6-triisopropylbenzene-1-sulfonyl chloride (28.9 g, 95 mmol) to the flask. After completion, heat the flask to ambient temperature and stir for 18 h. Cool the deep orange solution to 0 °C using an ice bath, add N,N-diisopropylethylamine (24.66 g, 191 mmol) via syringe, then add solid hydroxylamine hydrochloride (13.26 g, 191 mmol) all at once. Heat the mixture to room temperature and stir for 3 h. Quench the reaction mixture with water (200 mL) and separate the resulting layers. Extract the aqueous layer with dichloromethane (200 mL), wash the combined organic layers with brine, dry over sodium sulfate, and concentrate under reduced pressure to afford a deep orange oil. Purify by flash chromatography (15 - 50% ethyl acetate in hexanes gradient) to give oil S2 (19.8 g, 69% (2 steps)), which solidifies to a semi-solid upon drying in vacuo: 1 H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 6.31 (s, 1H), 5.91 (d, J = 4.6 Hz, 1H), 5.56 (dd, J = 8.2, 2.0 Hz, 1H), 4.07 (m, 2H), 4.02 (m, 1H), 3.91 (dd, J = 11.6, 2.4 Hz, 1H), 3.73 (dd, J = 11.6, 2.4 Hz, 1H), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.12 (s, 6H), 0.098 (s, 3H), 0.083 (s, 3H), 0.063 (s, 3H), 0.057 (s, 3H); LRMS m / z 602.3 [M+H] + .

[0740] To a 50 mL round-bottom flask, add S2 (23.3 g, 38.7 mmol) and THF (50 mL). Then, add triethylamine trihydrofluoride (6.30 mL, 38.7 mmol) all at once, and stir the mixture at ambient temperature for 18 h. Concentrate the mixture under reduced pressure, dissolve the residue in the minimum amount of methanol, and slowly add this solution to an Erlenmeyer flask containing rapidly stirred dichloromethane (500 mL) to precipitate the product; stir the mixture at room temperature for 15 min. Collect the pulverized solid by vacuum filtration and wash it successively with dichloromethane and ether. Dry the solid under vacuum to afford the white solid title compound (7.10 g, 71%): 1 H NMR (400 MHz, CD3OD) δ 7.16 (d, J = 8.2 Hz, 1H), 5.86 (d, J =5.6 Hz, 1H), 5.59 (d, J = 8.2 Hz, 1H), 4.19 - 4.04 (m, 2H), 3.93 (q, J = 3.3Hz, 1H), 3.77 (dd, J = 12.2, 2.9 Hz, 1H), 3.68 (dd, J = 12.1, 2.9 Hz, 1H); 1 HNMR (400 MHz, dimethyl sulfoxide-d6) δ 9.95 (s, 1H), 9.46 (s, 1H), 7.02 (d, J = 8.2 Hz,1H), 5.71 (d, J = 6.3 Hz, 1H), 5.54 (d, J = 7.7 Hz, 1H), 5.23 (d, J = 6.0 Hz,1H), 5.02 (d, J = 4.6 Hz, 1H), 4.98 (t, J = 5.1 Hz, 1H), 3.95 (q, J = 5.9 Hz,1H), 3.89 (td, J = 4.9 Hz, 3.0 Hz, 1H), 3.75 (q, J = 3.4 Hz, 1H), 3.50 (qdd,J = 11.9 Hz, 5.2 Hz, 3.5 Hz, 2H); 13 C NMR (101 MHz, dimethyl sulfoxide-d6) δ 150.0,143.9, 130.5, 98.89, 87.1, 85.0, 72.8, 70.8, 61.8. LRMS m / z 260.1 [M+H] + 。

[0741] Example 2: Synthesis of EIDD-2061

[0742]

