Tetrodotoxin derivative compound and use thereof as sodium channel blocker

Abstract

The present invention relates to a compound having an inhibitory effect on a plurality of sodium ion channels, or a pharmaceutically acceptable derivative thereof, a pharmaceutical composition comprising same, and a use thereof as a pan-sodium ion channel blocker.

Description

Tetrodotoxin derivatives and their use as sodium channel blockers Technical Field

[0001] This invention relates to a compound that inhibits multiple sodium ion channels or a pharmaceutically acceptable derivative thereof, pharmaceutical compositions thereof, and its use as a pan-sodium ion channel blocker. Background Technology

[0002] Tetrodotoxin (TTX) is an amino-perhydroquinazoline compound with the following structure:

[0003] Tetrodotoxin has a local irritant effect on the intestines. After absorption, it rapidly acts on nerve endings and the central nervous system, selectively and with high affinity blocking sodium ion channels on nerve excitation membranes, thus hindering nerve conduction and causing nerve paralysis leading to death. Clinically, tetrodotoxin is mainly used for analgesia, local anesthesia, sedation, antispasmodic effects, antihypertensive effects, and antiarrhythmic effects, but its use is significantly limited due to its strong toxicity.

[0004] Voltage-gated sodium channels (VGSCs) are microporous transmembrane glycoproteins widely distributed on the membranes of excitable cells such as neurons, primarily responsible for sodium absorption. +Transmembrane transport of sodium ions is the most important ion channel required for neurons to generate excitability and perform normal electrophysiological functions. Voltage-gated sodium channels consist of one α subunit and multiple β subunits. The α subunit is the main functional unit, and nine subtypes (Nav1.1-Nav1.9) have been identified so far. It consists of four highly similar homologous domains surrounding a center, forming the central pore of the ion channel. Each domain has six α-helical transmembrane segments (S1-S6), among which the amino acid sequence of S4 is highly conserved and is considered to be the voltage receptor of the voltage-gated sodium channel. There are four subtypes of β subunits (β1-β4), which play an auxiliary role in the localization and stability of the α subunit on the membrane and participate in regulating the voltage sensitivity and inactivation process of the α subunit. Voltage-gated sodium channels in different animals show extensive homology, but also significant differences. Based on their sensitivity to tetrodotoxin (TTX) blockade, sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R) types. TTX-R type sodium ion channels include Nav1.5, Nav1.8, and Nav1.9, while the rest are TTX-S type sodium ion channels. Nav1.7 is a transmembrane protein encoded by SCN9A, specifically expressed in peripheral sensory nerve endings and sympathetic ganglion neurons, and mainly expressed in large-diameter dorsal root ganglion (DRG) neurons and unmyelinated small-diameter DRG neurons, i.e., expressed in 85% of nociceptors. This indicates that Nav1.7 plays a crucial role in pain transmission. Nav1.7 plays a core role in pain signal transduction and maintenance, and has become an important target for analgesic drug development. The compounds in this invention are structurally modified and optimized targeting tetrodotoxin. The resulting innovative tetrodotoxin derivative molecules all exhibit significant inhibitory activity against TTX-S type sodium ion channels (including Nav1.3, Nav1.6, and Nav1.7), making them pan-sodium ion channel blockers.

[0005] In existing technologies, tetrodotoxin-based derivatives are mainly derived from the isolation and extraction of natural sources. Examples include 4,9-anhydro TTX (Nakamura M, Yasumoto T. Tetrodotoxin derivatives in puffer fish[J]. Toxicon, 1985, 23(2): 271-276.), 6-epi TTX, 11-deoxy TTX (Yasumoto T, Yotsu M, Murata M, et al. New tetrodotoxin analogs from the newt Cynops ensicauda[J]. j.am.chem.soc, 1988, 110(7): 2344-2345.). There are also literature reports on the laboratory synthesis of some tetrodotoxin derivatives. Examples include 11-Deoxytetrodotoxin (J.AM.CHEM.SOC.2002,124,7847-7852) and 8,11-Dideoxytetrodotoxin (Chem.Eur.J.2004,10,452-462). Summary of the Invention

[0006] A first aspect of the present invention provides a compound or a pharmaceutically acceptable derivative thereof having the structure of formula (I):

[0007] in,

[0008] X is selected from -(CH2) m - and carbonyl, wherein the -CH2- is optionally surrounded by at least one R X replace;

[0009] R1 is selected from hydrogen, -(C=O)OR3 and -O(C=O)R4;

[0010] R2 is selected from amino, guanidinyl, urea, and... The amino, guanidinyl, and urea groups are optionally surrounded by at least one R X replace;

[0011] R3 and R4 are each independently selected from C. 1-8 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6-20 Aryl, C 1-8 Alkyl-C 6-20 Aromatic, penta- to twentieth-membered heteroaryl and C 1-8 Alkyl-penta-to-twenti-heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R Xreplace;

[0012] R5 is selected from hydrogen, hydroxyl, and cyano groups;

[0013] R6 is selected from hydroxyl, mercapto, C 1-12 Alkyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6- 10 Aryl and five- to ten-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R X replace;

[0014] Alternatively, R5 and R6, together with the atoms they are attached to, form a five- to twelve-membered heterocycle, wherein the heterocycle is optionally bounded by at least one R X replace;

[0015] Each R X Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1- 8-alkyl, C 3-20 cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 1-8 Alkyl-ternary to octahedral heterocyclic groups, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aromatic, penta- to deca-aryl, C 1-8 Alkyl-penta-to-deca-aryl, The carboxyl, amino, formyl, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R. Y replace;

[0016] R7 is selected from hydroxyl, thiol, amino, C 1-12 Alkyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6-10 aryl and five- to ten-membered heteroaryl groups, wherein the amino, alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by at least one R Y replace;

[0017] Each R Y Independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, formyl, acetyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, -O-ternary to octahedral heterocyclic groups, C1- 8-alkyl-ternary to octahedral heterocyclic groups, C 6-10 Aryl, -OC 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, penta- to deca-aryl, -O- penta- to deca-aryl, C 1-8 Alkyl-penta-to-deca-aryl and The amino, formyl, acetyl, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with at least one group selected from halogen, hydroxyl, C... 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Substituents in cycloalkyl groups;

[0018] m is an integer selected from 1 to 6;

[0019] The premise is that the compound of formula (I) is not a compound with the following structure:

[0020] A second aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable carriers.

[0021] A third aspect of the invention provides a method of treating a disease or condition associated with sodium ion channels, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof, optionally in combination with another therapeutic agent. Accordingly, the invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease or condition associated with sodium ion channels, optionally in combination with another therapeutic agent. The invention further provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof for treating a disease or condition associated with sodium ion channels, optionally in combination with another therapeutic agent. In one embodiment, the sodium ion channel is a TTX-S sodium ion channel. In one embodiment, the disease or condition associated with sodium ion channels includes pain. In one embodiment, the pain includes: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, labor pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, HIV-related pain, acute pain, multiple sclerosis (MS)-related pain, familial rectal pain, fibromyalgia, or includes pain caused by: depression, cardiovascular disease, neurogenic cystitis, ulcerative colitis, respiratory disease, psychiatric disorders, peripheral nerve injury, HIV treatment-induced pain. Neuropathy, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia gravis, myotonia, myotonia, malignant hyperthermia, cystic fibrosis, pseudopolyaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythromelalgia, primary erythromelalgia, epilepsy, epileptic encephalopathy, focal and generalized tonic-clonic seizures, restless legs syndrome, arrhythmias, tachyarrhythmias, atrial fibrillation or ventricular fibrillation.

