Nucleoside antiviral prodrugs capable of being efficiently released by lung tissues as well as preparation method and application of nucleoside antiviral prodrugs

Abstract

The invention discloses a nucleoside antiviral NHC diester prodrug as shown in a formula I and pharmaceutically acceptable salts thereof, and a preparation method and medical application of the nucleoside antiviral NHC diester prodrug. Pharmacological experiments prove that the compound disclosed by the invention has relatively strong inhibitory activity on replication of multiple RNA viruses. Particularly, the compound has good lung microsome release efficiency, the species difference of the lung release efficiency is small, the consistency of the in-vivo drug effect of the antiviral drug and the in-vivo drug effect of the antiviral drug can be improved, and the risk of species difference of prodrug release antiviral active ingredients is avoided. Therefore, the compound provided by the invention has good broad-spectrum antiviral activity, and can be used as a broad-spectrum antiviral drug for treating various respiratory virus infections.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a nucleoside antiviral prodrug capable of being efficiently released in lung tissue, a preparation method thereof and use thereof. BACKGROUND

[0002] Respiratory viral infections seriously threaten human health. There is a very practical need to study broad-spectrum antiviral drugs.

[0003] Nucleoside antiviral drugs inhibit viral replication by inhibiting the RNA-dependent RNA polymerase (RDRP enzyme) of the virus. Since the RDRP enzyme is well conserved, nucleoside drugs generally have broad-spectrum antiviral activity. Since nucleoside drugs are usually prodrugs, they are metabolized in the liver after oral administration, resulting in a larger polarity of the antiviral active metabolite. This makes it difficult for them to pass through the cell membrane, and the drug concentration in the lung tissue is usually lower than that in the blood. Based on this phenomenon, we invented long-chain fatty acid prodrugs of N4-hydroxycytidine isobutyl ester to improve the affinity of the prodrug to the cell membrane, have good lung tissue targeting distribution ability for inhalation administration, and overcome the problem of insufficient effective antiviral drug concentration in the lung tissue (CN114805458). Subsequently, we found that different prodrug compounds have unexpected differences in antiviral activity, antibacterial activity, and prodrug toxicity (CN119708098), which may be related to the overall properties of the prodrug compound, or may be related to the carrier molecules and metabolic intermediates produced after the release of the prodrug. Therefore, based on the need to optimize the efficacy of antiviral drugs and reduce unknown safety risks, improving the ability of the prodrug to release nucleoside antiviral active ingredients in the lung tissue, reducing the residence time of the prodrug molecules in the lung tissue, and reducing the residence time of the metabolic intermediates are scientific problems to be explored. SUMMARY

[0004] The technical purpose of the present application is to provide a nucleoside antiviral NHC double ester prodrug capable of releasing NHC with small species difference and high release efficiency in lung tissue, as shown in the following formula I, and pharmaceutically acceptable salts thereof, a preparation method and medical use.

[0005] According to one aspect of the present application, one object of the present application is to provide a nucleoside antiviral NHC double ester prodrug as shown in the following formula I and pharmaceutically acceptable salts thereof:

[0006]

[0007] wherein R1 is selected from substituted or unsubstituted straight-chain or branched-chain C 3-20 alkylcarbonyl, the substitution means that the group is substituted with 1 to 3 R 11 substituents, the R 11 is selected from a hydrogen atom, C 3-6 cycloalkyl, C6-14 aryl, saturated or unsaturated three to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, halogen atom, oxo group, amino group, hydroxyl group, amido group;

[0008] R2is selected from linear or branched C 1-10 alkylcarbonyl, C 3-8 cycloalkylcarbonyl;

[0009] Preferably, R1is selected from substituted or unsubstituted C 5-15 linear or branched alkylcarbonyl, said substitution means that the group is substituted with 1 or 2 R 11 substituents, said R 11 is selected from hydrogen atom, C 3-6 cycloalkyl, C 6-10 aryl, saturated or unsaturated four to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O;

[0010] More preferably, R1is selected from substituted or unsubstituted C 5-15 linear or branched alkylcarbonyl, said substitution means that the group is substituted with 1 or 2 R 11 substituents, said R 11 is selected from hydrogen atom, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

[0011] Preferably, R2is selected from linear or branched C 1-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl;

[0012] More preferably, R2is selected from linear or branched C 1-5 alkylcarbonyl, C 3-5 cycloalkylcarbonyl;

[0013] More preferably, R2is selected from methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, tert-butylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl.

[0014] More preferably, the nucleoside antiviral NHC double ester prodrug of formula I and pharmaceutically acceptable salts thereof are selected from any one of the compounds represented by A1 to A32 in the following table:

[0015]

[0016]

[0017]

[0018]

[0019] According to a second aspect of the present application, another object of the present application is to provide a preparation method of the nucleoside antiviral NHC double ester prodrug and pharmaceutically acceptable salts thereof shown in Formula I, which comprises the following steps:

[0020]

[0021] In the first step, the starting material uridine (S1) is reacted with trimethylsilyl chloride, and phosphorus oxychloride is added dropwise under ice bath, and 1,2,4-triazole is added after stirring for 20 min, and after the reaction is completed, the trimethylsilyl protecting group is removed with acetic acid to obtain the intermediate M2;

[0022] In the second step, M2 is reacted with 2,2-dimethoxypropane under the catalysis of concentrated sulfuric acid to obtain compound M3;

[0023] In the third step, the acyl chloride represented by R1-Cl or the acid represented by R1-OH is esterified with M3 to obtain M4;

[0024] In the fourth step, the intermediate represented by M4 is reacted with hydroxylamine to obtain M5;

[0025] In the fifth step, M5 is condensed with the acid represented by R2-OH to obtain M6;

[0026] In the sixth step, M6 is removed from the acetone fork under the catalysis of acid to obtain the compound shown in Formula I.

[0027] The reactions of the above steps are all conventional chemical reaction operations in the prior art, and according to the reaction principle, those skilled in the art can make appropriate adjustments to the reaction conditions according to the prior art.

[0028] According to another aspect of the present application, another object of the present application is to provide a pharmaceutical composition comprising a therapeutically effective amount of the nucleoside antiviral NHC double ester prodrug and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable adjuvant.

[0029] According to another aspect of the present application, another object of the present application is to provide the use of the above-mentioned nucleoside antiviral NHC double ester prodrug and pharmaceutically acceptable salts thereof or the pharmaceutical composition in the preparation of a medicament for treating viral infections.

[0030] Preferably, the virus is an influenza virus, a rhabdovirus, a coronavirus, a human metapneumovirus.

[0031] Preferably, the virus is an influenza virus, a rhabdovirus, a coronavirus, a human metapneumovirus.

[0032] Preferably, the influenza virus includes Influenza A virus, Influenza B virus and Influenza C virus.

[0033] Preferably, the coronavirus subtype includes SARS-CoV (SARS coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus) and SARS-CoV-2 (2019 novel coronavirus), HCoV-229E, HCoV-NL63 and CCoV-HuPn-2018 (Canine coronavirus).

[0034] According to another aspect of the present application, another object of the present application is to provide a method for treating viral infectious diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of the above-mentioned nucleoside antiviral NHC double ester prodrug and pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical composition.

[0035] Advantages

[0036] The present application relates to nucleoside antiviral NHC double ester prodrugs and pharmaceutically acceptable salts thereof. Through pharmacological experiments, it has been verified that the compounds of the present application have better inhibitory activity on RNA-dependent RNA polymerase, and can inhibit the replication of a variety of RNA viruses. In particular, the compounds of the present application have good lung microsomal release efficiency, and the species difference in lung release efficiency is small, which can improve the consistency of in vivo pharmacodynamics of antiviral drugs in animals and in humans, and avoid the risk of species difference in the release of antiviral active ingredients from prodrugs. Therefore, the compounds of the present application have good broad-spectrum antiviral activity, and can be used as broad-spectrum antiviral drugs to treat a variety of viral infections. BRIEF DESCRIPTION OF DRAWINGS

[0037] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the drawings needed in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present application, and those skilled in the art can obtain other drawings according to these drawings without creative labor.

[0038] Figure 1 The lung microsomal test results of Mupiravir.

[0039] Figure 2 The lung microsomal test results of compound 19 in the prior art CN114805458A.

[0040] Figure 3Figure for the lung microsomal comparative test results of compound 19 in prior art CN114805458A and compound 0908 in prior art CN119708098A.

[0041] Figure 4 Figure for the NHC release time profile of 32 example compounds in the lung microsomal release experiment of Example 1 in mouse and human lung microsomes. DETAILED DESCRIPTION

[0042] Hereinafter, the present application will be described in detail. Before undertaking the description below, it should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present application will be defined only by the appended claims. It should also be understood that the terminology used in the description is not intended to limit the scope of the present application and the terms are used only to recite the particular embodiments of the present application. Therefore, the description is only for the preferred embodiments and should not be used to limit the scope of the present application. It should be understood that other equivalent ways or modifications of the present application can be derived from the description without departing from the spirit and scope of the present application.

[0043] In this document, the terms "comprise", "comprising", "include", "including", "have", "has", "contain", "containing", or any other similar phrase are all open-ended connecting adverbs, which are intended to encompass the elements listed thereafter, as well as other non-listed elements. For example, a composition or article containing elements A, B, and C should be construed to mean containing only A, B, and C, or any two of A, B, and C, or any one of A, B, and C, but not a combination of some of the elements. In addition, unless expressly specified to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, the phrase "A or B" is satisfied by either A being true (or present) and B being false (or not present), or A being false (or not present) and B being true (or present), or both A and B being true (or present). In addition, the terms "comprise", "comprising", "include", "including", "have", "has", "contain", "containing" are to be interpreted as specifying the presence of the stated features or components as alternatives only, and not as a limitation requiring the presence of other unrecited features or components. In other words, these terms are to be interpreted in the context of the present application.

