Azivudine prodrug compounds for treatment of tumors

Abstract

The invention discloses an alzvudine prodrug compound, which has the following structure: the compound disclosed by the invention has better tolerance and is more beneficial to drug development.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular, relates to an azithromycin prodrug compound for treating tumors. Background Art

[0002] Deoxycytidine kinase (DCK) is an enzyme with broad substrate specificity that phosphorylates pyrimidine and purine deoxynucleosides. It is a key enzyme in the salvage pathway of deoxynucleotide biosynthesis, maintaining normal DNA metabolism and phosphorylating a variety of antiviral and anticancer nucleoside analogs. These drugs are activated only upon phosphorylation, thereby inhibiting tumor growth. Over the past few decades, apoptosis has been extensively studied, and radiotherapy strategies targeting apoptosis have become an important approach to tumor treatment.

[0003] Azvudine (FNC) is a broad-spectrum RNA virus inhibitor. As a synthetic nucleoside analog of the viral RNA-dependent RNA polymerase (RdRp), it is metabolized intracellularly into a 5'-triphosphate metabolite (azvudine triphosphate) with antiviral activity. It can specifically act on the SARS-CoV-2 polymerase (RdRp). Its target is the viral RdRp, which can block the synthesis and replication of RNA chains in host cells by inhibiting the activity of RdRp. In July 2021, azivudine tablets were approved for marketing in my country for the treatment of adult HIV-1 infected patients with high viral loads. In July 2022, azivudine (FNC) was approved for the treatment of novel coronavirus infection.

[0004] Patent document CN201010506595.X discloses the use of azvudine (FNC) for treating tumors, such as colon cancer, liver cancer, gastric cancer, esophageal cancer, lung cancer, breast cancer, cervical cancer, leukemia, and lymphoma. It was found that azvudine (FNC) has a significant inhibitory effect on various human cancer cells and animal transplanted tumors.

[0005] The present invention further studies Azvudine (FNC) on the basis of the existing technology, and develops an Azvudine prodrug compound for treating tumors. Summary of the Invention

[0006] Specifically, the present invention provides a method for treating tumors, comprising administering to a subject in need thereof a compound having the following formula (I):

[0007]

[0008] Wherein, R1, R2, and R3 are each independently selected from any one substituent of the following group:

[0009] (1) Hydrogen, provided that R1, R2, and R3 are not simultaneously hydrogen;

[0010] (2)C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0011] (3)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ , -CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ;

[0012] (4) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; for example: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ );

[0013] (5)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0014] (6)R 1 、R2 Together with 3'-O and 5'-O, they form a ring with the carbon atom to which they are attached;

[0015] (7)R 1 、R 2 Together they form a cyclic phosphate;

[0016] Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0017] Among them, the above C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl can be arbitrarily selected from halogen, cyano, -OR a , halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, -NR a R b 、-SO3R a , -NO2, -SF5;

[0018] Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl; n represents 0, 1, 2 or 3.

[0019] In the above preferred technical solution, R1 represents hydrogen, and R2 and R3 each independently represent any substituent selected from the following group:

[0020] (1)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ , -CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ;

[0021] (2) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; for example: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ )

[0022] (3)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0023] Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl; n represents 0, 1, 2 or 3.

[0024] In the above preferred technical solution, R2 represents hydrogen, and R1 and R3 each independently represent any substituent selected from the following group:

[0025] (1)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,,-CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ;

[0026] (2) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; for example: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ )

[0027] (3)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0028] Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl; n represents 0, 1, 2 or 3.

[0029] In the above preferred technical solution, R3 represents hydrogen, and R1 and R2 each independently represent any substituent selected from the following groups:

[0030] (1)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ , -CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ;

[0031] (2) phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamidate, phosphate diamidate, thiophosphate, selenophosphate or borophosphate;

[0032] (3)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0033] Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl; n represents 0, 1, 2 or 3.

[0034] In the above preferred technical solution, R1, R2, and R3 each independently represent hydrogen or any substituent selected from the following group: -C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,-C(R L R L’ )OC(=O)R L ,-C(=O)CR L R L’ -NR L R L’ ,-C(=O)CR L R L’ -NR L R L’ , where R L 、R L’ Each independently represents hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl.

[0035] In the above preferred technical solution, R LIt represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, an isobutyl group, or a tert-butyl group.

[0036] In the above preferred technical solution, R1, R2, and R3 each independently represent: -P(=O)O(R L R L’ )-P(=O)(N L R L’ ), -P(=O)(NR L R L’ )2,-P(=O)(NR L R L’ )OR L , or -P(=O)(NH)CR a R b C(O)OR L .

[0037] In addition, the present invention also provides a method for treating tumors, comprising administering a compound having the following formula (II) to a subject in need thereof:

[0038]

[0039] Where X represents (CR a R b ) i , and, arbitrarily CR a R b Can be -C(O)-, O, -NR a -、C6-C 10 substituted by aryl or 5-10 membered heteroaryl;

[0040] Among them, i represents 1, 2, 3, 4, 5, 6;

[0041] Wherein, R3 represents a substituent selected from any of the following groups:

[0042] (1) Hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0043] (2)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,,-CRL R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ;

[0044] (2) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; for example: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ );

[0045] (4)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ;

[0046] Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0047] Among them, the above C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl can be arbitrarily selected from halogen, cyano, -OR a , halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, -NR a R b 、-SO3R a , -NO2, -SF5;

[0048] Among them, R a 、R b Each independently represents hydrogen, C1-C 10Alkyl group. n represents 0, 1, 2 or 3.

[0049] In the above preferred technical solution, R3 represents hydrogen.

[0050] In the above preferred technical solution, wherein R3 represents C1-C 10 alkyl.

[0051] In the above preferred technical solution, wherein R3 represents -C(=O)R L ,-C(=O)OR L ; Among them, R L Indicates C1-C 10 Alkyl, C3-C 10 Cycloalkyl.

[0052] In the above preferred technical solution, X represents CH2, CH(CH3), C(CH3)2, CH2CH2, CH(CH3)CH2, C(CH3)2CH2.

[0053] In the above preferred technical solution, wherein X represents -CH2-C(O)-C(O)-CH2, -C(O)-C(O)-, -C(O)-CH2-C(O)-, -C(O)-CH(CH3)-C(O)-, -C(O)-C(CH3)2-C(O)-, -C(O)-CH2CH2-C(O)-,

[0054] In the above preferred technical solution, X represents -CH2NHC(O)NHCH2- or -CH2OC(O)OCH2-.

[0055] In the above preferred technical solution, wherein X represents -(CH2) s’ -C(O)-(CH2) s -phenyl-(CH2) t -C(O)-(CH2) t’ -, wherein s, s', t, t' independently represent 0 or 1.

[0056] In the above preferred technical solution, X represents

[0057] In the above preferred technical solution, wherein X represents -(CH2) s’ -C(O)-(CH2) s -(5-10 membered heteroaryl)-(CH2) t -C(O)-(CH2) t’ -, wherein s, s', t, t' independently represent 0 or 1.

[0058] In the above preferred technical solution, the 5-10 membered heteroaryl group is selected from any one of the following groups:

[0059]

[0060]

[0061] In the above preferred technical solution, X represents

[0062] In addition, the present invention also provides a method for treating tumors, comprising administering a compound having the following formula (III) to a subject in need thereof:

[0063]

[0064] in,

[0065] Y1 means NR a or O;

[0066] Y2 represents -C(O)O-, -OC(O)-, -C(O)S-, or -SC(O)-;

[0067] R T represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C5-C 10 Aryl, 5-10 membered heteroaryl, benzyl, heterocyclic benzyl;

[0068] R3 represents a substituent selected from any of the following groups:

[0069] (1) Hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0070] (2)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,,-CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ;

[0071] (3) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; for example: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ );

[0072] (4)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ;

[0073] Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl);

[0074] Among them, the above C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl can be arbitrarily selected from halogen, cyano, -OR a , halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, -NR a R b 、-SO3R a , -NO2, -SF5;

[0075] Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl; n represents 0, 1, 2 or 3.

[0076] j represents 0, 1, 2, or 3.

[0077] In the above preferred technical solution, R3 represents hydrogen.