[0022] Therefore, the present invention also provides a method for analgesia, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof, optionally in combination with another therapeutic agent. Accordingly, the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof in the preparation of a medicament for analgesia, optionally in combination with another therapeutic agent. The present invention further provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof for analgesia, optionally in combination with another therapeutic agent. In one embodiment, the pain is as described above. Attached Figure Description

[0023] Figure 1 shows the analgesic effect of the tetrodotoxin synthesized in this invention in a mouse acetic acid writhing pain model.

[0024] Figure 2 shows the analgesic effect of compound 12 of the present invention in a mouse acetic acid writhing pain model.

[0025] Figure 3 shows the analgesic effect of compound 93 of the present invention in a mouse acetic acid writhing pain model.

[0026] Figure 4 shows the analgesic effect of compound 125 of the present invention in a mouse acetic acid writhing pain model. Detailed Implementation

[0027] definition

[0028] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0029] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps, although such other unlisted elements or method steps may not necessarily exist (i.e., these terms also cover the terms “consistently made up of” and “composed of”).

[0030] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0031] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, or, for example, 1 to 4 carbon atoms. For example, as used herein, the term "C" is used to refer to... 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl The terms "alkyl," "2-ethylbutyl," "1-ethylbutyl," "3,3-dimethylbutyl," "2,2-dimethylbutyl," "1,1-dimethylbutyl," "2,3-dimethylbutyl," "1,3-dimethylbutyl," or "1,2-dimethylbutyl," or their isomers, are used. "Subunit" refers to a group having two linkage sites for connection to the rest of the molecule, obtained by removing a hydrogen atom from a carbon atom containing a free valence electron. For example, "alkylene" or "alkyl subunit" refers to a saturated straight-chain or branched divalent hydrocarbon group. When the described groups are linked together, it should be understood that the number of linkage sites for each linked group increases. For example, if an alkyl group is further linked to other groups to give it two linkage sites, the alkyl group can be considered to form an alkylene group. Accordingly, "alkoxy" refers to the alkyl group described herein, which is linked to the remainder of the molecule via an oxygen atom.

[0032] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or fused polycyclic hydrocarbon cycloalloy, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), fused cycloalkyl groups, bridged rings, or spirocyclic structures. In this invention, the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo group (i.e., forming C=O). The term "C 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3 to 20 cyclic carbon atoms, for example, a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cyclic carbon atoms. The term "C"... 3-8"Cycloalkyl" refers to a cycloalkyl group having 3 to 8 cyclic carbon atoms, for example, a cycloalkyl group having 3, 4, 5, 6, 7 or 8 cyclic carbon atoms, or, for example, C. 3-6 Cycloalkyl groups can be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or they can be fused cycloalkyl, such as C 5-8 fused cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0033] As used herein, the term "heterocyclic group" or "heterocycle" refers to an aliphatic monocyclic, fused polycyclic, bridged, or spirocyclic group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, wherein the heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur atoms, wherein the carbon atoms and heteroatoms on the heterocyclic group are optionally substituted with oxo groups (e.g., forming C=O, S(=O), or S(=O)2), and the carbon atoms and heteroatoms on the heterocyclic group may also optionally be substituted with nitrogen-containing groups (e.g., forming C=NH). When a heterocyclic group is further linked with other groups to give the heterocyclic group two linkage sites, the heterocyclic group can be considered to form a heterocyclic subunit.

[0034] As used herein, the term "ternary to octagonal heterocyclic group" means a heterocyclic group containing 3 to 8 ring atoms, such as heterocyclic groups with 3, 4, 5, 6, 7, or 8 ring atoms, including but not limited to 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc., wherein each of the "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group" and "sulfur-containing heterocyclic group" optionally also contains one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 3-8 membered heterocyclic groups include, but are not limited to, ethylene oxide, aziridinyl, aziridine, oxetidine, tetrahydrofuranyl, pyrrolylyl, and pyrrolidone (e.g.) (Imidazolyl, pyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazineyl, trithianyl)

[0035] In this invention, the heterocyclic group can form a fused ring structure with a heterocyclic group or a cycloalkyl group. The connection point of the fused ring structure with other groups can be on any heterocyclic group or on a cycloalkyl group. Therefore, the heterocyclic group of this invention also includes (but is not limited to) heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, and monoheterocyclic fused monocycloalkyl groups, such as 3-7 membered (mono)heterocyclic fused 3-7 membered (mono)heterocyclic groups, 3-7 membered (mono)heterocyclic fused (mono)cycloalkyl groups, and 3-7 membered (mono)heterocyclic fused C 4-6 (Mono)cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentylazirylpropyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, and piperidinylmorpholinyl.

[0036] The term "aryl" can contain 6-20 carbon atoms (C64-C64). 6-20 Aryl groups, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, or for example, 6-14 carbon atoms (C 6-14 (aryl) or 6-10 carbon atoms (C 6-10 Aryl groups, such as phenyl, naphthyl, indaminozyl, fluorene, etc., are considered to be 6-membered aromatic carbon rings, such as phenyl; bicyclic groups with at least one aromatic carbon ring, such as naphthyl, indaminozyl, and 1,2,3,4-tetrahydroquinoline; and tricyclic groups with at least one aromatic carbon ring, such as fluorene. If the aryl substituent is a bicyclic or tricyclic ring and at least one of the rings is non-aromatic, then it should be considered to be linked by an aromatic ring. For example, aryl groups include 6-membered aromatic carbon rings fused with 5-7-membered heterocycles containing one or more heteroatoms selected from N, O, and S, provided that the linking site is an aromatic carbon ring.

[0037] The term "heteroaryl" includes 5- to 10-membered aromatic monocyclic rings, such as 5, 6, 7, 8, 9, or 10-membered aromatic monocyclic rings, containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, and in some embodiments 1 to 3 heteroatoms, with the remainder being carbon atoms; 8- to 12-membered bicyclic rings, such as 8, 9, 10, 11, or 12-membered bicyclic rings, containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, with the remainder being carbon atoms, and at least one heteroatom being present in the aromatic ring; and 11- to 14-membered tricyclic rings, such as 11, 12, 13, or 14-membered tricyclic rings, containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, with the remainder being carbon atoms, and at least one heteroatom being present in the aromatic ring. The term "penta- to twentieth-membered heteroaryl" refers to a heteroaryl group containing 5 to 20 ring atoms, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indazoleyl, quinolinyl, isoquinolinyl, and tetrazolyl (e.g., ...). (e.g., triazolyl, triazinyl, benzofuranyl, benzothiophenyl, benzimidazole, indoleyl, isoindoleyl, etc.)

[0038] As used herein, the term “halogenated” or “halogen” group is defined as including a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.

[0039] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and the substitution forms a stable compound. For example, two hydrogen atoms on a specified carbon atom may be replaced by the designated group via a double bond. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0040] If a substituent is described as "optionally substituted by at least one..." or "optionally substituted by one or more...", then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[0041] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent. The groups described herein may optionally be substituted with one or more substituents. Available substituents include, but are not limited to, deuterium, tritium, hydroxyl, amino, cyano, mercapto, azide, guanidinium, urea, halogen, alkyl, cycloalkyl, heterocyclic, alkoxy, alkenyl, aryl, heteroaryl, and heterocyclic groups as described herein.

[0042] As used herein, the term "at least one" or similar expression "one or more" means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, or ten.

[0043] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0044] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F,15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0045] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oximes can exist in equilibrium in solution in the following tautomer forms:

[0046] It should be understood that the scope of the present invention covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0047] Solid lines may be used in this article. ), solid wedge ( ) or virtual wedge ( The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0048] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0049] Pharmaceutically acceptable salts of the compounds of this invention include their acid addition salts and base addition salts, such as hexafluorophosphate and meglumine salts.