[0044] In this document, all features or conditions of a characteristic or a condition that are described in terms of a numerical range or a percentage range are only for the sake of brevity and convenience. Accordingly, the description of a numerical range or a percentage range is to be considered as having specifically disclosed all possible subranges and individual numerical values within the range, particularly the integers within the range, unless specifically stated otherwise. For example, a range of "1 to 8" is to be considered as having specifically disclosed all possible subranges, particularly the subranges of integers, such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., and all individual numerical values within the range, such as 1, 2, 3, 4, 5, 6, 7, 8, etc. The aforementioned interpretation method applies to all aspects of the present application, regardless of the breadth of the range, unless specifically stated otherwise.

[0045] If a numerical range or other numerical values or parameters are expressed in a range format, it is to be understood that each and every number within the range format is expressly stated to be included. For example, a stated range of "1 to 8" should be read as a disclosure of a range "1 to 8", "2 to 7", "3 to 6", "4 to 5", "5", "6", "7", "8", and "1", "2", "3", "4", "5", "6", "7", "8", and "1.1", "1.2", "1.3", "1.4", "1.5", "1.6", "1.7", "1.8", "2.1", "2.2", "2.3", "2.4", "2.5", "2.6", "2.7", "2.8", "3.1", "3.2", "3.3", "3.4", "3.5", "3.6", "3.7", "3.8", "4.1", "4.2", "4.3", "4.4", "4.5", "4.6", "4.7", "4.8", "5.1", "5.2", "5.3", "5.4", "5.5", "5.6", "5.7", "5.8", "6.1", "6.2", "6.3", "6.4", "6.5", "6.6", "6.7", "6.8", "7.1", "7.2", "7.3", "7.4", "7.5", "7.6", "7.7", "7.8", "8.1", "8.2", "8.3", "8.4", "8.5", "8.6", "8.7", and "8.8" etc. unless otherwise indicated. Further, where a range or a list of values is provided, it is understood that each intervening value, to the extent that there are existing intervening discrete values between the upper and lower limit, along with each

[0046] In this document, numerical values should be read as being precise to the number of significant figures provided unless otherwise indicated. For example, a numerical value of 40.0 should be read as encompassing a range of 39.50 to 40.49.

[0047] In this document, where a Markush group or subgroups of elements are utilized to describe a characteristic or an example of the application, it is to be understood that, unless otherwise specifically stated, each individual subgroup or any individual element of the Markush group or subgroups is also individually contemplated. For example, if X is described as "selected from the group consisting of X1, X2, and X3", it is to be understood that the description of X as X1 is specifically contemplated, as is the description of X as X1 and / or X2. Further, in this document, where a Markush group or subgroups of elements are utilized to describe a characteristic or an example of the application, it is to be understood that, unless otherwise specifically stated, any combination of subgroups or individual elements of the Markush group or subgroups is also contemplated. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3", and Y is described as "selected from the group consisting of Y1, Y2, and Y3", it is to be understood that the description of X as X1 or X2 or X3 and Y as Y1 or Y2 or Y3 is specifically contemplated.

[0048] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "C 1–6 " is intended to encompass C1, C2, C3, C4, C5, C6, C 1–6 , C 1–5 , C1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 .

[0049] To investigate the release efficiency of nucleoside prodrugs in lung microsomes, the inventors first conducted a study on the release performance of mupiravir (CAS: 2349386-89-4) in lung microsomes. The inventors unexpectedly discovered significant species differences in the ability of mupiravir to release its antiviral active ingredient, N-4-hydroxycytidine (NHC), in lung microsomes; its release efficiency in mouse lung microsomes was far higher than in human lung microsomes. (See Appendix) Figure 1 .

[0050] Subsequently, the inventors investigated the lung microsomal release efficiency of compound 19 in invention patent CN114805458A. Because compound 19 is a dual prodrug designed based on the distribution characteristics of lung tissue, its esterase hydrolysis release process involves two steps. The first step of enzymatic hydrolysis produces mupiravir (MPV), followed by further enzymatic hydrolysis of mupiravir to produce NHC. Therefore, we simultaneously tested the prototype compound 19, MPV, and NHC. The results showed that the prototype compound 19 could be rapidly hydrolyzed (>95% within 15 minutes) in both mouse and human lung microsomes. In mouse lung microsome experiments, the gradual hydrolysis of MPV to NHC was observed. However, in human lung microsome experiments, compound 19 was released after MPV, with the subsequent release of NHC being very slow. This suggests that compound 19 also exhibits significant species differences in lung tissue drug release; see appendix. Figure 2 This is related to the appendix Figure 1 The results of pulmonary microsomal release of mupiravir were consistent. This suggests that the clinically suitable oral isobutyrate prodrug may not be suitable for inhalation.

[0051] Furthermore, the inventors compared the performance of compound 19 in invention patent CN114805458A and compound 0908 in invention patent CN119708098A in releasing NHC from lung microsomes. The results showed that, compared to compound 19, although the release process was the same—both first releasing mupiravir followed by NHC—0908 exhibited enhanced NHC release from human lung microsomes, with less species variation than compound 19. (See appendix) Figure 3It was demonstrated that the ability of isobutyrate of the hydroxyl group at the 5-position of the NHC ribose ring to release NHC in lung microsomes is affected by the ester of the N4 hydroxyl group of NHC.

[0052] Based on the above findings, therefore, the technical object of the present application is to provide an NHC bisester prodrug which releases NHC with less species difference and high efficiency in lung tissue, represented by the following formula I, and a pharmaceutically acceptable salt thereof, a method of preparation, and a medical use.

[0053]

[0054] Definitions

[0055] The compounds of the present disclosure can contain one or more asymmetric centers and / or axial chirality, and thus can exist in various isomeric forms (e.g., enantiomeric and / or diastereomeric forms). For example, the compounds described herein can be in the form of a single enantiomer, diastereomer, atropisomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched for one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomer can be prepared by asymmetric synthesis. The present disclosure additionally encompasses the individual isomers substantially free of other isomers, and, optionally, mixtures of the various isomers including racemic mixtures. When stereochemistry is depicted specifically, it will be understood that, with respect to that particular chiral center or axial chirality, the compound predominantly exists in the stereochemical form depicted, e.g., the amount of other stereochemical forms is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or is not detectable. The presence and / or amount of a stereochemical form can be determined by one skilled in the art, including by using chiral HPLC, in view of the present disclosure.

[0056] The compounds of the present disclosure can have atropisomers. In any of the embodiments described herein, when applicable, the compounds of the present disclosure can exist as a mixture of atropisomers in any ratio. In some embodiments, when applicable, the compounds can exist as individual atropisomers substantially free (e.g., containing less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or containing an undetectable amount) of other atropisomers. Some exemplary isolated atropisomers of the compounds of the present disclosure are shown in the Examples section. As understood by one skilled in the art, when rotation about a single bond (e.g., an aryl-aryl single bond) is restricted, the compound can exist as a mixture of atropisomers, and each individual atropisomer is isolatable.

[0057] The term“alkyl” refers to a group (a“C 3–20 alkyl”) having 3 to 20 carbon atoms. In some embodiments, the alkyl group has 3 to 15 carbon atoms (a“C 3-15 alkyl”). In some embodiments, the alkyl group has 5 to 15 carbon atoms (a“C 5-15 alkyl”). In some embodiments, the alkyl group has 5 to 10 carbon atoms (a“C 1–6 alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (a“C 10 alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (a“C 11 alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (a“C 12 alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (a“C 15 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (a“C 16 alkyl”). Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an“unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents (e.g., phenyl, cyclopentyl, cyclohexyl, six-membered heterocyclyl, halogen).

[0058] The term“cycloalkyl” refers to a group of non-aromatic cyclic hydrocarbons having 3 to 8 ring carbon atoms (a“C 3-8 cycloalkyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms (a“C 3-8 cycloalkyl”). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms (a“C 3-6 cycloalkyl”). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms (a“C 3-6 cycloalkyl”). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms (a“C 5-10 cycloalkyl”). Exemplary C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 cycloalkyl groups include, but are not limited to, the above C 3-6cycloalkyl and cycloheptyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), and the like. As shown by the foregoing examples, in certain embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems in which a carbocyclic ring as defined above is fused (where the point of attachment is on the carbocyclic ring) or attached (where the point of attachment is on the carbocyclic ring) to one or more aryl or heteroaryl groups, and in this case the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise indicated, each instance of a carbocyclic group is independently optionally substituted, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted ( “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the carbocyclic group is an unsubstituted C 3-8 cycloalkyl. In certain embodiments, the carbocyclic group is a substituted C 3-8 cycloalkyl.

[0059] “Heteroaryl” refers to a 5- to 10-membered unsaturated aromatic ring system having 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). The point of attachment can be on a ring carbon or a ring nitrogen, as valency permits. The heteroaryl group can be monocyclic (“monocyclic heteroaryl”) or fused, bridged, or spiro ring system, such as a bicyclic ring system (“bicyclic heteroaryl”), and can be fully or partially saturated. The heteroaryl group can contain one or more heteroatoms in one or both rings of a bicyclic ring system. “Heteroaryl” also includes ring systems in which a heteroaryl group as defined above is fused (where the point of attachment is on the heteroaryl ring) or attached (where the point of attachment is on the heteroaryl ring) to one or more carbocyclic or heterocyclic groups, and in this case the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. Unless otherwise indicated, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted ( “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-10 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-10 membered heteroaryl.