[0743] Using a stir bar, add cytidine 5'-diphosphate disodium salt (0.137 g, 0.260 mmol) and adjusted (pH = 5) 2 N aqueous hydroxylamine solution (2.0 mL, 4.0 mmol) to a sealable pressure tube. After mixing the reagents, measure the pH of the solution (pH = 3), and additionally add a few drops of 10% w / w aqueous NaOH solution to readjust the solution to pH = 5. Seal the tube and stir and heat at 55 °C for 5 h. Cool the mixture to room temperature, open the sealed tube, and add 100 mM triethylamine bicarbonate solution (TEAB) (2 mL). Transfer the contents of the tube to a round-bottom flask and concentrate by rotary evaporation. Add the crude material to 100 mM TEAB, perform chromatography on DEAE, and then lyophilize the product to give the triethylammonium salt of the desired product.

[0744] Wash the ion exchange column (17 mL CV) packed with freshly prepared Dowex TM (Li + form) with 5 CV of water. Add the prepared triethylammonium salt to water and elute through the ion exchange column. Combine and lyophilize the fractions containing the product to give the fluffy brown solid title compound (0.030 g, 22%): 1 H NMR (400 MHz, D2O) δ 7.19 (d, J = 8.3 Hz,1H), 5.95 (d, J = 6.3 Hz, 1H), 5.82 (d, J = 8.3 Hz, 1H), 4.42-4.34 (m, 2H),4.24-4.10 (m, 3H); 31 P NMR (162 MHz, D2O) δ -8.5 (br s), -11.2 (d, J = 19.6Hz), -22.0 (t, J = 19.3 Hz); LRMS m / z 498.0 [M-H] - .

[0745] Example 3: Synthesis of EIDD-2101

[0746]

[0747] A 2 N aqueous hydroxylamine solution (pH 6) (8 mL, 16.0 mmol) of 5-methylcytidine solution (0.257 g, 1.00 mmol) was stirred and heated to 55 °C in a sealed tube for 5 h. The solution was cooled to room temperature, transferred to a round-bottom flask, concentrated by rotary evaporation, and co-evaporated with methanol (2 × 20 mL). The crude residue was added to methanol and fixed on silica gel. By flash chromatography (methanol gradient in dichloromethane 2-10%), the light purple solid title compound (140 mg, 51%) was produced: 1 H NMR (400 MHz, CD3OD) δ 6.99 (s, 1H), 5.86 (d, J = 5.7 Hz, 1H), 4.23 - 4.06 (m, 2H), 3.93 (q, J = 3.2 Hz, 1H), 3.78 (dd, J = 12.1 Hz, 2.8 Hz, 1H), 3.70 (dd, J = 12.1 Hz, 3.4 Hz, 1H), 1.79 (s, 3H); 13 C NMR (100 MHz, CD3OD) δ 152.0, 146.6, 128.4, 108.4, 89.4, 86.1, 74.4, 71.8, 62.8, 12.9; HRMS calculated for C 10 H 16 O6N3 [M+H] + ): 274.10336, found: 274.10350.

[0748] Example 4: Synthesis of EIDD-2103

[0749]

[0750] A solution of 2 N hydrochloric hydroxylamine (1.11 g, 16.0 mmol) in water (8 mL) was prepared and adjusted to pH = 5 using a small amount of aqueous NaOH (10% w / w). This solution and 5-fluorocytidine (0.261 g, 1.00 mmol) were added to a sealable pressure tube, the flask was sealed, and stirred and heated at 55 °C for 16 h. The mixture was cooled to room temperature, transferred to a round-bottom flask, and concentrated by rotary evaporation. The crude was suspended in methanol and fixed on Celite ®On diatomaceous earth. By automated flash chromatography (40 g column, methanol gradient in dichloromethane 0 - 20%), 600 mg of semi-pure pink solid was produced. This solid was dissolved in 2 mL of water and by automated reverse-phase chromatography (43 g column, methanol gradient in water 5 - 100%), the desired product free of organic and inorganic impurities was produced. This solid was dissolved in water, frozen in a dry ice / acetone bath, and lyophilized to produce the white flocculent solid of the title compound (0.066 g, 0.238 mmol, 24% yield). 1 H NMR (400MHz, D2O) δ 7.31 (d, J = 7.6 Hz, 1H), 5.87 (dd, J = 5.5 Hz, 1.8 Hz, 1H), 4.26(t, J = 5.5 Hz, 1H), 4.19 (t, J = 4.8 Hz, 1H), 4.07 (q, J = 3.8 Hz, 1H), 3.85(dd, J = 12.8 Hz, 3.1 Hz, 1H), 3.77 (dd, J = 12.7 Hz, 4.2 Hz, 1H); 13 C NMR(100 MHz, D2O) δ 150.0, 139.7, 137.4, 115.6 (d, J = 36.1 Hz), 88.0, 84.2,72.8, 69.8, 61.0; 19 F NMR (376 MHz, D2O) δ -164.70 (d, J = 7.6 Hz); HRMS calculated for C9H 13 FN3O6 [M+H] + ):278.07829, found: 278.07848.