[0050] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, which can be removed at appropriate subsequent stages using methods known in the art.

[0051] A "protecting group" (Pg) is a substituent used to block or protect a specific functional group from reacting with other functional groups on a compound. For example, an "amino protecting group" is a substituent attached to an amino group to block or protect the amino functional group. Suitable amino protecting groups include acetyl, triphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), cyclopentyloxycarbonyl, and methoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" is a substituent that effectively blocks or protects the function of a hydroxyl group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" is a substituent that effectively blocks or protects the function of a carboxyl group. Commonly used carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonamide)ethyl, 2-(p-nitrophenylthio)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description and instructions for use of the protecting group, see the reference: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0052] The term "pharmaceutically acceptable derivative" refers to a compound or pharmaceutically acceptable excipient existing in the form of a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, enantiomer, tautomer, or isotopically labeled compound or mixture thereof. "Pharmaceutically acceptable salt" includes, but is not limited to, salts made from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases may be selected from, for example, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, and zinc salts. Further, salts of pharmaceutically acceptable inorganic bases may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. In solid salts, one or more crystalline structures may exist, and hydrates may also be present. Pharmaceutically acceptable organic non-toxic base salts can be selected from, for example: primary amine, secondary amine and tertiary amine salts; substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0053] The term "effective amount" refers to the dose of a target compound or a pharmaceutically acceptable derivative thereof that is capable of eliciting a biological or medical response in a tissue, system, animal, or human that can be observed by researchers, veterinarians, clinicians, or other clinical personnel.

[0054] The term "composition" includes: a product containing a specific amount of a specific ingredient, and a product consisting of any combination of such specific amounts of the specific ingredients, directly or indirectly. A pharmaceutical composition includes: a product containing an active ingredient and an inert ingredient as a carrier, and a product made by combining, compounding, or aggregating any two or more ingredients directly or indirectly, or by the decomposition of one or more ingredients, or by other types of reactions or interactions between one or more ingredients.

[0055] The term "pharmaceutical acceptable" means that it is compatible with other components in the formulation and poses no unacceptable toxicity to the user.

[0056] The term "individual" refers to an individual suffering from a disease or ailment, including both mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds, fish, etc. In one implementation, the mammal is defined as a human.

[0057] The term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or stopping and extending the symptoms of a disease or symptom to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the treated condition. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to a patient taking the composition to prevent a certain disease risk, or taking it when the patient has one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0058] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0059] As used herein, the term “minimum effective dose” refers to the minimum dose of drug required to produce a statistically significant difference (P<0.05) in the average number of writhing movements in an ICR mouse acetic acid writhing model compared to a saline-treated control group.

[0060] As used herein, the term "maximum tolerated dose" refers to the highest dose at which, under specified experimental conditions and administration periods, no drug-related death or irreversible toxicity occurs in the test animals, and the incidence of toxicity does not exceed a preset threshold.

[0061] As used in this article, the term "therapeutic window" refers to the ratio of the maximum tolerated dose of a drug to its lowest effective dose.

[0062] The compounds of the present invention

[0063] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable derivative thereof having the structure of formula (I):

[0064] in,

[0065] X is selected from -(CH2) m - and carbonyl, wherein the -CH2- is optionally surrounded by at least one R X replace;

[0066] R1 is selected from hydrogen, -(C=O)OR3 and -O(C=O)R4;

[0067] R2 is selected from amino, guanidinyl, urea, and... The amino, guanidinyl, and urea groups are optionally surrounded by at least one R X replace;

[0068] R3 and R4 are each independently selected from C. 1-8 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6-20 Aryl, C 1-8 Alkyl-C 6-20 Aromatic, penta- to twentieth-membered heteroaryl and C 1-8 Alkyl-penta-to-twenti-heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R X replace;

[0069] R5 is selected from hydrogen, hydroxyl, and cyano groups;

[0070] R6 is selected from hydroxyl, mercapto, C 1-12 Alkyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6- 10 Aryl and five- to ten-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R X replace;

[0071] Alternatively, R5 and R6, together with the atoms they are attached to, form a five- to twelve-membered heterocycle, wherein the heterocycle is optionally bounded by at least one R X replace;

[0072] Each R X Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1- 8-alkyl, C 3-20 cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 1-8 Alkyl-ternary to octahedral heterocyclic groups, C 6-10 Aryl, C1-8 Alkyl-C 6-10 Aromatic, penta- to deca-aryl, C 1-8 Alkyl-penta-to-deca-aryl, The carboxyl, amino, formyl, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R. Y replace;

[0073] R7 is selected from hydroxyl, thiol, amino, C 1-12 Alkyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6-10 aryl and five- to ten-membered heteroaryl groups, wherein the amino, alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by at least one R Y replace;

[0074] Each R Y Independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, formyl, acetyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, -O-ternary to octahedral heterocyclic groups, C 1- 8-alkyl-ternary to octahedral heterocyclic groups, C 6-10 Aryl, -OC 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, penta- to deca-aryl, -O- penta- to deca-aryl, C 1-8 Alkyl-penta-to-deca-aryl and The amino, formyl, acetyl, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from at least one of halogen, hydroxyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Substituents of cycloalkyl groups;

[0075] m is an integer selected from 1 to 6.

[0076] In this invention, the compounds of formula (I) do not include the following structures:

[0077] In some embodiments, X is selected from methylene and carbonyl. In one specific embodiment, X is methylene. In another specific embodiment, X is carbonyl.

[0078] In one specific embodiment, R1 is hydrogen. In another specific embodiment, R1 is -(C=O)OR3, where R3 is benzyl.

[0079] In some embodiments, R2 is selected from urea and The urea group is optionally surrounded by at least one R X Substitution. In other embodiments, R2 is an amino group, wherein the amino group is optionally replaced by at least one R X replace.

[0080] In some implementations, R2 is

[0081] In some embodiments, the compounds of the present invention or pharmaceutically acceptable derivatives thereof have the structure of formula (II):

[0082] in,

[0083] R1 is defined as in equation (I);

[0084] R6 is selected from the following structures:

[0085] In some specific implementations, R5 is hydrogen.

[0086] In some specific implementation schemes, R6 is selected from C 1-12 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl and five- to ten-membered heteroaryl groups, wherein the alkyl, cycloalkyl, aryl, and heteroaryl groups are optionally surrounded by at least one R X Replacement. In some implementations, R X Selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-20 Cycloalkyl, three- to eight-membered heterocyclic groups and The carboxyl, formyl, alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by at least one R Y Substitution. In some embodiments, R7 is selected from hydroxyl, amino, C... 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6-10 aryl and five- to ten-membered heteroaryl groups, wherein the amino, alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by at least one R Y Replacement. In other implementations, R Y Selected from halogens, hydroxyl groups, amino groups, and C 1-8 Alkyl, -OC 1-8alkyl,

[0087] In some specific implementation schemes, R6 is selected from Methyl, ethyl, n-propyl, isopropyl Trifluoromethyl, Cyclopropyl Cyclobutyl, Cyclopentyl, Cyclohexyl, phenyl

[0088] In some preferred embodiments, R6 is selected from... In some particularly preferred embodiments, R6 is selected from...

[0089] In other embodiments, R5 and R6, together with the atoms they are attached to, form a five- to twelve-membered heterocycle, wherein the heterocycle is optionally surrounded by at least one R X Substitution. In some specific implementations, R5 and R6, together with the atoms they are attached to, form five- to eight-membered heterocycles.