[0060] “Aryl” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14Aryl" having 6 carbon ring atoms ("C6 aryl"; for example, phenyl). In some embodiments, aryl has 10 carbon ring atoms ("C10 aryl"; for example, naphthyl, such as 1 -naphthyl and 2-naphthyl). In some embodiments, aryl has 14 carbon ring atoms ("C14 aryl"; for example, anthryl). Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6 aryl. In certain embodiments, an aryl group is a substituted C6 aryl. In certain embodiments, an aryl group is an unsubstituted C10 aryl. In certain embodiments, an aryl group is a substituted C10 aryl. In certain embodiments, an aryl group is an unsubstituted C14 aryl. In certain embodiments, an aryl group is a substituted C14 aryl. 10 Aryl" having 6 carbon ring atoms ("C6 aryl"; for example, phenyl). In some embodiments, aryl has 10 carbon ring atoms ("C10 aryl"; for example, naphthyl, such as 1 -naphthyl and 2-naphthyl). In some embodiments, aryl has 14 carbon ring atoms ("C14 aryl"; for example, anthryl). Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6 aryl. In certain embodiments, an aryl group is a substituted C6 aryl. In certain embodiments, an aryl group is an unsubstituted C10 aryl. In certain embodiments, an aryl group is a substituted C10 aryl. In certain embodiments, an aryl group is an unsubstituted C14 aryl. In certain embodiments, an aryl group is a substituted C14 aryl. 14 Aryl" having 6 carbon ring atoms ("C6 aryl"; for example, phenyl). In some embodiments, aryl has 10 carbon ring atoms ("C10 aryl"; for example, naphthyl, such as 1 -naphthyl and 2-naphthyl). In some embodiments, aryl has 14 carbon ring atoms ("C14 aryl"; for example, anthryl). Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6 aryl. In certain embodiments, an aryl group is a substituted C6 aryl. In certain embodiments, an aryl group is an unsubstituted C10 aryl. In certain embodiments, an aryl group is a substituted C10 aryl. In certain embodiments, an aryl group is an unsubstituted C14 aryl. In certain embodiments, an aryl group is a substituted C14 aryl. 6-14 Aryl" having 6 carbon ring atoms ("C6 aryl"; for example, phenyl). In some embodiments, aryl has 10 carbon ring atoms ("C10 aryl"; for example, naphthyl, such as 1 -naphthyl and 2-naphthyl). In some embodiments, aryl has 14 carbon ring atoms ("C14 aryl"; for example, anthryl). Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6 aryl. In certain embodiments, an aryl group is a substituted C6 aryl. In certain embodiments, an aryl group is an unsubstituted C10 aryl. In certain embodiments, an aryl group is a substituted C10 aryl. In certain embodiments, an aryl group is an unsubstituted C14 aryl. In certain embodiments, an aryl group is a substituted C14 aryl. 6-14 Aryl" having 6 carbon ring atoms ("C6 aryl"; for example, phenyl). In some embodiments, aryl has 10 carbon ring atoms ("C10 aryl"; for example, naphthyl, such as 1 -naphthyl and 2-naphthyl). In some embodiments, aryl has 14 carbon ring atoms ("C14 aryl"; for example, anthryl). Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6 aryl. In certain embodiments, an aryl group is a substituted C6 aryl. In certain embodiments, an aryl group is an unsubstituted C10 aryl. In certain embodiments, an aryl group is a substituted C10 aryl. In certain embodiments, an aryl group is an unsubstituted C14 aryl. In certain embodiments, an aryl group is a substituted C14 aryl.

[0061] The term "administering" means implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0062] The term "treatment" means reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of the disease. For example, treatment can be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen) in order to delay or prevent development of the disease. Treatment can also continue after symptoms have resolved, such as to delay or prevent recurrence.

[0063] An "effective amount" of a compound described herein means an amount sufficient to elicit the desired biological response (i.e., treatment of a condition). As will be appreciated by those of ordinary skill in the art, the effective amount of a compound described herein can vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the manner of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the combined amount of a compound described herein in multiple doses.

[0064] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a disorder, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0065] The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bicarbonate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl)4-salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0066] The following examples are merely illustrative of the present application and do not in any way limit the scope of the application. Any modification obvious to those skilled in the art, without departing from the spirit and scope of the application, is intended to be within the scope of the application. Unless otherwise indicated, the reagents and instruments used in the following examples are commercially available products.

[0067] Example 1: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(O-dodecanoyl oximino)-2-oxo-3,4- dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclobutanecarboxylate Al (MCH-3117)

[0068]

[0069] Compound 1a (6.0 g, 24.6 mmol) was added to acetonitrile (39 mL), N-methylpyrrolidine (38.5 mL, 369 mmol) and trimethylsilyl chloride (15.6 mL, 123 mmol) were added, after addition, the reaction was carried out under nitrogen atmosphere at 30 °C for 60 min. Phosphorus oxychloride (4.5 mL, 49.2 mmol) was added dropwise under ice bath, after stirring for 20 min, 1,2,4-triazole (16.9 g, 246 mmol) was added, then after reaction for 60 min under ice bath, it was transferred to 30 °C for 2 h, TLC showed that the reaction was complete. The reaction was diluted with dichloromethane (37.5 mL), and quenched by adding saturated aqueous sodium chloride solution (150 mL). The organic phase was separated, the aqueous phase was extracted with dichloromethane 4 times, and the organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, methanol (30 mL) was added, stirred to dissolve and acetic acid (3 mL) was added, stirred at 30 °C for 10 h, a large amount of solid was precipitated, filtered and dried to obtain compound 2a as a light yellow solid (5.8 g, 79.9%).

[0070] Compound 2a (5.5 g, 18.6 mmol) was added to acetonitrile (55 mL), 2,2-dimethoxypropane (4.6 mL, 37.2 mmol) and concentrated sulfuric acid (2 mL) were added. Then the reaction was carried out under nitrogen atmosphere at 30 °C for 10 h, TLC showed that the reaction was complete, filtration gave compound 3a as a white solid (5.0 g, 80.0%).

[0071] Compound 3a (2.0 g, 6.0 mmol) was taken in DMF (10 mL), EDCI (1730 mg, 9 mmol), HOBT (1216 mg, 9 mmol), DMAP (144 mg, 1.2 mmol), triethylamine (910.7 mg, 9.0 mmol) and cyclobutylcarboxylic acid (661 mg, 6.6 mmol) were added, after addition, the reaction mixture was warmed to 50 °C for 12 h. TLC showed the completion of the reaction, it was cooled to room temperature, ethyl acetate (20 mL) and deionized water (50 mL) were added and extracted, the organic phase was dried over anhydrous sodium sulfate, filtered to get ethyl acetate solution of compound 4a-1.

[0072] To the ethyl acetate solution of compound 4a-1, hydroxylamine hydrochloride (625.4 mg, 9.0 mmol) and triethylamine (910.7 mg, 9.0 mmol) were added and the reaction mixture was stirred at 25 °C for 12 h. TLC showed the completion of the reaction. Ethyl acetate (10 mL) and deionized water (50 mL) were added and extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation to get compound 5a-1 as yellowish brown gummy substance (2.3 g, 100.0 %).

[0073] Compound 5a-1 (1.1 g, 2.88 mmol) was taken in DMF (7 mL), EDCI (829 mg, 4.32 mmol), HOBT (584 mg, 4.32 mmol), triethylamine (496 mg, 4.32 mmol) and lauric acid (634.6 mg, 3.17 mmol) were added, after addition, the reaction mixture was stirred at 25 °C for 12 h. TLC showed the completion of the reaction, ethyl acetate (20 mL) and deionized water (50 mL) were added and extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation, PE:EA = 2.5:1 silica gel column chromatography gave compound 6a-1 as light yellow solid (1.2 g, 73.9 %).

[0074] Compound 6a-1 was taken in formic acid (2.5 mL) and stirred at 25 °C for 12 h. TLC showed the completion of the reaction, methanol (5 mL) was added and the solvent was removed by rotary evaporation, PE:EA = 1.5:1 silica gel column chromatography gave compound A1 as white solid (180 mg, 69.2 %). 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.18 (dd, J = 23.1, 8.3 Hz, 1H), 6.08 - 5.67 (m, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.25 (d, J = 5.4 Hz, 1H), 4.20 (qt, J = 8.9, 4.4 Hz, 2H), 4.02 (q, J = 5.5 Hz, 1H), 3.99 - 3.94 (m, 1H), 3.91 (q, J = 5.1 Hz, 1H), 3.26 - 3.15 (m, 1H), 2.43 (t, J = 7.5 Hz, 2H), 2.16 (td, J = 8.9, 8.5, 7.0 Hz, 4H), 1.99 - 1.89 (m, 1H), 1.85 - 1.76 (m, 1H), 1.55 (q, J = 7.2 Hz, 2H), 1.25 (d, J = 6.3 Hz, 16H), 0.90 - 0.80 (m, 3H). MS m / z = 524.3 [M+H] + .

[0075] Example 2: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(2-methylheptanoyl)oximino)-2-oxo-3,4- dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclobutanecarboxylate A2 (MCH-3119)

[0076]

[0077] Compound 6a-2 was prepared according to the preparation of 6a-1 in Reference Example 1 as a pale yellow mucilage (1.07 g, 73.2%).