[0751] Example 5: Synthesis of EIDD-2216

[0752]

[0753] Prepare a solution of hydroxylamine hydrochloride 5 N in water (13.5 mL) in water (4.71 g, 67.8 mmol) and adjust it to pH = 6 using a small amount of aqueous NaOH (10% w / w). Add this solution and [1’,2’,3’,4’,5’- 13Cytidine (0.661 g, 2.26 mmol) was sealed in a flask and stirred and heated at 37 °C for 16 h. The mixture was cooled to room temperature (rt), transferred to a round-bottom flask, and concentrated by rotary evaporation. The crude material was added to water and most of the impurities were removed by automated reverse-phase flash chromatography (240 g C 18 column, acetonitrile gradient in water 0 - 100%) to yield 1.4 g of a wet solid. This solid was dissolved in water and more impurities were removed by a second automated reverse-phase chromatography (240 g C 18 column, acetonitrile gradient in water 0 - 100%) to yield 400 mg of a semi-pure material. The crude material was suspended in methanol and fixed on Celite TM diatomaceous earth. By automated flash chromatography (24 g column, methanol gradient in dichloromethane 5 - 25%), 200 mg of a nearly pure product was obtained. This solid was dissolved in water and the desired product free of organic and inorganic impurities was obtained by a final automated reverse-phase chromatography (48 g C 18 column, acetonitrile gradient in water 0 - 100%). This solid was dissolved in water, frozen in a dry ice / acetone bath, and lyophilized to yield the title compound as a pale purple flocculent solid (0.119 g, 20% yield), which was determined by NMR / LCMS analysis to be approximately 95% pure: 1 H NMR (400 MHz, D2O) δ 7.03 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 5.82 (ddd, J = 167.5 Hz, 5.3 Hz, 2.9 Hz, 1H), 5.70 (d, J = 8.2 Hz, 1H), 4.47 - 4.30 (br m, 1H), 4.23 - 4.03 (br m, 1H), 4.00 - 3.80 (br m, 2H), 3.65 - 3.50 (br m, 1H); 13 C NMR (100 MHz, D2O) δ 151.3, 146.6, 131.3, 98.7, 87.9 (dd, J = 43.1 Hz, 4.0 Hz), 84.0 (dd, J = 41.5 Hz, 38.0 Hz), 72.5 (dd, J = 43.3 Hz, 37.8 Hz), 69.8 (td, J = 37.9 Hz, 3.9 Hz), 61.1 (d, J = 41.5 Hz); LRMS m / z 265.1 [M+H] + .