[0090] In other embodiments, the compounds of the present invention or pharmaceutically acceptable derivatives thereof have the structure of formula (IV):

[0091] in,

[0092] R1 and R6 are defined as in equation (I).

[0093] In some embodiments, R2 is a urea group, wherein the urea group is optionally surrounded by at least one R X Replacement. In some implementations, R X for In some embodiments, R7 is selected from hydroxyl, C 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6-10 Aryl and five- to ten-membered heteroaryl groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by at least one R Y Replacement. In some implementations, R Y Selected from halogens, hydroxyl groups, amino groups, and C 1-8 Alkyl, -OC 1-8Alkyl group. In other embodiments, R Y C 1-8 Alkyl group, wherein the alkyl group is optionally substituted with at least one halogen. In some specific embodiments, R7 is selected from methyl, ethyl, n-propyl, isopropyl, ... Trifluoromethyl, Cyclopropyl Cyclobutyl, Cyclopentyl, Cyclohexyl, phenyl

[0094] In some embodiments, the compounds of the present invention or pharmaceutically acceptable derivatives thereof have the structure of formula (III):

[0095] in,

[0096] R1 and R7 are defined as in equation (I).

[0097] In some implementations, R2 is selected from...

[0098] In some preferred embodiments, R2 is selected from...

[0099] In one specific implementation, X is methylene, and R2 is selected from...

[0100] In some preferred embodiments, X is methylene, and R2 is selected from...

[0101] In some preferred embodiments, X is methylene, and R2 is selected from...

[0102] In some particularly preferred embodiments, X is methylene, and R2 is selected from...

[0103] In one specific implementation, X is a carbonyl group, and R2 is selected from...

[0104] In some preferred embodiments, X is a carbonyl group, and R2 is selected from...

[0105] In some preferred embodiments, X is a carbonyl group, and R2 is selected from...

[0106] In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5. In some implementations, m is 6.

[0107] This invention covers any combination of the above embodiments.

[0108] In some embodiments, the compounds of the present invention include, but are not limited to:

[0109] In some preferred embodiments, the compounds of the present invention comprise the following structures:

[0110] In some preferred embodiments, the compounds of the present invention comprise the following structures:

[0111] In some particularly preferred embodiments, the compounds of the present invention comprise the following structures:

[0112] The pharmaceutical compositions, formulations, and methods of treatment of the present invention

[0113] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable carriers.

[0114] In some embodiments, the pharmaceutical composition can be administered orally, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0115] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes.

[0116] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0117] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0118] The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the disease or condition, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician.

[0119] In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic agents (e.g., other drugs associated with sodium ion channels). In some embodiments, the treatment methods of the present invention may further include administering one or more additional therapeutic agents (e.g., other drugs associated with sodium ion channels).

[0120] Exemplary implementation schemes include:

[0121] Implementation Scheme 1. A compound or a pharmaceutically acceptable derivative thereof, said compound having the structure of formula (I):

[0122] in,

[0123] X is selected from -(CH2) m - and carbonyl, wherein the -CH2- is optionally surrounded by at least one R X replace;

[0124] R1 is selected from hydrogen, -(C=O)OR3 and -O(C=O)R4;

[0125] R2 is selected from guanidin, urea, and... The guanidinyl and urea groups are optionally surrounded by at least one R X replace;

[0126] R3 and R4 are each independently selected from C. 1-8 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6-20 Aryl, C 1-8 Alkyl-C 6-20 Aromatic, penta- to twentieth-membered heteroaryl and C 1-8Alkyl-penta-to-twenti-heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R X replace;

[0127] R5 is selected from hydrogen, hydroxyl, and cyano groups;

[0128] R6 is selected from hydroxyl, mercapto, C 1-12 Alkyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6- 10 Aryl and five- to ten-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R X replace;

[0129] Each R X Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1- 8-alkyl, C 3-20 cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 1-8 Alkyl-ternary to octahedral heterocyclic groups, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aromatic, penta- to deca-aryl, C 1-8 Alkyl-penta-to-deca-aryl, The carboxyl, amino, formyl, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by at least one R. Y replace;

[0130] R7 is selected from hydroxyl, thiol, C 1-12 Alkyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6- 10 Aryl and five- to ten-membered heteroaryl groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by at least one R Y replace;

[0131] Each R Y Independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, formyl, acetyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, -O-ternary to octahedral heterocyclic groups, C 1-8-alkyl-ternary to octahedral heterocyclic groups, C 6-10 Aryl, -OC 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, pentyl to decaaryl, -O-pentyl to decaaryl and C 1-8 Alkyl-penta-to-deca-aryl groups, wherein the formyl group, acetyl group, alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally substituted with at least one halogen or hydroxyl group;

[0132] m is an integer selected from 1 to 6;

[0133] The premise is that the compound of formula (I) does not have the following structure:

[0134] Implementation Scheme 2. The compound described in Implementation Scheme 1 or a pharmaceutically acceptable derivative thereof, wherein,

[0135] X is a methylene group, and formula (I) has the structure of formula (II):

[0136] in,

[0137] R1 is as defined in Implementation Scheme 1;

[0138] R6 is selected from the following structures:

[0139] Implementation Scheme 3. The compound described in Implementation Scheme 1 or a pharmaceutically acceptable derivative thereof, wherein,

[0140] X is a methylene group, and formula (I) has the structure of formula (III):

[0141] in,

[0142] R1 and R7 are as defined in Implementation Scheme 1.

[0143] Implementation Scheme 4. The compound described in Implementation Scheme 1 or a pharmaceutically acceptable derivative thereof, wherein,

[0144] X is a carbonyl group, and formula (I) has the structure of formula (IV):

[0145] in,

[0146] R1 and R6 are as defined in Implementation Scheme 1.

[0147] Implementation Scheme 5. The compound of Implementation Scheme 1 or a pharmaceutically acceptable derivative thereof, wherein R1 is hydrogen or -(C=O)OR3.

[0148] Implementation Scheme 6. The compound described in Implementation Scheme 5 or a pharmaceutically acceptable derivative thereof, wherein R3 is benzyl.

[0149] Implementation Scheme 7. The compound of Implementation Scheme 1 or a pharmaceutically acceptable derivative thereof, wherein R2 is selected from urea and The urea group is optionally surrounded by at least one R X replace.

[0150] Implementation Scheme 8. The compound of Implementation Scheme 7 or a pharmaceutically acceptable derivative thereof, wherein R X for

[0151] Implementation Scheme 9. The compound of Implementation Scheme 8 or a pharmaceutically acceptable derivative thereof, wherein R7 is selected from hydroxyl, C 1-12 Alkyl, C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 6-10 Aryl and five- to ten-membered heteroaryl groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by at least one R Y replace.

[0152] Implementation Scheme 10. The compound of Implementation Scheme 9 or a pharmaceutically acceptable derivative thereof, wherein R Y Selected from halogens, hydroxyl groups, amino groups, and C 1-8 Alkyl, -OC 1-8 Alkyl group, wherein the alkyl group is optionally substituted with at least one halogen.

[0153] Implementation Scheme 11. The compound of Implementation Scheme 8 or 9 or a pharmaceutically acceptable derivative thereof, wherein R7 is selected from methyl, ethyl, n-propyl, isopropyl, Trifluoromethyl, Cyclopropyl Cyclobutyl, Cyclopentyl, Cyclohexyl, phenyl

[0154] Implementation Scheme 12. The compound of Implementation Scheme 7 or a pharmaceutically acceptable derivative thereof, wherein R5 is hydrogen.