[0078] In the above preferred technical solution, wherein R3 represents C1-C 10 alkyl.

[0079] In the above preferred technical solution, wherein R3 represents -C(=O)R L ,-C(=O)OR L ; Among them, R L Indicates C1-C 10 Alkyl, C3-C 10 Cycloalkyl.

[0080] In the above preferred technical solution, Y1 represents O.

[0081] In the above preferred technical solution, wherein Y2 represents -C(O)O- or -OC(O)-.

[0082] Specifically, the present invention provides a method for treating tumors, comprising administering to a subject in need thereof a compound having the following structure:

[0083]

[0084]

[0085]

[0086]

[0087] DETAILED DESCRIPTION

[0088] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, it will be understood by those skilled in the art that the embodiments disclosed herein can be practiced without these details. Under the understanding that this disclosure is considered to be an illustration of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown, several embodiments are described below. The headings used throughout this disclosure are provided only for convenience and should not be interpreted as limiting the claims in any way. The embodiments illustrated under any heading may be combined with the embodiments illustrated under any other heading.

[0089] I. Definition

[0090] The terms "about" or "approximately" used in connection with a quantity are inclusive of the stated value and have the meaning dictated by the context (eg, includes the degree of error associated with measurement of the particular quantity).

[0091] Unless otherwise indicated, the compounds of the present invention may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.

[0092] "Prodrug" refers to a substance that is converted into the parent drug in vivo. In some cases, prodrugs are often used because they are easier to administer than the parent drug. For example, a prodrug may be bioavailable orally while the parent drug is not. In a pharmaceutical composition, a prodrug may also have a higher solubility than the parent drug. Examples of prodrugs, but not limited to, are any of the compounds administered in the form of an ester (prodrug) to facilitate transport across cell membranes, where water solubility is detrimental to migration, but once inside the cell where water solubility is beneficial, the ester is subsequently metabolically hydrolyzed to the active substance, the carboxylic acid. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, wherein the peptide is metabolized to release the active moiety.

[0093] As used herein, the term "administer" generally refers to administering a composition to a subject to achieve delivery of the agent in or contained in the composition to a target site or site to be treated. Those of ordinary skill in the art will appreciate that various approaches can be used for administering to a subject (e.g., mankind) under appropriate circumstances. For example, in some embodiments, administration can be parenteral. In some embodiments, administration can be by injection (e.g., intramuscular, intravenous, or subcutaneous injection). In some embodiments, administration can only involve a single dose. In some embodiments, administration can involve administering a fixed number of doses. In some embodiments, administration can involve intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., single doses separated by a common time period) administration. In some embodiments, administration can involve continuous administration (e.g., perfusion) for at least a selected time period.

[0094] The term "alkyl" is a hydrocarbon containing primary, secondary, or tertiary atoms. For example, an alkyl group may have from 1 to 25 carbon atoms (i.e., (C1-C 25 ) alkyl), 1 to 10 carbon atoms (i.e., (C1-C 10 ) alkyl), 1 to 8 carbon atoms (i.e., (C1-C8) alkyl) or 1 to 6 carbon atoms (i.e., (C1-C6) alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl

[0095] propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, tert-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2 CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3) , 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl -3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3). "Alkyl" also refers to a saturated, branched, or straight-chain hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkyl group can have from 1 to 10 carbon atoms (i.e., (C1-C1 10 )alkyl) or 1 to 6 carbon atoms (i.e., (C1-C6)alkyl) or 1-3 carbon atoms (i.e., (C1-C3)alkyl). Typical alkyl groups include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0096] As used herein, the term "(C1-n)alkyl" (also described as "(C1-C n) alkyl”), where n is an integer, alone or in combination with another group, means a non-cyclic, straight-chain or branched alkyl group containing 1 to n carbon atoms. “(C 1-6 )alkyl includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (isopropyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, and hexyl. The abbreviation Me represents a methyl group; Et represents an ethyl group, Pr represents a propyl group, iPr represents a 1-methylethyl group, Bu represents a butyl group, and tBu represents a 1,1-dimethylethyl group.

[0097] "Alkylene" (including those that are part of other groups) refers to branched and unbranched divalent "alkyl" groups. As used herein, an alkylene group can have 1 to 25 carbon atoms (i.e., C 1-25 alkylene), 1 to 8 carbon atoms (i.e., C 1-8 alkylene), 1 to 6 carbon atoms (i.e., C 1-6 alkylene) or 1 to 4 carbon atoms (i.e., C 1-4 Examples include methylene, ethylene, propylene, 1-methylethylene, butene, 1-methylpropylene, 1,1-dimethylethylene, or 1,2-dimethylethylene. Unless otherwise specified, the definitions propylene and butene include all possible isomeric forms of the group in question having the same carbon number. Thus, for example, propylene also includes 1-methylethylene, and butene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0098] "Alkenyl" is a straight or branched chain hydrocarbon containing primary, secondary, or tertiary carbon atoms and having at least one site of unsaturation (i.e., a carbon-carbon sp2 double bond). For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C 20 Suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH), allyl (-CHCH=CH), cyclopentenyl (-C5H7), and 5-hexenyl (-CHCHCHCHCH=CH).

[0099] As used herein, the term "(C 2-n ) alkenyl”, where n is an integer, means, alone or in combination with another group, an unsaturated, non-cyclic, straight-chain or branched group containing two to n carbon atoms, at least two of which are bonded to each other by a double bond. Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise indicated, the term “(C 2-n) alkenyl" shall be understood to include individual stereoisomers where possible, including but not limited to (E) and (Z) isomers and mixtures thereof. Unless otherwise indicated, when (C 2-n ) When an alkenyl group is substituted, it is understood that substitution is made on any carbon atom which would otherwise bear a hydrogen atom such that the substitution would result in a chemically stable compound, such as will be recognized by one skilled in the art.

[0100] "Alkynyl" is a straight or branched chain hydrocarbon containing primary, secondary, or tertiary carbon atoms and having at least one site of unsaturation (i.e., a carbon-carbon sp triple bond). For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C 20 alkynyl), 2 to 8 carbon atoms (i.e., C2-C8 alkynes), or 2 to 6 carbon atoms (i.e., C 2- Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and the like.

[0101] As used herein, the term "(C 2-n )alkynyl”, where n is an integer, means, alone or in combination with another group, an unsaturated, non-cyclic, straight-chain or branched group containing two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by a triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl. Unless otherwise specified, when (C 2-n ) alkynyl groups, when substituted, are understood to be substituted on any carbon atom which would otherwise bear a hydrogen atom such that the substitution would result in a chemically stable compound, such as will be recognized by one skilled in the art.

[0102] As used herein, the term "aryl" refers to a single aromatic ring or a bicyclic or polycyclic ring. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl or an ortho position, spirocycle, or bridged bicyclic or polycyclic group with about 9 to 14 atoms, wherein at least one ring is aromatic (for example, an aryl fused to one or more aryl groups or carbocyclic rings). Such bicyclic or polycyclic rings can optionally be substituted with one or more (for example, 1, 2, or 3) oxo groups on any carbocyclic ring portion of the bicyclic or polycyclic ring. It should be understood that the connection point of the bicyclic or polycyclic group as defined above can be in any position of the ring, including the aryl or carbocyclic ring portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, etc.

[0103] "Arylalkyl" refers to an alkyl group as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group as described herein (i.e., an aryl-alkyl- moiety). The alkyl group of an "arylalkyl" group typically has from 1 to 6 carbon atoms (i.e., an aryl(C1-C6)alkyl group). Arylalkyl groups include, but are not limited to, benzyl, 2-phenyleth-1-yl, 1-phenylprop-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, and the like.

[0104] As used herein, the term "aryl-(C 1-n) "Alkyl-", wherein n is an integer, alone or in combination with another group, means an alkyl group as defined above having from 1 to n carbon atoms, which itself is substituted with an aryl group as defined above. Examples of aryl-(C1-n)alkyl- include, but are not limited to, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl, and phenylpropyl. Unless otherwise specified, when an aryl-(C1-n)alkyl- group is substituted, it is understood that the substituents may be attached to the aryl or its alkyl portion, or both, such that the substitution will result in a chemically stable compound, such as will be recognized by those skilled in the art.

