N4-hydroxycytidine and derivatives and Anti-viral uses related thereto

Abstract

To provide certain N4-hydroxycytidine derivatives, pharmaceutical compositions, and methods related thereto.SOLUTION: In certain embodiments, the present disclosure relates to the treatment or prophylaxis of human coronavirus 2019-nCoV. In certain embodiments, the present disclosure contemplates derivatives of the compounds disclosed herein, such as compounds containing one or more identical or different substituents. In certain embodiments, the present disclosure contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Confirmation of government support This invention was made with government support under Grant Nos. HDTRA1-13-C-0072 and HDTRA1-15-C-0075 awarded by the Department of Defense and Grant Nos. HHSN272201500008C and 75N93019C00058 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 971,559, filed February 7, 2020, U.S. Provisional Patent Application No. 62 / 988,133, filed March 11, 2020, U.S. Provisional Patent Application No. 62 / 994,604, filed March 25, 2020, and U.S. Provisional Patent Application No. 63 / 006,625, filed April 7, 2020, each of which is incorporated by reference herein in its entirety.

[0003] The present disclosure relates to N4-hydroxycytidine nucleosides and derivatives, and compositions and methods related thereto. In certain embodiments, the disclosure relates to the treatment or prevention of viral infections, specifically 2019-nCoV. [Background technology]

[0004] Coronaviruses are enveloped, positive-strand RNA viruses that cause a significant number of respiratory illnesses in humans. The two previous coronaviruses to emerge and cause human disease were SARS and MERS. SARS has been associated with over 8,000 human cases and 774 deaths. Since 2012, MERS has been associated with over 2,500 human cases and 919 deaths. In 2019, 2019-nCoV, a novel coronavirus now known as SARS-CoV-2, was discovered in humans in Wuhan, China. Reports in early February 2020 indicated that the novel coronavirus has infected over 28,000 people, with over 560 documented deaths. Additionally, human-to-human transmission of 2019-nCoV has been documented. Analysis of the single completed whole-genome sequence revealed that 2019-nCoV belongs to the betacoronavirus family but is divergent from SARS and MERS. 2019-nCoV is a highly pathogenic human pathogen about which relatively little is known. SARS-CoV-2 / 2019-nCoV causes the disease known as COVID-19. COVID-19 can include severe respiratory illness in humans and also appears to cause neurological disorders, including dizziness, impaired consciousness, acute cerebrovascular disease, epilepsy, hyposmia, hypovisual impairment, and neuralgia (medRxiv, 2020, 1-26). SARS-CoV-2 entry into the CNS may be facilitated through viral interaction with the ACE2 receptor in the systemic circulation or after viral spread across the cribriform plate. Further research is needed to further characterize the virus and identify ways to prevent and treat the disease.

[0005] Stuyver et al. reported that β-DN(4)-hydroxycytidine (NHC) was found to have antipestivirus and antihepasibiotic activity. Antimicrob Agents Chemother, 2003, 47(1):244-54. Constantini et al. reported an evaluation of the effectiveness of 2'-C-MeC, 2'-F-2'-C-MeC, and NHC against Norwalk virus. See also Purohit et al., J Med Chem, 2012, 55(22):9988-9997; Ivanov et al., Collection of Czechoslovak Chem Commun, 2006, 71(7):1099-1106; and Fox et al., JACS, 1959, 81:178-87. There is a need for novel compounds and treatments for viral infections. The compounds and methods disclosed herein address these needs. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Stuyver et al., Antimicrob Agents Chemother, 2003, 47(1):244-54 [Non-patent document 2] Purohit et al.,J Med Chem,2012,55(22):9988-9997 [Non-patent document 3] Ivanov et al.,Collection of Czechoslovak Chem Commun,2006,71(7):1099-1106 [Non-patent document 4] Fox et al., JACS, 1959, 81:178-87 Summary of the Invention

[0007] The present disclosure relates to certain N4-hydroxycytidine and derivatives, combinations, pharmaceutical compositions, and methods related thereto. In certain embodiments, the present disclosure relates to compounds having formula I, as defined herein: [ka] or a pharmaceutically acceptable salt, derivative, or prodrug thereof.

[0008] In certain embodiments, the present disclosure contemplates derivatives of the compounds disclosed herein, such as compounds containing one or more of the same or different substituents.

[0009] In certain embodiments, the present disclosure contemplates a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound disclosed herein, hi certain embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, or aqueous buffer, such as saline or phosphate buffer.

[0010] In certain embodiments, the disclosed pharmaceutical compositions can include the compounds disclosed herein and a propellant. In certain embodiments, the propellant is a vaporized 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.

[0011] In certain embodiments, the present disclosure contemplates a pressurized or non-pressurized container containing a compound or pharmaceutical composition as described herein. In certain embodiments, the container is a manual pump spray, an inhaler, a metered dose inhaler, a dry powder inhaler, a nebulizer, a vibrating mesh nebulizer, a jet nebulizer, or an ultrasonic nebulizer.

[0012] In certain embodiments, the present disclosure relates to a method of increasing bioavailability for treating or preventing a viral infection, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0013] In certain embodiments, the viral infection is a human coronavirus, SARS, MERS, or 2019-nCoV infection.

[0014] In certain embodiments, the compound or pharmaceutical composition is administered orally, intravenously, or through the lung, ie, intrapulmonary administration.

[0015] In certain embodiments, the present disclosure relates to the use of the compounds described herein in the production of a medicament for treating or preventing a viral infection, such as a 2019-nCoV viral infection.

[0016] In certain embodiments, the present disclosure relates to methods of making the compounds disclosed herein by combining the starting materials and reagents disclosed herein under conditions such that the compounds are formed. The compounds made by the disclosed methods can be used to treat or prevent COVID-19 caused by 2019-nCoV / SARS-CoV-2 as disclosed herein.

[0017] Additional advantages will be set forth in part in the specification which follows, and in part will be obvious from the specification, or may be learned by practice of the embodiments described hereinafter. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive. [Brief explanation of the drawings]

[0018] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. [Figure 1] 1 is a scheme illustrating the preparation of β-DN-hydroxycytidine. The synthetic steps are: a.) tert-butyldimethylsilyl chloride, 4-dimethylaminopyridine, diisopropylethylamine, dichloromethane; b.) (2,4,6-iPr)PhSOCl, diisopropylethylamine, 4-dimethylaminopyridine, dichloromethane; c.) NHOH-HCl, diisopropylethylamine, dichloromethane; d.) F source; and e.) aqueous NHOH, AcOH, 50°C. [Figure 2] Certain exemplary compounds are illustrated. [Figure 3] Certain exemplary compounds are illustrated. [Figure 4] 1 shows mean plasma concentrations and pharmacokinetic parameters from mice treated with exemplary compounds. [Figure 5] 1 shows nucleoside accumulation in mouse organs in mice treated with exemplary compounds. [Figure 6] 1 shows triphosphate accumulation in mouse organs in mice treated with exemplary compounds. [Figure 7] 1 shows N4-hydroxycytidine nucleoside tissue concentrations from cynomolgus monkeys orally administered EIDD-1931 (100 mg / kg). [Figure 8] 1 shows N4-hydroxycytidine nucleoside tissue concentrations from cynomolgus monkeys administered EIDD-1931 (10 mg / kg) intravenously. [Figure 9] The structures of compounds orally administered to cynomolgus monkeys are shown. [Figure 10] 1 shows mean N4-hydroxycytidine nucleoside plasma concentrations from cynomolgus monkeys orally administered with ester derivatives. [Figure 11] 1 shows the mean maximum concentrations of N4-hydroxycytidine nucleosides in plasma from cynomolgus monkeys orally administered with ester derivatives. [Figure 12]1 shows the effect of EIDD-2801 prophylactic treatment on lung virus titers in SARS-infected mice. [Figure 13] 1 shows the effect of EIDD-2801 treatment time on pulmonary hemorrhage scores in SARS-infected mice. [Figure 14] 1 shows the effect of EIDD-2801 treatment time on lung viral titers in SARS-infected mice. [Figure 15] 1 shows the effect of EIDD-2801 treatment on pulmonary hemorrhage scores in MERS-infected mice. [Figure 16] Arithmetic mean plasma concentrations of EIDD-1931 (single ascending doses of EIDD-2801 from 50 to 1600 mg) are shown. [Figure 17-1] Arithmetic mean plasma concentrations of EIDD-1931 (multiple ascending doses of 50 to 800 mg EIDD-2801 twice daily) on Day 1 (top) and Day 6 (bottom) are shown. [Figure 17-2] Arithmetic mean plasma concentrations of EIDD-1931 (multiple ascending doses of 50 to 800 mg EIDD-2801 twice daily) on Day 1 (top) and Day 6 (bottom) are shown. [Figure 18] Arithmetic mean plasma concentrations of EIDD-1931 (food effect) are shown. DETAILED DESCRIPTION OF THE INVENTION

[0019] Before describing the present disclosure in more detail, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure, which will be limited by the appended claims.

[0020] 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 disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, the preferred methods and materials are now described.

[0021] All publications and patents cited herein are incorporated by reference to disclose and describe the methods and / or materials for which the publications are cited, as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0022] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated from or combined with any of the other several embodiments without departing from the scope or spirit of the disclosure. Any recited method may be carried out in the order of events recited or in any other order which is logically possible.

[0023] Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art, and such techniques are fully explained in the literature.

[0024] In certain embodiments, the agent may be in the form of a salt or prodrug, and is administered in the methods disclosed herein by weight. This refers to the weight of the listed compound. If in the form of a salt or prodrug, the weight is the molar equivalent of the corresponding salt or prodrug.

[0025] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0026] "Subject" refers to any animal, preferably a human patient, livestock, or household pet.

[0027] As used herein, the terms "prevent" and "preventing" include prevention of recurrence, spread, or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, onset is delayed or the severity of the disease is reduced.

[0028] As used herein, the terms "treat" and "treating" are not limited to cases where a subject (e.g., a patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure also contemplate treatment that merely alleviates symptoms and / or slows the progression of the disease.

[0029] As used herein, the term "in combination with," when used to describe administration with an additional therapy, means that the agent may be administered before, together with, or after the additional therapy, or a combination thereof.

[0030] As used herein, "alkyl" means a straight- or branched-chain saturated hydrocarbon moiety, such as one containing 1 to 10 carbon atoms. "Higher alkyl" refers to a saturated hydrocarbon having 11 or more carbon atoms. "C6-C 16 " refers to an alkyl containing 6 to 16 carbon atoms. Similarly, "C6-C 22" refers to an alkyl containing 6 to 22 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like, while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.

[0031] As used herein, the term "alkenyl" refers to an unsaturated, straight-chain, or branched hydrocarbon moiety containing a double bond. Unless otherwise specified, C-C 24 (For example, 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 groups are contemplated. Alkenyl groups can contain more than one unsaturated bond.Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 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 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 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl.The term "vinyl" refers to a group having the structure -CH=CH2, 1-propenyl refers to a group having the structure -CH=CH-CH3, and 2-propenyl refers to a group having the structure -CH2-CH=CH2. (Z. 1 Z 2 )C=C(Z 3 Z 4 ) are intended to include both the E and Z isomers. This may be assumed in the structural formulae herein, where an asymmetric alkene is present, or may be indicated explicitly by the bond symbol C=C.

[0032] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon moiety containing a triple bond. Unless otherwise specified, C2-C 24 (For example, 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 groups are contemplated. The alkynyl group may contain more than one unsaturated bond. Examples include 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- C2-C6 alkynyls such as 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.

[0033] Non-aromatic monocyclic or polycyclic alkyls are referred to herein as "carbocycle" or "carbocyclyl" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.

[0034] A "heterocarbocycle" or "heterocarbocyclyl" group is a carbon ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0035] The term "aryl" preferably refers to an aromatic homocyclic (i.e., hydrocarbon) monocyclic, bicyclic, or tricyclic ring-containing group having 6 to 12 members, such as phenyl, naphthyl, and biphenyl. Phenyl is a preferred aryl group. The term "substituted aryl" preferably refers to an aryl group substituted with one or more groups selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocyclo (optionally substituted), halo, 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, amide, lactam, urea, urethane, sulfonyl, and the like, optionally wherein one or more pairs of substituents, together with the atoms to which they are attached, form a 3- to 7-membered ring.

[0036] As used herein, "heteroaryl" or "heteroaromatic" refers to an aromatic heterocarbocycle having one to four heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least one carbon atom, including both monocyclic and polycyclic ring systems. Polycyclic ring systems can, but need not, contain one or more non-aromatic rings, so long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. Use of the term "heteroaryl" is intended to include N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent.

[0037] As used herein, "heterocycle" or "heterocyclyl" refers to monocyclic and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least one carbon atom. The monocyclic and polycyclic ring systems can be aromatic, non-aromatic, or mixtures of aromatic and non-aromatic rings. Heterocycles include heterocarbocycles, heteroaryls, and the like.

[0038] "Alkylthio" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge. An example of an alkylthio is methylthio (i.e., -S-CH).

[0039] "Alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, and t-butoxy.

[0040] "Alkylamino" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an amino bridge. An example of an alkylamino is methylamino (i.e., -NH-CH3).

[0041] "Alkanoyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a carbonyl bridge (ie, --(C.dbd.O)alkyl).

[0042] "Alkylsulfonyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfonyl bridge, such as mesyl (i.e., -S(=O)2 alkyl), and "arylsulfonyl" refers to an aryl attached through a sulfonyl bridge (i.e., -S(=O)2 aryl).

[0043] "Alkylsulfamoyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfamoyl bridge (i.e., -NHS(=O)2 alkyl), and "arylsulfamoyl" refers to an aryl attached through a sulfamoyl bridge (i.e., -NHS(=O)2 aryl).

[0044] "Alkylsulfinyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfinyl bridge (ie, --S(.dbd.O)alkyl).

[0045] The terms "cycloalkyl" and "cycloalkenyl" refer to monocyclic, bicyclic, or tricyclic ring groups of 3 to 15 carbon atoms that are fully saturated and partially unsaturated, respectively. The term "cycloalkenyl" includes bicyclic and tricyclic ring systems that are not aromatic as a whole but contain aromatic moieties (e.g., fluorene, tetrahydronapthalene, dihydroindene, etc.). The rings of polycyclic cycloalkyl groups can be fused, bridged, and / or joined through one or more spiro bonds. The terms "substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups, respectively, substituted with one or more groups preferably selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), alkanoyl (optionally substituted), ariol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl, and the like.

[0046] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine.

[0047] The term "substituted" refers to a molecule in which at least one hydrogen atom has been replaced with a substituent. When substituted, one or more of the groups is a "substituent." A molecule can be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Exemplary substituents in this context include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NR a R b , -NR a C(=O)R b , -NR a C(=O)NR a NRb , -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 context, R a and R b may be the same or different and independently be hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0048] As used herein, the term "optionally substituted" means that substitution with an additional group is optional, and thus the specified atom may not be substituted. Thus, in using the term "optionally substituted," the present disclosure includes examples in which the group is substituted and examples in which it is not substituted.

[0049] Examples of prodrugs that can be used to improve 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate esters, optionally substituted 2-hydroxypropanoate esters, S-thiocarbonates, optionally substituted S-thiocarbonates, dithiocarbonates, optionally substituted dithiocarbonates, Thiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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, sulfenyl, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, imidate, optionally substituted imidate, hydrazonate, optionally substituted hydrazonate, oximyl, optionally substituted oximyl, imidinyl, optionally substituted imidinyl, imidyl, optionally substituted imidyl, aminal, optionally substituted aminal, hemiaminal, optionally substituted hemiaminal, acetal, optionally substituted acetal, hemiacetal, optionally substituted hemiacetal, carbonimidate, optionally substituted carbonimidate, thiocarbonimidate, Examples of the acyloxybenzyl ester include optionally substituted thiocarbonimidates, carbonimidyls, optionally substituted carbonimidyls, carbamimidates, optionally substituted carbamimidates, carbamimidyls, optionally substituted carbamimidyls, 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, and BAB esters.

[0050] As used herein, the term "subject" (alternatively, "patient" or "participant," such as a clinical trial participant) refers to a mammal that has been the object of treatment, observation, or experimentation. The mammal may be male or female. The mammal may be one or more selected from the group consisting of a human, bovine (e.g., cow), porcine (e.g., pig), ovine (e.g., sheep), capra (e.g., goat), equine (e.g., horse), canine (e.g., domestic dog), feline (e.g., house cat), Lagomorpha (rabbit), rodent (e.g., rat or mouse), or Procyon lotor (e.g., raccoon). In certain embodiments, the subject is a human.