[0155] Implementation Scheme 13. The compound of Implementation Scheme 7 or a pharmaceutically acceptable derivative thereof, wherein R6 is selected from C 1-12 Alkyl, C3-8 cycloalkyl, C 6-10 Aryl and five- to ten-membered heteroaryl groups, wherein the alkyl, cycloalkyl, aryl, and heteroaryl groups are optionally surrounded by at least one R X replace.

[0156] Implementation Scheme 14. The compound of Implementation Scheme 13 or a pharmaceutically acceptable derivative thereof, wherein R X Selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-20 Cycloalkyl, ternary to octa-membered heterocyclic groups, wherein the carboxyl, formyl, alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by at least one R Y replace.

[0157] Implementation Scheme 15. The compound of Implementation Scheme 14 or a pharmaceutically acceptable derivative thereof, wherein R Y Selected from halogens, hydroxyl groups, amino groups, and C 1-8 Alkyl, -OC 1-8 alkyl.

[0158] Implementation Scheme 16. The compound of any one of Implementation Schemes 13-15 or a pharmaceutically acceptable derivative thereof, wherein R6 is selected from... Methyl, ethyl, n-propyl, isopropyl Trifluoromethyl, Cyclopropyl Cyclobutyl, Cyclopentyl, Cyclohexyl, phenyl

[0159] Preferably, R6 is selected from...

[0160] More preferably, R6 is selected from

[0161] Implementation Scheme 17. The compound of Implementation Scheme 1 or a pharmaceutically acceptable derivative thereof, wherein X is methylene or carbonyl.

[0162] Implementation Scheme 18. The compound of Implementation Scheme 17 or a pharmaceutically acceptable derivative thereof, wherein X is a methylene group and R2 is selected from...

[0163] Preferably, X is a methylene group, and R2 is selected from...

[0164] Implementation Scheme 19. The compound of Implementation Scheme 17 or a pharmaceutically acceptable derivative thereof, wherein X is a carbonyl group and R2 is selected from...

[0165] Preferably, X is a carbonyl group, and R2 is selected from...

[0166] Implementation Scheme 20. A compound or a pharmaceutically acceptable derivative thereof having the structure described herein.

[0167] Implementation Scheme 21. A pharmaceutical composition comprising a therapeutically effective amount of any one of Implementation Schemes 1-20 or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable carriers.

[0168] Implementation Scheme 22. Use of any compound of any one of Implementation Schemes 1-20 or a pharmaceutically acceptable derivative thereof, or the pharmaceutical composition of Implementation Scheme 18, in the preparation of a medicament for treating diseases or conditions associated with sodium ion channels or for analgesia.

[0169] Implementation Scheme 23. The use described in Implementation Scheme 22, wherein,

[0170] The sodium ion channel-related diseases or conditions include pain, which includes: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, contractions, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, HIV-related pain, acute pain, multiple sclerosis (MS)-related pain, familial rectal pain, fibromyalgia, or includes pain caused by: depression, cardiovascular disease, neurogenic cystitis, ulcerative colitis, respiratory disease, psychiatric disorders, peripheral nerve injury, HIV. V treatment-induced neuropathy, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia gravis, myotonia, malignant hyperthermia, cystic fibrosis, pseudopolyaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythromelalgia, primary erythromelalgia, epilepsy, epileptic encephalopathy, focal and generalized tonic-clonic seizures, restless legs syndrome, arrhythmias, tachyarrhythmias, atrial fibrillation or ventricular fibrillation;

[0171] The analgesics targeted include: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, contractions, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, HIV-related pain, acute pain, multiple sclerosis (MS)-related pain, familial rectal pain, fibromyalgia, or pain caused by: depression, cardiovascular disease, neurogenic cystitis, ulcerative colitis, respiratory disease, psychiatric disorders, peripheral nerve injury, and HIV treatment-induced neuropathic pain. Pathological changes, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia gravis, myotonia, myotonia, malignant hyperthermia, cystic fibrosis, pseudopolyaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythromelalgia, primary erythromelalgia, epilepsy, epileptic encephalopathy, focal and generalized tonic-clonic seizures, restless legs syndrome, arrhythmias, tachyarrhythmias, atrial fibrillation or ventricular fibrillation.

[0172] Synthetic methods of compounds of formula (I)

[0173] This invention provides a compound of formula (V) having the following structure:

[0174] Wherein, X is as defined in formula (I) in this paper, R8 is selected from hydrogen, hydroxyl and amino, and PG1 and PG2 are independently selected from acetyl, triphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), cyclopentyloxycarbonyl and phosphonooxycarbonyl (Fmoc).

[0175] In some embodiments, X in compound (V) is a carbonyl group. In some embodiments, R8 in compound (V) is a hydroxyl group. In other embodiments, R8 in compound (V) is hydrogen. In some embodiments, X in compound (V) is a methylene group. In some embodiments, R8 in compound (V) is an amino group. In some embodiments, PG1 in compound (V) is a benzyloxycarbonyl group (Cbz). In some embodiments, PG2 in compound (V) is a benzyloxycarbonyl group (Cbz).

[0176] In some implementations, the compound of formula (V) is

[0177] In some implementations, the compound of formula (V) is

[0178] In some embodiments, the compound of formula (V) is used as an intermediate in the preparation of the compound of formula (I) or a pharmaceutically acceptable derivative thereof. Therefore, the present invention also relates to a method for preparing the compound of formula (I) or a pharmaceutically acceptable derivative thereof, comprising using the compound of formula (V); or to the use of the compound of formula (V) in the preparation of the compound of formula (I) or a pharmaceutically acceptable derivative thereof.

[0179] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable derivative thereof can be synthesized via the following route:

[0180] Where R represents any suitable group at the corresponding position in this paper. Beneficial effects

[0181] The compounds of formula (I) or their pharmaceutically acceptable derivatives provided by this invention exhibit excellent blocking effects on sodium ion channels. Furthermore, compared to tetrodotoxin, the compounds of formula (I) or their pharmaceutically acceptable derivatives provided by this invention can be synthesized in large quantities through chemical synthesis, are readily available, and possess superior analgesic potency. Therefore, while achieving the same or comparable therapeutic effects, they offer better drug safety and have broader application prospects.

[0182] Example

[0183] Synthesis and Preparation Examples

[0184] Unless otherwise specified, all reagents and solvents used in the synthesis are provided by domestic manufacturers and can be used without further purification.

[0185] Synthesis of intermediates:

[0186] Intermediate Synthesis Example 1: Synthesis of (6S,8S)-8a-((E)-2,3-bis((benzyloxy)carbonyl)guanidine)-4-hydroxy-6-methoxy-2,2-dimethyl-9-oxooctahydro-5,8-(epoxymethoxy)[1,3]dioxane[4,5-e]isobenzofuran-4-carboxylic acid (B1)

[0187] The starting materials S8 and TTX-42 can be prepared according to the method described in patent application CN 113956266 A, the entire contents of which are incorporated herein by reference.

[0188] Step 3: Synthesis of (6S,8S)-8a-((E)-2,3-bis((benzyloxy)carbonyl)guanidine)-4-hydroxy-6-methoxy-2,2-dimethyl-9-oxooctahydro-5,8-(epoxymethoxy)[1,3]dioxane[4,5-e]isobenzofuran-4-carboxylic acid (B1)

[0189] TTX-42 (160 mg, 0.25 mmol), acetonitrile (2 mL), 2,2,6,6-tetramethylpiperidine oxide (7 mg, 0.04 mmol), and 7% potassium dihydrogen phosphate aqueous solution (2 mL) were added to a reaction flask. The mixture was heated to 40 °C, and 7.5% sodium hypochlorite solution (0.1 mL) and sodium chlorite (45.22 mg, 0.50 mmol) were added over approximately 10 minutes. The reaction mixture was stirred overnight at 40 °C. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (1 mL) and sodium sulfite aqueous solution (1 mL) were added. The mixture was extracted with ethyl acetate (5 mL x 3), and the organic phases were combined and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (methanol / dichloromethane = 10%) to give compound B1 (100 mg, yield: 61%).