[0105] The term "carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) ring with 3 to 7 carbon atoms as a monocyclic or polycyclic ring system. In one embodiment, the carbocycle is a monocycle (i.e., (C3-C6) carbocycle) comprising 3-6 ring carbons. Carbocycle includes a bicyclic and polycyclic carbocycle with 7 to 12 carbon atoms and up to about 20 carbon atoms, provided that the maximum monocyclic ring of the polycyclic carbocycle is 7 carbon atoms. The term "spirocarbocycle" refers to a carbocyclic ring system (e.g., spiropentanes, spiro[4,5]decanes, spiro[4.5]decanes, etc.) in which the ring of the ring system is connected to a single carbon atom. The term "fused carbocycle" refers to a carbocyclic ring system in which the rings of the ring system are attached to two adjacent carbon atoms, such as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or a bicyclo [5,6] or [6,6] system arranged with 9 or 10 ring atoms (e.g., decalin, norsabine, normethane). The term "bridged carbocycle" refers to a carbocyclic ring system in which the rings of the ring system are attached to two non-adjacent carbon atoms (e.g., norbornane, bicyclo [2.2.2] octane, etc.). A "carbocycle" or "carbocyclyl" may be optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

[0106] "Carbocyclylalkyl" refers to an alkyl group as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced by a carbocyclyl group as described herein (i.e., a carbocyclyl-alkyl-moiety). The alkyl group of a "carbocyclylalkyl" group is typically 1 to 6 carbon atoms (i.e., a carbocyclyl (C1-C6) alkyl group). Typical carbocyclylalkyl groups include, but are not limited to, carbocyclyl-CH2-, carbocyclyl-CH(CH3)-, carbocyclyl-CH2CH2-, 2-(carbocyclyl)ethyl-1-yl, and the like, wherein the "carbocyclyl" moiety includes any of the above-mentioned carbocyclyl groups.

[0107] "Cycloalkyl" refers to a non-aromatic hydrocarbon ring composed of carbon atoms and hydrogen atoms, having three to fifteen carbon atoms, in certain embodiments three to ten carbon atoms or three to seven carbon atoms, and which is saturated or partially unsaturated and is attached to the rest of the molecule by a single bond. Cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, cycloheptenyl, and cyclooctyl.

[0108] As used herein, the term "(C 3-m )cycloalkyl", where m is an integer, alone or in combination with another group, means a cycloalkyl substituent containing 3 to m carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0109] The term "(C 3-m )cycloalkyl-(C1-n)alkyl-", wherein n and m are both integers, alone or in combination with another group, means an alkyl group having 1 to n carbon atoms as defined above, which itself is substituted by a cycloalkyl group having 3 to m carbon atoms as defined above. (C 3-7 )cycloalkyl-(C 1-6 Examples of )alkyl- include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl, and 2-cyclohexylethyl. Unless otherwise indicated, when (C 3-m )cycloalkyl-(C 1-n ) When the alkyl- group is substituted, it is understood that the substituents may be attached to the cycloalkyl group or its alkyl portion, or both, such that the substitution will result in a chemically stable compound, such as will be recognized by those skilled in the art.

[0110] As used herein, the term "combination therapy" refers to those situations in which a subject receives two or more therapeutic or preventive regimens (e.g., two or more therapeutic or preventive agents) simultaneously. In some embodiments, the two or more regimens can be administered simultaneously; in some embodiments, such regimens can be administered sequentially (e.g., all "dosages" of the first regimen are administered before the second regimen of any dose is administered); in some embodiments, such agents are administered with overlapping dosing regimens. In some embodiments, "administering" a combination therapy may involve administering one or more agents or modes to subjects receiving other agents or modes in the combination. For clarity, combination therapy does not require that each agent be administered together in a single composition (or not even simultaneously), but in some embodiments, two or more agents or their active parts can be administered together in a combined composition, or even in a combined compound (e.g., as part of a single chemical complex or covalent entity).

[0111] As used herein, the term "comparable" refers to two or more agents, entities, situations, sets of conditions, etc. that may not be identical to one another but are sufficiently similar to allow comparisons to be made between them such that one skilled in the art would understand that conclusions can reasonably be drawn based on the observed differences or similarities. In some embodiments, comparable conditions, environments, individuals, or groups of populations are characterized by a plurality of substantially identical characteristics and one or a few slightly varied characteristics. One of ordinary skill in the art would understand, in context, what degree of identity is required for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable in any given case. For example, one of ordinary skill in the art would understand that environments, individuals, or groups of populations are comparable to one another when characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in results or observed phenomena obtained under or with different environments, individuals, or groups of populations are caused or indicated by changes in those varied characteristics.

[0112] Unless the context requires otherwise, throughout this disclosure and claims, the word "comprise" and variations such as "include" and "comprising" are to be construed in an open, inclusive sense, ie, to mean "including, but not limited to."

[0113] "Diastereomers" refers to stereoisomers that have two or more chiral centers or axes and whose molecules are not mirror images of each other. Diastereomers typically have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical methods, such as electrophoresis and chromatography.

[0114] As used herein, the term "dosage form" refers to a physical discrete unit of an active agent (e.g., a therapeutic agent, a prophylactic agent, or a diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, this amount is a unit dose (or its entire portion) suitable for administration according to a dosage regimen that has been determined to be associated with an expectation or beneficial outcome when administered to a relevant population (i.e., with a preventive or therapeutic dosage regimen). It will be understood by those of ordinary skill in the art that the total amount of the composition or medicament administered to a particular subject is determined by one or more attending physicians and may involve the administration of a variety of dosage forms.

[0115] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment disclosed herein. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0116] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0117] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[0118] "Mammal" includes humans as well as domestic animals such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals, etc.

[0119] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl may or may not be substituted, and that the description includes substituted heterocyclyls and heterocyclyls that are not substituted. It should be understood that when a variable is substituted, for example, as described by the phrase "(C1-C6)alkyl, alone or as part of a group, optionally substituted", the phrase means that the variable (C1-C6)alkyl can be substituted when alone, and the variable "(C1-C6)alkyl" can also be substituted when it is part of a larger group, such as aryl(C1-C6)alkyl or -(C1-C6)alkyl-SO2-(C1-C6)alkyl-(C3-C7)carbocyclic group. Similarly, other variables (eg, (C1-C6)alkenyl, (C1-C6)alkynyl, aryl, heteroaryl, heterocycle, etc.) may also be substituted "either individually or as part of a group" when stated.

[0120] As used herein, the term "oxo" refers to an oxygen atom attached as a substituent to a carbon atom through a double bond (=0).

[0121] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substance that is formulated in combination with the pharmacologically active ingredient of the pharmaceutical composition and is compatible with the other ingredients of the formulation and is suitable for use in humans or domestic animals without undue toxicity, irritation, allergic response, or the like.

[0122] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from suitable bases such as alkali metals (eg, sodium), alkaline earth metals (eg, magnesium), ammonium, and NX4+ (wherein X is C1-4 alkyl). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, salts of organic carboxylic acids such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphoric acid, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, nicotinic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. Pharmaceutically acceptable salts of compounds containing a hydroxy group include the anion of the compound in combination with a suitable cation such as Na+ and NX4+ (wherein X is independently selected from H or a C1-4 alkyl group).

[0123] For therapeutic use, salts of the active ingredients of the compounds disclosed herein will generally be pharmaceutically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be used, for example, to prepare or purify the compounds of the embodiments disclosed herein. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the embodiments disclosed herein.

[0124] Metal salts are typically prepared by reacting metal hydroxides with compounds according to embodiments disclosed herein. Examples of metal salts prepared in this manner are salts containing Li+, Na+, and K+. Less soluble metal salts can be precipitated from solutions of more soluble salts by adding appropriate metal compounds.

[0125] Additionally, salts can be formed by acid addition of certain organic and inorganic acids (e.g., HCl, HBr, H2SO4, H3PO4 or organic sulfonic acids) to basic centers (typically amines). Finally, it should be understood that the compositions herein comprise the compounds disclosed herein in unionized form as well as in zwitterionic form.