[0754] Example 6: Synthesis of EIDD - 2261

[0755]

[0756] Uridine (1.00 g, 4.09 mmol), K2CO3 (0.679 g, 4.91 mmol), and deuterium oxide (8.2 mL) were added to a sealable pressure tube. The mixture was purged with nitrogen for 15 minutes, the tube was sealed, and the contents were stirred and heated at 95 °C for 16 h. The mixture was cooled to room temperature, the tube was opened, the mixture was transferred to a round-bottom flask, and concentrated by rotary evaporation. The resulting crude material was co-evaporated with methanol (×3) to remove water. NMR analysis indicated that the deuterium incorporated at the 5-position of the nucleobase was >95%. The light brown solid S28 (1.00 g, 100%) was used in the next step without further purification: 1 H NMR(400 MHz, CD3OD) δ 7.76 (s, 1H), 5.88 (d, J = 4.2 Hz, 1H), 4.17-4.12 (m, 2H),4.00-3.96 (m, 1H), 3.84 (dd, J = 12.3 Hz, 2.8 Hz, 1H), 3.72 (dd, J = 12.3 Hz,3.5 Hz, 1H); 13 C NMR (100 MHz, CD3OD) δ 185.6, 177.4, 160.4, 141.1, 91.8,85.8, 75.9, 71.2, 62.4。

[0757] Under a nitrogen atmosphere, S28 (1.00 g, 4.09 mmol) and dichloromethane (8 mL) were added to a round-bottom flask. The resulting mixture was cooled to 0 °C, and 4-dimethylaminopyridine (0.050 g, 0.408 mmol) and imidazole (1.11 g, 16.3 mmol) were added all at once. Solid tert-butyldimethylchlorosilane (2.15 g, 14.3 mmol) was added all at once, the mixture was warmed to ambient temperature, and stirred for 16 h. Water (25 mL) was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 25 mL). The combined organic layers were washed with brine (1 × 25 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation. Automated flash chromatography (40 g column, hexane–ethyl acetate gradient 0–35%) gave an off-white foam S29 (2.52 g, 84%): 11H NMR (400 MHz, CDCl3) δ 8.08(br s, 1H), 8.03 (s, 1H), 5.89 (d, J = 3.6 Hz, 1H), 4.12-4.06 (m, 3H), 3.99(dd, J = 11.5 Hz, 1.8 Hz, 1H), 3.76 (d, J = 12.0 Hz, 1H), 0.96 (s, 9H), 0.92(s, 9H), 0.90 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H), 0.10 (s, 3H), 0.09 (s,3H), 0.08 (s, 3H), 0.07 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 163.7, 150.3,140.3, 89.0, 84.3, 76.1, 70.5, 61.6, 26.0 (3C), 25.8 (3C), 25.7 (3C), 18.4,18.3, 17.9, -4.2, -4.6, -4.8, -4.9, -5.4, -5.6; HRMS calculated for C 27 H 54 DN2NaO6Si [M+Na] + ):610.32446, found: 610.32482.

[0758] At 0 °C under a nitrogen atmosphere, p-toluenesulfonyl chloride (0.545 g, 2.86 mmol), 4-dimethylaminopyridine (0.175 g, 1.43 mmol), and triethylamine (0.80 mL, 5.71 mmol) were successively added to a stirred solution of S29 (0.840 g, 1.43 mmol) in acetonitrile (14.3 mL). The mixture was stirred at 0 °C for 2.5 h, during which time solid hydroxylamine hydrochloride (0.993 g, 14.3 mmol) was added in one portion. The mixture was heated at 50 °C for 3 days and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and then washed with water (2 × 100 mL) and brine (1 × 100 mL) and concentrated by rotary evaporation. A mixture of starting material and the desired product was produced by automated flash chromatography (40 g column, hexanes / ethyl acetate gradient 5 - 35%). The off-white foam S30 (0.332 g, 39%) was produced by a second automated flash chromatography (24 g column, hexanes / ethyl acetate gradient 10 - 40%): 11H NMR (400 MHz, CDCl3) δ 8.37(br s, 1H), 5.92 (d, J = 4.6 Hz, 1H), 4.10-4.05 (m, 2H), 4.04-4.00 (m, 1H), 3.91 (dd, J = 11.6 Hz, 2.4 Hz, 1H), 3.73 (dd, J = 11.6 Hz, 1.8 Hz, 1H), 0.95(s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.12 (s, 6H), 0.10 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H).