[0051] As used herein, the term "subject in need thereof" (alternatively, "patient in need thereof") refers to a subject diagnosed with or suspected of having a viral infection, such as infection with SARS-CoV-2 (either symptomatic or asymptomatic), a subject at risk of exposure to a viral infection, such as at risk of exposure to a viral infection, such as infection with SARS-CoV-2 (e.g., healthcare workers who may be at risk of exposure to SARS-CoV-2), and a subject exposed to a viral infection, such as infection with SARS-CoV-2, as defined herein (e.g., household contacts of a COVID-19 patient or an asymptomatic patient infected with SARS-CoV-2).

[0052] For clarity, the terms "2019-nCoV," "SARS-CoV-2," "SARS-CoV-2 / 2019-nCoV," and "2019-nCoV / SARS-CoV-2" are used interchangeably and refer individually and collectively to the novel coronavirus discovered in Wuhan, China, in 2019, and its variants, including, but not limited to, the more virulent strains recently seen in Brazil (known as P.1), the United Kingdom (known as 20I / 501Y.V1, VOC 202012 / 01, or B.1.1.7), and South Africa (known as 20H / 501Y.V2 or B.1.351), as well as additional variants and lineages derived therefrom. Certain variants are described in more detail in the following references, each of which is incorporated by reference in its entirety for its teachings on viral variants: Horby P, Huntley C, Davies N, et al. NERVTAG note on B.1.1.7 severity.SAGE meeting report.January 21,2021, Wu K,Werner AP,Moliva JI,et al.mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants.bioRxiv.Posted January 25,2021,Xie X,Zou J,Fontes-Garfias CR,et al.Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera.bioRxiv.Posted January 7,2021.Greaney AJ, Loes AN, Crawford KHD, et al.Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies.bioRxiv.January 4,2021, Weisblum Y, Schmidt F,Zhang F,et al.Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants.eLife 2020;9:e61312, Resende PC, Bezerra JF, de Vasconcelos RHT, at al.Spike E484K mutation in the first SARS-CoV-2 reinfection case confirmed in Brazil,2020.January 10,2021.

[0053] The term "COVID-19" refers to the disease caused by viral infection with SARS-CoV-2 / 2019-nCoV.

[0054] Those skilled in the art will recognize that certain compounds, particularly those containing certain heteroatoms and double or triple bonds, may be tautomers, which are structural isomers that readily interconvert. Thus, tautomeric compounds may be depicted in several different ways that are equivalent. Non-limiting examples of such tautomers include those illustrated below. [ka]

[0055] compound In certain embodiments, the present disclosure provides a compound of formula I [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: X is CH2, CHCH3, C(CH3)2, CHF, CF2, or CD2; Y is N or CR'; Z is N or CR″; R' is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, or carbonyl, and R' is optionally selected from one or more of the same or different R 10 is replaced by R″ is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, hydroxyl, thiol, or carbonyl, and R″ is optionally selected from one or more of the same or different R 10 is replaced by R 1 , R 2 , R 3 , and R 5 are independently H, [ka] [ka] or, together with the oxygen to which each is attached, R 1 , R 2 , R 3 , and R 5is 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid 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 ester, oxymethoxyamino ester, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oximyl, optionally substituted imidinyl, optionally substituted imidyl, optionally substituted aminal, optionally substituted hemiaminal, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carbonyl and R, to form an optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 1 , R 2 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by Y 1 is O or S, Y 3 is OH or BH3 - M + and M is Li, Na, K, NH, (CHCH)NH, (CHCHCHCH)N; R 6is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, cyano, or lipid; R 6 optionally, one or more of the same or different R 10 is replaced by R 7 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 7 optionally, one or more of the same or different R 10 is replaced by R 8is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 8 optionally, one or more of the same or different R 10 is replaced by R 9 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 9 optionally, one or more of the same or different R 10 is replaced by R 7 , R 8 , and R 9can form a ring with the α-carbon to which they are attached and the amino group attached to the α-carbon, R 8 and R 9 can form a ring with the α-carbon to which they are attached, R 10 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 12 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 12 optionally, one or more of the same or different R 16 is replaced by R 13is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 13 optionally, one or more of the same or different R 16 is replaced by R 14 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 14 optionally, one or more of the same or different R 16 is replaced by R 15is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 15 optionally, one or more of the same or different R 16 is replaced by R 16 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 16 optionally, one or more of the same or different R 17 is replaced by R 17is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22 Aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0056] In certain embodiments, the lipid is a fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids.

[0057] In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega-unsaturated, or omega-polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids.

[0058] In certain embodiments, lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids that have one or more of their carbon units substituted with oxygen, nitrogen, or sulfur.

[0059] In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega-unsaturated, or omega-polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids having one or more of their carbon units substituted with oxygen, nitrogen, or sulfur.

[0060] In certain embodiments, the lipid is a fatty alcohol, fatty amine, or fatty thiol derived from an optionally substituted essential and / or non-essential fatty acid.

[0061] In certain embodiments, the lipid is an optionally substituted unsaturated, polyunsaturated, omega-unsaturated, or omega-polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids.

[0062] In certain embodiments, the lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and / or non-essential fatty acids having one or more of their carbon units optionally substituted with oxygen, nitrogen, or sulfur.

[0063] In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega-unsaturated, or omega-polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids having one or more of their carbon units replaced with optionally substituted oxygen, nitrogen, or sulfur.

[0064] In certain embodiments, the lipid is hexadecyloxypropyl.

[0065] In a particular embodiment, the lipid is 2-aminohexadecyloxypropyl.

[0066] In certain embodiments, the lipid is 2-aminoarachidyl.

[0067] In a particular embodiment, the lipid is 2-benzyloxyhexadecyloxypropyl.

[0068] In particular embodiments, the lipid is lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, or lignoceryl.

[0069] In certain embodiments, the lipid is a sphingolipid of the formula: [ka] During the ceremony, Sphingolipid R 20 is hydrogen, alkyl, C(=O)R 21 , C(=O)OR 21 , or C(=O)NHR 21 and Sphingolipid R 19 is hydrogen, fluoro, OR 21 , OC(=O)R 21 ,OC(=O)OR 21 , or OC(=O)NHR 21 and Sphingolipid R 18 is a saturated or unsaturated alkyl chain of more than 6 and less than 22 carbons, optionally substituted with one or more halogens or hydroxy, or has the formula: [ka] n is 8 to 14 or 8 to 14 or less; o is 9 to 15 or 9 to 15 or less; the sum of m and n is 8 to 14 or 8 to 14 or less; the sum of m and o is 9 to 15 or 9 to 15 or less; or [ka] n is 4 to 10 or 4 or less to 10 or less; o is 5 to 11 or 5 or less to 11 or less; the sum of m and n is 4 to 10 or 4 or less to 10 or less; and the sum of m and o is 5 to 11 or 5 or less to 11 or less; or [ka] wherein n is 6 to 12, or n is 6 or less to 12 or less, and the sum of m and n is 6 to 12, or n is 6 or less to 12 or less, Sphingolipid R 22 is OR 21 , OC(=O)R 21 ,OC(=O)OR 21 , or OC(=O)NHR 21 and Sphingolipid R 21 is hydrogen, cyano, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, or lipid; R 21 optionally, one or more of the same or different R 23 is replaced by Sphingolipid R 23is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl.

[0070] In certain embodiments, the R 20 is H, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or phenyl.

[0071] In certain embodiments, the sphingolipid is a sphingolipid of the formula: [ka] During the ceremony, Sphingolipid R 20 is hydrogen, hydroxy, fluoro, OR 21 , OC(=O)R 21 ,OC(=O)OR 21 , or OC(=O)NHR 21 and Sphingolipid R 19 is hydrogen, hydroxy, fluoro, OR 21 , OC(=O)R 21 ,OC(=O)OR 21 , or OC(=O)NHR 21 and Sphingolipid R 18 is a saturated or unsaturated alkyl chain of more than 6 and less than 22 carbons, optionally substituted with one or more halogens, or has the formula: [ka] n is 8 to 14 or 8 or less and 14 or less, and the sum of m and n is 8 to 14 or 8 or less and 14 or less, Sphingolipid R 21 is hydrogen, cyano, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, or lipid; R 21 optionally, one or more of the same or different R 23 is replaced by Sphingolipid R 23is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, esteryl, formyl, carboxy, carbamoyl, amido, or acyl.

[0072] In certain embodiments, the R 21 is H, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl.

[0073] Suitable sphingolipids include, but are not limited to, sphingosine, ceramide, or sphingomyelin, and optionally, a 2-aminoalkyl substituted with one or more substituents.

[0074] Other suitable sphingolipids include 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, which may optionally be substituted with one or more substituents. ol, 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-dihydroxyoctadecan-2-yl)acetamide, N-((2S,3S,5S)-3,5-dihydroxyoctadecan-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-methyloctadecane-3-one, (Z)-2-amino-5-hydroxy-2-methyloctadecane-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,Examples of suitable fluorocarbons include, but are not limited to, 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.

[0075] In an exemplary embodiment of Formula I, R 1 is hydrogen, [ka] is.

[0076] In exemplary embodiments of Formula I, R' is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl.

[0077] In exemplary embodiments of Formula I, R″ is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl.

[0078] In an exemplary embodiment of Formula I, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0079] In an exemplary embodiment of Formula I, R 7is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0080] In an exemplary embodiment of Formula I, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0081] In an exemplary embodiment of Formula I, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0082] In certain embodiments, the present disclosure provides a compound of formula II [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: X is CH2, CHCH3, C(CH3)2, CHF, CF2, or CD2; Y is N or CR'; Z is N or CR″; R' is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, or carbonyl, and R' is optionally selected from one or more of the same or different R 10 is replaced by R″ is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, hydroxyl, thiol, or carbonyl, and R″ is optionally selected from one or more of the same or different R 10 is replaced by R 1 , R 2 , R 3 , and R 5 are independently H, [ka] [ka] [ka] or, together with the oxygen to which each is attached, R 1 , R 2 , R 3 , and R 5is 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thio Carbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally substituted optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 1 , R 2 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by However, R 1 , R 2 , R 3 , and R 5 However, provided that they are not all H, R 6 ~R 17 and the lipid is as defined in Formula I.

[0083] In exemplary embodiments of Formula II, R' is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl.

[0084] In exemplary embodiments of Formula II, R″ is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl.

[0085] In an exemplary embodiment of Formula II, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0086] In an exemplary embodiment of Formula II, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0087] In an exemplary embodiment of Formula II, R 8is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0088] In an exemplary embodiment of Formula II, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0089] In certain embodiments, the present disclosure provides a compound of formula III [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: X is CH2, CHCH3, C(CH3)2, CHF, CF2, or CD2; Z is N or CR″; R″ is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, hydroxyl, thiol, or carbonyl, and R″ is optionally selected from one or more of the same or different R 10 is replaced by R 1 ~R3 and R 5 is as defined in formula II, with the proviso that R 1 , R 2 , R 3 , and R 5 However, provided that they are not all H, R 6 ~R 17 and the lipid is as defined in Formulas I and II.

[0090] In exemplary embodiments of Formula III, R″ is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl.

[0091] In an exemplary embodiment of Formula III, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0092] In an exemplary embodiment of Formula III, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0093] In an exemplary embodiment of Formula III, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0094] In an exemplary embodiment of Formula III, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0095] In certain embodiments, the present disclosure provides a compound of formula IV [ka] or a pharmaceutical or physiological salt thereof, wherein: X is CHCH3, C(CH3)2, CHF, CF2, or CD2; R 1 ~R 3 and R 5 is as defined in formulas II and III, provided that R 1 , R 2 , R 3 , and R 5 However, provided that they are not all H, R 6 ~R 17and the lipid is as defined in Formulas I-III.

[0096] In an exemplary embodiment of Formula IV, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0097] In an exemplary embodiment of Formula IV, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0098] In an exemplary embodiment of Formula IV, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0099] In an exemplary embodiment of Formula IV, R9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0100] In certain embodiments, the present disclosure provides a compound of formula V [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, R 1 ~R 3 and R 5 is as defined in formulas II-IV, R 6 ~R 17 and the lipids are as defined in Formulas I-IV.

[0101] In an exemplary embodiment of Formula V, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0102] In an exemplary embodiment of Formula V, R 7is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0103] In an exemplary embodiment of Formula V, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0104] In an exemplary embodiment of Formula V, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0105] In certain embodiments, the present disclosure provides a compound of formula VI [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 ~R 3 is as defined in Formulas II-V, R 6 ~R 17 and the lipids are as defined in Formulas I-V.

[0106] In an exemplary embodiment of Formula VI, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0107] In an exemplary embodiment of Formula VI, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0108] In an exemplary embodiment of Formula VI, R 8is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0109] In an exemplary embodiment of Formula VI, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0110] In certain embodiments, the present disclosure provides compounds of formula VIa-f [ka] [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, In the formula, R 1 ~R 3 is as defined in Formulas II-VI, and R 6 ~R 17 and the lipids are as defined in Formulas I-VI.

[0111] In exemplary embodiments of Formulas VIa-f, R 6is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0112] In exemplary embodiments of Formulas VIa-f, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0113] In exemplary embodiments of Formulas VIa-f, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0114] In exemplary embodiments of Formulas VIa-f, R 9is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0115] In certain embodiments, the present disclosure provides a compound of formula VII [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 , R 2 , and R 5 is as defined in Formulas II-VI, and R 6 ~R 17 and the lipids are as defined in Formulas I-VI.

[0116] In an exemplary embodiment of Formula VII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0117] In an exemplary embodiment of Formula VII, R 7is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0118] In an exemplary embodiment of Formula VII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0119] In an exemplary embodiment of Formula VII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0120] In certain embodiments, the present disclosure provides a compound of formula VIII [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 , R 3 , and R 5 is as defined in formulas II-VII, and R 6 ~R 17 and the lipid is as defined in Formulas I-VII.

[0121] In an exemplary embodiment of Formula VIII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0122] In an exemplary embodiment of Formula VIII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0123] In an exemplary embodiment of Formula VIII, R 8is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0124] In an exemplary embodiment of Formula VIII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0125] In certain embodiments, the present disclosure provides a compound of formula IX [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 2 , R 3 , and R 5 is as defined in Formulas II to VIII, and R 6 ~R 17 and the lipid is as defined in Formulas I-VIII.

[0126] In an exemplary embodiment of Formula IX, R 6is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0127] In an exemplary embodiment of Formula IX, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0128] In an exemplary embodiment of Formula IX, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0129] In an exemplary embodiment of Formula IX, R 9is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0130] In certain embodiments, the present disclosure provides a compound of formula X [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 and R 5 is as defined in Formulas II-IX, and R 6 ~R 17 and the lipids are as defined in Formulas I-IX.

[0131] In an exemplary embodiment of Formula X, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0132] In an exemplary embodiment of Formula X, R 7is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0133] In an exemplary embodiment of Formula X, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0134] In an exemplary embodiment of Formula X, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0135] In certain embodiments, the present disclosure provides a compound of formula XI [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 and R 3 is as defined in formulas II to X, and R 6 ~R 17 and the lipids are as defined in Formulas IX.

[0136] In an exemplary embodiment of Formula XI, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0137] In an exemplary embodiment of Formula XI, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0138] In an exemplary embodiment of Formula XI, R 8is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0139] In an exemplary embodiment of Formula XI, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0140] In certain embodiments, the present disclosure provides a compound of formula XII [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 and R 2 is as defined in Formulas II-XII, and R 6 ~R 17 and the lipids are as defined in Formulas I-XI.

[0141] In an exemplary embodiment of Formula XII, R 6is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0142] In an exemplary embodiment of Formula XII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0143] In an exemplary embodiment of Formula XII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0144] In an exemplary embodiment of Formula XII, R 9is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0145] In certain embodiments, the present disclosure provides a compound of formula XIII [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 2 and R 5 is as defined in Formulas II-XII, and R 6 ~R 17 and the lipids are as defined in Formulas I-XII.

[0146] In an exemplary embodiment of Formula XIII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0147] In an exemplary embodiment of Formula XIII, R 7is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0148] In an exemplary embodiment of Formula XIII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0149] In an exemplary embodiment of Formula XIII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0150] In certain embodiments, the present disclosure provides a compound of formula XIV [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 2 and R 3 is as defined in formulas II to XIII, and R 6 ~R 17 and the lipids are as defined in Formulas I-XIII.

[0151] In an exemplary embodiment of Formula XIV, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0152] In an exemplary embodiment of Formula XIV, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0153] In an exemplary embodiment of Formula XIV, R 8is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0154] In an exemplary embodiment of Formula XIV, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0155] In certain embodiments, the present disclosure provides a compound of formula XV [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 3 and R 5 is as defined in formulas II to XIV, and R 6 ~R 17 and the lipids are as defined in Formulas I-XIV.