[0126] A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for delivering the biologically active compound to a mammal (eg, a human). Such a medium includes all pharmaceutically acceptable excipients. BRIEF DESCRIPTION OF THE DRAWINGS

[0127] Figure 1 Antitumor activity of the compounds of the examples Specific embodiments

[0129] Example 1

[0130]

[0131] Step 1

[0132] 4-Amino-1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (FNC) (200 mg, 0.70 mmol), N-methylmorpholine (71 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol), and acetic acid (46 mg, 0.77 mmol) were dissolved in a mixture of DMF (3 mL) and DMSO (1 mL) at room temperature. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol) was then added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 55°C and reacted overnight. LCMS monitored the substantial consumption of the starting material. The reaction mixture was purified by preparative pre-HPLC, and the resulting product was lyophilized to obtain 44.7 mg of N-(1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide (FNC-1) as a white solid in a 19.5% yield. MS m / z: 328.9 [M+H]. 1H NMR(400MHz, DMSO-d6)δ:10.98(s,1H),8.11(dd,J=7.6,1.1Hz,1H),7.25(d,J=7.6Hz,1H),6.48(d,J=5.9Hz,1H),6.40(dd,J=12.1,5.1H z,1H),5.72(t,J=6.1Hz,1H),5.27(dt,J=53.4,4.8Hz,1H),4.45(ddd,J=21.8,6.0,4.6Hz,1H),3.75(td,J=5.9,4.4Hz,2H),2.11(s,3H).

[0133] Example 2

[0134]

[0135] Step 1

[0136] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (300 mg, 1.05 mmol) was dissolved in a mixed solvent (150 mL) of ethyl acetate / acetonitrile (2:1), heated to 80°C and refluxed for 1 h, and then 2-methylpropyl chloroformate (80 uL, 0.59 mmol) was added dropwise. After the addition was completed, the reaction was maintained at 80°C for 4 hours. TLC revealed the formation of a new product. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by silica gel column chromatography. The crude product was then directly isolated by preparative HPLC to afford 28 mg of 2-methylpropyl N-{1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}carbamate (FNC-2) as a white solid. Yield: 6.83%; purity: 96.44%. MS m / z: 387.1 [M+H]. 1 H NMR(400MHz, DMSO-d6)δ10.81(s,1H),8.10(d,J=7.6Hz,1H),7.09(d,J=7.6Hz, 1H),6.48(dd,J=5.8,1.3Hz,1H),6.40(dd,J=12.1,5.1Hz,1H),5.77-5.69(m,1H ),5.27(dt,J=53.5,4.8Hz,1H),4.45(ddd,J=21.9,5.9,4.6Hz,1H),3.91(d,J= 6.6Hz,2H),3.82-3.70(m,2H),1.91(hept,J=6.7Hz,1H),0.91(d,J=6.7Hz,6H).

[0137] Example 3

[0138]

[0139] Step 1

[0140] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (200 mg, 0.7 mmol), 4-methylmorpholine (71 mg, 0.7 mmol) and 1-hydroxybenzotriazole (104 mg, 0.77 mmol) were dissolved in a DMF / DMSO (3:1) mixed solvent (4 mL), and valproic acid (111 mg, 0.77 mmol) was added dropwise. After the addition was complete, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (174 mg, 0.91 mmol) was added. After the solution was clarified, the temperature was raised to 55°C under argon and the reaction was allowed to proceed overnight. TLC confirmed the complete reaction of the starting material. LC-MS revealed the desired product, which was directly isolated by preparative HPLC to afford 113 mg of N-{1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}-2-propylpentanamide (FNC-3) as a white solid. Yield: 39.14%; purity: 98.49%. MS m / z: 413.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.13(d,J=7.6Hz,1H),7.33(d,J=7.6Hz,1H ), 6.40 (dd, J=12.1, 5.1Hz, 1H), 5.28 (dt, J=53.4, 4.8Hz, 1H), 4.46 (dd, J=21.8, 4. 5Hz,1H),3.81-3.71(m,2H),2.68-2.56(m,1H),1.53(ddd,J=17.5,12.1,7.4Hz,2 H),1.34(ddd,J=13.1,10.9,5.6Hz,2H),1.29-1.13(m,5H),0.86(t,J=7.3Hz,6H).

[0141] Example 4

[0142]

[0143] Step 1

[0144] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (200 mg, 0.7 mmol), 4-methylmorpholine (71 mg, 0.7 mmol) and 1-hydroxybenzotriazole (104 mg, 0.77 mmol) were dissolved in a DMF / DMSO (3:1) mixed solvent (4 mL), and propionic acid (57 mg, 0.77 mmol) was added dropwise. After the addition was complete, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (174 mg, 0.91 mmol) was added. After the solution was clarified, the temperature was raised to 55°C under argon and the reaction was allowed to proceed overnight. TLC confirmed the complete reaction of the starting material. LC-MS revealed the desired product, which was directly isolated by preparative HPLC to afford 38 mg of N-{1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}propanamide (FNC-4) as a white solid. Yield: 15.94%, purity: 95.34%. MS m / z: 343.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.11(d,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),6.48(d,J=5.9Hz,1H),6.40(dd,J=12.2,5.2Hz,1H),5.73(t ,J=6.1Hz,1H),5.27(dt,J=53.4,4.8Hz,1H),4.45(dt,J=21.9,5.3Hz,1H),3.75(h,J=6.1Hz,2H),2.42(q,J=7.4Hz,2H),1.03(t,J=7.4Hz,3H).

[0145] Example 5

[0146]

[0147] Step 1

[0148] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (200 mg, 0.7 mmol), 4-methylmorpholine (71 mg, 0.7 mmol) and 1-hydroxybenzotriazole (104 mg, 0.77 mmol) were dissolved in a DMF / DMSO (3:1) mixed solvent (4 mL), and isobutyric acid (68 mg, 0.77 mmol) was added dropwise. After the addition was complete, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (174 mg, 0.91 mmol) was added. After the solution was clarified, the temperature was raised to 55°C under argon and the reaction was allowed to proceed overnight. TLC confirmed the complete reaction of the starting material, and LC-MS revealed the desired product. Preparative HPLC directly isolated the product, yielding 82 mg of N-{1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}-2-methylpropanamide (FNC-5), as a white solid. Yield: 32.88%, purity: 97.39%. MS m / z: 357.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.12(d,J=7.6Hz,1H),7.30(d,J=7.6Hz,1H),6.49(d,J=5.9Hz,1H),6.40(dd,J=12.1,5.1Hz,1H),5.73(t,J =6.1Hz,1H),5.27(dt,J=53.4,4.8Hz,1H),4.45(ddd,J=21.9,6.0,4.6Hz,1H),3.76(h,J=6.1Hz,2H),2.73(p,J=6.8Hz,1H),1.07(d,J=6.8Hz,6H)

[0149] Example 6

[0150]

[0151] Step 1

[0152] 4-Amino-1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (FNC) (200 mg, 0.70 mmol), N-methylmorpholine (71 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol), and n-butyric acid (68 mg, 0.77 mmol) were dissolved in a mixture of DMF (3 mL) and DMSO (1 mL) at room temperature. The atmosphere was purged with nitrogen three times, and the mixture was heated to 55°C and reacted overnight. LCMS monitoring indicated that the starting material was largely consumed. The reaction mixture was purified by preparative pre-HPLC, and the resulting product was lyophilized to obtain 105.8 mg of N-(1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)butanamide (FNC-7) as a white solid in a 40.7% yield. MS m / z: 357.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ: 10.95 (s, 1H), 8.11 (d, J = 7.6Hz, 1H), 7.28 (d, J = 7.6Hz, 1H), 6.48 (d, J = 5.7Hz, 1H), 6.40 (dd, J = 12.2, 5.1Hz, 1H), 5.72 (t ,J=6.1Hz,1H),5.37-5.15(m,1H),4.53-4.35(m,1H),3.76(t,J=5.3Hz, 2H), 2.39(t,J=7.2Hz,2H), 1.57(q,J=7.4Hz,2H), 0.88(t,J=7.4Hz,3H).