[0078] Compound A2 was prepared according to the preparation of Al in Reference Example 1 as a white solid (170 mg, 18.5%). 1H NMR (400 MHz, DMSO-d6) δ 11.05 (d, J = 120.3 Hz, 1H), 7.19 (dd, J = 31.6, 8.3 Hz, 1H), 5.87 - 5.65 (m, 2H), 5.43 (d, J = 5.7 Hz, 1H), 5.25 (d, J = 5.3 Hz, 1H), 4.33 - 4.12 (m, 2H), 4.02 (q, J = 5.2 Hz, 1H), 3.97 (ddd, J = 8.7, 6.1, 3.6 Hz, 1H), 3.91 (q, J = 5.1 Hz, 1H), 3.22 (tt, J = 8.6, 1.4 Hz, 1H), 2.73 (p, J = 6.9 Hz, 1H), 2.16 (td, J = 8.9, 8.5, 7.1 Hz, 4H), 2.02 - 1.88 (m, 1H), 1.88 - 1.74 (m, 1H), 1.57 (dt, J = 12.3, 8.3 Hz, 1H), 1.36 (dt, J = 11.4, 6.3 Hz, 1H), 1.26 (h, J = 6.0, 4.0 Hz, 6H), 1.10 (dd, J = 12.1, 7.0 Hz, 3H), 0.91 - 0.80 (m, 3H). MS m / z = 468.2 [M+H] + .

[0079] Example 3: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(6-phenylhexanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolane-2-yl}methyl- cyclobutanecarboxylate A3 (MCH-3187)

[0080]

[0081] Compound 6a-3 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucus (1.2 g, 54.0%).

[0082] Compound A3 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (320 mg, 28.7%). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.30 - 7.05 (m, 6H), 6.15 - 5.63 (m, 2H), 5.44 (d, J = 5.6 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 4.20 (qd, J = 12.0, 4.3 Hz, 2H), 4.02 (q, J = 5.4 Hz, 1H), 3.96 (dd, J = 5.0, 3.6 Hz, 1H), 3.91 (q, J = 5.1 Hz, 1H), 3.28 - 3.14 (m, 1H), 2.57 (t, J = 7.7 Hz, 2H), 2.47 - 2.35 (m, 2H), 2.16 (td, J = 9.0, 8.5, 6.9 Hz, 4H), 2.03 - 1.74 (m, 2H), 1.58 (p, J = 7.7 Hz, 4H), 1.31 (qd, J = 8.5, 5.9 Hz, 2H). MS m / z = 516.2 [M+H] + .

[0083] Example 4: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(hexadecanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolanyl-2-yl}methyl- cyclobutanecarboxylate A4 (MCH-3603)

[0084]

[0085] Compound 6a-4 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucus (1.1 g, 44.4%).

[0086] Compound A4 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (300 mg, 29.2%). 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.18 (dd, J = 22.9, 8.3 Hz, 1H), 6.07 - 5.66 (m, 2H), 5.42 (d, J = 5.6 Hz, 1H), 5.24 (d, J = 5.4 Hz, 1H), 4.20 (qt, J = 9.0, 4.4 Hz, 2H), 4.02 (q, J = 5.4 Hz, 1H), 3.99 - 3.94 (m, 1H), 3.91 (q, J = 5.1 Hz, 1H), 3.27 - 3.14 (m, 1H), 2.41 (dt, J = 17.1, 7.4 Hz, 2H), 2.16 (td, J = 9.0, 8.5, 7.1 Hz, 4H), 2.02 - 1.88 (m, 1H), 1.81 (ddd, J = 13.2, 8.6, 6.0 Hz, 1H), 1.60 - 1.49 (m, 2H), 1.24 (s, 24H), 0.90 - 0.81 (m, 3H). MS m / z = 580.3 [M+H] + .

[0087] Example 5: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(undecanoyl)-hydroxyimino)- 2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclobutanecarboxylate A5 (zzy-0317)

[0088]

[0089] Compound 6a-5 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucus (700 mg, 35.1%).

[0090] Compound A5 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (200 mg, 10.8%). 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.15 (d, J = 8.2 Hz, 1H), 5.77 - 5.72 (m, 2H), 5.42 (d, J = 5.6 Hz, 1H), 5.24 (d, J = 5.3 Hz, 1H), 4.21 - 4.13 (m, 2H), 4.02 (q, J = 4.4, 3.4 Hz, 1H), 3.96 - 3.88 (m, 2H), 3.21 (td, J = 8.5, 1.2 Hz, 1H), 2.42 - 2.14 (m, 6H), 1.96 - 1.81 (m, 2H), 1.53 (d, J = 7.3 Hz, 2H), 1.25 (d, J = 4.8 Hz, 14H), 0.86 (d, J = 6.3 Hz, 3H). MS m / z = 510.2 [M+H] +.

[0091] Example 6: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(3-cyclopentylpropanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclobutanecarboxylate A6 (zzy-0325)

[0092]

[0093] Compound 6a-6 was prepared according to the preparation of 6a-1 in Reference Example 1 as yellow mucus (400 mg, 50.4%).

[0094] Compound A6 was prepared according to the preparation of A1 in Reference Example 1 as white solid (110 mg, 15.1%). 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 6.36 (dd, J = 25.9, 8.2 Hz, 1H), 4.92 (t, J = 6.6 Hz, 2H), 4.61 (d, J = 5.6 Hz, 1H), 4.43 (d, J = 5.4 Hz, 1H), 3.39 (td, J = 11.0, 9.8, 4.5 Hz, 2H), 3.22 - 3.15 (m, 1H), 3.16 - 3.04 (m, 2H), 2.42 - 2.34 (m, 1H), 1.62 - 1.31 (m, 6H), 1.16 - 0.99 (m, 2H), 0.77 - 0.19 (m, 11H). MS m / z = 466.2 [M+H] + .

[0095] Example 7: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(4-methylpentanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclobutanecarboxylate A7 (zzy-0326)

[0096]

[0097] Compound 6a-7 was prepared according to the preparation of 6a-1 in Reference Example 1 as yellow mucus (450 mg, 59.8%).

[0098] Compound A7 was prepared according to the preparation of A1 in Reference Example 1 as white solid (100 mg, 14.5%). 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 6.32 (d, J = 8.2 Hz, 1H), 4.91 (t, J = 6.6 Hz, 2H), 4.60 (d, J = 5.6 Hz, 1H), 4.42 (d, J = 5.4 Hz, 1H), 3.37 (qd, J = 12.1, 4.3 Hz, 2H), 3.18 (dd, J = 7.4, 3.5 Hz, 1H), 3.09 (td, J = 11.3, 10.3, 4.7 Hz, 2H), 2.38 (t, J = 8.5 Hz, 1H), 1.60 - 1.27 (m, 6H), 1.16 - 0.99 (m, 2H), 0.72 - 0.59 (m, 3H), 0.05 (s, 6H). MS m / z = 440.2 [M+H] + .

[0099] Example 8: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(O-nonanoyl-hydroxyimino)-2-oxo-3,4- dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclobutanecarboxylate A8 (zzy-0331)

[0100]

[0101] Compound 6a-8 was prepared according to the preparation of 6a-1 in Reference Example 1 as a light yellow mucilage (500 mg, 61.1%).

[0102] Compound A8 was prepared according to the preparation of A1 in Reference Example 1 as a milky white solid (160 mg, 21.2%). 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 6.35 (dd, J = 23.4, 8.2 Hz, 1H), 4.95 - 4.87 (m, 2H), 4.61 (d, J = 5.6 Hz, 1H), 4.43 (d, J = 5.4 Hz, 1H), 3.37 (qd, J = 12.1, 4.4 Hz, 2H), 3.19 (d, J = 5.4 Hz, 1H), 3.15 - 3.03 (m, 2H), 2.38 (td, J = 8.6, 1.2 Hz, 1H), 1.60 (t, J = 7.6 Hz, 2H), 1.33 (td, J = 9.0, 8.5, 7.0 Hz, 5H), 1.12 - 0.94 (m, 2H), 0.71 (t, J = 7.4 Hz, 2H), 0.44 - 0.38 (m, 9H). MS m / z = 482.1 [M+H] + .

[0103] Example 9: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(2-(morpholin-4-yl)acetyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclobutanecarboxylate A9 (zzy-0335)

[0104]

[0105] Compound 6a-9 was prepared according to the preparation of 6a-1 in Reference Example 1 as a dark yellow mucilage (490 mg, 61.4%).

[0106] Compound A9 was prepared according to the preparation of Al in Reference Example 1 as a white solid (170 mg, 23.1%). 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.47 (d, J = 2.2 Hz, 1H), 5.73 (d, J = 8.2 Hz, 1H), 4.64 (d, J = 5.6 Hz, 1H), 4.52 (dd, J = 8.2, 2.0 Hz, 1H), 4.29 (d, J = 5.8 Hz, 1H), 4.15 (d, J = 5.1 Hz, 1H), 3.09 (qd, J = 12.0, 4.2 Hz, 2H), 2.91 (dt, J = 11.1, 6.0 Hz, 1H), 2.83 (tt, J = 9.8, 4.2 Hz, 2H), 2.26 (s, 5H), 2.13 (td, J = 11.5, 10.1, 7.1 Hz, 1H), 1.43 (p, J = 1.9 Hz, 3H), 1.15 - 1.02 (m, 4H), 0.93 - 0.79 (m, 1H), 0.73 (dt, J = 11.5, 6.3 Hz, 1H). MS m / z = 469.1 [M+H] + .

[0107] Example 10: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(4-ethyloctanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclobutanecarboxylate A10 (zzy-0336)

[0108]

[0109] Compound 6a-10 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucilage (420 mg, 49.9%).