[0156] In an exemplary embodiment of Formula XV, R 6is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0157] In an exemplary embodiment of Formula XV, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0158] In an exemplary embodiment of Formula XV, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0159] In an exemplary embodiment of Formula XV, R 9is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0160] In certain embodiments, the present disclosure provides a compound of formula XVI [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 2 is as defined in Formulas II to XV, and R 6 ~R 17 and the lipids are as defined in Formulas I-XV.

[0161] In an exemplary embodiment of Formula XVI, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0162] In an exemplary embodiment of Formula XVI, R 7is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0163] In an exemplary embodiment of Formula XVI, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0164] In an exemplary embodiment of Formula XVI, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0165] In certain embodiments, the present disclosure provides a compound of formula XVII [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 3 is as defined in Formulas II to XVI, and R 6 ~R 17 and the lipids are as defined in Formulas I-XVI.

[0166] In an exemplary embodiment of Formula XVII, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0167] In an exemplary embodiment of Formula XVII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0168] In an exemplary embodiment of Formula XVII, R 8is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0169] In an exemplary embodiment of Formula XVII, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0170] In certain embodiments, the present disclosure provides a compound of formula XVIII [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 is as defined in formulas II to XVII, and R 6 ~R 17 and the lipids are as defined in Formulas I-XVII.

[0171] In an exemplary embodiment of Formula XVIII, R 6is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0172] In an exemplary embodiment of Formula XVIII, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0173] In an exemplary embodiment of Formula XVIII, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0174] In an exemplary embodiment of Formula XVIII, R 9is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0175] In certain embodiments, the present disclosure provides a compound of formula XIX [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 5 is as defined in formulas II to XVIII, and R 6 ~R 17 and the lipids are as defined in Formulas I-XVIII.

[0176] In an exemplary embodiment of Formula XIX, R 6 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0177] In an exemplary embodiment of Formula XIX, R 7is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0178] In an exemplary embodiment of Formula XIX, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0179] In an exemplary embodiment of Formula XIX, R 9 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0180] In certain embodiments, the present disclosure provides a compound of formula XX [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: X is CH2, CHCH3, C(CH3)2, CHF, CF2, or CD2; Y is N or CR'; Z is N or CR″; R' is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, or carbonyl, and R' is optionally selected from one or more of the same or different R 10 is replaced by R″ is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, hydroxyl, thiol, or carbonyl, and R″ is optionally selected from one or more of the same or different R 10 is replaced by In the formula, R 1 ~R 3 and R 5 is as defined in Formulas II to XIX, However, R 1 , R 2 , R 3 , and R 5 However, provided that they are not all H, R 6 ~R 17 and the lipids are as defined in Formulas I-XIX.

[0181] In an exemplary embodiment of Formula XX, R 6is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0182] In an exemplary embodiment of Formula XX, R 7 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0183] In an exemplary embodiment of Formula XX, R 8 is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0184] In an exemplary embodiment of Formula XX, R 9is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, or N,N-dipropylamino.

[0185] In certain embodiments, the compound of formula XX is not one of the following structures: [ka] [ka]

[0186] In an exemplary embodiment, the compound is selected from: [ka]

[0187] In an exemplary embodiment, the compound is selected from: [ka]

[0188] In an exemplary embodiment, the compound is selected from: [ka]

[0189] In an exemplary embodiment, the compound is selected from: [ka]

[0190] In an exemplary embodiment, the compound is selected from: [ka]

[0191] In an exemplary embodiment, the compound is selected from: [ka]

[0192] In an exemplary embodiment, the compound is selected from: [ka]

[0193] In certain embodiments, the present disclosure provides a compound of formula XXI [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein R 1 H, [ka] and R 6 is alkyl or carbocyclyl. In particular examples, R 6 is selected from C3-C6 cycloalkyl, C3-C7 n-alkyl, and C3-C7 branched alkyl. 6 is isopropyl.

[0194] How to use In certain embodiments, the present disclosure relates to a method of treating or preventing a viral infection, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0195] In certain embodiments, the present disclosure relates to a method for treating or preventing a viral infection in the central nervous system (CNS), comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0196] In certain embodiments, the present disclosure relates to a method of treating or preventing a coronavirus infection in the CNS, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0197] In certain embodiments, the present disclosure relates to a method for treating or preventing a SARS-CoV-2 infection in the CNS, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0198] In certain embodiments, the present disclosure relates to a method for treating or preventing a viral infection in the CNS, comprising administering an effective amount of EIDD-1931 to a subject in need thereof.

[0199] In certain embodiments, the present disclosure relates to a method of treating or preventing a coronavirus infection in the CNS, comprising administering an effective amount of EIDD-1931 to a subject in need thereof.

[0200] In certain embodiments, the present disclosure relates to a method for treating or preventing a SARS-CoV-2 infection in the CNS, comprising administering an effective amount of EIDD-1931 to a subject in need thereof.

[0201] In certain embodiments, the present disclosure relates to a method for treating or preventing a viral infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0202] In certain embodiments, the present disclosure relates to a method of treating or preventing a coronavirus infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0203] In certain embodiments, the present disclosure relates to a method for treating or preventing SARS-CoV-2 infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0204] In certain embodiments, the present disclosure relates to a method for treating or preventing a viral infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0205] In certain embodiments, the present disclosure relates to a method of treating or preventing a coronavirus infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0206] In certain embodiments, the present disclosure relates to a method for treating or preventing SARS-CoV-2 infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0207] In certain embodiments, the present disclosure relates to a method for treating or preventing a viral infection in the CNS, comprising administering an effective amount of EIDD-2898 to a subject in need thereof.

[0208] In certain embodiments, the present disclosure relates to a method of treating or preventing a coronavirus infection in the CNS, comprising administering an effective amount of EIDD-2898 to a subject in need thereof.

[0209] In certain embodiments, the present disclosure relates to a method for treating or preventing a SARS-CoV-2 infection in the CNS, comprising administering an effective amount of EIDD-2898 to a subject in need thereof.

[0210] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of a disease caused by a viral infection in the CNS, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0211] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by coronavirus infection in the CNS, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0212] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by SARS-CoV-2 infection in the CNS, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

[0213] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of a disease caused by a viral infection in the CNS, comprising administering an effective amount of EIDD-1931 to a subject in need thereof.

[0214] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by coronavirus infection in the CNS, comprising administering an effective amount of EIDD-1931 to a subject in need thereof.

[0215] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by SARS-CoV-2 infection in the CNS, comprising administering an effective amount of EIDD-1931 to a subject in need thereof.

[0216] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of a disease caused by a viral infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0217] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by coronavirus infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0218] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by SARS-CoV-2 infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0219] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of a disease caused by a viral infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0220] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by coronavirus infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0221] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by SARS-CoV-2 infection in the CNS, comprising administering an effective amount of EIDD-2801 to a subject in need thereof.

[0222] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of a disease caused by a viral infection in the CNS, comprising administering an effective amount of EIDD-2898 to a subject in need thereof.

[0223] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by coronavirus infection in the CNS, comprising administering an effective amount of EIDD-2898 to a subject in need thereof.

[0224] In certain embodiments, the present disclosure relates to a method for treating or preventing neurological manifestations of disease caused by SARS-CoV-2 infection in the CNS, comprising administering an effective amount of EIDD-2898 to a subject in need thereof.

[0225] In certain embodiments, the compound is administered by inhalation through the lungs.

[0226] In some embodiments, the subject is at risk for, exhibits symptoms of, or has been diagnosed with infection by a human coronavirus, SARS coronavirus, MERS coronavirus, or 2019-nCoV.

[0227] In certain embodiments, the subject has been diagnosed with gastroenteritis, acute respiratory illness, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fever, acquired immune deficiency syndrome, or hepatitis.

[0228] formulation In an exemplary embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier, and an exemplary compound described herein.

[0229] In certain exemplary embodiments, the pharmaceutical compositions comprise or are in the form of pharmaceutically acceptable salts, as generally described below. Some suitable pharmaceutically acceptable organic and / or inorganic acids, but non-limiting examples, are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, and citric acid, as well as other pharmaceutically acceptable acids known per se (see the references mentioned below).

[0230] When exemplary compounds contain both acidic and basic groups, the compounds may form internal salts, which may also be used in the compositions and methods described herein. When exemplary compounds contain a hydrogen-donating heteroatom (e.g., NH), salts are contemplated that encompass isomers formed by the transfer of the hydrogen atom to a basic group or atom within the molecule.

[0231] 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, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodine, isethionate, etc. The salts include esters of hydroxybenzoates, ... For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), which is incorporated herein by reference.

[0232] Exemplary physiologically acceptable salts of the compounds are salts that are formed in a subject to which the compound is administered for the treatment or prevention of a disease. Suitable salts include salts of lithium, sodium, potassium, magnesium, calcium, manganese, and bile salts.

[0233] Exemplary compounds can be administered in the form of prodrugs. Prodrugs can include covalently bonded carriers that release the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved to the parent compound, either by routine manipulation or in vivo. Prodrugs include, for example, compounds in which a hydroxyl group is bonded to any group that is cleaved to form a free hydroxyl group when administered to a subject. Examples of prodrugs 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate esters, optionally substituted 2-hydroxypropanoate esters, S-thiocarbonates, optionally substituted S-thiocarbonates, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbonates, optionally substituted thiocarbonates, Carbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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, sulfenyl, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, imidate, optionally substituted imidate, hydrazonate, optionally substituted hydrazonate, oximyl, optionally substituted oximyl, imidinyl, optionally substituted imidinyl, imidyl, optionally substituted imidyl, aminal, optionally substituted aminal, hemiaminal, optionally substituted hemiaminal, acetal, optionally substituted acetal, hemiacetal, optionally substituted hemiacetal, carbonimidate, optionally substituted carbonimidate, thiocarbonimidate, optionally substituted thiocarbonimidate Examples of suitable prodrugs include acetone, carbonimidyl, optionally substituted carbonimidyl, carbamimidate, optionally substituted carbamimidate, carbamimidyl, optionally substituted carbamimidyl, thioacetal, optionally substituted thioacetal, S-acyl-2-thioethyl, optionally substituted S-acyl-2-thioethyl, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)ester, optionally substituted bis-(acyloxybenzyl)ester, (acyloxybenzyl)ester, optionally substituted (acyloxybenzyl)ester, or BAB ester, and acetate, formate, and benzoate derivatives of alcohol functional groups in the compounds. Methods for constructing compounds as prodrugs are described in Testa and Mayer, Hydrolysis in Drug and This can be found in the book Prodrug Metabolism, Wiley (2006). Typical prodrugs form active metabolites by transformation of the prodrug by hydrolytic enzymes, hydrolysis of amides, lactams, peptides, carboxylic acid esters, epoxides, or cleavage of esters of inorganic acids.

[0234] In exemplary embodiments, the pharmaceutical composition comprises an effective amount of the exemplary compound and a pharmaceutically acceptable carrier. Generally, for pharmaceutical use, the present compound can be formulated as a pharmaceutical product, comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally one or more additional pharmaceutically active compounds. The preparation can be prepared in a manner known per se, which usually involves mixing, under aseptic conditions as necessary, at least one compound according to the present disclosure with one or more pharmaceutically acceptable carriers, if desired, in combination with other pharmaceutically active compounds. Reference is again made 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 above-mentioned additional references, and to standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. The disclosed pharmaceutical compositions may be in unit dosage form and may be suitably packaged, for example, in a box, blister, vial, bottle, sachet, ampoule, or any other suitable single-dose or multi-dose holder or container (which may be appropriately labeled), optionally with one or more leaflets containing product information and / or instructions for use. Generally, such a unit dosage will contain 1 to 1000 mg, usually 5 to 500 mg, of at least one compound of the present disclosure, e.g., about 10, 25, 50, 100, 200, 300, 400, 800 mg per unit dosage.

[0235] The compounds can be administered by a variety of routes, including oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal, depending primarily on the particular preparation used. The compounds are generally administered in an "effective amount," which means any amount of compound that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered. Typically, depending on the condition being prevented or treated and the route of administration, such an effective amount will be 0.01 to 1000 mg per kilogram of patient body weight per day, which may be administered as a single daily dose, divided into one or more daily doses, more frequently 0.1 to 500 mg, such as about 5, 10, 20, 50, 100, 150, 200, or 250 mg, per kilogram of patient body weight per day. The amount administered, the route of administration, and any further treatment regimen can be determined by the treating clinician, depending on factors such as the patient's age, sex, and general condition, as well as the nature and severity of the disease / condition being treated. Reference is again made to US Pat. Nos. 6,372,778, 6,369,086, 6,369,087 and 6,372,733 and the further references mentioned above, as well as to standard handbooks such as the latest edition of Remington's Pharmaceutical Sciences.

[0236] Depending on the mode of administration, the compounds described herein can be formulated in various ways. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled-release formulations, suspensions, emulsions, creams, gels, ointments, salves, lotions, or aerosols. In certain embodiments, the formulations are used in a simple, precise dosage, preferably suitable for oral administration in solid dosage forms. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms such as solutions, syrups, suspensions, shakes, etc. can also be used. In another embodiment, the formulation is administered topically. Suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels. In one embodiment, the topical formulation is a gel. In another embodiment, the formulation is administered intranasally.

[0237] The preparation containing one or more of the compounds described herein can be prepared using pharmaceutically acceptable carriers, which are made of materials that are considered safe and effective, and can be administered to individuals without causing undesired biological side effects or undesired interactions.Carrier refers to all the components present in pharmaceutical preparations other than active ingredients.As generally used herein, " carrier " includes but is not limited to diluents, binders, lubricants, disintegrants, fillers, pH modifiers, preservatives, antioxidants, solubility enhancers and coating compositions.

[0238] Carriers also include all components of coating compositions, which may include plasticizers, pigments, colorants, stabilizers, and lubricants. Delayed-release, sustained-release, and / or pulse-release dosage formulations can be prepared as described in standard references such as "Pharmaceutical dosage forms tablets," eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), "Remington - The science and practice of pharmacy," 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical dosage forms and drug delivery systems," 6th Edition, Ansel et al. (Media, PA: Williams and Wilkins, 1995). These references provide information on carriers, materials, equipment, and processes for preparing tablets and capsules, as well as delayed-release dosage forms of tablets, capsules, and granules.

[0239] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, methacrylic resins commercially available under the trade name EUDRAGIT™ (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

[0240] In addition, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, lubricants, stabilizers, pore formers, and surfactants.

[0241] Optional pharmaceutically acceptable excipients present in drug-containing tablets, beads, granules, or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also known as "fillers," are typically needed to increase the bulk of solid dosage forms so that they provide a practical size for tablet compression or bead and granule formation. 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, silicon dioxide, titanium oxide, magnesium aluminum silicate, and powdered sugar.

[0242] Binders are used to impart cohesive qualities to solid dosage forms, thus ensuring that tablets or beads or granules remain intact after formation of the dosage form. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, celluloses including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and begum, and synthetic polymers such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone.

[0243] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

[0244] Disintegrants are used to facilitate the breakup or "disintegration" of the dosage form after administration and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clay, cellulose, arginine, gums, and cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).

[0245] Stabilizers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.

[0246] The surfactant may be anionic, cationic, amphoteric, or nonionic surfactant. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include sodium, potassium, and ammonium long-chain alkyl sulfonates and alkylaryl sulfonates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfonates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthiol)-sulfosuccinate; and alkyl sulfates, such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMER™ 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallowamide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0247] If desired, the tablets, beads, granules, or particles may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.

[0248] The concentration of exemplary compounds relative to pharmaceutically acceptable carriers, excipients, and / or other substances can vary from about 0.5 to about 100% by weight (weight percent). For oral use, pharmaceutical compositions generally contain from about 5 to about 100% by weight of the active material. For other uses, pharmaceutical compositions generally have from about 0.5 to about 50% by weight of the active material.

[0249] The compositions described herein can be formulated for modified or controlled release. Examples of controlled release dosage forms include sustained release dosage forms, delayed release dosage forms, pulsed release dosage forms, and combinations thereof.

[0250] Sustained-release formulations are generally prepared as diffusion or osmotic systems, as described, for example, in "Remington - The Science and Practice of Pharmacy" (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000). Diffusion systems typically consist of two types of devices: reservoirs and matrices, and are well known and described in the art. Matrix devices are generally prepared by compressing a drug into tablet form using a slowly dissolving polymeric carrier. The three main types of materials used to prepare matrix devices are insoluble plastics, hydrophilic polymers, and fatty 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, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and CARBOPOL™ 934, polyethylene oxide, and mixtures thereof. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate, as well as wax-based materials including hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof.

[0251] In certain preferred embodiments, the plastic material is a pharmaceutically acceptable acrylic polymer, including, but not limited to, acrylic and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, 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 copolymer.