[0153] Example 7

[0154]

[0155] Step 1

[0156] 4-Amino-1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (FNC) (200 mg, 0.70 mmol), N-methylmorpholine (71 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol), and valeric acid (79 mg, 0.77 mmol) were dissolved in a mixture of DMF (3 mL) and DMSO (1 mL) at room temperature. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol) was then added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 55°C and reacted overnight. LCMS monitored the substantial consumption of the starting material. The reaction mixture was purified by preparative pre-HPLC, and the resulting product was lyophilized to afford 116 mg of N-(1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)pentanamide (FNC-7) as a white solid in a 44.7% yield. MS m / z: 371.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ: 10.95 (s, 1H), 8.28-7.97 (m, 1H), 7.28 (d, J = 7.5Hz, 1H), 6 .48(d,J=5.9Hz,1H),6.40(dd,J=12.1,5.1Hz,1H),5.73(d,J=7.3Hz,1H),5.27(dt, J=53.4,4.8Hz,1H),4.45(dt,J=21.7,4.8Hz,1H),3.84-3.70(m,2H),2.41(t,J=7.4 Hz, 2H), 1.53 (p, J = 7.4Hz, 2H), 1.30 (dt, J = 14.8, 7.3Hz, 2H), 0.87 (t, J = 7.3Hz, 3H).

[0157] Example 8

[0158]

[0159] Step 1

[0160] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (400 mg, 1.4 mmol), 4-methylmorpholine (283 mg, 2.8 mmol) and 1-hydroxybenzotriazole (378 mg, 2.8 mmol) were dissolved in a DMF / DMSO (3:1) mixed solvent (4 mL), and acetic acid (168 mg, 2.8 mmol) was added dropwise. After the addition was complete, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (537 mg, 2.8 mmol) was added. After the solution was clarified, the temperature was raised to 55°C under argon and the reaction was allowed to proceed overnight. TLC confirmed the complete reaction of the starting material, and LC-MS revealed the desired product. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography. The crude product was then directly isolated by preparative HPLC to give 42 mg of methyl [(2R,3R,4S,5R)-3-(acetoxy)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-2-azido-4-fluorooxolan-2-yl] acetate (FNC-8-2) as a white solid. The yield was 8.18% and the purity was 99.7%. MS m / z: 371.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ7.63(dd,J=7.5,1.9Hz,1H),7.41(d,J=9.6Hz,2H),6.50(dd,J=13.7,5.3Hz,1H),5.79(d, J=7.5Hz,1H),5.72(d,J=21.0Hz,1H),5.52(ddd,J=52.4,5.4,4.2Hz,1H),4.52(s,2H),2.16(s,3H),2.08(s,3H).

[0161] Example 9

[0162]

[0163] Step 1

[0164] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (400 mg, 1.4 mmol), 4-methylmorpholine (283 mg, 2.8 mmol) and 1-hydroxybenzotriazole (378 mg, 2.8 mmol) were dissolved in a DMF / DMSO (3:1) mixed solvent (4 mL), and acetic acid (168 mg, 2.8 mmol) was added dropwise. After the addition was complete, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (537 mg, 2.8 mmol) was added. After the solution was clarified, the temperature was raised to 55°C under argon and the reaction was allowed to proceed overnight. TLC confirmed the complete reaction of the starting material, and LC-MS revealed the desired product. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography. The crude product was then directly isolated by preparative HPLC to obtain 20 mg of methyl [(2R,3R,4S,5R)-2-azido-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-hydroxyoxolan-2-yl]acetate (FNC-8) as a white solid. The yield was 3.76% and the purity was 99.05%. MS m / z: 370.9 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.02(dd,J=7.6,1.3Hz,1H),7.27(d,J=7.6Hz,1H),6.74(d,J=5.6Hz,1H),6.46(dd, J=13.6,4.9Hz,1H),5.31(dt,J=52.9,4.4Hz,1H),4.56(dt,J=20.3,4.6Hz,1H),4.48-4.37(m,2H),2.11(d,J=4.3Hz,6H).

[0165] Example 10

[0166]

[0167] Step 1

[0168] 4-Amino-1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (FNC) (350 mg, 1.22 mmol), N-methylmorpholine (123 mg, 1.22 mmol), 1-hydroxybenzotriazole (164 mg, 1.22 mmol), and isobutyric acid (118.6 mg, 1.35 mmol) were dissolved in a mixture of DMF (3 mL) and DMSO (1 mL) at room temperature. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234 mg, 1.22 mmol) was then added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 55°C and reacted overnight. LCMS monitored the substantial consumption of the starting material. The reaction solution was purified by preparative pre-HPLC, and the resulting product was lyophilized to obtain 25 mg of methyl ((2R,3R,4S,5R)-2-azido-4-fluoro-3-hydroxy-5-(4-isobutyramido-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)isobutyrate (FNC-9), MS m / z: 427.0 [M+H], 1 H NMR(400MHz, DMSO-d6)δ:10.99(s,1H),8.02(dd,J=7.5,1.4Hz,1H),7.31(d,J=7.6Hz,1H),6.72(d,J=5.8Hz,1H),6.46(dd,J=13.4,5.0Hz,1H),5 .42-5.24(m,1H),4.56(ddd,J=20.7,5.9,4.3Hz,1H),4.51-4.37(m,2H) ,2.69(dp,J=33.6,6.9Hz,2H),1.13(dd,J=7.0,1.6Hz,6H),1.11(s,6H).

[0169] Example 11

[0170]

[0171]

[0172] Step 1

[0173] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (400 mg, 1.4 mmol) was dissolved in DMF (5 mL) and stirred in an ice-water bath for 30 min. Then, tert-butyldimethylsilyl chloride (632 mg, 4.19 mmol) and imidazole (381 mg, 5.59 mmol) were added. After the addition was complete, the temperature was raised to room temperature and the reaction was allowed to proceed overnight. The original After the reaction was complete, water was added under ice-bath to quench the reaction. The organic phase was extracted with ethyl acetate, collected, and concentrated under reduced pressure. Silica gel column chromatography was used to separate (4-amino-1-[(2R,3S,4R,5R)-5-azido-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC-11-1), 153 mg, as a light yellow solid, in a yield of 21.23%. MS m / z: 515.1 [M+H].

[0174] Step 2

[0175] 4-(4-amino-1-[(2R, 3S, 4R, 5R)-5-azido-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC-11-1) (252 mg, 0.49 mmol) was dissolved in THF (3 mL). DMAP (12 mg, 0.098 mmol) and di-tert-butyl dicarbonate (118 mg, 0.54 mmol) were added under stirring at room temperature. After the addition was completed, the mixture was kept under argon atmosphere. The reaction was stirred at room temperature overnight under a protective atmosphere. LC-MS monitored the complete reaction of the starting material. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 153 mg of tert-butyl N-{1-[(2R,3S,4R,5R)-5-azido-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}carbamate (FNC-11-2) as a light yellow oil in a yield of 50.83%. MS m / z: 615.1 [M+H].

[0176] Step 3

[0177] Dissolve tert-butyl N-{1-[(2R,3S,4R,5R)-5-azido-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}carbamate (FNC-11-2) (134 mg, 0.22 mmol) in THF (2 mL), and add tetrabutylammonium fluoride (34 mg, 0.13 mmol) while stirring in an ice bath. Remove the ice bath after the addition is complete. The reaction was stirred at room temperature for 30 minutes. LC-MS monitored the complete reaction of the starting material. The reaction was quenched by adding 5 mL of saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phase was collected, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 68 mg of tert-butyl N-{1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}carbamate (FNC-11-3) as a light yellow solid in a yield of 80.76%. MS m / z: 387.0 [M+H].

[0178] Step 4

[0179] Tert-butyl N-{1-[(2R, 3S, 4R, 5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}carbamate (FNC-11-3) (68 mg, 0.18 mmol), DMAP (43 mg, 0.36 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (68 mg, 0.36 mmol) were dissolved in DMF (2 mL), and isobutyric acid (31 mg, 0.36 mmol) was added under stirring. After the addition was complete, the reaction was stirred at room temperature overnight. LC-MS monitored the complete reaction of the starting material. The reaction was quenched by adding 5 mL of water and extracted three times with ethyl acetate. The organic phase was collected, concentrated under reduced pressure, and separated by silica gel column chromatography to afford 56 mg of methyl [(2R,3R,4S,5R)-2-azido-5-(4-{[(tert-butoxy)carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-[(2-methylpropanoyl)oxy]oxolan-2-yl]methyl 2-methylpropanoate (FNC-11-4) as a light yellow solid in a yield of 60.43%. MS m / z: 527.1 [M+H].