[0759] At 0 °C under a nitrogen atmosphere, S30 (0.332 g, 0.551 mmol), tetrabutylammonium fluoride (0.196 g, 2.64 mmol), tetrahydrofuran (THF) (8.25 mL), and dimethylformamide (DMF) (2.75 mL) were added to a round-bottom flask. Acetic acid (0.157 mL, 2.75 mmol) was added all at once via syringe. The mixture was heated to 45 °C and stirred and heated for 4 days, then concentrated by rotary evaporation. Automated flash chromatography (40 g column, methanol gradient in dichloromethane 0 - 20%) gave the white solid title compound (0.106 g, 74%). Final NMR analysis showed that the deuterium incorporated at the 5-position of the nucleobase was >95%. 1 1H NMR (400 MHz, D2O) δ 7.16 (s, 1H), 5.85 (d, J = 5.6 Hz, 1H), 4.14 (t, J = 5.5 Hz, 1H), 4.10 (dd, J = 5.6 Hz, 3.8 Hz, 1H), 3.93 (q, J = 3.4 Hz, 1H), 3.77 (dd, J = 12.2 Hz, 2.9 Hz, 1H), 3.68 (dd, J = 12.2 Hz, 3.4 Hz, 1H); 13 13C NMR (100 MHz, CD3OD) δ 151.8, 146.3, 132.1, 89.7, 86.1, 74.6, 71.8, 62.8; HRMS calculated for C9H13DN3O6 [M+H]+: 261.09399, found: 261.09371.

[0760] Example 7: Synthesis of EIDD-2345

[0761]

[0762] Under room temperature and nitrogen atmosphere, S8 (3.13 g, 11.0 mmol) and dichloromethane (75 mL) were added to a round-bottom flask. At room temperature, pyridinium dichromate (8.28 g, 22.0 mmol), acetic anhydride (10.4 mL, 110 mmol) and tert-butanol (21.1 mL, 220 mmol) were successively added to this stirred mixture. The mixture was stirred at room temperature for 22 h, and then washed with water (1 × 75 mL). The aqueous layer was extracted with dichloromethane (2 × 75 mL), the combined organic layers were washed with brine (1 × 100 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue obtained was added to ethyl acetate, filtered through a CELITE™ diatomaceous earth plug, and then washed with ethyl acetate. The filtrate was concentrated by rotary evaporation and purified by automated flash chromatography (120 g column, hexane-ethyl acetate gradient 40 - 80%) to give an off-white foam S31 (3.10 g, 72%): 1 1H NMR (400 MHz, CDCl3) δ 8.36 (br s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 5.76 (dd, J = 8.0 Hz, 2.3 Hz, 1H), 5.59 (s, 1H), 5.27 (dd, J = 6.0 Hz, 1.8 Hz, 1H), 5.19 (d, J = 6.0 Hz, 1H), 4.62 (d, J = 1.8 Hz, 1H), 1.56 (s, 3H), 1.48 (s, 9H), 1.39 (s, 3H).

[0763] Under room temperature and nitrogen atmosphere, a portion of NaBD4 (1.234 g, 29.5 mmol) was added to a stirred solution of S31 (2.61 g, 7.37 mmol) in deuterated ethanol (75 mL). The mixture was stirred at room temperature for 1 h, heated to 55 °C for 6 h, and then left overnight at room temperature. The mixture was cooled to 0 °C and the excess reagent was quenched with deuterated acetic acid. The mixture was concentrated by rotary evaporation to give crude S32 (2.57 g), which was used directly in the next step without further purification.