[0252] In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers, which are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

[0253] In a preferred embodiment, the acrylic polymer is an acrylic resin lacquer, such as that commercially available from Rohm Pharma under the trade name EUDRAGIT™. In a more preferred embodiment, the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names EUDRAGIT™ RL30D and EUDRAGIT™ RS30D, respectively. EUDRAGIT™ RL30D and EUDRAGIT™ RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, with the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT™ RL30D and 1:40 in EUDRAGIT™ RS30D. The average molecular weight is approximately 150,000. EUDRAGIT™ S-100 and EUDRAGIT™ L-100 are also preferred. The code names RL (high permeability) and RS (low permeability) refer to the permeability properties of these drugs. EUDRAGIT™ RL / RS mixtures are insoluble in water and digestive fluids. However, multiparticulate systems formulated to contain them are swellable and permeable in aqueous solutions and digestive fluids.

[0254] The above-described polymers, such as EUDRAGIT® RL / RS, can be mixed together in any desired ratio to ultimately obtain a sustained-release formulation with a desired dissolution profile. A desired sustained-release multiparticulate system can be obtained, for example, from 100% EUDRAGIT® RL, 50% EUDRAGIT® RL, and 50% EUDRAGIT® RS, and from 10% EUDRAGIT® RL and 90% EUDRAGIT® RS. Those skilled in the art will recognize that other acrylic polymers, such as EUDRAGIT® L, can also be used.

[0255] Alternatively, sustained-release formulations can be prepared using osmotic systems or by applying semi-permeable coatings to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low-permeability and high-permeability coating materials in appropriate proportions.

[0256] The above-described devices with different drug release mechanisms can be combined in a final dosage form containing single or multiple units. Examples of multiple units include, but are not limited to, multi-layer tablets and capsules containing tablets, beads, or granules, etc.

[0257] The immediate release portion may be added to the sustained release system by means of applying an immediate release layer over a sustained release core using a coating or compression process, or in a multiple unit system such as a capsule containing sustained release beads and immediate release beads.

[0258] Sustained-release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art, such as direct compression, wet granulation, or dry granulation. These formulations usually incorporate polymers, diluents, binders, and lubricants, as well as active pharmaceutical ingredients. Common diluents include inert powdered substances such as starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, cereal flour, and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, sodium chloride, and inorganic salts such as 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 acacia, alginate, methylcellulose, and polyvinylpyrrolidone, can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose, and wax can also function as binders.In tablet formulation, lubricants are required to prevent tablets and tablet presses from sticking to the die.Lubricants are selected from slippery solids such as talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oil.

[0259] Sustained-release tablets containing wax materials are generally prepared using methods known in the art, such as direct blending, congealing, and aqueous dispersion methods. In the congealing method, the drug is mixed with the wax material, either spray-congealed or congealed, screened, and processed.

[0260] Delayed-release formulations are created by coating a solid dosage form with a polymer film that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

[0261] Delayed-release dosage units can be prepared, for example, by coating a drug or drug-containing composition with a selected coating material. The drug-containing composition can be, for example, a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles, or granules for incorporation into either a tablet or a capsule. Preferred coating materials include biodegradable, slowly hydrolyzable, slowly water-soluble, and / or enzymatically degradable polymers, and can be conventional "enteric" polymers. As understood by those skilled in the art, enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or gradually erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the large intestine.Suitable coating materials for achieving delayed release include 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; preferably acrylic acid, methacrylic acid, methyl acrylate, acrylic acid polymers and copolymers formed from acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and EUDRAGIT™ (Rohm) polymers, including EUDRAGIT™ L30D-55 and L100-55 (soluble at pH 5.5 or above), EUDRAGIT™ L-100 (soluble at pH 6.0 or above), EUDRAGIT™ S (soluble at pH 7.0 or above as a result of a high degree of esterification), and EUDRAGIT™ NE, RL, and RS (water-insoluble polymers with different degrees of permeability and extensibility). Other methacrylic resins commercially available under the tradenames of Pharma (Westerstadt, Germany); 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 azopolymers, 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.

[0262] The preferred coating weight for a particular coating material can be readily determined by one skilled in the art by evaluating the individual release profiles for tablets, beads, and granules prepared with different amounts of various coating materials. It is the combination of materials, methods, and application modes that produces the desired release characteristics, which can only be determined from clinical studies.

[0263] The coating composition may contain conventional additives such as plasticizers, pigments, colorants, stabilizers, and lubricants. Plasticizers are usually present to reduce coating brittleness and generally represent about 10% to 50% by weight 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 acetyl citrate, castor oil, and acetylated monoglycerides. Stabilizers are preferably used to stabilize the particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Lubricants are recommended to reduce tackiness during film formation and drying and generally represent about 25% to 100% by weight of the polymer weight in the coating solution. One effective lubricant is talc. Other lubricants such as magnesium stearate and glycerol monostearate can also be used. Pigments such as titanium dioxide can also be used. Small amounts of anti-foaming agents such as silicones (e.g., simethicone) can also be added to the coating composition.

[0264] The formulation can provide pulsatile delivery of one or more compounds. "Pulsatile" means that multiple drug doses are released at spaced time intervals. Generally, upon ingestion of the dosage form, release of the first dose is substantially immediate; i.e., the first drug release "pulse" occurs within about one hour of ingestion. This initial pulse is followed by a first time interval (lag time) during which little or no drug is released from the dosage form, after which the second dose is released. Similarly, a second, approximately drug-free interval can be designed between the second and third drug release pulses. The duration of the approximately drug-free interval will vary depending on the dosage form design, e.g., twice-daily dosing profile, three times-daily dosing profile, etc. For dosage forms providing a twice-daily dosing profile, the approximately drug-free interval between the first and second doses has a duration of about 3 to 14 hours. For dosage forms providing a three times daily profile, the substantially drug-free interval has a duration of about 2 to 8 hours between each of the three doses.

[0265] In one embodiment, a pulsatile release profile is achieved by a sealed capsule that is closed and preferably contains at least two drug-containing "dosage units," with each dosage unit within the capsule providing a different drug release profile. Control of the delayed-release dosage units is achieved by a controlled-release polymer coating on the dosage unit or by incorporating the active agent into a controlled-release polymer matrix. Each dosage unit may comprise a compressed or molded tablet, with each tablet within the capsule providing a different drug release profile. For dosage forms that mimic a twice-daily dosing profile, the first tablet releases drug substantially immediately after ingestion of the dosage form, and the second tablet releases drug approximately 3 to less than 14 hours after ingestion of the dosage form. For dosage forms that mimic a three times daily dosing profile, the first tablet releases drug substantially immediately after ingestion of the dosage form, the second tablet releases drug about 3 hours to less than 10 hours after ingestion of the dosage form, and the third tablet releases drug at least 5 hours to about 18 hours after ingestion of the dosage form. The dosage form may contain more than three tablets. The dosage form generally does not exceed three tablets, although dosage forms with more than three tablets are available.

[0266] Alternatively, each dosage unit within the capsule may contain multiple drug-containing beads, granules, or particles. As known to those skilled in the art, drug-containing "beads" refer to beads made of a drug and one or more excipients or polymers. Drug-containing beads can be produced by applying a drug to an inert support, such as inert sugar beads coated with the drug, or by creating a "core" containing both the drug and one or more excipients. As is also well known, drug-containing "granules" and "particles" include drug particles that may or may not contain one or more additional excipients or polymers. In contrast to drug-containing beads, granules and particles do not contain an inert support. Granules generally contain drug particles and require further processing. Particles are generally smaller than granules and are not further processed. While beads, granules, and particles can be formulated to provide immediate release, beads and granules are generally used to provide delayed release.

[0267] In one embodiment, the compound is formulated for topical administration.Suitable topical dosage forms include lotions, creams, ointments, and gels.A "gel" is a semi-solid system containing an active agent, i.e., a dispersion of a compound, in a liquid vehicle that is semi-solidified by the action of a thickening agent or polymer material dissolved or suspended in the liquid vehicle.The liquid may contain a lipophilic component, an aqueous component, or both.Some emulsions may be gels or may otherwise contain gel components.However, some gels are not emulsions because they do not involve the homogenization of immiscible components.The preparation methods of lotions, creams, ointments, and gels are well known in the art.

[0268] Combination therapy The compounds described herein can be administered adjunctively with other active compounds.These compounds include, but are not limited to, analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptic drugs, antihistamines, antimigraine drugs, antimuscarinic drugs, anxiety drugs, sedatives, hypnotics, antipsychotic drugs, bronchodilators, antiasthmatic drugs, cardiovascular drugs, corticosteroids, dopamine-producing drugs, electrolytes, gastrointestinal drugs, muscle relaxants, nutrients, vitamins, parasympathetic drugs, stimulants, anorectal drugs, antinarcoleptic drugs, and antiviral drugs.In certain embodiments, the antiviral drug is a non-CNS-targeted antiviral compound.As used herein, "adjunctive administration" means that the compound can be administered in the same dosage form or in a separate dosage form with one or more other active agents.The additional active agent can be formulated for immediate release, controlled release, or a combination thereof.

[0269] Specific examples of compounds that may be adjunctively administered with the compound include aceclofenac, acetaminophen, admexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion ... Spiron, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carfizomib, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptyline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamph etamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproex, zizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamate, fenoprofen, fentanyl, fludiazepam, fluoxetine, flufenaz , flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, zincovir, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketaserin, ketoprofen, ketorolac, resopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol,Mefenamic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methylsalicylate, methysergide(e), metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (anti-narcolepsy), molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, na Latriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ordansetron, opipramol, orphenadrine, oxaflozane, oxaprazine, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirlindole , piroxicam, pizotifen, pizotyline, polygonum cuspidatum, pramipexole, prednisolone, prednisone, pregabalin, propanolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxitine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, These include, but are not limited to, tetrabenodine, thiazides, thioridazine, thiothixene, tiapride, thiacypirone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone, and isomers and combinations thereof.

[0270] In certain embodiments, exemplary compounds and pharmaceutical compositions include abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, AT-527, atazanavir, atripla, valapiravir, BCX4430 / gardesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, ocosanol, edoxuvir, edoxuvir. phenytoin, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, GS-5734 / remdesivir, ibacitabine, Immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine , ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sophos It may be administered in combination with another antiviral agent such as buvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, or zidovudine, as well as combinations thereof.

[0271] In certain embodiments, exemplary compounds and pharmaceutical compositions include chloroquine, chloroquine phosphate, hydroxychloroquine, hydroxychloroquine sulfate, Ampligen, APN01, Ganovo, IFX-1, BXT-25, CYNK-001, tocilizumab, leronlimab, Ii-key, COVID-19S-trimer, camrelizumab, thymosin, brilacidin, INO-4800, prescovix, cobicistat, mR It may be administered in combination with another agent such as NA-1273, Arbidol, umifenovir, REGN3048, REGN3051, TNX-1800, fingolimod, methylprednisolone, nitazoxanide, benzoparpine B, C-467929, C-473872, NSC-306711, N-65828, C-21, CGP-42112A, L-163491, xanthoangelol, or bevacizumab, and combinations thereof.

[0272] In certain embodiments, the exemplary compounds and pharmaceutical compositions disclosed herein comprise: WO2003 / 090690A2、WO2003 / 090690A3、WO2003 / 090691A2、WO2003 / 090691A3、WO2004 / 005286A2、WO2004 / 005286A3、WO2004 / 006843A2、WO2004 / 006843A3、WO2004 / 031224A2、WO2004 / 031224A3、WO2004 / 035576A2、WO2004 / 035576A3、WO2004 / 035577A2、WO2004 / 035577A3、WO2004 / 050613A2、WO2004 / 050613A3、WO2004 / 064845A1、WO2004 / 064846A1、WO2004 / 096286A2、WO2004 / 096286A3、WO2004 / 096287A2、WO2004 / 096287A3、WO2004 / 096818A2、WO2004 / 096818A3、WO2004 / 100960A2、WO2005 / 002626A2、WO2005 / 002626A3、WO2005 / 012324A2、WO2005 / 012324A3、WO2005 / 028478A1、WO2005 / 039552A2、WO2005 / 039552A3、WO2005 / 042772A1、WO2005 / 042773A1、WO2005 / 047898A2、WO2005 / 047898A3、WO2005 / 063744A2、WO2005 / 063744A3、WO2005 / 063751A1、WO2005 / 064008A1、WO2005 / 064008A9、WO2005 / 066189A1、WO2005 / 070901A2、WO2005 / 070901A3、WO2005 / 072748A1、WO2005 / 117904A2、WO2005 / 117904A3、WO2006 / 015261A2、WO2006 / 015261A3、WO2006 / 017044A2、WO2006 / 017044A3、WO2006 / 020276A2、WO2006 / 020276A3、WO2006 / 033703A1、WO2006 / 047661A2、WO2006 / 047661A3、WO2006 / 069193A2、WO2006 / 069193A3、WO2006 / 091905A1、WO2006 / 110157A2、WO2006 / 110157A3、WO2006 / 110157A9、WO2006 / 125048A2、WO2006 / 125048A3、WO2007 / 009109A2、WO2007 / 009109A3、WO2007 / 011658A1、WO2007 / 014174A2、WO2007 / 014174A3、WO2007 / 014352A2、WO2007 / 014352A3、WO2007 / 079260A1、WO2007 / 079260A9、WO2007 / 126812A2、WO2007 / 126812A3、WO2008 / 003149A2、WO2008 / 003149A3、WO2008 / 005519A2、WO2008 / 005519A3、WO2008 / 005542A2、WO2008 / 005542A3、WO2008 / 005555A1、WO2008 / 009076A2、WO2008 / 009076A3、WO2008 / 009077A2、WO2008 / 009077A3、WO2008 / 009078A2、WO2008 / 009078A3、WO2008 / 009079A2、WO2008 / 009079A3、WO2008 / 010921A2、WO2008 / 010921A3、WO2008 / 011116A2、WO2008 / 011116A3、WO2008 / 011117A2、WO2008 / 011117A3、WO2008 / 013834A1、WO2008 / 016522A2、WO2008 / 016522A3、WO2008 / 077649A1、WO2008 / 077650A1、WO2008 / 077651A1、WO2008 / 100447A2、WO2008 / 100447A3、WO2008 / 103949A1、WO2008 / 133669A2、WO2008 / 133669A3、WO2009 / 005674A2、WO2009 / 005674A3、WO2009 / 005676A2、WO2009 / 005676A3、WO2009 / 005677A2、WO2009 / 005677A3、WO2009 / 005687A1、WO2009 / 005690A2、WO2009 / 005690A3、WO2009 / 005693A1、WO2009 / 006199A1、WO2009 / 006203A1、WO2009 / 009001A1、WO2009 / 009001A9、WO2009 / 088719A1、WO2009 / 105513A2、WO2009 / 105513A3、WO2009 / 132123A1、WO2009 / 132135A1、WO2010 / 002998A1、WO2010 / 005986A1、WO2010 / 011959A1、WO2010 / 075127A1、WO2010 / 077613A1、WO2010 / 080389A1、WO2010 / 093608A1、WO2010 / 132601A1、WO2010 / 151472A1、WO2010 / 151487A1、WO2010 / 151488A1、WO2011 / 005842A1、WO2011 / 011303A1、WO2011 / 031669A1、WO2011 / 031965A1、WO2011 / 035231A1、WO2011 / 049825A1、WO2011 / 079016A1、WO2011 / 088303A1、WO2011 / 088345A1、WO2011 / 106445A1、WO2011 / 139820Al、WO2011 / 143105A1、WO2011 / 143106A1、WO2011 / 146817A1、WO2011 / 150288A1、WO2011 / 156416A1、WO2011 / 156610A2、WO2011 / 156610A3、WO2011 / 156757A1、WO2011 / 163518A1、WO2012 / 003497A1、WO2012 / 003498A1、WO2012 / 012465A1、WO2012 / 012776A1、WO2012 / 037038A1、WO2012 / 039787A1、WO2012 / 039791A1、WO2012 / 068234A2、WO2012 / 068234A3、WO2012 / 068535A1、WO2012 / 078915A1、WO2012 / 087596A1、WO2012 / 088153A1、WO2012 / 088156A1、WO2012 / 088178A1、WO2012 / 138669A1、WO2012 / 138670A1、WO2012 / 142523A2、WO2012 / 142523A3、WO2012 / 145728A1、WO2012 / 151165A1、WO2013 / 006721A1、WO2013 / 006722A1、WO2013 / 006738A1、WO2013 / 010112A1、WO2013 / 025788A1、WO2013 / 040492A2、WO2013 / 040492A3、WO2013 / 066748A1、WO2013 / 075029A1、WO2013 / 082003A1、WO2013 / 090840A1、WO2013 / 090929A1、WO2013 / 096512A1、WO2013 / 096681A1、WO2013 / 103724A1、WO2013 / 103738A1、WO2013 / 106732A1、WO2013 / 115916A1、WO2013 / 116720A1、WO2013 / 116730A1、WO2013 / 138236A1、WO2013 / 158776A1、WO2013 / 159064A1、WO2013 / 173488A1、WO2013 / 173492A1、WO2013 / 185090A1、WO2013 / 185093A1、WO2013 / 185103A1、WO2014 / 008285A1、WO2014 / 028343A1、WO2014 / 055618A1、WO2014 / 070939A1、WO2014 / 074620A1、WO2014 / 100323A1、WO2014 / 100500A1、WO2014 / 110296A1、WO2014 / 110297A1、WO2014 / 110298A1、WO2014 / 134566A2、WO2014 / 134566A3、WO2014 / 145095A1、WO2015 / 023893A1、WO2015 / 069939A1、WO2015 / 084741A2、WO2015 / 084741A3、WO2015 / 099989A1、WO2015 / 100144A1、WO2015 / 108780A1、WO2015 / 120057A1、WO2015 / 130964A1、WO2015 / 130966A1、WO2015 / 179448A1、WO2015 / 191526A2、WO2015 / 191526A3、WO2015 / 191726A1、WO2015 / 191743A1、WO2015 / 191745A1、WO2015 / 191752A1、WO2015 / 191754A2、WO2015 / 191754A3、WO2015 / 196137A1、WO2016 / 007765A1、WO2016 / 018697A1、WO2016 / 028866A1、WO2016 / 033243A1、WO2016 / 033243A9、WO2016 / 036759A1、WO2016 / 096116A1、WO2016 / 096116A1、WO2016 / 105532A1、WO2016 / 105534A1、WO2016 / 105564A1、WO2016 / 106237A1、WO2016 / 141092A1、WO2016 / 161382A1、WO2016 / 168349A1、WO2016 / 186967A1、WO2016 / 205141A1、WO2017 / 004012A1、WO2017 / 004244A1、WO2017 / 035230A1、WO2017 / 048727A1、WO2017 / 049060A1、WO2017 / 059120A1、WO2017 / 059224A2、WO2017 / 059224A3、WO2017 / 083304A1、WO2017 / 106346A2、WO2017 / 106346A3、WO2017 / 106556A1、WO2017 / 184668A1、WO2017 / 184670A2、WO2017 / 184670A3、WO2017 / 205078A1、WO2017 / 205115A1、WO2017 / 223268A1、WO90 / 15065A1、WO92 / 09705A1、WO93 / 07157A1、WO93 / 10820A1、WO94 / 03467A2、WO94 / 03467A3、WO94 / 24144A2、WO94 / 24144A3、WO95 / 07919A1、WO95 / 07920A1、WO96 / 26933A1、WO98 / 17647A1、WO2009 / 114512、WO2014 / 028756、JP5971830、US2016 / 0122374、US2017 / 0071964、WO2007 / 075145、WO2005 / 021518、WO2007 / 120160、WO2009 / 119167、WO2013 / 049382、WO2018 / 042343、WO2007 / 067515、EP2112164、WO2009 / 128、WO2018 / 115527963、WO2009 / 128963、WO2008 / 035894、WO2008 / 060331、WO2007 / 044695、CN1911963、CN1903878、WO2006 / 095180、WO2006 / 086561、CN1664100、CN1660912、WO2006 / 051091、WO2006 / 051091、CN1673231、US2006 / 0240551、WO2005 / 054469、WO2005 / 060520、US2005 / 0106563、US2005 / 0069869, WO2005 / 012360, CN1566155, WO2005 / 007671, WO2005 / 058815, WO2017 / 09587 5, WO2005 / 05824, WO2011 / 072487, WO2016 / 180335, WO2004 / 096852, WO2005 / 097165, US2009 / , 0053173, CN101942026, CN101173275, CN1648249, US2005 / 0004063, JP2007 / 043942, WO2005 / 023083, US2006 / 00 39926, WO2005 / 081716, WO2015 / 081155, WO2010 / 063685, US2007 / 0003577, US2006 / 0002947, WO2015 / 042373, WO2 The compounds disclosed in WO2017 / 070626, WO2018 / 048937A1, WO2019 / 200005A1, WO2020 / 117966A1, or WO2019 / 173310, each of which is incorporated by reference herein for their teaching of exemplary compounds and pharmaceutical compositions that can be administered in combination with any of the compounds disclosed herein.