[0190] 1H NMR (400MHz, CDCl3) δ11.49(s,1H),8.92(s,1H),7.44-7.27(m,10H),5.25-5.19(m,3H),5.18-5.09(m,3H),4.76(s,1H),4.65(d,J=1.5Hz,1 H),4.56(dd,J=8.1,1.1Hz,1H),3.98(t,J=1.5Hz,1H),3.28(s,3H),2.10(s,1H),1.44(s,3H),1.27(d,J=4.8Hz,3H); LCMS(m / z):656.2[M+1] + .

[0191] Intermediate Synthesis Example 2: Synthesis of (6S,8S)-8a-((E)-2,3-bis((benzyloxy)carbonyl)guanidine)-4-hydroxy-6-methoxy-2,2-dimethyl-9-oxooctahydro-5,8-(epoxymethoxy)[1,3]dioxane[4,5-e]isobenzofuran-4-carboxaldehyde (B2)

[0192] Add 2 mL of anhydrous dichloromethane to a 10 mL reaction flask, purge three times with nitrogen, add 30 mg (0.23 mmol) of oxalyl chloride, lower the temperature to -78 °C, and add 37 mg (0.47 mmol) of dimethyl sulfoxide dropwise. After the addition is complete, stir the reaction for 30 minutes, then add a solution of 100 mg (0.16 mmol) of TTX-42 / 0.5 mL of dichloromethane dropwise. After the addition is complete, stir the reaction at -78 °C for 25 minutes, then add 79 mg (0.78 mmol) of triethylamine dropwise. After the addition is complete, react the reaction at room temperature for 2 hours. Monitor the reaction of the starting material by HPLC to ensure complete reaction. Add 10 mL of water to the reaction solution, extract with dichloromethane (10 mL x 3), combine the organic phases, wash with water in 10 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 0-60%) to give a white solid compound B2 (52 mg, yield: 51%).

[0193] 1H NMR (400MHz, CDCl3) δ11.85-11.36(m,1H),7.46-7.30(m,6H),7.26-7.11( m,4H),6.24-5.71(m,1H),5.48-5.30(m,1H),5.27-4.93(m,5H),4.86-4.7 4(m,1H),4.71-4.61(m,1H),4.58-4.29(m,1H),4.21-4.09(m,1H),3.36-3 .21(m,3H),1.48-1.35(m,3H),1.34-1.19(m,3H); LCMS(m / z):640.2[M+1] + .

[0194] Intermediate Synthesis Example 3: Synthesis of (6S,8S)-8a-((E)-2,3-bis((benzyloxy)carbonyl)guanidine)-4-hydroxy-6-methoxy-2,2-dimethyl-9-oxooctahydro-5,8-(epoxymethoxy)[1,3]dioxane[4,5-e]isobenzofuran-4-methylamine (B3)

[0195] Step 1: Synthesis of (6S,8S)-8a-((E)-2,3-bis((benzyloxy)carbonyl)guanidine)-4-hydroxy-6-methoxy-2,2-dimethyl-9-oxooctahydro-5,8-(epoxymethoxy)[1,3]dioxane[4,5-e]isobenzofuran-4-carboxaldehyde oxime (B2-1)

[0196] Compound B2 (700 mg, 1.09 mmol), methanol (50 mL), and hydroxylamine hydrochloride (167.40 mg, 2.41 mmol) were added to a reaction flask, followed by the addition of sodium acetate (134.60 mg, 1.64 mmol) under ice bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and reacted for 48 hours. HPLC monitoring was used until the reactants were completely reacted. The reaction mixture was concentrated and dried to obtain a residue. Ethyl acetate (30 mL) was added to the residue, and the mixture was filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated and dried to obtain a crude product. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 0-50%) to give a white solid compound B2-1 (666 mg, yield: 93%).

[0197] 1H NMR (400MHz, CDCl3) δ11.58(s,1H),8.92(s,1H),7.90(s,1H),7.51(d,J=8.3Hz,1H),7.40-7.29(m,10H),5.23-5.18(m,3H),5.17-5.11(m, 3H),4.63(s,1H),4.56(s,1H),4.43-4.37(m,1H),4.11(s,1H),4.00(s,1H),3.27(s,3H),1.41(s,3H),1.22(s,3H); LCMS(m / z):655.2[M+1] + .

[0198] Step 2: Synthesis of compound B3

[0199] Nickel chloride hexahydrate (752 mg, 3.16 mmol) was dissolved in methanol (32 mL) and dichloromethane (8 mL). Compound B2-1 (828 mg, 1.27 mmol) was added. Under nitrogen protection, the reaction solution was cooled to -45°C, and then sodium borohydride (100 mg) was added. The mixture was stirred until the reaction was initiated (the reaction solution darkened in color and produced a large number of bubbles). The remaining sodium borohydride (187 mg) was then added in portions. After the addition was complete, the reaction was continued for 30 minutes. HPLC monitoring was used until the reactants reacted completely. Acetic acid (2 mL) was added to the reaction solution, the cooling bath was removed, and the mixture was stirred until the solution turned light green. Then, dichloromethane (20 mL) was added, followed by slow addition of saturated sodium bicarbonate solution until the pH reached 8. The mixture was filtered, and the filter cake was slurried with dichloromethane / methanol (10 / 1, 30 mL x 2) and filtered again. The filtrates were combined and separated. The aqueous phase was extracted with dichloromethane / methanol (10 / 1, 20 mL x 2). All organic phases were then combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried to obtain the crude product. The crude product was purified by rapid column chromatography (MeOH / DCM = 0-10%) to give a white solid compound B3 (558 mg, yield: 67.4%).

[0200] 1H NMR(400MHz, CDCl3)δ11.53(s,1H),8.92(s,1H),7.43-7.30(m,10H),5.24- 5.19(m,2H),5.16(d,J=8.9Hz,2H),5.12-5.08(dd,J=6.1,4.1Hz,2H),4.61( d,J=1.5Hz,1H),4.42(s,1H),4.33(d,J=8.3Hz,1H),3.91(s,1H),3.27(s,3 H), 3.24 (s, 1H), 2.91 (d, J = 13.5Hz, 1H), 1.38 (s, 3H), 1.24 (d, J = 8.2Hz, 6H). LCMS (m / z): 641.2 [M+1] + .

[0201] Synthesis of the target compound:

[0202] The target compound was synthesized according to the following synthetic route:

[0203] Synthesis route:

[0204] Where R represents any suitable group at the corresponding position in this paper.

[0205] Example 1: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((6-methoxy-1H-indole)-3-sulfonamido)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 1)

[0206] Step 1: Synthesis of Compounds 1-2

[0207] Compound 1-1 (1.0 g, 6.79 mmol), pyridine sulfur trioxide (1.62 g, 10.19 mmol), and pyridine (20 mL) were added to a reaction flask, and the mixture was stirred at 130 °C for five hours. After the reaction was complete, the reaction solution was concentrated and dried to obtain crude compound 1-2 (2.1 g), which was directly used in the next reaction. LCMS (m / z): 227.0 [M+1] + .