[0110] Compound A10 was prepared according to the preparation of Al in Reference Example 1 as a white solid (160 mg, 20.6%). 1H NMR (400 MHz, DMSO-d6) δ 11.06 (dd, J = 115.4, 2.2 Hz, 1H), 7.47 - 7.04 (m, 1H), 6.10 - 5.66 (m, 2H), 5.44 (d, J = 5.6 Hz, 1H), 5.27 (d, J = 5.4 Hz, 1H), 4.20 (qd, J = 12.1, 4.4 Hz, 2H), 4.02 (q, J = 5.5 Hz, 1H), 3.96 (q, J = 4.6 Hz, 1H), 3.91 (q, J = 5.1 Hz, 1H), 3.21 (p, J = 8.5 Hz, 1H), 2.47 - 2.40 (m, 2H), 2.21 - 2.10 (m, 4H), 2.04 - 1.89 (m, 1H), 1.84 - 1.74 (m, 1H), 1.51 (s, 2H), 1.27 - 1.22 (m, 9H), 0.85 (dt, J = 19.3, 6.9 Hz, 6H). MS m / z = 496.2 [M+H] + .

[0111] Example 11: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(4-cyclohexylbutanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolane-2-yl}methyl- cyclobutanecarboxylate Al l (zzy-0339)

[0112]

[0113] Compound 6a-11 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucus (400 mg, 47.7%).

[0114] Compound Al l was prepared according to the preparation of Al in Reference Example 1 as a white solid (180 mg, 23.2%). 1H NMR (400 MHz, DMSO-d6) δ 10.91 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 24.2, 8.3 Hz, 1H), 5.78 - 5.70 (m, 2H), 5.44 (d, J = 5.6 Hz, 1H), 5.26 (d, J = 5.4 Hz, 1H), 4.22 - 4.15 (m, 2H), 4.04 - 3.98 (m, 1H), 3.96 (dd, J = 5.1, 3.7 Hz, 1H), 3.91 (q, J = 5.2 Hz, 1H), 3.25 - 3.17 (m, 1H), 2.42 (t, J = 7.5 Hz, 2H), 2.16 (td, J = 9.0, 8.5, 7.1 Hz, 4H), 2.01 - 1.81 (m, 2H), 1.67 (d, J = 13.5 Hz, 5H), 1.55 (dt, J = 15.2, 7.6 Hz, 3H), 1.17 (ddd, J = 11.3, 7.6, 3.8 Hz, 5H), 0.85 (q, J = 10.8, 10.3 Hz, 2H). MS m / z = 494.1 [M+H] + .

[0115] Example 12: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(O-(tridecanoyl)-hydroxyl)-2-oxo-3,4- dihydropyrimidin-l(2H)-yl]oxolanyl-2-yl}methyl-cyclobutanecarboxylate A12 (zzy-0340)

[0116]

[0117] Compound 6a-12 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucus (410 mg, 45.2%).

[0118] Compound A12 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (180 mg, 21.3%). 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.18 (dd, J = 23.0, 8.2 Hz, 1H), 5.88 - 5.57 (m, 2H), 5.44 (d, J = 5.6 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 4.20 (qd, J = 12.1, 4.4 Hz, 2H), 4.02 (q, J = 5.5 Hz, 1H), 3.93 (dq, J = 23.7, 5.0 Hz, 2H), 3.20 (q, J = 8.5 Hz, 1H), 2.43 (t, J = 7.5 Hz, 2H), 2.16 (td, J = 9.0, 8.5, 7.0 Hz, 5H), 1.95 (dq, J = 11.1, 8.5 Hz, 1H), 1.81 (dd, J = 11.3, 6.6 Hz, 1H), 1.57 - 1.49 (m, 2H), 1.25 (d, J = 10.4 Hz, 17H), 0.85 (t, J = 6.7 Hz, 3H). MS m / z = 538.3 [M+H] + .

[0119] Example 13: {1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-{[(4-methylpentanoyl)oxy]methyl}oxolan-2- yl]-2-oxo-1,2-dihydropyrimidin-4-yl}amidododecanoic acid ester A13 (MCH-3125)

[0120]

[0121] Compound 4a-2 was prepared according to the preparation of 4a-1 in Reference Example 1 as a colorless sticky solid (2.3 g, 88.4%).

[0122] Compound 5a-2 was prepared according to the preparation of 5a-1 in Reference Example 1 as a light yellow solid (2.6 g, 100.0%).

[0123] Compound 6a-13 was prepared according to the preparation of 6a-1 in Reference Example 1 as a light yellow sticky liquid (900 mg, 47.5%).

[0124] Compound A13 was prepared according to the preparation of A1 in Reference Example 1 as a colorless transparent sticky liquid (350 mg, 41.8%). 1HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.22 (dd, J = 27.1, 8.2 Hz, 1H), 6.02 - 5.62 (m, 2H), 5.43 (d, J = 5.5 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 4.27 - 4.11 (m, 2H), 4.04 (p, J = 5.3 Hz, 1H), 3.99 - 3.87 (m, 2H), 2.43 (t, J = 7.5 Hz, 2H), 2.37 - 2.31 (m, 2H), 1.54 (dq, J = 13.3, 6.6, 5.6 Hz, 3H), 1.43 (dt, J = 8.2, 6.9 Hz, 2H), 1.25 (d, J = 5.3 Hz, 16H), 0.90 - 0.82 (m, 9H). MS m / z = 540.2 [M+H] + .

[0125] Example 14: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-((2-methyl)-heptanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-(4- methyl)pentanoate A14 (MCH-3127)

[0126]

[0127] Compound 6a-14 was prepared according to the preparation of 6a-1 in Reference Example 1 as a pale yellow transparent mucilage (600 mg, 35.0%).

[0128] Compound A14 was prepared according to the preparation of A1 in Reference Example 1 as a colorless transparent mucilage (240 mg, 43.5%). 1 HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.22 (dd, J = 27.1, 8.2 Hz, 1H), 6.02 - 5.62 (m, 2H), 5.43 (d, J = 5.5 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 4.27 - 4.11 (m, 2H), 4.04 (p, J = 5.3 Hz, 1H), 3.99 - 3.87 (m, 2H), 2.43 (t, J = 7.5 Hz, 2H), 2.37 - 2.31 (m, 2H), 1.54 (dq, J = 13.3, 6.6, 5.6 Hz, 3H), 1.43 (dt, J = 8.2, 6.9 Hz, 2H), 1.25 (d, J = 5.3 Hz, 16H), 0.90 - 0.82 (m, 9H). MS m / z = 540.2 [M+H] + .

[0129] Example 15: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-((6-phenyl)-hexanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-(4- methyl)pentanoate A15 (MCH-3177)

[0130]

[0131] Compound 6a-15 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucilage (800 mg, 42.0%).

[0132] Compound A15 was prepared according to the preparation of Al in Reference Example 1 as a colorless transparent solid (280 mg, 37.6%). 1 HNMR (400 MHz, DMSO-d6) δ 11.05 (d, J = 118.0 Hz, 1H), 7.39 - 6.94 (m, 6H), 6.11 - 5.66 (m, 2H), 5.44 (dd, J = 5.6, 3.6 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 4.36 - 4.11 (m, 2H), 4.04 (p, J = 5.0, 4.5 Hz, 1H), 4.01 - 3.87 (m, 2H), 2.57 (t, J = 7.7 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 2.34 (t, J = 7.7 Hz, 2H), 1.74 - 1.49 (m, 5H), 1.44 (ddp, J = 10.6, 7.2, 3.3 Hz, 2H), 1.31 (h, J = 7.4, 6.6 Hz, 2H), 0.85 (dd, J = 6.6, 3.9 Hz, 6H). MS m / z = 532.1 [M+H] + .

[0133] Example 16: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(hexadecanoyl)-hydroxyimino)- 2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-(4-methyl)pentanoate A16 (MCH-3601)

[0134]

[0135] Compound 6a-16 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucilage (1.05 g, 45.3%).

[0136] Compound A16 was prepared according to the preparation of Al in Reference Example 1 as a white solid (210 mg, 21.4%). 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.21 (dd, J = 27.0, 8.3 Hz, 1H), 6.05 - 5.65 (m, 2H), 5.42 (d, J = 5.5 Hz, 1H), 5.24 (d, J = 5.3 Hz, 1H), 4.27 - 4.12 (m, 2H), 4.04 (q, J = 5.4 Hz, 1H), 3.98 - 3.89 (m, 2H), 2.47 - 2.37 (m, 2H), 2.37 - 2.29 (m, 2H), 1.54 (h, J = 6.6 Hz, 3H), 1.48 - 1.41 (m, 2H), 1.24 (s, 24H), 0.86 (d, J = 6.4 Hz, 9H). MS m / z = 596.3 [M+H] + .

[0137] Example 17: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(octanoyl)-hydroxyimino)-2-oxo-3,4- dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-(4-methyl)pentanoate A17 (MCH-3608)

[0138]

[0139] Compound 6a-17 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow-brown mucus (1.1 g, 84.0%).

[0140] Compound A17 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (230 mg, 19.0%). 1 H NMR (400 MHz, DMSO-d6) δ 11.28 - 10.80 (m, 1H), 7.22 (dd, J = 27.7, 8.2 Hz, 1H), 5.96 - 5.64 (m, 2H), 5.44 (d, J = 5.4 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 4.34 - 4.11 (m, 2H), 4.04 (p, J = 5.1 Hz, 1H), 4.01 - 3.87 (m, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.44 (t, J = 7.5 Hz, 1H), 2.33 (d, J = 7.7 Hz, 1H), 1.54 (q, J = 7.7, 5.8 Hz, 3H), 1.43 (q, J = 7.4 Hz, 2H), 1.26 (h, J = 5.4 Hz, 8H), 0.86 (d, J = 6.4 Hz, 9H). MS m / z = 484.2 [M+H] + .