[0273] EIDD-1931 and its prodrugs, such as EIDD-2801, can be combined or formulated with another antiviral agent, such as: Nucleoside reverse transcriptase inhibitors (NRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Integrase inhibitors (INSTIs) Fusion inhibitors (FIs) Chemokine receptor antagonist · Entry inhibitors.

[0274] Specific examples of drugs include abacavir, acyclovir, adefovir, amantadine, amprenavir, Ampligen, Arbidol, AT-527, atazanavir, atripla, varapiravir, BCX4430 / galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, and foscarne. rituximab, fosphonet, ganciclovir, GS-5734 / remdesivir, ibasitabine, Immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, CD24Fc, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconari ral, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, zidovudine, or chloroquine, chloroquine phosphate, hydroxychloroquine, hydroxychloroquine Quinolsulfate, Ampligen, APN01, Ganovo, IFX-1, BXT-25, CYNK-001, tocilizumab, leronlimab, Ii-key, COVID-19S-trimer, camrelizumab, thymosin, brilacidin, INO-4800, Prezicobix, cobicistat, mRNA-1273, Erbil, umifenovir, REGN3048, REGN3051, TNX-1800, fingolimod, methylprednisolone, nitazoxanide, benzoparpine B, C-467929, C-473872, NSC-306711,These include N-65828, C-21, CGP-42112A, L-163491, xanthoangelol, bevacizumab, patient-derived polyclonal and monoclonal antibodies (including those derived from patients with COVID-19 or monoclonal or polyclonal antibodies that bind to SARS-CoV-2). Furthermore, the compounds of the present invention can be combined with compounds suitable for preventing lung damage associated with COVID-19, including, for example, anti-IL-6 and TNF inhibitors, in particular, for example, tocilizumab (Actemra), siltuximab (Sylvant), tocilizumab, sarilumab, olokizumab (CDP6038), elcilimomab, BMS-945429 (ALD518), sirukumab (CNTO136), revilimab (BCD-089), as well as CPSI-2364 and ALX-0061, ARGX-109, FE3 01, FM10, infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), etanercept (Enbrel), CD24Fc, thalidomide (Immunoprin) and its derivatives lenalidomide (Revlimid) and pomalidomide (Pomalyst, Immunovid), xanthine derivatives (e.g., pentoxifylline), and bupropion and 5-HT agonist hallucinogens, including (R)-DOI, TCB-2, LSD, and LA-SS-Az.

[0275] In embodiments, exemplary compounds and pharmaceutical compositions include: [ka] and derivatives and prodrugs thereof.

[0276] In an embodiment, [ka] and derivatives and prodrugs thereof, [ka] and derivatives and prodrugs thereof.

[0277] In an embodiment, [ka] teeth, [ka] and derivatives and prodrugs thereof.

[0278] In an embodiment, [ka] teeth, [ka] and derivatives and prodrugs thereof.

[0279] In an embodiment, [ka] teeth, [ka] and derivatives and prodrugs thereof.

[0280] Specific Embodiments In certain embodiments, a pharmaceutically acceptable excipient and a compound of formula XXI [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 is H, [ka] and R 6 is alkyl or carbocyclyl. In some examples, the compound may have the structure: [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof.

[0281] In another embodiment, a pharmaceutically acceptable excipient and a compound of Formula I [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: X is CH2, CHCH3, C(CH3)2, CHF, CF2, or CD2; Y is N or CR'; Z is N or CR″; R' is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, or carbonyl, and R' is optionally selected from one or more of the same or different R 10 is replaced by R″ is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, hydroxyl, thiol, or carbonyl, and R″ is optionally selected from one or more of the same or different R 10 is replaced by R 1 , R 2 , R 3 , and R 5are each independently H, or together with the oxygen to which they are attached, form 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, esters, optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally substituted R, which forms an optionally substituted thiocarbonimidate, an optionally substituted carbonimidyl, an optionally substituted carbamimidate, an optionally substituted carbamimidyl, an optionally substituted thioacetal, an optionally substituted S-acyl-2-thioethyl, an (acyloxybenzyl)ether, an (acyloxybenzyl)ester, a PEG ester, a PEG carbonate, an optionally substituted bis-(acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, or a BAB ester; 1 , R 2 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by R 10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, and lipid is C 11 ~C 22 Higher alkyl, C 11 ~C 22Pharmaceutical compositions are disclosed in which the lipid is an aryl substituted with a higher alkoxy, polyethylene glycol, or alkyl group, or a lipid as described herein.

[0282] In some instances, R 1 , R 2 , R 3 , and R 5 are independently H, [ka] [ka] may be selected from Y 1 is O or S, Y 3 is OH or BH3 - M + and M is Li, Na, K, NH, (CHCH)NH, (CHCHCHCH)N; R 6 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, cyano, or lipid; R 6 optionally, one or more of the same or different R 10 is replaced by R 7is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 7 optionally, one or more of the same or different R 10 is replaced by R 8 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 8 optionally, one or more of the same or different R 10 is replaced by R 9is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 9 optionally, one or more of the same or different R 10 is replaced by R 7 , R 8 , and R 9 can form a ring with the α-carbon to which they are attached and the amino group attached to that α-carbon, R 8 and R 9 can form a ring with the α-carbon to which they are attached.

[0283] In other examples, R 1 is hydrogen, [ka] is.

[0284] In some examples, R' is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl. In some examples, R" is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl. In some examples, the compound is selected from: [ka]

[0285] In some examples, the compound is selected from the following: [ka]

[0286] In some examples, the compound is selected from the following: [ka]

[0287] In some examples, the compound is selected from the following: [ka]

[0288] Also provided is a pharmaceutical composition for the treatment of 2019nCoV / SARS-CoV-2 infection, wherein the compound is a compound of formula II [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: X is CH2, CHCH3, C(CH3)2, CHF, CF2, or CD2; Y is N or CR'; Z is N or CR″; R' is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, or carbonyl, and R' is optionally selected from one or more of the same or different R 10 is replaced by R″ is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, hydroxyl, thiol, or carbonyl, and R″ is optionally selected from one or more of the same or different R 10 is replaced by R 1 , R 2 , R 3 , and R 5are each independently H, or together with the oxygen to which they are attached, form 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, esters, optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally substituted R, which forms an optionally substituted thiocarbonimidate, an optionally substituted carbonimidyl, an optionally substituted carbamimidate, an optionally substituted carbamimidyl, an optionally substituted thioacetal, an optionally substituted S-acyl-2-thioethyl, an (acyloxybenzyl)ether, an (acyloxybenzyl)ester, a PEG ester, a PEG carbonate, an optionally substituted bis-(acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, or a BAB ester; 1 , R 2 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by However, R 1 , R 2 , R 3 , and R 5 However, provided that they are not all H, R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0289] In some examples, R' is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl. In other examples, R" is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl.

[0290] Also, a pharmaceutically acceptable excipient and a compound of formula III [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: X is CH2, CHCH3, C(CH3)2, CHF, CF2, or CD2; Z is N or CR″; R″ is hydrogen, deuterium, halogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocarbocyclyl, cycloalkyl, heterocyclyl, hydroxyl, thiol, or carbonyl, and R″ is optionally selected from one or more of the same or different R 10 is replaced by R 1 , R 2 , R 3 , and R 5are each independently H, or together with the oxygen to which they are attached, form 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, esters, optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally substituted R, which forms an optionally substituted thiocarbonimidate, an optionally substituted carbonimidyl, an optionally substituted carbamimidate, an optionally substituted carbamimidyl, an optionally substituted thioacetal, an optionally substituted S-acyl-2-thioethyl, an (acyloxybenzyl)ether, an (acyloxybenzyl)ester, a PEG ester, a PEG carbonate, an optionally substituted bis-(acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, or a BAB ester; 1 , R 2 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by However, R 1 , R 2 , R 3 , and R 5 However, provided that they are not all H, R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions wherein R" is an aryl substituted with a higher alkoxy, polyethylene glycol, or alkyl group, or a lipid as described herein. In some examples, R" is methyl, fluoro, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, thiomethyl, carboxylic acid, formyl, vinyl, or ethynyl.

[0291] Also, a compound of formula IV may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula IV. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: X is CHCH3, C(CH3)2, CHF, CF2, or CD2; R 1 , R 2 , R 3 , and R 5are each independently H, or together with the oxygen to which they are attached, form 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, esters, optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally substituted R, which forms an optionally substituted thiocarbonimidate, an optionally substituted carbonimidyl, an optionally substituted carbamimidate, an optionally substituted carbamimidyl, an optionally substituted thioacetal, an optionally substituted S-acyl-2-thioethyl, an (acyloxybenzyl)ether, an (acyloxybenzyl)ester, a PEG ester, a PEG carbonate, an optionally substituted bis-(acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, or a BAB ester; 1 , R 2 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by However, R 1 , R 2 , R 3 , and R 5 However, provided that they are not all H, R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0292] Also, a compound of formula V may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula V. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: R 1 , R 2 , R 3 , and R 5are, together with the oxygen to which they are attached, each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, Optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally substituted R, is selected from the group consisting of an optionally substituted thiocarbonimidate, an optionally substituted carbonimidyl, an optionally substituted carbamimidate, an optionally substituted carbamimidyl, an optionally substituted thioacetal, an optionally substituted S-acyl-2-thioethyl, an (acyloxybenzyl)ether, an (acyloxybenzyl)ester, a PEG ester, a PEG carbonate, an optionally substituted bis-(acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, or a BAB ester; 1 , R 2 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0293] Also, a pharmaceutically acceptable excipient and a compound of formula VI [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein R 1 , R 2 , and R 3together with the oxygen to which they are attached, each independently represents an optionally substituted carbonate, an optionally substituted carbamate, an optionally substituted thioester, an optionally substituted branched thioester, an optionally substituted thiocarbonate, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid 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 ester, oxymethoxyamino ester, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oximyl, optionally substituted imidinyl, optionally substituted imidyl, optionally substituted aminal, optionally substituted hemiaminal, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carbonimine R, is selected from an optionally substituted thiocarbonimidate, an optionally substituted carbonimidyl, an optionally substituted carbamimidate, an optionally substituted carbamimidyl, an optionally substituted thioacetal, an optionally substituted S-acyl-2-thioethyl, an (acyloxybenzyl)ether, an (acyloxybenzyl)ester, a PEG ester, a PEG carbonate, an optionally substituted bis-(acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, or a BAB ester; 1 , R 2 , and R 3 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, and lipid is C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions, wherein the compound is an aryl substituted with a higher alkoxy, polyethylene glycol, or alkyl group, or a lipid as described herein. In some examples, the compound has the formula VIa-f. [ka]

[0294] In other examples, the compound is: [ka] is selected from.