[0180] Step 5

[0181] Methyl [(2R,3R,4S,5R)-2-azido-5-(4-{[(tert-butoxy)carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-[(2-methylpropionyl)oxy]oxolan-2-yl]methyl 2-methylpropanoate (FNC-11-4) (56 mg, 0.11 mmol) was dissolved in DCM (2 mL), and trifluoroacetic acid (0.73 mL) was added with stirring. After the addition was complete, the reaction was stirred at room temperature for 2 hours, and LC MS monitored the complete reaction of the starting material. The reaction was quenched by adding 5 mL of saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic phase was collected, concentrated under reduced pressure, and separated by preparative HPLC to afford 31 mg of methyl [(2R,3R,4S,5R)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-2-azido-4-fluoro-3-[(2-methylpropanoyl)oxy]oxolan-2-yl]methyl 2-methylpropanoate (FNC-11) as a white solid in a yield of 70.2%. MS m / z: 427.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ7.64 (dd, J=7.5, 1.8Hz, 1H), 7.51 (d, J=30.2Hz, 2H), 6.49(dd,J=14.3,5.2Hz,1H),5.81(d,J=7.5Hz,1H),5.76-5.66(m,1H),5.53 (ddd,J=52.2,5.2,3.9Hz,1H),4.60-4.44(m,2H),2.69(p,J=7.0Hz,1H),2.6 0(p,J=7.0Hz,1H),1.16(dd,J=7.0,5.0Hz,6H),1.12(dd,J=7.0,0.9Hz,6H).

[0182] Example 12

[0183]

[0184] Step 1

[0185] At room temperature, 4-amino-1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (FNC) (187 mg, 0.65 mmol), N-methylmorpholine (66 mg, 0.65 mmol), 1-hydroxybenzotriazole (89 mg, 0.65 mmol), (S)-4-(4-methoxythiophene)-1-nitropropane 2-[2',3',5,6]benzo[1,2-d]oxazol-7-yl]-2-methyl-4-oxobutanoic acid (139) (229 mg, 0.72 mmol) was dissolved in a mixture of DMF (3 mL) and DMSO (1 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg, 0.65 mmol) was added. The atmosphere was purged with nitrogen three times and the temperature was raised to 55°C for overnight reaction. LCMS monitoring indicated that the starting material was largely consumed. The reaction solution was purified by preparative pre-HPLC, and the resulting product was lyophilized to obtain 101.2 mg of (S)-N-(1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-(4-methoxythieno[2',3',5,6]benzo[1,2-d]oxazol-7-yl)-2-methyl-4-oxobutanamide (FNC-12) as a white solid in a yield of 26.5%. MS m / z: 588.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ: 11.16 (s, 1H), 8.93 (s, 1H), 8.60 (s, 1H), 8.11 (d, J = 7.6Hz, 1H), 7. 78(s,1H),7.27(d,J=7.5Hz,1H),6.49(d,J=5.9Hz,1H),6.41(dd,J=12.0,5.1Hz,1H),5.72( t,J=6.0Hz,1H),5.28(dt,J=53.3,4.8Hz,1H),4.49-4.36(m,1H),4.06(s,3H),3.76(t,J=5. 5Hz, 2H), 3.63 (dd, J=17.6, 9.4Hz, 1H), 3.24 (dd, J=14.7, 7.0Hz, 2H), 1.22 (d, J=6.9Hz, 3H).

[0186] Example 13

[0187]

[0188]

[0189] Step 1

[0190] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (400 mg, 1.4 mmol) was dissolved in DMF (5 mL) and stirred in an ice-water bath for 30 min. Then, tert-butyldimethylsilyl chloride (632 mg, 4.19 mmol) and imidazole (381 mg, 5.59 mmol) were added and the mixture was heated to 400 °C. The reaction was allowed to proceed overnight at room temperature. TLC monitored the complete reaction of the starting material. The reaction was quenched by adding water in an ice bath. The organic phase was extracted with ethyl acetate, collected, and concentrated under reduced pressure. 4-Amino-1-[(2R,3S,4R,5R)-5-azido-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluoro-4-hydroxyoxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC-12-1-1) was isolated by silica gel column chromatography to give 393 mg of 4-amino-1-[(2R,3S,4R,5R)-5-azido-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluoro-4-hydroxyoxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC-12-1-1) as a light yellow solid in a yield of 70.09%. MS m / z: 401.0 [M+H].

[0191] Step 2

[0192] 4-Amino-1-[(2R, 3S, 4R, 5R)-5-azido-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluoro-4-hydroxyoxolane-2-yl]-1,2-dihydropyrimidin-2-one (FNC-12-1-1) (393 mg, 0.98 mmol) was dissolved in THF (5 mL), and DMAP (60 mg, 0.49 mmol) and di-tert-butyl dicarbonate (534 mg, 2.45 mmol) were added under stirring at room temperature. After the addition was complete, The reaction was stirred at room temperature overnight under argon protection. LC-MS monitored the complete reaction of the starting material. The product was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 560 mg of tert-butyl (1-((2R,3S,4R,5R)-5-azido-4-((tert-butoxycarbonyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorotetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate (FNC-12-1-2) as a light yellow oil in a yield of 95.24%. MS m / z: 601.1 [M+H].

[0193] Step 3

[0194] Tert-butyl (1-((2R,3S,4R,5R)-5-azido-4-((tert-butoxycarbonyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorotetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate (FNC-12-1-2) (560 mg, 0.93 mmol) was dissolved in THF (8 mL), and tetrabutylammonium fluoride (167 mg, 0.64 mmol) was added under stirring in an ice bath. After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 2 h. After 30 minutes, LC-MS monitored the complete reaction of the starting material. The reaction was quenched by adding 5 mL of saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phase was collected, concentrated under reduced pressure, and separated by silica gel column chromatography to afford 162 mg of tert-butyl (2R,3R,4S,5R)-2-azido-5-(4-{[(tert-butoxy)carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-yl carbonate (FNC-12-1-3) as a light yellow oil in a yield of 41.63%. MS m / z: 487.0 [M+H].

[0195] Step 4

[0196] Tert-butyl (2R, 3R, 4S, 5R)-2-azido-5-(4-{[(tert-butoxy)carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-yl carbonate (FNC-12-1-3) (162 mg, 0.29 mmol) was dissolved in THF (2 mL) and stirred under ice bath for 30 minutes. NaH (8.1 mg, 0.35 mmol) was then added and the temperature was slowly raised to room temperature and stirred for 30 minutes. Methyl iodide (63 mg, 0.4 After the addition of 4 mmol), the reaction was stirred at room temperature for 2 hours. LC-MS analysis indicated the formation of the desired product. The reaction was quenched by adding 5 mL of water and extracted three times with ethyl acetate. The organic phase was collected, concentrated under reduced pressure, and separated by silica gel column chromatography to afford 65 mg of tert-butyl (2R,3R,4S,5R)-2-azido-5-(4-{[(tert-butoxy)carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(methoxymethyl)oxolan-3-yl carbonate (FNC-12-1-4) as a light yellow solid in a yield of 36.7%. MS m / z: 445.0 [(M-tBu)+H].