[0141] Example 18: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-((4-methyl)pentanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-(4- methyl)pentanoate A18 (MCH-3609)

[0142]

[0143] Compound 6a-18 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucilage (1.13 g, 91.2%).

[0144] Compound A18 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (190 mg, 16.7%). 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (d, J = 2.2 Hz, 1H), 7.25 - 7.13 (m, 1H), 5.87 - 5.66 (m, 2H), 5.45 (dd, J = 5.6, 3.2 Hz, 1H), 5.26 (d, J = 5.4 Hz, 1H), 4.30 - 4.10 (m, 2H), 4.04 (p, J = 5.2 Hz, 1H), 3.99 - 3.86 (m, 2H), 2.48 - 2.38 (m, 2H), 2.38 - 2.30 (m, 2H), 1.53 (dtt, J = 13.3, 6.6, 3.4 Hz, 2H), 1.48 - 1.39 (m, 4H), 0.87 (dd, J = 9.2, 6.5 Hz, 12H). MS m / z = 454.1 [M-H] +

[0145] Example 19: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-((2-ethyl)butanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-(4- methyl)pentanoate A19 (MCH-3612)

[0146]

[0147] Compound 6a-19 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucilage (820 mg, 66.2%).

[0148] Compound A19 was prepared according to the preparation of A1 in Reference Example 1 as a colorless transparent mucilage (300 mg, 39.8%). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (d, J = 117.8 Hz, 1H), 7.23 (dd, J = 36.5, 8.2 Hz, 1H), 6.02 - 5.66 (m, 2H), 5.45 (t, J = 5.4 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 4.32 - 4.12 (m, 2H), 4.07 - 4.02 (m, 1H), 4.00 - 3.88 (m, 2H), 2.63 - 2.53 (m, 1H), 2.33 (q, J = 9.3, 8.5 Hz, 2H), 1.66 - 1.47 (m, 5H), 1.43 (dt, J = 8.3, 6.9 Hz, 2H), 0.88 - 0.80 (m, 12H). MS m / z = 456.2 [M+H] + .

[0149] Example 20: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-((3-cyclopentyl)propionyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-(4- methyl)pentanoate A20 (MCH-3613)

[0150]

[0151] Compound 6a-20 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow solid (790 mg, 60.6%).

[0152] Compound A20 was prepared according to the preparation of Al in Reference Example 1 as a white solid (185 mg, 25.4%). 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (d, J = 111.9 Hz, 1H), 7.22 (dd, J = 29.4, 8.3 Hz, 1H), 6.09 - 5.67 (m, 2H), 5.45 (dd, J = 5.6, 3.2 Hz, 1H), 5.26 (d, J = 5.4 Hz, 1H), 4.32 - 4.12 (m, 2H), 4.04 (q, J = 5.4 Hz, 1H), 4.02 - 3.84 (m, 2H), 2.45 (dd, J = 8.3, 7.1 Hz, 2H), 2.39 - 2.30 (m, 2H), 1.74 (tt, J = 12.8, 7.1 Hz, 3H), 1.65 - 1.39 (m, 9H), 1.16 - 1.00 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H). MS m / z = 482.2 [M+H] + .

[0153] Example 21 : {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(undecanoyl)-oximino)-2-oxo- 3,4-dihydropyrimidin-1 (2H)-yl]oxolan-2-yl}methyl-(4-methyl)pentanoate A21 (zzy-0318)

[0154]

[0155] Compound 6a-21 was prepared according to the preparation of 6a-1 in Reference Example 1 as yellow sticky liquid (1.1 g, 44.4%).

[0156] Compound A21 was prepared according to the preparation of A1 in Reference Example 1 as white solid (300 mg, 29.2%). 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.98 - 5.59 (m, 2H), 5.42 (d, J = 5.4 Hz, 1H), 5.24 (d, J = 5.3 Hz, 1H), 4.26 - 4.15 (m, 2H), 4.04 (q, J = 5.4 Hz, 1H), 3.97 - 3.90 (m, 2H), 2.43 (t, J = 7.5 Hz, 2H), 2.34 (t, J = 7.7 Hz, 2H), 1.59 - 1.50 (m, 3H), 1.43 (dt, J = 8.6, 7.1 Hz, 3H), 1.25 (q, J = 4.3, 3.7 Hz, 13H), 0.85 (dd, J = 6.8, 5.1 Hz, 9H). MS m / z = 526.2 [M+H] + .

[0157] Example 22: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(dodecanoyl)-oximino)-2-oxo- 3,4-dihydropyrimidin-1 (2H)-yl]oxolan-2-yl}methyl-acetate A22 (MCH-3129)

[0158]

[0159] Compound 4a-3 was prepared according to the preparation of 4a-1 in Reference Example 1 as brown sticky solid (2.6 g, 100.0%).

[0160] Compound 5a-3 was prepared according to the preparation of 5a-1 in Reference Example 1 as brown sticky liquid (1.7 g, 75.1%).

[0161] Compound 6a-22 was prepared according to the preparation of 6a-1 in Reference Example 1 as light yellow sticky liquid (520 mg, 41.4%).

[0162] Compound A22 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (220 mg, 45.5%). 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.22 (dd, J = 22.8, 8.2 Hz, 1H), 6.06 - 5.67 (m, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.26 (d, J = 5.2 Hz, 1H), 4.27 - 4.09 (m, 2H), 4.04 (p, J = 5.0 Hz, 1H), 4.01 - 3.88 (m, 2H), 2.41 (dt, J = 18.3, 7.4 Hz, 2H), 2.05 (s, 3H), 1.53 (dd, J = 10.2, 3.8 Hz, 2H), 1.25 (d, J = 5.3 Hz, 16H), 0.92 - 0.79 (m, 3H). MS m / z = 484.2 [M+H] + .

[0163] Example 23: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(2-methylheptanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-acetate A23 (MCH-3135)

[0164]

[0165] Compound 6a-23 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucilaginous (600 mg, 53.5%).

[0166] Compound A23 was prepared according to the preparation of A1 in Reference Example 1 as a colorless transparent mucilaginous (198 mg, 36.1%). 1H NMR (400 MHz, DMSO-d6) δ 11.27 - 10.69 (m, 1H), 7.22 (dd, J = 30.3, 8.2 Hz, 1H), 5.75 (q, J = 5.4, 4.5 Hz, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.27 (d, J = 5.3 Hz, 1H), 4.27 - 4.10 (m, 2H), 4.04 (p, J = 5.4 Hz, 1H), 3.99 - 3.87 (m, 2H), 2.74 (p, J = 6.9 Hz, 1H), 2.05 (s, 3H), 1.64 - 1.51 (m, 1H), 1.36 (dt, J = 11.5, 5.8 Hz, 1H), 1.25 (qt, J = 6.5, 4.5, 3.7 Hz, 6H), 1.10 (dd, J = 11.9, 6.9 Hz, 3H), 0.91 - 0.80 (m, 3H). MS m / z = 428.2 [M+H] + .

[0167] Example 24: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(6-phenyl-hexanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl} methyl-acetate A24 (MCH-3185)

[0168]

[0169] Compound 6a-24 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucilaginous (750 mg, 36.4 %).

[0170] Compound A24 was prepared according to the preparation of Al in Reference Example 1 as a white foamy solid (280 mg, 40.5 %). 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.22 - 7.11 (m, 4H), 6.08 - 5.69 (m, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.27 (d, J = 5.4 Hz, 1H), 4.28 - 4.10 (m, 2H), 4.04 (q, J = 5.3 Hz, 1H), 4.01 - 3.86 (m, 2H), 2.57 (t, J = 7.7 Hz, 2H), 2.44 (t, J = 7.5 Hz, 2H), 2.05 (s, 3H), 1.58 (p, J = 7.6 Hz, 4H), 1.31 (ddt, J = 8.8, 6.4, 3.9 Hz, 2H). MS m / z = 476.1 [M+H] + .

[0171] Example 25: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(dodecanoyl)-oximino)-2-oxo- 3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclopropanecarboxylate A25 (MCH-3137)

[0172]

[0173] Compound 4a-4 was prepared according to the preparation of 4a-1 in Reference Example 1 as a off-white solid (2.01 g, 83.0%).

[0174] Compound 5a-4 was prepared according to the preparation of 5a-1 in Reference Example 1 as a off-white solid (1.6 g, 87.5%).

[0175] Compound 6a-25 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow gum (770 g, 64.3%).

[0176] Compound A25 was prepared according to the preparation of Al in Reference Example 1 as a white solid (300 mg, 42.7%). 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.22 (dd, J = 20.1, 8.3 Hz, 1H), 6.05 - 5.69 (m, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.26 (d, J = 5.2 Hz, 1H), 4.36 - 4.13 (m, 2H), 4.05 (q, J = 5.3 Hz, 1H), 4.01 - 3.88 (m, 2H), 2.41 (dt, J = 18.6, 7.4 Hz, 2H), 1.68 (tt, J = 7.9, 4.6 Hz, 1H), 1.62 - 1.44 (m, 2H), 1.25 (d, J = 5.5 Hz, 16H), 0.99 - 0.89 (m, 2H), 0.89 - 0.80 (m, 5H). MS m / z = 510.3 [M+H] + .

[0177] Example 26: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(2-methylheptanoyl)-oximino)-2-oxo- 3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclopropanecarboxylate A26 (MCH-3139)

[0178]

[0179] Compound 6a-26 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow gum (720 g, 66.9%).