[0764] At 0 °C, solid imidazole (1.90 g, 27.9 mmol) and 4-dimethylaminopyridine (0.171 g, 1.40 mmol) were added to a stirred suspension of crude S32 (2.00 g of impure material, 5.74 mmol) in dichloromethane (70 mL). Solid tert-butyldimethylchlorosilane (2.11 g, 14.0 mmol) was added, and the mixture was heated to room temperature and stirred for 4 days. The mixture was washed successively with water and brine (each 1 × 70 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation. Automated flash chromatography (120 g column, hexane–ethyl acetate gradient 0–35%) gave white solid S33 (1.42 g, 66%, 2 steps): 1 1H NMR (400 MHz, CDCl3) δ 8.30 (br s, 1H), 7.72 (m, 1H), 5.99 (d, J = 2.8 Hz, 1H), 5.69 (dd, J = 8.2 Hz, 2.3 Hz, 1H), 4.77 (dd, J = 6.1 Hz, 2.9 Hz, 1H), 4.69 (dd, J = 6.2 Hz, 2.8 Hz, 1H), 4.33 (d, J = 3.0 Hz, 1H), 1.60 (s, 3H), 1.37 (s, 3H), 0.91 (s, 9H), 0.11 (s, 3), 0.10 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 162.7, 149.9, 140.5, 114.1, 102.1, 91.9, 86.5, 85.4, 80.3, 27.4, 25.9 (3C), 25.4, 18.4, -5.4, -5.5; HRMS calcd for C18H29D2N2O6Si [M+H]+: 401.20714, found: 401.20663.

[0765] Under nitrogen atmosphere at 0 °C, tosyl chloride (1.35 g, 7.09 mmol), 4-dimethylaminopyridine (0.433 g, 3.55 mmol) and triethylamine (9.88 mL, 70.9 mmol) were successively added to a stirred solution of S33 (1.42 g, 3.55 mmol) in acetonitrile (35 mL). The resulting mixture was stirred at 0 °C for 2.5 h. Hydroxylamine hydrochloride (2.46 g, 35.5 mmol) was added and the mixture was heated at 50 °C for 2 days. The mixture was cooled back to room temperature, diluted with ethyl acetate (100 mL), washed with water (2 × 50 mL) and brine (1 × 50 mL), and concentrated by rotary evaporation. Automated flash chromatography (120 g column, CH2Cl2 / MeOH gradient 1 - 3.5%) gave off-white solid S34 (0.416 g, 28%). 1 H NMR (400 MHz, CDCl3) δ 8.36 (br s, 1H), 7.00 (m, 1H), 5.97 (d, J = 3.1 Hz, 1H), 5.58 (d, J = 8.2 Hz, 1H), 4.77 (dd, J = 6.2 Hz, 3.2 Hz, 1H), 4.68 (dd, J = 6.3 Hz, 3.2 Hz, 1H), 4.22 (d, J = 3.2 Hz, 1H), 1.59 (s, 3H), 1.36 (s, 3H), 0.92 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 149.0, 145.4, 131.4, 114.1, 98.3, 90.8, 85.5, 84.5, 80.2, 27.4, 25.9(3C), 25.5, 18.4, -5.4, -5.5; HRMS calcd for C 18 H 29 D2N3O6Si [M+H] + ) : 416.21804, found: 416.21827.

[0766] Under a nitrogen atmosphere, a 1.0 M THF solution containing TBAF (1.50 mL, 1.5 mmol) was added to a stirred solution of S34 (0.416 g, 1.00 mmol) in THF (5 mL), and the resulting mixture was kept at 0 °C for 24 h. The reaction mixture was concentrated by rotary evaporation and purified by automated flash chromatography (40 g column, methanol gradient in dichloromethane 0 - 8%) to give white solid S35 (0.257 g, 85%): 1 H NMR (400 MHz, CD3OD) δ 7.02 (m, 1H), 5.81 (d, J = 3.2 Hz, 1H), 5.58 (d, J = 8.2 Hz, 1H), 4.86 (dd, J = 6.4 Hz, 3.2 Hz, 1H),4.79 (dd, J = 6.5 Hz, 3.6 Hz, 1H), 4.09 (d, J = 3.7 Hz, 1H), 1.54 (s, 3H),1.34 (s, 3H); 13 C NMR (100 MHz, CD3OD) δ 151.3, 146.2, 133.4, 115.2, 99.4,92.9, 87.2, 84.9, 82.1, 27.6, 25.6; HRMS calculated for C 12 H 16 D2N3O6 [M+H] + ) : 302.13157, found: 302.13130.