[0295] Also, a pharmaceutically acceptable excipient and a compound of formula VII [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, for the treatment of 2019nCoV / SARS-CoV-2 infection, R 1 , R 2 , and R 5are, together with the oxygen to which they are attached, each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, Optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 1 , R 2 , and R 5 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0296] Also, a pharmaceutically acceptable excipient and a compound of formula VIII [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, for the treatment of 2019nCoV / SARS-CoV-2 infection, R 1 , R 3 , and R 5are, together with the oxygen to which they are attached, each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, Optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 1 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0297] Also, a compound of formula IX can be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula IX. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, for the treatment of 2019nCoV / SARS-CoV-2 infection, R 2 , R 3 , and R 5are, together with the oxygen to which they are attached, each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, Optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 2 , R 3 , and R 5 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0298] Also, a compound of formula X may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula X. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, for the treatment of 2019nCoV / SARS-CoV-2 infection, -OR 1 , and -OR 5are each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 1 and R 5 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0299] Also, a compound of formula XI may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula XI. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: -OR 1 , and -OR 3are each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 1 and R 3 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0300] Also, a compound of formula XII may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula XII. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, for the treatment of 2019nCoV / SARS-CoV-2 infection, -OR 1 , and -OR 2are each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 1 and R 2 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0301] Also, a compound of formula XIII may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula XIII. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: -OR 2 , and -OR 5are each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,selected from an N-disubstituted D-amino acid ester, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oximyl, optionally substituted imidinyl, optionally substituted imidyl, optionally substituted aminal, optionally substituted hemiaminal, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carbonimidate, optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, optionally substituted thioacetal, optionally substituted S-acyl-2-thioethyl, optionally substituted bis-(acyloxybenzyl)ester, optionally substituted (acyloxybenzyl)ester, or BAB ester; R, 2 and R 5 optionally, one or more of the same or different R 10 is replaced by R 10 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22 Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0302] Also, a compound of formula XIV may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula XIV. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: -OR 2 , and -OR 3are each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 2 and R 3 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0303] Also, a compound of formula XV may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula XV. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: -OR 3 , and -OR 5are each independently 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 3 and R 5 optionally, one or more of the same or different R 10 is replaced by R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0304] Also, a compound of formula XVI may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula XVI. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: -OR 2is 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thio Carbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 2 optionally, one or more of the same or different R 10 is replaced by R 10 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22 Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0305] Also, a compound of formula XVII can be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula XVII. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein: -OR 3is 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, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thio Carbamates, optionally substituted oxymethoxycarbonyls, oxymethoxycarbonates, optionally substituted oxymethoxycarbonates, optionally substituted oxymethoxythiocarbonyls, optionally substituted oxymethylcarbonyls, optionally substituted oxymethylthiocarbonyls, oxymethoxythiocarbonates, optionally substituted oxymethoxythiocarbonates, L-amino acid esters, D-amino acid esters, oxymethoxyamino 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 sulfenyls, sulfinyls, sulfonyls, sulfites, sulfates, sulfonamides, optionally substituted imidates, optionally substituted hydrazonates, optionally substituted oximyls, optionally substituted imidinyls, optionally substituted imidyls, optionally substituted aminals, optionally substituted hemiaminals, optionally substituted acetals, optionally substituted hemiacetals, optionally substituted carbonimidates, optionally R, is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 3 optionally, one or more of the same or different R 10 is replaced by R 10 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22 Disclosed herein are pharmaceutical compositions that are aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0306] Also, a compound of formula XIX may be prepared by mixing a pharmaceutically acceptable excipient with the compound of formula XIX. [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, for the treatment of 2019nCoV / SARS-CoV-2 infection, -OR 5is an optionally substituted thioester, an optionally substituted branched thioester, an optionally substituted thiocarbonate, a sulfenyl thiocarbonate, an optionally substituted sulfenyl thiocarbonate, a 2-hydroxypropanoate ester, an optionally substituted 2-hydroxypropanoate ester, an optionally substituted S-thiocarbonate, an optionally substituted dithiocarbonate, an optionally substituted thiocarbamate, an optionally substituted oxymethoxycarbonyl, an oxymethoxycarbonyl ester, optionally substituted oxymethoxycarbonate, optionally substituted oxymethoxythiocarbonyl, optionally substituted oxymethylcarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid ester, D-amino acid ester, oxymethoxyamino 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 ester, optionally substituted sulfenyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oximyl, optionally substituted imidinyl, optionally substituted imidyl, optionally substituted aminal, optionally substituted hemiaminal, optionally substituted acetal, optionally substituted hemiacetal, optionally substituted carbonimidate, optionally substituted R is selected from optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, 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; 5optionally, one or more of the same or different R 10 is replaced by R 10 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22Higher alkyl, C 11 ~C 22 Disclosed herein are pharmaceutical compositions in which R is an aryl substituted with a higher alkoxy, polyethylene glycol, or alkyl group, or a lipid as described herein. 5 is as follows: [ka] [ka] is selected from R 6 is hydrogen, C2-C7n-alkyl, optionally substituted C8n-alkyl, C9-C 22 n-Alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, C3-C9 cycloalkyl, C 11 ~C 22 Cycloalkyl, optionally substituted C 10 Cycloalkyl, cycloalkenyl, -O(C1-C6n-alkyl), -O(optionally substituted C7n-alkyl), -O(C8-C 21 n-alkyl), -O(branched alkyl), carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, -N(C2-C 21 n-alkyl), -N(optionally substituted C alkyl), -NH(optionally substituted C alkyl), -NH(C-C n-alkyl), -NH(optionally substituted C n-alkyl), -NH(C-C 15 n-alkyl), -NH(optionally substituted C 16 n-alkyl), -NH(C 17 n-alkyl), -NH(optionally substituted C 18 n-alkyl), -NH(C 19 ~C 21n-alkyl), -NH(branched alkyl), -N(branched alkyl), carbocyclamino, heterocarbocyclamino, optionally substituted arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, cyano, or lipid; 6 optionally, one or more of the same or different R 10 is replaced by R 7 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 7 optionally, one or more of the same or different R 10 is replaced by R 8is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 8 optionally, one or more of the same or different R 10 is replaced by R 9 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 9 optionally, one or more of the same or different R 10 is replaced by R 7 , R 8 , and R 9can form a ring with the α-carbon to which they are attached and the amino group attached to that α-carbon, R 8 and R 9 can form a ring with the α-carbon to which they are attached.

[0307] In some examples of compounds disclosed herein, R 1 , R 2 , R 3 , and R 5 are, independently, the following: [ka] [ka] is selected from However, R 1 , R 2 , R 3 , and R 5 However, provided that they are not all H, R 6 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, cyano, or lipid; R 6 optionally, one or more of the same or different R 10 is replaced by R 7is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 7 optionally, one or more of the same or different R 10 is replaced by R 8 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 8 optionally, one or more of the same or different R 10 is replaced by R 9is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 9 optionally, one or more of the same or different R 10 is replaced by R 7 , R 8 , and R 9 can form a ring with the α-carbon to which they are attached and the amino group attached to the α-carbon, R 8 and R 9 can form a ring with the α-carbon to which they are attached, R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0308] In other examples of compounds disclosed herein, R 1 , R 2 , and R 3 are, independently, the following: [ka] [ka] is selected from R 6 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, optionally substituted phenyl, optionally substituted aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, cyano, or lipid; R 6 optionally, one or more of the same or different R 10 is replaced by R 7is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 7 optionally, one or more of the same or different R 10 is replaced by R 8 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 8 optionally, one or more of the same or different R 10 is replaced by R 9is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 9 optionally, one or more of the same or different R 10 is replaced by R 7 , R 8 , and R 9 can form a ring with the α-carbon to which they are attached and the amino group attached to the α-carbon, R 8 and R 9 can form a ring with the α-carbon to which they are attached, R 10is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclylamino, arylamino, heteroarylamino, heterocyclylamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; R 10 optionally, one or more of the same or different R 11 is replaced by R 11 is hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkeneamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; Lipids are C 11 ~C 22 Higher alkyl, C 11 ~C 22Aryl substituted with higher alkoxy, polyethylene glycol, or alkyl groups, or lipids as described herein.

[0309] Also included are compounds comprising a pharmaceutically acceptable excipient and a compound having the structure [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, for the treatment of COVID-19.

[0310] Further disclosed is a pharmaceutical composition of the compound disclosed herein, further comprising a propellant.The propellant is 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.Also disclosed is a pressurized container containing the pharmaceutical composition disclosed herein.The container can be a manual pump spray, an inhaler, a metered dose inhaler, a dry powder inhaler, a nebulizer, a vibrating mesh nebulizer, a jet nebulizer, or an ultrasonic nebulizer.

[0311] Also disclosed are methods for treating or preventing 2019nCoV / SARS-CoV-2 infection, comprising administering to a patient in need thereof an effective amount of a composition disclosed herein. The method for treating or preventing 2019nCoV / SARS-CoV-2 infection comprises administering to a patient in need thereof an effective amount of a compound having the structure: [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, to a patient.

[0312] Also provided is a method of treating or preventing COVID in a patient in need thereof, comprising the step of: [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof.

[0313] Also, a compound having the following structure [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, and a pharmaceutically acceptable excipient, or a tautomer thereof, or a pharmaceutical or physiological salt thereof, and further comprising abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, valapiravir, BCX4430 / galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir , dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, GS-5734 / remdesivir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, ibuprofen Interferon type 1, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir Disclosed herein are pharmaceutical compositions comprising one or more antiviral agents such as fluvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, or zidovudine, and combinations thereof.

[0314] Also included are compounds comprising a pharmaceutically acceptable excipient and a compound having the structure [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, with abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, valapiravir, galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, Enfuvirtide, Entecavir, Famciclovir, Favipiravir, Fomivirsen, Fosamprenavir, Foscarnet, Fosfonet, Ganciclovir, Remdesivir, Ibacitabine, Immunovir, Idoxuridine, Imiquimod, Indinavir, Inosine, Interferon III, Interferon II, Interferon I, Lamivudine, Ledipasvir, Lopinavir, Lovirid, Maraviroc, Moroxydine, Methisan Zon, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, and one or more antiviral agents selected from the group consisting of tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine, and combinations thereof.

[0315] Also provided is a compound for the treatment of 2019nCoV / SARS-CoV-2 infection, the compound comprising: [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein the one or more antiviral agents are abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, valapiravir, galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, remdesivir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipavir, Subvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, Disclosed herein is a compound selected from the group consisting of stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine, and combinations thereof.

[0316] Also included are compounds comprising a pharmaceutically acceptable excipient and a compound having the structure [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, with abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, valapiravir, galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricilamine, benzodiazepine, benzophenone, benzothiazolin ... Tabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, remdesivir, ibacitabine, Immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviridone, maraviroc, mogamulizumab Roxyzine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir and one or more antiviral agents selected from the group consisting of tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine, and combinations thereof.

[0317] Also provided is a compound for the treatment of COVID-19, the compound comprising: [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, wherein the one or more antiviral agents are abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, valapiravir, galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, remdesivir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, levovir Dipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sophos Disclosed is a compound selected from the group consisting of buvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine, and combinations thereof.

[0318] Also provided is a method for treating a 2019nCoV / SARS-CoV-2 infection, comprising administering to a subject an effective amount of a compound having the structure: [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, with abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, valapiravir, galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, em Tricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, remdesivir, ibacitabine, Immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, lovirid, mast cell Raviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, terbicycline and one or more antiviral agents selected from the group consisting of vudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine, and combinations thereof.

[0319] Also provided is a method for treating COVID-19, comprising administering to a subject an effective amount of a compound having the structure: [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof, with abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, valapiravir, galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, em Tricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, remdesivir, ibacitabine, Immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, lovirid, mast cell Raviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, terbicycline and one or more antiviral agents selected from the group consisting of vudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine, and combinations thereof.

[0320] Also disclosed are methods for 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 some examples, the compound is [ka] or a tautomer thereof, or a pharmaceutical or physiological salt thereof.

[0321] Also disclosed is a method of treating a viral CNS infection in a patient, comprising administering to the patient having the viral CNS infection an effective amount of a composition or compound disclosed herein. The viral CNS infection can be 2019-nCoV / SARS-CoV-2. [Example]

[0322] The following examples are provided below to illustrate compositions, methods, and results according to the subject matter of the present disclosure. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention, which would be apparent to those skilled in the art.

[0323] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight. There are many variations and combinations of reaction conditions, such as component concentrations, temperatures, pressures, and other reaction ranges, as well as conditions that can be used to optimize the purity and yield of the products obtained from the described processes. Only reasonable and routine experimentation will be required to optimize such process conditions.

[0324] All chemical reactions were performed under a nitrogen atmosphere in oven-dried glassware except where noted. Chemicals and solvents were reagent grade and purchased from commercial suppliers (typically Aldrich, Fisher, Acros, Carbosynth Limited, and Oakwood Chemical) and used as received except where noted. In particular, EIDD-1910, EIDD-1993, and EIDD-2003 were purchased from Carbosynth Limited. Solvents used for reactions (tetrahydrofuran, methanol, acetonitrile, dichloromethane, toluene, pyridine, dimethylformamide) were 99.9% or greater anhydrous in all cases. Unless otherwise noted, all reactions were followed by thin-layer chromatography. Thin-layer chromatography analysis was performed on silica gel using irradiation with a UV lamp (254 nm) or staining and heating with KMnO4. RediSep® 40-60 micron (60 Å particle size) silica gel purchased from Teledyne Isco was used. f Manual flash column chromatography was performed using silica gel as the stationary phase. Automated gradient flash column chromatography was performed on a Teledyne Isco CombiFlash Companion using pre-packed RediSep®. f Conventional phase separation was performed using silica gel as the stationary phase and pre-packed RediSep® f C 18 Reverse-phase separation was performed using a high-performance gold stationary phase. Triphosphate purification was performed using ion exchange chromatography using DEAE (diethylaminoethyl) Sephadex A-25 as the stationary phase and TEAB (triethylammonium bicarbonate) in water as the mobile phase.

[0325] 1H NMR spectra were measured on a Varian 400 MHz instrument and processed using MestReNova software, version 9.0.1. Chemical shifts were measured relative to the appropriate solvent peak: CDCl3 (δ 7.27), dimethylsulfoxide-d6 (δ 2.50), CD3OD (δ 3.31), DO (δ 4.79). The following abbreviations were used to denote bonds: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, br = broadened. Chemical shifts are relative to the appropriate solvent peak. 13 C NMR spectra were measured on a 100 MHz Varian instrument: CDCl (δ 77.0), dimethylsulfoxide-d (δ 39.5), CD OD (δ 49.0). 19 F spectra were measured on a 376 MHz Varian instrument, 31 P spectra were measured on a 162 MHz Varian instrument. 19 F spectrum, 31 P spectrum, and 13 The chemical shifts of the C spectrum (DO only) were compared with the corresponding 1 The absolute reference function for the 1 H NMR spectra was used to calibrate with MestReNova software.

[0326] Nominal (low resolution) liquid chromatography / mass spectrometry was performed using a Zorbax Eclipse XDB C column eluted with a methanol / water mixture (typically 95 / 5 isotonic) and an Agilent 6120 liquid chromatography / mass spectrometry quadrupole instrument. 18 Analysis was performed using an Agilent 1200 system LC (UV absorbance detector at 254 nm) using a 4.6 x 50 mm, 3.5 micron column. High-resolution mass analysis was performed by the Emory University Center for Mass Spectrometry on a Thermo LTQ-FTMS using either APCI or ESI.

[0327] Example 1: Synthesis of N4-hydroxycytidine or 1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(hydroxyamino)pyrimidin-2-one (EIDD-1931) Protection of the uridine by persilylation was followed by activation of the 4-position of the nucleobase with a hindered arylsulfonyl group (see Figure 1). Displacement of this group with hydroxylamine introduced the N-4-hydroxy moiety. Global deprotection using any one of a number of available fluoride sources afforded the desired product.

[0328] The compound could be made in one step from cytidine by heating in a pH-adjusted solution of hydroxylamine. Although shorter, this route tended to result in lower yields and required purification by reverse-phase flash column chromatography, limiting its use to smaller production runs.

[0329] An alternative synthetic route is shown below. [ka]

[0330] A three-neck, 2 L flask equipped with an overhead stirrer and nitrogen inlet was charged with uridine (25 g, 102 mmol) and 1 L of dichloromethane. The resulting solution was cooled to 0 °C, and 4-dimethylaminopyridine (1.251 g, 10.24 mmol) and imidazole (27.9 g, 409 mmol) were added sequentially. tert-Butyldimethylsilyl chloride (61.7 g, 409 mmol) was added over 10 minutes, and the resulting mixture was warmed to ambient temperature and stirred for 18 hours. Water (300 mL) was added to the reaction mixture, which was stirred at room temperature for 2 hours. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were washed with brine (1 × 300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 75 g of a clear, colorless oil. Purification by flash chromatography (5-20% gradient of ethyl acetate in hexanes) gave S1 (45 g, 75%) as a clear, colorless oil that solidified upon drying in vacuo. 1 H NMR (400MHz, CDCl3) δ8.09(s, 1H), 8.02(d, J=8.2Hz, 1H), 5.87(d, J=3.6Hz, 1H ), 5.67(dd, J=8.1, 2.2Hz, 1H), 4.07(q, J=3.8, 3.3Hz, 1H), 3.98(dd, J=11.7, 1. 7Hz, 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).

[0331] A 1 L round-bottom flask was charged with S1 (28 g, 47.7 mmol) and dichloromethane (700 mL). The solution was cooled to 0 °C using an ice bath, and 4-dimethylaminopurine (0.583 g, 4.77 mmol) and N,N-diisopropylethylamine (41.7 mL, 239 mmol) were added sequentially. 2,4,6-triisopropylbenzene-1-sulfonyl chloride (28.9 g, 95 mmol) was slowly added to the flask. After the addition was complete, the flask was warmed to ambient temperature and stirred for 18 h. The dark orange solution was cooled to 0 °C in an ice bath, and N,N-diisopropylethylamine (24.66 g, 191 mmol) was added via syringe, followed by solid hydroxylamine hydrochloride (13.26 g, 191 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with water (200 mL) and the resulting layers were separated. The aqueous layer was extracted with dichloromethane (200 mL), and the combined organics were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a dark orange oil. Purification by flash chromatography (15–50% gradient of ethyl acetate in hexanes) gave S2 (19.8 g, 69% over two steps) as an oil that solidified to a semisolid upon drying in vacuo. 1 H NMR (400MHz, CDCl3) δ8.15(s, 1H), 6.31(s, 1H), 5.91(d, J=4.6Hz, 1H), 5.56(dd, J=8.2, 2.0Hz, 1H), 4.07(m, 2H), 4.02(m, 1H), 3.91(dd, J=11.6, 2.4Hz , 1H), 3.73(dd, J=11.6, 2.4Hz, 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] + .