[0180] Compound A26 was prepared according to the preparation of A1 in Reference Example 1 as a yellow transparent mucus (243 mg, 37.0%). 1 HNMR (400 MHz, Deuterium Oxide) δ 11.04 (d, J = 122.0 Hz, 1H), 7.22 (dd, J = 26.4, 8.2 Hz, 1H), 5.85 - 5.69 (m, 2H), 5.42 (d, J = 5.5 Hz, 1H), 5.25 (d, J = 5.3 Hz, 1H), 4.32 - 4.12 (m, 2H), 4.05 (q, J = 5.4 Hz, 1H), 3.99 - 3.88 (m, 2H), 2.81 - 2.66 (m, 1H), 1.68 (tt, J = 7.8, 4.6 Hz, 1H), 1.64 - 1.53 (m, 1H), 1.37 (dt, J = 12.0, 6.0 Hz, 1H), 1.25 (d, J = 4.5 Hz, 6H), 1.10 (dd, J = 10.9, 6.9 Hz, 3H), 0.96 - 0.89 (m, 2H), 0.89 - 0.81 (m, 5H). MS m / z = 454.1 [M+H] + .

[0181] Example 27: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(6-phenylhexanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl- cyclopropylcarboxylate A27 (MCH-3179)

[0182]

[0183] Compound 6a-27 was prepared according to the preparation of 6a-1 in Reference Example 1 as a transparent mucus (580 mg, 32.2%).

[0184] Compound A27 was prepared according to the preparation of A1 in Reference Example 1 as a transparent solid (164 mg, 30.5%). 1H NMR (400 MHz, Chloroform-d) δ 10.89 (s, 1H), 7.32 - 7.09 (m, 6H), 6.10 - 5.70 (m, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.27 (d, J = 5.3 Hz, 1H), 4.29 - 4.12 (m, 2H), 4.05 (q, J = 5.4 Hz, 1H), 4.01 - 3.88 (m, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.48 - 2.39 (m, 2H), 1.68 (td, J = 8.0, 4.1 Hz, 1H), 1.62 - 1.51 (m, 4H), 1.31 (h, J = 7.4, 6.5 Hz, 2H), 0.97 - 0.80 (m, 4H). MS m / z = 502.1 [M+H] + .

[0185] Example 28: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(hexadecanoyl)-hydroxyimino)- 2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-cyclopropanecarboxylate A28 (MCH-3602)

[0186]

[0187] Compound 6a-28 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucus (600 mg, 24.8%).

[0188] Compound A28 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (250 mg, 44.6%). 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.22 (dd, J = 19.9, 8.3 Hz, 1H), 6.12 - 5.62 (m, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 4.33 - 4.12 (m, 2H), 4.05 (q, J = 5.3 Hz, 1H), 4.01 - 3.89 (m, 2H), 2.41 (dt, J = 18.7, 7.4 Hz, 2H), 1.68 (tt, J = 7.9, 4.6 Hz, 1H), 1.59 - 1.50 (m, 2H), 1.24 (s, 24H), 0.92 (ddd, J = 8.0, 5.1, 2.1 Hz, 2H), 0.85 (dq, J = 6.6, 2.9 Hz, 5H). MS m / z = 566.2 [M+H] + .

[0189] Example 29: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(dodecanoyl)-hydroxyimino)- 2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-propanoate A29 (MCH- 3149)

[0190]

[0191] Compound 4a-5 was prepared according to the preparation of 4a-1 in Reference Example 1 as a yellow gum (2.1 g, 89.4%).

[0192] Compound 5a-5 was prepared according to the preparation of 5a-1 in Reference Example 1 as a brown gum (1.89 g, 99.0%).

[0193] Compound 6a-29 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow gum (820 mg, 44.4%).

[0194] Compound A29 was prepared according to the preparation of Al in Reference Example 1 as a white solid (273 mg, 36.1%). 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.21 (dd, J = 22.2, 8.2 Hz, 1H), 6.07 - 5.67 (m, 2H), 5.45 (d, J = 5.6 Hz, 1H), 5.28 (d, J = 5.3 Hz, 1H), 4.29 - 4.11 (m, 2H), 4.03 (p, J = 5.0 Hz, 1H), 3.99 - 3.88 (m, 2H), 2.47 - 2.31 (m, 4H), 1.54 (q, J = 7.2 Hz, 2H), 1.25 (d, J = 5.1 Hz, 16H), 1.03 (t, J = 7.5 Hz, 3H), 0.85 (t, J = 6.5 Hz, 3H). MS m / z = 498.2 [M+H] + .

[0195] Example 30: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(0-(2-methylheptanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-propanoate A30 (MCH-3151)

[0196]

[0197] Compound 6a-30 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow gum (730 mg, 57.2%).

[0198] Compound A30 was prepared according to the preparation of A1 in Reference Example 1 as a white solid (250 mg, 37.6%). 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (d, J = 115.7 Hz, 1H), 7.22 (dd, J = 29.7, 8.2 Hz, 1H), 6.05 - 5.68 (m, 2H), 5.45 (dd, J = 5.6, 1.1 Hz, 1H), 5.28 (d, J = 5.3 Hz, 1H), 4.29 - 4.10 (m, 2H), 4.03 (p, J = 5.3 Hz, 1H), 3.99 - 3.86 (m, 2H), 2.79 - 2.54 (m, 1H), 2.36 (q, J = 7.5 Hz, 2H), 1.67 - 1.49 (m, 1H), 1.37 (dd, J = 12.5, 6.4 Hz, 1H), 1.25 (tt, J = 6.1, 3.3 Hz, 6H), 1.15 - 0.97 (m, 6H), 0.94 - 0.79 (m, 3H). MS m / z = 442.2 [M+H] + .

[0199] Example 31 : {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(0-(6-phenylhexanoyl)- hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1 (2H)-yl]oxolan-2-yl}methyl- propionate A31 (MCH-3175)

[0200]

[0201] Compound 6a-31 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucilaginous (620 g, 35.2%).

[0202] Compound A31 was prepared according to the preparation of A1 in Reference Example 1 as a transparent solid (185 mg, 32.3%). 1H NMR (400 MHz, DMSO-d6) δ 11.04 (d, J = 117.6 Hz, 1H), 7.37 - 7.08 (m, 6H), 6.06 - 5.66 (m, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.25 (d, J = 5.3 Hz, 1H), 4.30 - 4.08 (m, 2H), 4.04 (q, J = 5.4 Hz, 1H), 4.00 - 3.85 (m, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.44 (t, J = 7.5 Hz, 2H), 2.40 - 2.33 (m, 2H), 1.58 (p, J = 7.6 Hz, 4H), 1.39 - 1.26 (m, 2H), 1.03 (td, J = 7.5, 3.8 Hz, 3H). MS m / z = 490.1 [M+H] + .

[0203] Example 32: {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(O-(hexadecanoyl)-hydroxyimino)- 2-oxo-3,4-dihydropyrimidin-l(2H)-yl]oxolan-2-yl}methyl-propionate A32 (MCH-3199)

[0204]

[0205] Compound 6a-32 was prepared according to the preparation of 6a-1 in Reference Example 1 as a yellow mucus (900 mg, 37.9%).

[0206] Compound A32 was prepared according to the preparation of Al in Reference Example 1 as a white solid (350 mg, 41.7%). 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.21 (dd, J = 22.2, 8.3 Hz, 1H), 6.18 - 5.62 (m, 2H), 5.42 (d, J = 5.6 Hz, 1H), 5.25 (d, J = 5.3 Hz, 1H), 4.28 - 4.12 (m, 2H), 4.04 (q, J = 5.3 Hz, 1H), 3.99 - 3.90 (m, 2H), 2.43 (t, J = 7.5 Hz, 2H), 2.36 (q, J = 7.4 Hz, 2H), 1.55 (q, J = 7.1 Hz, 2H), 1.24 (s, 24H), 1.04 (t, J = 7.5 Hz, 3H), 0.90 - 0.82 (m, 3H). MS m / z = 554.2 [M+H] + .

[0207] Test Example 1 Pulmonary microparticle release experiment

[0208] 1.1.1 Solution preparation

[0209] 1) Preparation of PBS buffer: weigh 322.37 mg of NaH2PO4·2H2O, dissolve in 10.329 mL of ultrapure water, then weigh 2381.23 mg of Na2HPO4·12H2O, dissolve in 33.216 mL of ultrapure water, take 7 mL of the above NaH2PO4·2H2O solution and 29.842 mL of the Na2HPO4·12H2O solution, mix well, and you get the PBS buffer (freshly prepared on the day of the test).

[0210] 2) Preparation of NADPH solution: weigh 15.905 mg of NADPH, dissolve in 1.906 mL of PBS buffer to get a concentration of 10 mmol·L -1 NADPH solution (freshly prepared on the day of the test).

[0211] 1.1.2 Preparation and treatment of in vitro incubation test samples of human lung microsomes and mouse lung microsomes

[0212] Incubation system: take one set of empty sample tubes, add 230 μL of PBS buffer, then add 10 μL of the original drug working solution (concentration of 150000 ng·mL -1 ), add 30 μL of human (mouse) lung microsomal solution (10 mg / mL), then add 30 μL of NADPH solution, vortex well, and prepare three parallel samples of human (mouse) lung microsomal incubation.

[0213] Place the prepared samples in a 37°C water bath shaker for incubation, and at 0h, 0.25h, 0.5h, 0.75h and 1h, take out 50 μL and add to another set of sample tubes containing 150 μL of acetonitrile (containing benadryl, 2.500 ng·mL -1 ), mix well, and place in a -20°C refrigerator for testing.

[0214] 1.2 Analysis method of biological samples

[0215] 1.2.1 Reagents and chemicals

[0216] Methanol and acetonitrile are purchased from Honeywell. EDTA-K2 is purchased from National Pharmaceutical Group Chemical Reagent Co., Ltd. The rest of the reagents are chromatographic grade.