[0208] Step 2: Synthesis of compounds 1-3

[0209] Compounds 1-2 (2.1 g, crude) were dissolved in a mixed solution of DMF (122 mg, 0.92 mmol) and dichloromethane (20 mL). The solution was cooled to 0 °C under nitrogen protection, and oxalyl chloride (1.4 g, 11.10 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at 15 °C for two hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (EA / PE = 0-28%) to give compounds 1-3 (450 mg, two-step yield: 27%). LCMS (m / z): 246.0, 248 [M+1] + .

[0210] Step 3: Synthesis of compounds 1-4

[0211] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (86 mg, 1.09 mmol) and dichloromethane (5 mL). Compound 1-3 (6-methoxy-3-sulfonylchloroindole) (58 mg, 0.24 mmol) was added under stirring, and the reaction was carried out at 15 °C for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (EA / PE = 0-70%) to give compound 1-4 (100 mg, yield: 75.4%). LCMS (m / z): 850.3 [M+1] + .

[0212] Step 4: Synthesis of Compound 1

[0213] Compounds 1-4 (100 mg, 0.12 mmol) were dissolved in a mixture of water (5 mL) and trifluoroacetic acid (5 mL), and the mixture was heated to 60 °C and stirred for 24 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-8.5%) to give compound 1 (12.0 mg, yield: 15.4%).

[0214] 1H NMR (400MHz, MeOD) δ7.75(dd,J=12.3,6.0Hz,2H),7.40-7.25(m,5H),6.99(d,J=2.2Hz,1H),6.88(dd,J=8.8,2.2Hz,1H),5.54(d ,J=9.4Hz,1H),5.08(s,2H),4.14(s,2H),3.89(s,2H),3.84(s,3H),3.44(s,2H),2.23(d,J=8.8Hz,1H); LCMS(m / z):662.2[M+1] + .

[0215] Example 2: Synthesis of 6-methoxy-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 2)

[0216] Compound 1 (8.0 mg, 0.01 mmol), 10% Pd / C (4 mg), and methanol (10 mL) were added to a reaction flask. Hydrogen was substituted, and the mixture was stirred for 4 hours under hydrogen protection and at 25 °C. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried, and then lyophilized to give compound 2 (5.0 mg, yield: 78.3%) as a white solid.

[0217] 1 H NMR (400MHz, MeOD) δ7.80-7.73(m,2H),7.01(d,J=2.2Hz,1H),6.88(dd,J=8.8,2.1Hz,1H),5.52(d,J=9.4H z,1H),4.15(s,2H),3.90(s,2H),3.84(s,3H),3.45(s,2H),2.19(d,J=7.7Hz,1H); LCMS(m / z):528.1[M+1] + .

[0218] Example 3: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((6-(tert-butyl)-1H-indole)-3-sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 3)

[0219] Step 1: Synthesis of compound 3-2

[0220] Compound 3-1 (1.0 g, 5.77 mmol), pyridine sulfur trioxide (1.38 g, 8.67 mmol), and pyridine (10 mL) were added to a reaction flask. The mixture was heated to 130 °C and stirred for 5 hours. After the reaction was complete, the reaction solution was concentrated and dried to obtain crude compound 3-2 (2.6 g), which was directly used in the next reaction. LCMS (m / z): 253.1 [M+1] + .

[0221] Step 2: Synthesis of compound 3-3

[0222] The crude compound 3-2 (2.6 g) was dissolved in a mixed solution of DMF (133 mg, 0.78 mmol) and dichloromethane (20 mL). The solution was cooled to 0 °C under nitrogen protection, and oxalyl chloride (1.19 g, 9.40 mmol) was added dropwise. After the addition was complete, the mixture was stirred at approximately 15 °C for two hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-7.8%) to give compound 3-3 (600 mg, two-step yield: 38.2%). LCMS (m / z): 272.0, 274.0 [M+1] + .

[0223] Step 3: Synthesis of compounds 3-4

[0224] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (50 mg, 0.63 mmol) and dichloromethane (5 mL). Compound 3-3 (51 mg, 0.19 mmol) was added under ice bath conditions, and the mixture was stirred at approximately 15 °C for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-35%) to give compound 3-4 (110 mg, yield: 80.5%). LCMS (m / z): 876.3 [M+1] + .

[0225] Step 4: Synthesis of Compound 3

[0226] Compounds 3-4 (110 mg, 0.13 mmol) were dissolved in a mixed solution of water (6 mL) and trifluoroacetic acid (6 mL), and the mixture was stirred at 60 °C for 24 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-7.0%) to give compound 3 (19.0 mg, yield: 22.0%).

[0227] 1 H NMR (400MHz, MeOD) δ7.91-7.77(m,2H),7.51(s,1H),7.44-7.25(m,6H),5.57(d,J=9.3Hz,1H),5.12(s,2H), 4.17(s,2H),3.92(s,2H),3.45(s,2H),2.27(d,J=9.2Hz,1H),1.40(d,J=3.5Hz,9H); LCMS(m / z):688.2[M+1] + .

[0228] Example 4: Synthesis of 6-tert-butyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 4)

[0229] Compound 3 (15.0 mg, 0.02 mmol), 10% Pd / C (8 mg), and methanol (10 mL) were added to a reaction flask. Hydrogen was substituted, and the mixture was stirred for 4 hours under hydrogen protection and at 25 °C. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried, and then lyophilized to give white compound 4 (8.0 mg, yield: 65.7%).

[0230] 1 H NMR(400MHz,MeOD)δ7.86-7.79(m,2H),7.51(d,J=1.2Hz,1H),7.36(d,J=8.5Hz,1H),5.52(d,J=9.4Hz,1H), 4.16(s,2H),3.91(d,J=8.5Hz,2H),3.44(s,2H),2.24(d,J=9.4Hz,1H),1.39(s,9H); LCMS(m / z):554.2[M+1] + .

[0231] Example 5: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((6-fluoro-1H-indole)-3-sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 5)

[0232] Step 1: Synthesis of Compound 5-2

[0233] Compound 5-1 (1.0 g, 7.40 mmol), pyridine sulfur trioxide (1.53 g, 9.62 mmol), and pyridine (10 mL) were added to a reaction flask, and the mixture was stirred at 130 °C for 5 hours. After the reaction was complete, the reaction solution was concentrated and dried to obtain crude compound 5-2 (2.5 g), which was directly used in the next reaction. LCMS (m / z): 216.0 [M+1] + .

[0234] Step 2: Synthesis of Compound 5-3

[0235] Compound 5-2 (2.5 g, crude) was dissolved in a mixed solution of DMF (90 mg, 1.23 mmol) and dichloromethane (20 mL). The solution was cooled to 0 °C under nitrogen protection, and oxalyl chloride (1.03 g, 8.12 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at 15 °C for two hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-18.6%) to give compound 5-3 (950 mg, two-step yield: 54.9%). LCMS (m / z): 234.0, 236.0 [M+1] + .

[0236] Step 3: Synthesis of Compounds 5-4

[0237] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (62 mg, 0.78 mmol) and dichloromethane (5 mL). Compound 5-3 (6-fluoro-3-sulfonylchloroindole) (54 mg, 0.23 mmol) was added, and the mixture was stirred at 15 °C for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 5-4 (90 mg, yield: 68.9%). LCMS (m / z): 838.2 [M+1] + .

[0238] Step 3: Synthesis of Compound 5

[0239] Compound 5-4 (90 mg, 0.11 mmol) was dissolved in a mixed solution of water (4 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at 60 °C for 24 hours. After the reaction was complete, the mixture was directly concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-10.0%) to give compound 5 (13.5 mg, yield: 19.3%) as a white solid.