[0332] A 50 mL round-bottom flask was charged with S2 (23.3 g, 38.7 mmol) and THF (50 mL). Triethylamine trihydrofluoride (6.30 mL, 38.7 mmol) was added in one portion, and the mixture was stirred at ambient temperature for 18 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in a minimum amount of methanol. This solution was slowly added to an Erlenmeyer flask containing rapidly stirred dichloromethane (500 mL) to precipitate the product, and the mixture was stirred at room temperature for 15 min. The crushed solid was collected by vacuum filtration and washed with dichloromethane and then ether. The solid was dried under vacuum to give the title compound (7.10 g, 71%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.16 (d, J=8.2Hz, 1H), 5.86 (d, J=5.6Hz, 1H), 5.59 (d, J=8.2Hz, 1H), 4.19~ 4.04(m, 2H), 3.93(q, J=3.3Hz, 1H), 3.77(dd, J=12.2, 2.9Hz, 1H), 3.68(dd, J=12.1, 2.9Hz, 1H), 1 H NMR (400MHz, dimethyl sulfoxide-d6) δ9.95(s, 1H), 9.46(s, 1H), 7.02(d, J=8.2Hz, 1H ), 5.71(d, J=6.3Hz, 1H), 5.54(d, J=7.7Hz, 1H), 5.23(d, J=6.0Hz, 1H), 5.02(d , J=4.6Hz, 1H), 4.98(t, J=5.1Hz, 1H), 3.95(q, J=5.9Hz, 1H), 3.89(td, J=4.9H) z, 3.0Hz, 1H), 3.75(q, J=3.4Hz, 1H), 3.50(qdd, J=11.9Hz, 5.2Hz, 3.5Hz, 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] + .

[0333] Example 2: Synthesis of EIDD-2061 [ka] A sealable pressure tube was charged with a stir bar, cytidine triphosphate disodium salt (0.137 g, 0.260 mmol), and 2 N aqueous hydroxylamine solution adjusted to pH = 5 (2.0 mL, 4.0 mmol). After mixing the reagents, the pH of the solution was measured (pH = 3), and an additional 10% w / w aqueous solution was added dropwise. NaOH solution was added to readjust the solution to pH = 5. The tube was sealed and heated with stirring at 55 °C for 5 hours. The mixture was cooled to room temperature, the sealed tube was opened, and a solution of 100 mM triethylammonium bicarbonate (TEAB) (2 mL) was added. The contents of the tube were transferred to a round-bottom flask and concentrated by rotary evaporation. The crude material was taken up in 100 mM TEAB and chromatographed on DEAE. The product was then lyophilized to afford the triethylammonium salt of the desired product.

[0334] Freshly prepared Dowex™ (Li + An ion exchange column (17 mL CV) of (C14-20) was rinsed with 5 CV of water. The prepared triethylammonium salt was taken up in water and eluted through the ion exchange column. The fractions containing the product were combined and lyophilized to give the title compound (0.030 g, 22%) as a fluffy tan solid. 1 H NMR (400MHz, D2O) δ7.19(d, J=8.3Hz, 1H), 5.95(d, J=6.3Hz, 1H), 5.82(d, J=8.3Hz, 1H), 4.42~4.34(m, 2H), 4.24~4.10(m, 3H), 31 P NMR (162MHz, D2O) δ-8.5(br s), -11.2(d, J=19.6Hz), -22.0(t, J=19.3Hz), LRMS m / z 498.0[MH] - .

[0335] Example 3: Synthesis of EIDD-2101 [ka] A solution of 5-methylcytidine (0.257 g, 1.00 mmol) in 2 N aqueous hydroxylamine with pH 6 (8 mL, 16.0 mmol) was heated to 55 °C in a sealed tube with stirring for 5 h. The solution was cooled to room temperature, transferred to a round-bottom flask, concentrated by rotary evaporation, and coevaporated with methanol (MeOH) (2 × 20 mL). The crude residue was taken up in MeOH and immobilized on silica gel. Flash chromatography (2-10% gradient of MeOH in dichloromethane) afforded the title compound (140 mg, 51%) as a pale purple solid. 1 H NMR (400MHz, CD3OD) δ6.99(s, 1H), 5.86(d, J=5.7Hz, 1H), 4.23~4.06(m, 2H), 3.93(q, J=3 .2Hz, 1H), 3.78(dd, J=12.1Hz, 2.8Hz, 1H), 3.70(dd, J=12.1Hz, 3.4Hz, 1H), 1.79(s, 3H), 13 C NMR (100MHz, CD3OD) δ152.0, 146.6, 128.4, 108.4, 89.4, 86.1, 74.4, 71.8, 62.8, 12.9, C 10 H 16 O6N3[M+H] + HRMS calculated for: 274.10336, found: 274.10350.

[0336] Example 4: Synthesis of EIDD-2103 [ka] A 2N solution of hydroxylamine hydrochloride (1.11 g, 16.0 mmol) in water (8 mL) was prepared and adjusted to pH = 5 with a small amount of aqueous NaOH (10% w / w). A sealable pressure tube was charged with this solution and 5-fluorocytidine (0.261 g, 1.00 mmol), the flask was sealed, and the mixture was heated with stirring 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 material was suspended in methanol and immobilized on CELITE® diatomaceous earth. Automated flash chromatography (40 g column, 0-20% gradient of methanol in dichloromethane) afforded 600 mg of a semi-clear pink solid. This solid was dissolved in 2 mL of water and purified by automated reverse-phase chromatography (43 g column, 5-100% gradient of methanol in water) to afford the desired product, free of organic and inorganic impurities. The solid was dissolved in water, frozen in a dry ice / acetone bath, and lyophilized to give the title compound (0.066 g, 0.238 mmol, 24% yield) as a white fluffy solid. 1 H NMR(400MHz,D2O)δ7.31(d, J=7.6Hz, 1H), 5.87(dd, J=5.5Hz, 1.8Hz, 1H), 4.26(t, J=5.5Hz, 1H), 4.19(t , J=4.8Hz, 1H), 4.07(q, J=3.8Hz, 1H), 3.85(dd, J=12.8Hz, 3.1Hz, 1H), 3.77(dd, J=12.7Hz, 4.2Hz, 1H), 13 C NMR (100MHz, D2O) δ150.0, 139.7, 137.4, 115.6 (d, J=36.1Hz), 88.0, 84.2, 72.8, 69.8, 61.0, 19 F NMR (376MHz, D2O) δ-164.70 (d, J=7.6Hz), C9H 13 FN3O6[M+H] + HRMS calculated value: 278.07829; found value: 278.07848.

[0337] Example 5: Synthesis of EIDD-2216 [ka] A 5N solution of hydroxylamine hydrochloride (4.71 g, 67.8 mmol) in water (13.5 mL) was prepared and adjusted to pH = 5 with a small amount of aqueous NaOH (10% w / w). In a sealable pressure tube, this solution and [1',2',3',4',5'- 13 C5] cytidine (0.661 g, 2.26 mmol) was charged, the flask was sealed, and heated with stirring 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 taken up in water and subjected to automated reverse-phase flash chromatography (240 g C 18 The bulk of the impurities were removed by column chromatography (0-100% gradient of acetonitrile in water) to give 1.4 g of a wet solid. This solid was dissolved in water and purified by a second automated reverse-phase chromatography (240 g C 18 More impurities were removed by column chromatography (0-100% gradient of acetonitrile in water) to give 400 mg of semi-pure material. The material was dissolved in methanol and immobilized on CELITE™ diatomaceous earth. Automated flash chromatography (24 g column, 5-25% gradient of methanol in dichloromethane) gave 200 mg of nearly pure product. The solid was dissolved in water and purified by final automated reverse-phase chromatography (48 g C 18 Column, 0-100% gradient of acetonitrile in water) afforded the desired product free of organic and inorganic impurities. The solid was dissolved in water, frozen in a dry ice / acetone bath, and lyophilized to afford the title compound (0.119 g, 20%) as a pale purple fluffy solid that was approximately 95% pure by NMR / LCMS analysis. 1 H NMR (400MHz, D2O) δ7.03(dd, J=8.2Hz, 2.2Hz, 1H), 5.82(ddd, J=167.5Hz, 5.3Hz, 2.9Hz, 1H), 5.70(d, J=8.2Hz, 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), 13C NMR (100MHz, D2O) δ151.3, 146.6, 131.3, 98.7, 87.9 (dd, J=43.1Hz, 4.0Hz), 84.0 (dd, J=41.5Hz) , 38.0Hz), 72.5(dd, J=43.3Hz, 37.8Hz), 69.8(td, J=37.9Hz, 3.9Hz), 61.1(d, J=41.5Hz), LRMS m / z 265.1[M+H] + .

[0338] Example 6: Synthesis of EIDD-2261 [ka] A sealable pressure tube was charged with uridine (1.00 g, 4.09 mmol), K2CO3 (0.679 g, 4.91 mmol), and deuterium oxide (8.2 mL). The mixture was purged with nitrogen for 15 minutes, the tube was sealed, and the contents were heated with stirring at 95 °C for 16 hours. The mixture was cooled to room temperature, the tube was unsealed, and the mixture was transferred to a round-bottom flask and concentrated by rotary evaporation. The resulting crude product was coevaporated with methanol (3x) to remove water. NMR analysis indicated greater than 95% deuterium incorporation at the 5-position on the nucleobase. The light brown solid S28 (1.00 g, 100%) was used in the next step without further purification. 1 H NMR (400MHz, CD3OD) δ7.76 (s, 1H), 5.88 (d, J=4.2Hz, 1H), 4.17~4.12 (m, 2H), 4.0 0~3.96(m, 1H), 3.84(dd, J=12.3Hz, 2.8Hz, 1H), 3.72(dd, J=12.3Hz, 3.5Hz, 1H), 13 C NMR (100MHz, CD3OD) δ185.6, 177.4, 160.4, 141.1, 91.8, 85.8, 75.9, 71.2, 62.4.

[0339] A round-bottom flask was charged with S28 (1.00 g, 4.09 mmol) and dichloromethane (8 mL) under nitrogen. 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 in one portion. tert-Butyldimethylsilyl chloride (2.15 g, 14.3 mmol) was added in one portion as a solid, and the mixture was allowed to warm 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, 0-35% gradient of ethyl acetate in hexanes) gave S29 (2.52 g, 84%) as an off-white foam. 1 H NMR (400MHz, CDCl3)δ8.08(br s, 1H), 8.03(s, 1H), 5.89(d, J=3.6Hz, 1H), 4.12~4.06(m, 3H), 3.99(dd, J=11.5Hz, 1.8Hz, 1H), 3.76(d, J=12.0Hz, 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 C NMR (100MHz, CDCl3) δ163.7, 150.3, 140.3, 89.0, 84.3, 76.1, 70.5, 61.6, 26.0(3 C), 25.8(3C), 25.7(3C), 18.4, 18.3, 17.9, -4.2, -4.6, -4.8, -4.9, -5.4, -5.6, C 27 H 54 DN2NaO6Si[M+Na] + HRMS calculated for: 610.32446, found: 610.32482.

[0340] To a stirred solution of S29 (0.840 g, 1.43 mmol) in acetonitrile (14.3 mL) at 0 °C under nitrogen, 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 added sequentially. The mixture was stirred at 0 °C for 2.5 h, at which time hydroxylamine hydrochloride (0.993 g, 14.3 mmol) was added in one portion as a solid. 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), then washed with water (2 × 100 mL) and brine (1 × 100 mL), dried over Na SO , filtered, and concentrated by rotary evaporation. Automated flash chromatography (40 g column, 5-35% gradient of ethyl acetate in hexanes) yielded a mixture of starting material and desired product. A second automated flash chromatography (24 g column, 10-40% gradient of ethyl acetate in hexanes) afforded S30 (0.332 g, 39%) as an off-white foam. 1 H NMR (400MHz, CDCl3)δ8.37(br s, 1H), 5.92(d, J=4.6Hz, 1H), 4.10~4.05(m, 2H), 4.04~4.00(m, 1H), 3.91(dd, J=11.6Hz, 2.4Hz, 1H), 3.73(dd, J=11.6H) z, 1.8Hz, 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).

[0341] A round-bottom flask was charged with S30 (0.332 g, 0.551 mmol), tetramethylammonium fluoride (0.196 g, 2.64 mmol), tetrahydrofuran (THF) (8.25 mL), and dimethylformamide (DMF) (2.75 mL) at 0 °C under nitrogen. Acetic acid (0.157 mL, 2.75 mmol) was added in one portion via syringe. The mixture was warmed to 45 °C and heated with stirring for 4 days, then concentrated by rotary evaporation. Automated flash chromatography (40 g column, 0-20% gradient of methanol in dichloromethane) afforded the title compound (0.106 g, 74%) as a white solid. Final NMR analysis indicated greater than 95% deuterium incorporation at the 5-position of the nucleobase. 1 H NMR (400MHz, D2O) δ7.16(s, 1H), 5.85(d, J=5.6Hz, 1H), 4.14(t, J=5.5Hz, 1H), 4.10(dd, J=5.6Hz, 3 .8Hz, 1H), 3.93(q, J=3.4Hz, 1H), 3.77(dd, J=12.2Hz, 2.9Hz, 1H), 3.68(dd, J=12.2Hz, 3.4Hz, 1H), 13 C NMR (100MHz, CD3OD) δ151.8, 146.3, 132.1, 89.7, 86.1, 74.6, 71.8, 62.8, C9H 13 DN3O6[M+H] + HRMS calculated value for: 261.09399, found value: 261.09371.

[0342] Example 7: Synthesis of EIDD-2345 [ka] A round-bottom flask was charged with S8 (3.13 g, 11.0 mmol) and dichloromethane (75 mL) at room temperature under nitrogen. To this stirred mixture, pyridinium dichromate (8.28 g, 22.0 mmol), acetic anhydride (10.4 mL, 110 mmol), and t-butanol (21.1 mL, 220 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 22 hours and then washed with water (1 × 75 mL). The aqueous layer was extracted with dichloromethane (2 × 75 mL), and the combined organic layers were washed with brine (1 × 100 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation. The resulting residue was taken up in ethyl acetate and filtered through a plug of CELITE™ diatomaceous earth, followed by ethyl acetate washing. The filtrate was concentrated by rotary evaporation and purified by automated flash chromatography (120 g column, 40-80% gradient of ethyl acetate in hexanes) to give S31 (3.10 g, 72%) as an off-white foam. 1 H NMR (400MHz, CDCl3)δ8.36(br s,1H), 7.42(d, J=8.0Hz, 1H), 5.76(dd, J=8.0Hz, 2.3Hz, 1H), 5.59(s, 1H), 5.27(dd, J=6.0Hz, 1 .8Hz, 1H), 5.19(d, J=6.0Hz, 1H), 4.62(d, J=1.8Hz, 1H), 1.56(s, 3H), 1.48(s, 9H), 1.39(s, 3H).

[0343] To a stirred solution of S31 (2.61 g, 7.37 mmol) in deuterated ethanol (75 mL) at room temperature under nitrogen, NaBD4 (1.234 g, 29.5 mmol) was added all at once. The mixture was stirred at room temperature for 1 h, heated to 55 °C for 6 h, and then stirred at room temperature overnight. The mixture was cooled to 0 °C, and excess reagent was quenched with deuterated acetic acid. The mixture was concentrated by rotary evaporation to give crude S32 (2.57 g), which was taken directly into the next step without further purification.

[0344] To a stirred suspension of crude S32 (2.00 g impurity, 5.74 mmol) in dichloromethane (70 mL) at 0 °C, solid imidazole (1.90 g, 27.9 mmol) and 4-dimethylaminopyridine (0.171 g, 1.40 mmol) were added. Solid t-butyldimethylsilyl chloride (2.11 g, 14.0 mmol) was added, and the mixture was warmed to room temperature and stirred for 4 days. The mixture was washed sequentially with water and brine (1 × 70 mL each), dried over NaSO, filtered, and concentrated by rotary evaporation. Automated flash chromatography (120 g column, 0–35% gradient of ethyl acetate in hexanes) afforded S33 (1.42 g, 66% over two steps) as a white solid. 1 H NMR (400MHz, CDCl3)δ8.30(br s, 1H), 7.72(m, 1H), 5.99(d, J=2.8Hz, 1H), 5.69(dd, J=8.2Hz, 2.3Hz, 1H), 4.77(dd, J=6.1Hz, 2.9Hz, 1H), 4.69( dd, J=6.2Hz, 2.8Hz, 1H), 4.33(d, J=3.0Hz, 1H), 1.60(s, 3H), 1.37(s, 3H), 0.91(s, 9H), 0.11(s, 3), 0.10(s, 3H), 13 C NMR (100MHz, CDCl3) δ162.7, 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, C 18 H 29 D2N2O6Si[M+H] + HRMS calculated for: 401.20714, found: 401.20663.