[0217] 1.2.2 LC-MS / MS biological sample analysis method, see Table 1 below

[0218] Table 1

[0219]

[0220]

[0221] 2 Data collection and processing calculation

[0222] 2.1 Data statistics and concentration calculation

[0223] The Analyst 1.6.2 version software was used for chromatographic peak collection, integration, calculation and processing; the ratio of the peak area of the test substance to the internal standard was taken as the vertical coordinate (y), and the concentration was taken as the horizontal coordinate (x), and the weighted least squares method (W = 1 / x 2 ) was used for regression operation, and the regression equation was: y = ax + b or y = ax 2 + bx + c. When analyzing the drug concentration in the sample, a standard curve was established for each analysis batch (Run) to calculate the concentration of the test substance in the quality control and unknown sample of the analysis batch. The ratio of the peak area of the test substance in the sample to the peak area of the internal standard was substituted into the corresponding standard curve to calculate the concentration of each test substance.

[0224] 2.2 Data processing and calculation

[0225] Microsoft Excel 2010 was used for calculation of average value, standard deviation and CV, etc. and data processing.

[0226] Concentration unit: ng·mL -1 , the original data retained 3 decimal places, the average value and SD value calculated retained 4 decimal places, and the CV value retained 2 decimal places. Divide by the main molar concentration to get the mass of NHC released per millimole (ng), and use graphpad prism software to draw the drug-time curve.

[0227] 3 Experimental results

[0228] The drug-time curves of NHC released by 32 example compounds in mouse and human lung microsomes are shown in the following Figure 4 .

[0229] Test Example 2 cytotoxicity experiment

[0230] Cells: MDCK cell culture medium: DMEM medium + FBS (10%) + double antibody (1%)

[0231] Operation method:

[0232] 1. Digest the MDCK cells, seed 96-well plates (8000 cells / well), and culture for 24 h.

[0233] 2. Add drug-containing medium and culture for 24 h.

[0234] 3. Aspirate the drug-containing medium, add MTS, and incubate in the incubator for 90 min.

[0235] 4. Read OD value at 490 nm by microplate reader.

[0236] Table 2. Results of cytotoxicity test of compounds

[0237]

[0238] Note: CC50: half maximal inhibitory concentration

[0239] Test Example 3 Anti-VSV virus activity test experiment

[0240] Test principle: The green fluorescent signal of recombinant vesicular stomatitis virus inserted with green fluorescent protein (GFP) was measured using African green monkey kidney cells (Vero) as host cells, so as to measure the inhibition efficiency of the sample.

[0241] Test materials and methods:

[0242] Virus strain: Vesicular stomatitis virus with green fluorescent protein reporter gene (National Bio-Medical Analysis Center), cultured and passaged in African green monkey kidney cells (Vero), -80°C.

[0243] Cell culture medium: MEM medium (CM50011, MACGENE) containing 10% fetal bovine serum (HQ30071-T500, Hongquan Biotechnology).

[0244] Sample treatment: The sample was prepared into a stock solution with DMSO, and then diluted with cell culture medium.

[0245] Positive control drug: Mipafibrate, Shanghai Bide Pharmaceutical Technology Co., Ltd. (Batch number: 152DGA).

[0246] Test method: Vero cells 2x104 / well were inoculated in a 96-well culture plate and cultured at 37°C in 5% CO2. After 12 hours, the culture medium was replaced with a culture medium containing the drug or DMSO, and the cells were pretreated for 2 hours. The diluted virus suspension was added, and the culture was incubated at 37°C in 5% CO2. After 24 hours, the GFP signal was detected by fluorescence microplate reader at an excitation wavelength of 488 nm and an emission wavelength of 535 nm. The inhibition rate was calculated according to the formula: inhibition rate = 1-[(fluorescence intensity of drug group-background fluorescence intensity) / (fluorescence intensity of DMSO group-background fluorescence intensity)]. The cell viability was tested by cck-8 method for drug mock group. The test results are shown in Table 3 below.

[0247] Table 3. Results of anti-VSV virus activity test of example compounds

[0248]

[0249] Note: CC 50 : half maximal inhibitory concentration; EC50 Antiviral median effective concentration; SI: selectivity index, SI = CC 50 / IC 50 .

[0250] Test Example 4. Anti-influenza virus PR8 activity test experiment

[0251] Cells: MDCK cells

[0252] Virus: PR8

[0253] Plating medium: DMEM medium + FBS (10%) + double antibody (1%)

[0254] Drug-containing medium: virus culture medium + TPCK at a final concentration of 2 μg / ml

[0255] Operation method:

[0256] 1. Digest MDCK cells, seed 96-well plates (8000 cells / well), and culture for 24 h.

[0257] 2. Wash the adherent cells with normal saline (1 time). Add the target drug to the target dilution concentration to the 96-well plate, 100 μl / well.

[0258] 3. Add 10 μl of PR8 virus diluent with a final dilution of 20000 times, and culture for 48 h.

[0259] 4. Absorb the virus-containing and drug-containing medium, add MTS, and incubate for 2 h before detection.

[0260] 5. Data processing: inhibition rate (%) = (OD value of drug-added well - OD value of virus well) / (OD value of NT well - OD value of virus well) * 100%

[0261] Table 4. Anti-influenza virus PR8 activity test results of the compounds of the examples

[0262]

[0263] Note: CC 50 : median cell inhibition concentration; EC 50 Antiviral median effective concentration; SI: selectivity index, SI = CC 50 / IC 50 .

[0264] The above merely provides a specific implementation of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can easily think of changes or replacements within the technical range disclosed by the present application, which should be encompassed in the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A class of nucleoside antiviral NHC diester prodrugs represented by the following formula I: and pharmaceutically acceptable salts thereof. wherein R1is selected from substituted or unsubstituted linear or branched C 3-20 alkylcarbonyl, the substitution meaning that the group is substituted with 1 to 3 R 11 substituents, said R 11 selected from a hydrogen atom, C 3-6 cycloalkyl, C 6-14 aryl, saturated or unsaturated three- to six-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, halogen atom, oxo group, amino group, hydroxyl group, amido group; R2is selected from linear or branched C 1-10 alkylcarbonyl, C 3-8 cycloalkylcarbonyl.

2. The nucleoside antiviral NHC diester prodrug according to claim 1, and pharmaceutically acceptable salts thereof, characterized in that, R1is selected from substituted or unsubstituted C 5-15 linear or branched alkylcarbonyl, the substitution meaning that the group is substituted with 1 or 2 R 11 substituents, said R 11 is selected from a hydrogen atom, C 3-6 cycloalkyl, C 6-10 aryl, saturated or unsaturated four- to six-membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O; More preferably, R1is selected from substituted or unsubstituted C 5-15 linear or branched alkylcarbonyl, the substitution meaning that the group is substituted with 1 or 2 R 11 substituents, said R 11 selected from a hydrogen atom, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, 3. The nucleoside antiviral NHC diester prodrug according to claim 1, and pharmaceutically acceptable salts thereof, characterized in that, R2is selected from linear or branched C 1-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl; More preferably, R2is selected from linear or branched C 1-5 alkylcarbonyl, C 3-5 cycloalkylcarbonyl; More preferably, R2 is selected from methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl.

4. The nucleoside antiviral NHC diester prodrug and pharmaceutically acceptable salts thereof according to claim 1, characterized in that, The nucleoside antiviral NHC diester prodrugs represented by formula I and pharmaceutically acceptable salts thereof are selected from any one of the compounds represented by A1 to A32 in the following table:

5. A method for preparing the nucleoside antiviral NHC diester prodrugs and pharmaceutically acceptable salts thereof according to any one of claims 1 to 4, the method comprising the following steps: In the first step, the starting material uridine (S1) is reacted with trimethylsilyl chloride, and phosphorus oxychloride is added dropwise under ice bath, and 1,2,4-triazole is added after stirring for 20 min, and after the reaction is complete, the trimethylsilyl protecting group is removed with acetic acid to obtain intermediate M2; In the second step, M2 is reacted with 2,2-dimethoxypropane under the catalysis of concentrated sulfuric acid to obtain compound M3; In the third step, the acyl chloride represented by R1-Cl or the acid represented by R1-OH is esterified with M3 to obtain M4; In the fourth step, the intermediate represented by M4 is reacted with hydroxylamine to obtain M5; In the fifth step, M5 is condensed with the acid represented by R2-OH to obtain M6; In the sixth step, M6 is deprotected under acid catalysis to obtain the compound represented by formula I.

6. A pharmaceutical composition comprising a therapeutically effective amount of the nucleoside antiviral NHC diester prodrugs and pharmaceutically acceptable salts thereof according to any one of claims 1 to 4, and pharmaceutically acceptable adjuvants.

7. Use of the nucleoside antiviral NHC diester prodrugs and pharmaceutically acceptable salts thereof according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating viral infections; wherein The virus is a coronavirus, an influenza virus, a human metapneumovirus, a rhabdovirus, a paramyxovirus, a respiratory syncytial virus, a flaviviridae virus, a filoviridae virus, a porcine epidemic diarrhea virus, a bunyaviridae virus, or a arenavirus.

8. Use according to claim 7, characterized in that, The virus is an influenza virus, a rhabdovirus, a coronavirus, a human metapneumovirus; Preferably, the influenza virus includes Influenza A virus, Influenza B virus, and Influenza C virus; Preferably, the coronavirus subtype includes SARS-CoV (SARS coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), and SARS-CoV-2 (2019 novel coronavirus), HCoV-229E, HCoV-NL63, and CCoV-HuPn-2018 (canine coronavirus).

9. A method of treating a viral infectious disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the nucleoside antiviral NHC double ester prodrug according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 6.

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