[0767] At room temperature, Dowex 50WX8 hydrogen form exchange resin (0.30 g) was added to a stirred solution of S35 (0.140 g, 0.465 mmol) in methanol (8.4 mL) and water (0.93 mL), and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered and the filtrate was concentrated by rotary evaporation. Purification by automated flash chromatography (40 g column, methanol gradient in dichloromethane 5 - 20%) gave the off-white solid title compound (0.050 g, 41%): 1 H NMR (400 MHz, CD3OD) δ 7.17(m, 1H), 5.86 (d, J = 5.6 Hz, 1H), 5.60 (d, J = 8.2 Hz, 1H), 4.15 (t, J = 5.5Hz, 1H), 4.11 (dd, J = 5.6 Hz, 3.5 Hz, 1H), 3.94 (d, J = 3.8 Hz, 1H); 1313C NMR (100 MHz, CD3OD) δ 151.8, 146.3, 132.2, 99.3, 89.7, 86.0, 74.6, 71.7, HRMS calculated for C9H 10 D2N3O6 [M+H] + ): 260.08571, found: 260.08578.

[0768] Example 8: Synthesis of EIDD-2898

[0769]

[0770] To a 2 L three-necked round-bottom flask was added 1-[(3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidine-2,4-dione (61.4 g, 251.43 mmol) and acetone (1400 mL). T...

Claims

1. A unit dosage form comprising: A compound represented by the following chemical formula, or its tautomer, its pharmaceutically acceptable salt or physiologically acceptable salt, A lubricant selected from magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, polyethylene glycol, talc, and mineral oil; A disintegrant, binder and / or coating selected from starch, gelatin, sugar, polyethylene glycol, wax, gum arabic, tragacanth, sodium alginate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, clay, cellulose, algin, gum, kaolin, and cross-linked PVP; and A diluent selected from dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silica, titanium oxide, powdered cellulose, crystalline cellulose, and magnesium aluminum silicate; wherein the amount of the compound present is 200 mg; wherein the unit dosage form is in a form selected from tablets, capsules, powders, and suspensions.

2. The unit dosage form according to claim 1, wherein The unit dosage form is formulated for oral administration.

3. The unit dosage form according to claim 1, wherein, The lubricant is magnesium stearate.

4. The unit dosage form according to claim 1, wherein, The diluent is microcrystalline cellulose.

5. The unit dosage form according to claim 1, wherein, The binder is hydroxypropyl cellulose.

6. The unit dosage form according to claim 1, wherein, The unit dosage form is packaged as a capsule.

7. Use of a compound in the preparation of a medicament for the treatment of COVID-19, wherein the compound has the following chemical formula: wherein the dosage of the compound is 800 mg each time, twice a day.

8. The use according to claim 7, wherein the medicament comprises 200 mg of the compound.

9. The use according to claim 7, wherein the medicament comprises: A lubricant selected from magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, polyethylene glycol, talc, and mineral oil; A disintegrant, binder and / or coating selected from starch, gelatin, sugar, polyethylene glycol, wax, gum arabic, tragacanth, sodium alginate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, clay, cellulose, algin, gum, kaolin, and cross-linked PVP; and A diluent selected from dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silica, titanium oxide, powdered cellulose, crystalline cellulose, and magnesium aluminum silicate.

10. The use according to claim 9, wherein the lubricant is magnesium stearate.

11. The use according to claim 9, wherein the diluent is microcrystalline cellulose.

12. The use according to claim 9, wherein the binder is hydroxypropyl cellulose.

13. The use according to claim 7, wherein the medicament is a capsule.

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