[0345] To a stirred solution of S33 (1.42 g, 3.55 mmol) in acetonitrile (35 mL) under nitrogen at 0 °C, p-toluenesulfonyl chloride (1.35 g, 7.09 mmol), 4-dimethylaminopyridine (0.433 g, 3.55 mmol), and triethylamine (9.88 mL, 70.9 mmol) were added sequentially. 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 with stirring at 50 °C for 2 days. The mixture was recooled to room temperature, diluted with ethyl acetate (100 mL), and then washed with water (2 × 50 mL) and brine (1 × 50 mL), dried over Na SO , filtered, and concentrated by rotary evaporation. Automated flash chromatography (120 g column, 1-3.5% gradient of methanol in dichloromethane) afforded S34 (0.416 g, 28%) as an off-white solid. 1 H NMR (400MHz, CDCl3)δ8.36(br s, 1H), 7.00(m, 1H), 5.97(d, J=3.1Hz, 1H), 5.58(d, J=8.2Hz, 1H), 4.77(dd, J=6.2Hz, 3.2Hz, 1H), 4.68(dd, J =6.3Hz, 3.2Hz, 1H), 4.22(d, J=3.2Hz, 1H), 1.59(s, 3H), 1.36(s, 3H), 0.92(s, 9H), 0.11(s, 3H), 0.10(s, 3H), 13 C NMR (100MHz, CDCl3) δ149.0, 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, C 18 H 29 D2N3O6Si[M+H] + HRMS calculated value: 416.21804, measured value: 416.21827

[0346] To a stirred solution of S34 (0.416 g, 1.00 mmol) in THF (5 mL) under nitrogen at 0 °C, a 1.0 M THF solution of TBAF (1.50 mL, 1.5 mmol) was added 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, 0–8% gradient of methanol in dichloromethane) to give S35 (0.257 g, 85%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.02(m, 1H), 5.81(d, J=3.2Hz, 1H), 5.58(d, J=8.2Hz, 1H), 4.86(dd, J=6.4 Hz, 3.2Hz, 1H), 4.79(dd, J=6.5Hz, 3.6Hz, 1H), 4.09(d, J=3.7Hz, 1H), 1.54(s, 3H), 1.34(s, 3H), 13 C NMR (100MHz, CD3OD) δ151.3, 146.2, 133.4, 115.2, 99.4, 92.9, 87.2, 84.9, 82.1, 27.6, 25.6, C 12 H 16 D2N3O6[M+H] + HRMS calculated value: 302.13157, found value: 302.13130.

[0347] To a stirred solution of S35 (0.140 g, 0.465 mmol) in methanol (8.4 mL) and water (0.93 mL) at room temperature, Dowex 50WX8 hydrogen form (0.30 g) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered, and the filtrate was concentrated by rotary evaporation. Automated flash chromatography (40 g column, 5-20% gradient of methanol in dichloromethane) afforded the title compound (0.050 g, 41%) as an off-white solid. 1 H NMR (400MHz, CD3OD) δ7.17(m, 1H), 5.86(d, J=5.6Hz, 1H), 5.60(d, J=8.2Hz, 1H ), 4.15(t, J=5.5Hz, 1H), 4.11(dd, J=5.6Hz, 3.5Hz, 1H), 3.94(d, J=3.8Hz, 1H), 13C NMR (100MHz, CD3OD) δ151.8, 146.3, 132.2, 99.3, 89.7, 86.0, 74.6, 71.7, C9H 10 D2N3O6[M+H] + HRMS calculated for: 260.08571, found: 260.08578.

[0348] Example 8: Synthesis of EIDD-2898 [ka] A 3-neck 2 L round bottom flask was charged with 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). The resulting slurry was stirred at room temperature, and sulfuric acid (2 mL) was added. Stirring was continued overnight. The clear, colorless solution was quenched and adjusted to basic pH with 100 mL of trimethylamine. The crude solution was concentrated under reduced pressure to give a pale yellow oil. The residue was dissolved in 600 mL of ethyl acetate and washed with water × 2, bicarbonate × 2, water, brine × 2, and dried over sodium sulfate. The colorless solution was concentrated under reduced pressure to give 1-[(3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrimidine-2,4-dione (45 g) as a white solid.

[0349] A 200 mL round-bottom flask was charged with 1-[(3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrimidine-2,4-dione (2.36 g, 8.3 mmol) and dichloromethane (50 mL). The reaction was stirred until a solution formed. Then, (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (2.16 g, 9.96 mmol) and N,N-dimethylpyridin-4-amine (0.1 g, 0.8300 mmol) were added. The reaction was cooled to 0 °C in an ice bath. A solution of N,N'-dicyclohexylcarbodiimide (2.06 g, 9.96 mmol) in dichloromethane was slowly added. The reaction mixture was allowed to warm to room temperature and was monitored by thin layer chromatography (ethyl acetate).

[0350] A precipitate formed after approximately 1 hour, and no starting material was detected after 3 hours. The solid was filtered and rinsed with ethyl acetate. The filtrate was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure to give a white sticky solid. The gummy solid was triturated with ether and filtered to remove the solid. The filtrate was concentrated under reduced pressure to give approximately 8 g of a highly viscous oil. The product was purified by SGC, and fractions 6–25 were pooled, concentrated under reduced pressure, and dried in vacuo to give [(3aR,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate (3.8 g, 7.8592 mmol, 94.667% yield) as a foamy white solid.

[0351] The 1,2,4-triazole was taken up in anhydrous acetonitrile and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C, POCl3 was added dropwise, and stirring was continued for 2 hours. After 2 hours, triethylamine was added dropwise and stirring was continued for 1 hour. The reaction mixture was then slowly warmed to room temperature, and the uridine-derived substrate from the above reaction was added as a solution in acetonitrile. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, taken up in dichloromethane, and extracted with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography.

[0352] To a solution of the substrate in acetonitrile (10 mL / gm), 50% hydroxylamine in water was added dropwise and stirred at room temperature for 2-3 hours. After completion of the reaction, the solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using hexane and ethyl acetate as eluents.

[0353] 1 g of substrate was taken up in 20 mL of methanol and treated with 2 mL of concentrated HCl (36%). 30% completion was observed after 3-4 hours. An additional 5 mL of concentrated HCl was added and stirred overnight. After completion of the reaction, the solvent was removed, the crude product was taken up in minimal methanol, and added dropwise to excess diethyl ether with stirring. The product was crashed out of solution, allowed to settle, the ether was decanted, fresh ether was added, stirred, allowed to settle, and decanted. The same process was repeated twice. After decanting the ether, the solid was dried on a rotary evaporator and under high vacuum to yield a free-flowing white solid. The ether was trapped in the solid and difficult to remove. The solid was dissolved in methanol, evaporated, and dried to yield a colorless foam that still retained the methanol. The foam was taken up in water, and a purple solution was observed. The purple solution was purified by reverse-phase ISCO column chromatography using water and acetonitrile. The product-containing fractions were evaporated under reduced pressure and lyophilized to yield a colorless solid.

[0354] Example 9: Synthesis of EIDD-2800 [ka] A three-neck, 1 L round-bottom flask equipped with an overhead stirrer, temperature probe, and addition funnel was charged with uridine (25 g, 102.38 mmol) and ethyl acetate (500 mL). The white slurry was stirred at ambient temperature, and triethylamine (71.39 mL, 511.88 mmol) and 4-dimethylaminopyridine (0.63 g, 5.12 mmol) were added to the mixture. The slurry was cooled in an ice bath, and isobutyl anhydride (56.02 mL, 337.84 mmol) was slowly added to the reaction mixture over 5 minutes. The temperature rose 25 °C during the addition. The resulting slurry was stirred at ambient temperature and monitored by thin-layer chromatography. After 1 hour, a clear, colorless solution formed, and thin-layer chromatography indicated the absence of starting material. The reaction was quenched with 200 mL of water and stirred at room temperature for 20 minutes. The layers were separated, and the organics were washed with water (2 x 100 mL), saturated aqueous bicarbonate solution (100 mL x 2), 100 mL of water, brine (100 mL x 2), and then dried over sodium sulfate. The organics were filtered, and the filtrate was concentrated under reduced pressure at 45 °C to give a yellow oil. The oil was used in the next step without further purification.

[0355] A three-necked, 2-L flask equipped with an argon inlet, overhead stirrer, and temperature probe was charged with 1H-1,2,4-triazole (50.88 g, 736.68 mmol), triethylamine (114.17 mL, 818.54 mmol), and acetonitrile (350 mL). The reaction mixture was stirred at room temperature for 20 minutes. A solution of [(2R,3R,4R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-bis(2-methylpropanoyloxy)tetrahydrofuran-2-yl]methyl 2-methylpropanoate (46.5 g, 102.32 mmol) in ethyl acetate (350 mL) was added, and the mixture was cooled to below 5°C using an ice bath. Stirring was continued for 20 minutes. Phosphorus(V) oxychloride (14.35 mL, 153.48 mmol) was then added slowly under argon over 15 minutes below 20° C. The reaction was monitored by thin layer chromatography (100% ethyl acetate) to identify the product (R f =0.78), the starting material (R f =0.89) was consumed in a new spot in less than 2 hours. The reaction was quenched with 500 mL of water and 400 mL of ethyl acetate. The quenched reaction was allowed to stir at room temperature for 15 minutes. The layers were separated, and the organic layer was washed with water (2 x 100 mL), 200 mL of 0.5 N HCl, and brine (2 x 100 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give [(2R,3R,4R)-3,4-bis(2-methylpropanoyloxy)-5-[2-oxo-4-(1,2,4-triazol-1-yl)pyrimidin-1-yl]tetrahydrofuran-2-yl]methyl 2-methylpropanoate (49 g, 96.93 mmol, 94.735% yield) as a yellow oil. The crude material was used in the next step without further purification.

[0356] A 500 mL round-bottom flask was charged with [(2R,3R,4R)-3,4-bis(2-methylpropanoyloxy)-5-[2-oxo-4-(1,2,4-triazol-1-yl)pyrimidin-1-yl]tetrahydrofuran-2-yl]methyl 2-methylpropanoate (48.9 g, 96.73 mmol), ethyl acetate (400 mL), and isopropyl alcohol (100 mL). The reaction mixture was stirred at room temperature until all starting material was dissolved. The orange solution was treated with hydroxylamine (6.52 mL, 106.41 mmol), and the resulting pale yellow solution was stirred at room temperature and monitored by thin-layer chromatography (ethyl acetate). After 1 h, no starting material was observed. The reaction was quenched with 500 mL of water, and the layers were separated. The organics were washed with 100 mL of water, 2 x 100 mL of brine, and then dried over sodium sulfate. The organics were filtered and concentrated under reduced pressure to give the crude product. The crude product was dissolved in 180 mL of hot methyl tert-butyl ether and cooled to room temperature. Seed crystals were added, and the flask was placed in the freezer. The white solid that formed was collected by filtration, washed with a minimum amount of methyl tert-butyl ether, and dried under vacuum to give the desired product.

[0357] Example 10: Synthesis of EIDD-2801 [ka] A 1 L round-bottom flask was charged with uridine (25 g, 102.38 mmol) and acetone (700 mL). The reaction mixture was stirred at room temperature. The slurry was then treated with sulfuric acid (0.27 mL, 5.12 mmol). Stirring was continued at room temperature for 18 hours. The reaction was quenched with 100 mL of trimethylamine and used in the next step without further purification.

[0358] A 1 L round-bottom flask was charged with the reaction mixture from the previous reaction. Triethylamine (71.09 mL, 510.08 mmol) and 4-dimethylaminopyridine (0.62 g, 5.1 mmol) were then added. The flask was cooled using an ice bath, and 2-methylpropanoyl 2-methylpropanoate (17.75 g, 112.22 mmol) was then slowly added. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 600 mL of ethyl acetate and washed with two portions of saturated aqueous bicarbonate solution, two portions of water, and two portions of brine. The organics were dried over sodium sulfate and concentrated under reduced pressure to give a clear, colorless oil. The crude product was used in the next step without further purification.

[0359] A 1 L round-bottom flask was charged with the crude product from above (36 g, 101.59 mmol) and acetonitrile (406.37 mL). The reaction mixture was stirred until all starting materials were dissolved. 1,2,4-triazole (50.52 g, 731.46 mmol) was then added, followed by N,N-diethylethanamine (113.28 mL, 812.73 mmol). The reaction mixture was stirred at room temperature until all solids were dissolved. The reaction was then cooled to 0 °C using an ice bath. Phosphorus oxychloride (24.44 mL, 152.39 mmol) was slowly added. The formed slurry was stirred under argon while slowly warming to room temperature. The reaction was then stirred until complete by thin-layer chromatography (ethyl acetate). The reaction was then quenched by adding 100 mL of water. The slurry then became a dark solution and was then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water and brine. The organics were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (2 x 330 g columns). All fractions containing the product were collected and concentrated under reduced pressure.

[0360] A 500 mL round-bottom flask was charged with the product from the previous step (11.8 g, 29.11 mmol) and isopropyl alcohol (150 mL). The reaction mixture was stirred at room temperature until all solids dissolved. Hydroxylamine (1.34 mL, 43.66 mmol) was then added, and stirring was continued at ambient temperature. When the reaction was complete by high-performance liquid chromatography (HPLC), some of the solvent was removed under high vacuum at ambient temperature. The remaining solvent was removed under reduced pressure at 45 °C. The resulting residue was dissolved in ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an oil. Upon standing at room temperature, crystals formed. The crystals were collected by filtration, washed with three portions of ether, and dried under vacuum to give the product as a white solid.

[0361] A 200 mL round-bottom flask was charged with the product from the previous step (6.5 g, 17.6 mmol) and formic acid (100 mL, 2085.6 mmol). The reaction mixture was stirred overnight at room temperature. The progress of the reaction was monitored by HPLC. The reaction mixture was concentrated under reduced pressure at 42° C. to give a clear, pale pink oil. 30 mL of ethanol was then added. The solvent was then removed under reduced pressure. Methyl tert-butyl ether (50 mL) was added to the solid and heated. Isopropyl alcohol was then added, and heating was continued until all solid material was dissolved (5 mL). The solution was then cooled and allowed to stand at room temperature. A solid began to form after approximately 1 hour. The solid was collected by filtration, washed with methyl tert-butyl ether, and dried in vacuo to give EIDD-2801 as a white solid. The filtrate was concentrated under reduced pressure to give a sticky solid, which was dissolved in a small amount of isopropyl alcohol by heating. The solution was allowed to stand at room temperature overnight. A solid formed in the flask and was collected by filtration, rinsed with isopropyl alcohol and methyl tert-butyl ether, and dried under vacuum to yield more of the desired product.

[0362] EIDD-2801 (25 g) was dissolved in 250 mL of isopropyl alcohol by heating at 70 °C to give a clear solution. The warm solution was polish filtered, and the filtrate was transferred to a 3-neck 2 L flask with an overhead stirrer. Upon warming back up to 70 °C, methyl tert-butyl ether (250 mL) was slowly added to the flask. The clear solution was seeded and allowed to slowly cool to room temperature with stirring for 18 hours. The formed EIDD-2801 solid was filtered, washed with methyl tert-butyl ether, and dried under vacuum at 50 °C for 18 hours. The filtrate was concentrated and redissolved in 50 mL of isopropyl alcohol and 40 mL of methyl tert-butyl ether by warming to give a clear solution, which was then allowed to stand at room temperature to give a second crop of EIDD-2801.

[0363] Example 11: [ka] To a stirred solution of uridine (1 equiv) in acetone (0.08 M) cooled to 0 °C was added concentrated H2SO4 (2.3 equiv). The reaction mixture was stirred at room temperature for 4 h, then cooled back to 0 °C, and triethylamine (10 equiv) was added dropwise to neutralize the reaction. The solvent was then removed in vacuo, and the crude material was purified by SiO2 column chromatography to give 1.

[0364] A solution of 1 (1 equiv.), chloromethyl pivalate 2 (1.5 equiv.), and NaH (1.5 equiv.) in dimethylformamide (0.1 M) was stirred at room temperature for 5 h. It was then cooled to 0 °C, and methanol was added. The solvent was removed in vacuo, and the crude material was purified by SiO column chromatography to give 3. To a solution of 3 (1 equiv.) in anhydrous dichloromethane (0.1 M) cooled to 0 °C, di...

Claims

[Claim 1] The invention described in this specification.

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