[0197] Step 5

[0198] Dissolve tert-butyl (2R, 3R, 4S, 5R)-2-azido-5-(4-{[(tert-butoxy)carbonyl]amino}-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(methoxymethyl)oxolan-3-yl carbonate (FNC-12-1-4) (65 mg, 0.11 mmol) in DCM (2 mL), add trifluoroacetic acid (0.8 mL) with stirring, and stir at room temperature for 2 hours. At this time, LC-MS monitored the complete reaction of the starting material. The reaction was quenched by adding 5 mL of saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic phase was collected, concentrated under reduced pressure, and separated by preparative HPLC to afford 21 mg of 4-amino-1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(methoxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (FNC-12-1) as a white solid in a yield of 53.85%. MS m / z: 301.0 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (q, J = 4.7 Hz, 1H), 7.44 (dd, J = 7.5, 1.6 Hz, 1H), 6.33 (dd, J = 12.4, 5.3 Hz, 2H), 5.70 (d, J = 7.5 Hz, 1H), 5.60 (t, J = 6.0 Hz, 1H), 5.09 (dt, J = 53.9, 5.0 Hz, 1H), 4.34 (dd, J = 22.7, 4.7 Hz, 1H), 3.65 (d, J = 5.0 Hz, 2H), 2.69 (d, J = 4.7 Hz, 3H). Example 14

[0199]

[0200] Step 1

[0201] 4-Amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (FNC) (300 mg, 1.05 mmol) was dissolved in pyridine (3 mL). Trimethylsilyl chloride (456 mg, 4.19 mmol) was added dropwise under ice-cooling. After the addition was complete, the mixture was stirred under ice-cooling for 2 h. Then, n-pentyl chloroformate (316 mg, 2.1 mmol) was added and the temperature was raised to 45°C to react overnight. TLC confirmed the complete reaction of the starting material. Ethanol (8 mL) was then added and the reaction was stirred at 45°C for 2 h. Water (4 mL) was then added and the reaction was continued at 45°C for 2 h. The target product was detected by LC-MS. The product was diluted with ethyl acetate and washed three times with brine. The organic phase was collected and separated by silica gel column chromatography to obtain a crude product. The crude product was then separated by preparative HPLC to obtain 274 mg of N-{1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}carbamic acid pentyl ester (FNC-15) as a white solid. Yield: 65.29%. MS m / z: 415.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 8.10 (d, J = 7.7Hz, 1H), 7.10 (d, J = 7.6Hz, 1H),6.48(d,J=5.9Hz,1H),6.40(dd,J=12.1,5.1Hz,1H),5.72(d,J=6.2Hz,1H), 5.27(dt,J=53.5,4.8Hz,1H),4.45(dt,J=22.0,5.0Hz,1H),4.11(t,J=6.7Hz,2 H),3.81-3.70(m,2H),1.65-1.55(m,2H),1.39-1.22(m,6H),0.92-0.83(m,3H).

[0202] Biological evaluation

[0203] Test Example 1: In vitro plasma metabolic stability and metabolites of the compounds of the present invention

[0204] The following methods are used to determine the in vitro plasma metabolic stability and metabolites of the compounds of the present invention.

[0205] Sample Incubation: Preheat CD-1 mouse plasma or human plasma in a 37°C water bath for 15 minutes. Add 2 μL of compound working solution to each of the 1.1 mL twelve-tube microtubes containing 398 μL of plasma. Mix thoroughly with a pipette and place in a 37°C CO2 incubator (5% CO2). Initiate the reaction at 100 rpm and begin recording time. At 0, 30, 60, 120, and 240 minutes, pipette 30 μL of the reaction solution into a 1.1 mL microtube containing 300 μL of stop solution to terminate the reaction. Vortex for 1 minute to mix thoroughly. Centrifuge all samples at 4,000 rpm and 4°C for 15 minutes. Mix 100 μL of the supernatant with 100 μL of ultrapure water and analyze by LC-MS / MS.

[0206] Preparation of a 1μM parent drug control sample: Dilute the parent drug compound azithromycin stock solution with DMSO to a 200μM working solution for later use. Add 398μL of blank plasma to 4000μL of stop solution to inactivate the plasma. Add 2μL of the above working solution and vortex for 1 minute to mix thoroughly. Centrifuge the sample at 4,000 rpm and 4°C for 15 minutes. Mix 100μL of the supernatant with 100μL of ultrapure water and analyze the sample by LC-MS / MS.

[0207] Sample analysis and data processing and analysis: After sample processing, the sample was semi-quantitatively determined by LC-MS / MS to determine the peak area ratio of each compound in the sample to the internal standard peak area of ​​tolbutamide or terfenadine in the stop solution. The slope (slope = -ke) was measured by plotting the natural logarithm of the percentage of the compound remaining versus time, and t was calculated according to the first-order kinetic equation. 1 / 2 :

[0208]

[0209] C t =C0*e -ke*t

[0210] lnC t =lnC0-ke*t

[0211] According to the above formula, when When The control sample concentration of the parent drug is 1 μM, and the concentration of the parent drug generated at each time point is calculated as follows:

[0212]

[0213]

[0214]

[0215]

[0216]

[0217] Examples 4, 6, 7, 8 and 9 of the present invention can be rapidly and efficiently metabolized into the drug prototype, i.e., azithromycin, in mouse / human plasma in vitro.

[0218] Test Example 2: In vitro hepatocyte metabolic stability and metabolites of the compounds of the present invention

[0219] The following methods were used to determine the in vitro hepatocyte metabolic stability and metabolites of the compounds of the present invention.

[0220] Sample incubation: The revived hepatocyte suspension (2×10 6 cells / mL) in a carbon dioxide incubator for pre-incubation for 10 minutes. Add 400 μL of the working solution of the compound of the present invention to the corresponding wells of a 24-well cell culture plate. Add 400 μL of the preheated hepatocyte suspension to the corresponding wells to start the reaction, and gently shake the 24-well cell culture plate to mix. Place the 24-well cell culture plate in a 37°C carbon dioxide incubator (5% carbon dioxide), start the reaction at 100 rpm, and start recording the time. At 0, 15, 30, 60, 90, and 120 minutes of incubation, transfer 30 μL of the reaction solution from the 24-well cell culture plate to a 1.1 mL microtube containing 300 μL of stop solution to stop the reaction, and vortex for 1 minute to mix. Centrifuge all samples at 4,000 rpm and 4°C for 15 minutes. Take 100 μL of the supernatant and mix evenly with 100 μL of ultrapure water, and analyze the samples using LC-MS / MS.

[0221] 1 μM parent drug control sample preparation: dilute the parent drug compound FNC stock solution with DMSO to 2 mM working solution, and then further dilute it with incubation buffer to 2 μM working solution for use; add 15 μL blank hepatocyte suspension (2×10 6 Cells / mL) were inactivated. 15 μL of the above 2 μM working solution was added and vortexed for 1 minute to mix thoroughly. The sample was centrifuged at 4,000 rpm and 4°C for 15 minutes. 100 μL of the supernatant was mixed with 100 μL of ultrapure water and analyzed by LC-MS / MS.

[0222] Sample analysis and data processing and analysis: After sample processing, the sample was semi-quantitatively determined by LC-MS / MS to determine the peak area ratio of each compound in the sample to the internal standard peak area of ​​tolbutamide or terfenadine in the stop solution. The slope (slope = -ke) was measured by plotting the natural logarithm of the percentage of the compound remaining versus time, and t was calculated according to the first-order kinetic equation. 1 / 2 :

[0223]

[0224] C t =C0*e -ke*t

[0225] lnC t =lnC0-ke*t

[0226] According to the above formula, when When The control sample concentration of the parent drug is 1 μM, and the concentration of the parent drug generated at each time point is calculated as follows:

[0227]

[0228]

[0229]

[0230]

[0231] Examples 2, 3, 6 and 13 of the present invention can be rapidly and efficiently metabolized into the drug prototype, i.e., azithromycin, in mouse / human liver cells.

[0232] Test Example 3: In vivo antitumor activity of the compounds of the present invention

[0233] The following method was used to determine the antitumor activity of the compounds of the present invention under in vivo conditions.

[0234] CT26 tumor cells were cultured in a suitable culture medium. Cells in the exponential growth phase were collected and inoculated subcutaneously on the right back of the experimental mice. Tumor growth was observed regularly after inoculation. The tumors were grown to an average volume of approximately 50 mm. 3 Mice were randomly divided into groups based on tumor size and body weight. The day of grouping was defined as Day 0. The test substance was administered orally once daily. Efficacy was evaluated by calculating the tumor volume inhibition rate (TGI) based on tumor volume, and safety was evaluated based on changes in animal body weight and mortality.

[0235] Our Example 8, at a dose of 2 mg / kg, demonstrated significant tumor inhibition in the CT-26 model, with a Day 16 TGI of 97%. This inhibitory effect was superior to that of azithromycin (FNC) at a dose of 1 mg / kg (TGI of 85%). Furthermore, Example 8 was well tolerated by the animals at this dose. Furthermore, two other compounds, Example 9 and Example 7, were evaluated in the CT-26 model. At a dose of 2 mg / kg, their TGIs were 69% and -28%, respectively, which were weaker than that of FNC at a dose of 1 mg / kg. All test groups were well tolerated by the animals.

[0236]

[0237]

[0238] 1 On the 16th day, the tumor tissue of the control group was too large, and the mice in the control group were subsequently sacrificed, so the TGI on the 16th day was compared.

Claims

1. A method for treating tumors, comprising administering to a subject in need thereof a compound having the following formula (I): in, R1, R2, and R3 are each independently selected from any substituent of the following group: (1) Hydrogen, provided that R1, R2, and R3 are not simultaneously hydrogen; (2)C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); (3)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,-CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ; (4) Phosphate residues or their derivative residues, including monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; for example: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ ); (5)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); (6)R 1 、R 2 Together with 3'-O and 5'-O, they form a ring with the carbon atom to which they are attached; (7)R 1 、R 2 Together they form a cyclic phosphate; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); Among them, the above C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl can be arbitrarily selected from halogen, cyano, -OR a , halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, -NR a R b 、-SO3R a , -NO2, -SF5; Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl; n represents 0, 1, 2 or 3.

2. The method for treating tumors according to claim 1, wherein: R1 represents hydrogen, and R2 and R3 each independently represent any substituent selected from the following group: (1)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,-CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ; (2) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; for example: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ ) (3)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl; n represents 0, 1, 2 or 3.

3. The method for treating tumors according to claim 1, wherein: R2 represents hydrogen, and R1 and R3 each independently represent any substituent selected from the following group: (1)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,,-CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ; (2) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; for example: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ ) (3)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl; n represents 0, 1, 2 or 3.

4. The method for treating tumors according to claim 1, wherein: R3 represents hydrogen, and R1 and R2 each independently represent any substituent selected from the following group: (1)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,-CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ; (2) phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamidate, phosphate diamidate, thiophosphate, selenophosphate or borophosphate; (3)-P(=O)(NR L R L’ )(NR L R L’ ), -P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl; n represents 0, 1, 2 or 3.

5. The method for treating tumors according to claim 1, wherein: R1, R2, and R3 each independently represent hydrogen or any substituent selected from the following group: -C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,-C(R L R L’ )OC(=O)R L ,-C(=O)CR L R L’ -NR L R L’ ,-C(=O)CR L R L’ -NR L R L’ , where R L 、R L’ Each independently represents hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl.

6. The method for treating tumors according to claim 1, wherein: R L It represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, an isobutyl group, or a tert-butyl group.

7. The method for treating tumors according to claim 1, wherein: R1, R2, and R3 each independently represent: -P(=O)O(R L R L’ )-P(=O)(N L R L’ ), -P(=O)(NR L R L’ )2,-P(=O)(NR L R L’ )OR L , or -P(=O)(NH)CR a R b C(O)OR L .

8. A method for treating tumors, comprising administering to a subject in need thereof a compound having the following formula (II): in, X represents (CR a R b ) i , and, arbitrarily CR a R b Can be -C(O)-, O, -NR a -、C6-C 10 substituted by aryl or 5-10 membered heteroaryl; Among them, i represents 1, 2, 3, 4, 5, 6; Wherein, R3 represents a substituent selected from any of the following groups: (1) Hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); (2)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,,-CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ; (3) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; such as: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ ); (4)-P(=O)(NR L R L’ )(NR L R L’ ),-P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); Among them, the above C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl can be arbitrarily selected from halogen, cyano, -OR a , halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, -NR a R b 、-SO3R a , -NO2, -SF5; Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl, C6-C 10 aryl, 5-10 membered heteroaryl; n represents 0, 1, 2 or 3.

9. The method for treating tumors according to claim 8, wherein: R3 represents hydrogen.

10. The method for treating tumors according to claim 8, wherein: R3 represents C1-C 10 alkyl.

11. The method for treating tumors according to claim 8, wherein: R3 represents -C(=O)R L ,-C(=O)OR L ; Among them, R L Indicates C1-C 10 Alkyl, C3-C 10 Cycloalkyl.

12. The method for treating tumors according to claim 8, wherein: X represents CH2, CH(CH3), C(CH3)2, CH2CH2, CH(CH3)CH2, C(CH3)2CH2.

13. The method for treating tumors according to claim 8, wherein: X represents -CH2-C(O)-C(O)-CH2, -C(O)-C(O)-, -C(O)-CH2-C(O)-, -C(O)-CH(CH3)-C(O)-, -C(O)-C(CH3)2-C(O)-, -C(O)-CH2CH2-C(O)-, -C(O)-CH2SSCH2-C(O)-, -C(O)-SS-C(O)-, 14. The method for treating tumors according to claim 8, wherein: X represents -CH2NHC(O)NHCH2- or -CH2OC(O)OCH2-.

15. The method for treating tumors according to claim 8, wherein: X represents -(CH2) s’ -C(O)-(CH2) s -phenyl-(CH2) t -C(O)-(CH2) t’ -, wherein s, s', t, t' independently represent 0 or 1.

16. The method for treating tumors according to claim 8, wherein: X represents 17. The method for treating tumors according to claim 8, wherein: X represents -(CH2) s’ -C(O)-(CH2) s -(5-10 membered heteroaryl)-(CH2) t -C(O)-(CH2) t’ -, wherein s, s', t, t' independently represent 0 or 1.

18. The method for treating tumors according to claim 17, wherein: The 5-10 membered heteroaryl group is selected from any one of the following groups:

19. The method for treating tumors according to claim 18, wherein: X represents 20. A method for treating tumors, comprising administering to a subject in need thereof a compound having the following formula (III): in, Y1 means NR a or O; Y2 represents -C(O)O-, -OC(O)-, -C(O)S-, or -SC(O)-; R T represents hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C5-C 10 Aryl, 5-10 membered heteroaryl, benzyl, heterocyclic benzyl; R3 represents a substituent selected from any of the following groups: (1) Hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); (2)-C(=O)R L ,-C(=O)OR L ,-C(=O)NR L R L’ ,,-CR L R L’ OC(=O)R L ,-C(=O)CR L R L’ NR L R L’ ; (3) Phosphate residues or their derivative residues include monophosphate, diphosphate, triphosphate, phosphonate, phosphate polyester, phosphate monoamide, phosphate diamide, thiophosphate, selenophosphate or borophosphate; such as: -P(=O)(OR L R L’ ),-P(=O)(OR L )OP(O)(OR L R L’ ); (4)-P(=O)(NR L R L’ )(NR L R L’ ),-P(=O)(NR L R L’ )OR L ; Among them, R L 、R L’ Indicates C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, -(CR a R b ) n -(C6-C 10 aryl); Among them, the above C1-C 10 Alkyl, C2-C 10 Alkenyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl can be arbitrarily selected from halogen, cyano, -OR a , halogenated C1-C 10 Alkyl, C1-C 10 Alkoxy, -NR a R b 、-SO3R a , -NO2, -SF5; Among them, R a 、R b Each independently represents hydrogen, C1-C 10 Alkyl; n represents 0, 1, 2 or 3; j represents 0, 1, 2 or 3.

21. The method for treating tumors according to claim 20, wherein: R3 represents hydrogen.

22. The method for treating tumors according to claim 20, wherein: R3 represents C1-C 10 alkyl.

23. The method for treating tumors according to claim 20, wherein: R3 represents -C(=O)R L ,-C(=O)OR L ; Among them, R L Indicates C1-C 10 Alkyl, C3-C 10 Cycloalkyl.

24. The method for treating tumors according to claim 20, wherein: Y1 represents O.

25. The method for treating tumors according to claim 20, wherein: Y2 represents -C(O)O- or -OC(O)-.

26. A method for treating a tumor, wherein: The method comprises administering to a subject in need thereof a compound having the following structure:

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