[0240] 1 H NMR (400MHz, MeOD) δ7.96-7.82(m,2H),7.39-7.25(m,5H),7.21(dd,J=9.5,2.3Hz,1H),7.02(td,J=9.3,2.3Hz,1H),5.53( d,J=9.4Hz,1H),5.07(s,2H),4.13(s,2H),3.89(s,2H),3.52-3.37(m,2H),2.22(d,J=9.7Hz,1H); LCMS(m / z):650.2[M+1] + .

[0241] Example 6: Synthesis of 6-fluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 6)

[0242] Compound 5 (10.0 mg, 0.02 mmol), 10% Pd / C (5 mg), and methanol (10 mL) were added to a reaction flask. Hydrogen was substituted, and the mixture was stirred at 25 °C for 4 hours under hydrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried, and then lyophilized to give compound 6 (6.0 mg, yield: 75.6%).

[0243] 1 H NMR (400MHz, MeOD) δ7.98-7.78(m,2H),7.21(dd,J=9.4,2.2Hz,1H),7.02(td,J=9.3,2.3Hz,1H),5.51(d, J=9.3Hz,1H),4.14(s,2H),3.90(s,2H),3.52-3.41(m,2H),2.23(d,J=9.4Hz,1H); LCMS(m / z):516.1[M+1] + .

[0244] Example 7: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((5-fluoro-1H-indole)-3-sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 7)

[0245] Step 1: Synthesis of Compound 7-2

[0246] Compound 7-1 (500 mg, 3.70 mmol) and acetonitrile (10 mL) were added to a reaction flask and cooled to approximately -10 °C. Then, chlorosulfonic acid (517 mg, 4.44 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the reaction temperature was raised to 15 °C, and the reaction was stirred for 3 hours. After the reaction was complete, ice water was slowly added to the reaction solution, followed by extraction with dichloromethane (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude compound 7-2 (200 mg, yield: 23.1%), which was directly used in the next reaction. LCMS (m / z): 233.9, 235.9 [M+1] + .

[0247] Step 2: Synthesis of Compound 7-3

[0248] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (62 mg, 0.78 mmol) and dichloromethane (5 mL), and then compound 7-2 (5-fluoro-3-sulfonylchloroindole) (54 mg, 0.23 mmol) was added. The mixture was stirred at approximately 15 °C for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether: 0-45%) to give compound 7-3 (122 mg, yield: 93.3%). LCMS (m / z): 838.2 [M+1] + .

[0249] Step 3: Synthesis of Compound 7

[0250] Compound 7-3 (122 mg, 0.15 mmol) was dissolved in a mixed solution of water (8 mL) and trifluoroacetic acid (6 mL), and the mixture was stirred at 60 °C for 24 hours. After the reaction was complete, the mixture was directly concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-10%) to give compound 7 (55 mg, yield: 58.1%) as a white solid.

[0251] 1 H NMR (400MHz, DMSO) δ7.84(s,1H),7.52(d,J=7.6Hz,1H),7.40(dd,J=8.9,4.4Hz,1H),7.35-7.20(m,5H),7.06-6.88(m,1H),5.51 (d,J=9.4Hz,1H),5.09(s,2H),4.08(d,J=15.7Hz,2H),3.83(s,2H),3.36(s,2H),2.21(d,J=9.4Hz,1H); LCMS(m / z):650.2[M+1] + .

[0252] Example 8: Synthesis of 5-fluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 8)

[0253] Compound 7 (20.0 mg, 0.03 mmol) and 10% Pd / C (10 mg) were added to methanol (10 mL), hydrogen was substituted, and the mixture was stirred at 25 °C for 4 hours under hydrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried, and then lyophilized to give compound 8 (10.1 mg, yield: 63%) as a white solid.

[0254] 1 H NMR(400MHz,D2O)δ7.93(s,1H),7.52-7.37(m,2H),7.05(t,J=9.2Hz,1H),5.29(d,J=9.5Hz,1H),4.10(d,J=17.5Hz,1 H),4.01(s,1H),3.85(s,1H),3.78(d,J=7.8Hz,1H),3.42-3.31(m,2H),2.17(d,J=9.6Hz,1H); LCMS(m / z):516.1[M+1] + .

[0255] Example 9: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((4-fluoro-1H-indole)-3-sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 9)

[0256] Step 1: Synthesis of Compound 9-2

[0257] Compound 9-1 (1.0 g, 7.4 mmol), pyridine sulfur trioxide (1.76 g, 11 mmol), and pyridine (10 mL) were added to a reaction flask, and the mixture was stirred at 130 °C for 5 hours. After the reaction was complete, the reaction solution was concentrated and dried to obtain crude compound 9-2 (2.7 g), which was directly used in the next reaction. LCMS (m / z): 216.0 [M+1] + .

[0258] Step 2: Synthesis of Compound 9-3

[0259] The crude compound 9-2 (1 g, 2.74 mmol) was dissolved in a mixture of dichloromethane (5 mL) and a catalytic amount of DMF. The solution was cooled to 0 °C under nitrogen protection, and oxaloyl chloride (1.18 g, 9.3 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 15 °C for two hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-7.8%) to give compound 9-3 (150 mg, two-step yield: 23.4%). LCMS (m / z): 234.0, 236.0 [M+1] + .

[0260] Step 3: Synthesis of compound 9-4

[0261] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (50 mg, 0.62 mmol) and dichloromethane (5 mL). Compound 9-3 (43.6 mg, 0.19 mmol) was added under stirring, and the reaction was stirred at 15 °C for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-35%) to give compound 9-4 (110 mg, yield: 84.1%). LCMS (m / z): 838.2 [M+1] + .

[0262] Step 4: Synthesis of Compound 9

[0263] Compound 9-4 (110 mg, 0.13 mmol) was dissolved in a mixed solution of water (10 mL) and trifluoroacetic acid (10 mL). The mixture was heated to 60 °C and stirred for 24 hours under nitrogen protection. After the reaction was complete, the solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-7.0%) to give compound 9 (20 mg, yield: 23.4%) as a white solid.

[0264] 1H NMR(400MHz,MeOD)δ7.89(d,J=2.7Hz,1H),7.41-7.21(m,7H),6.94(dd,J=11.0,7.8Hz,1H),5.52(d,J=9.5Hz,1 H),5.05(s,2H),4.12(s,2H),3.89(s,2H),3.48(d,J=1.6Hz,2H),2.20(d,J=9.5Hz,1H); LCMS(m / z):650.2[M+1] + .

[0265] Example 10: Synthesis of 4-fluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 10)

[0266] Compound 9 (12 mg, 0.02 mmol), 10% Pd / C (10 mg), and methanol (5 mL) were added to a reaction flask. Hydrogen was displaced, and the mixture was stirred for 3 hours under hydrogen protection. The reaction was monitored by HPLC until the reactants had completely reacted. The mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated and dried to give a white solid compound 10 (9.0 mg, yield: 94.5%).

[0267] 1 H NMR (400MHz, MeOD) δ7.93(d,J=6.1Hz,1H),7.37(d,J=8.2Hz,1H),7.31-7.24(m,1H),6.97(dd,J=11.1,7.9Hz,1H),5.52(d ,J=9.4Hz,1H),4.17(s,2H),3.92(d,J=13.9Hz,2H),3.50(d,J=10.4Hz,2H),2.24(d,J=9.2Hz,1H); LCMS(m / z):516.1[M+1] + .

[0268] Example 11: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((6-(trifluoromethyl)-1H-indole)-3-sulfonylamino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 11)

[0269] Step 1: Synthesis of Compound 11-2

[0270] Compound 11-1 (820 mg, 4.43 mmol), pyridine sulfur trioxide (846 mg, 5.32 mmol), and pyridine (8 mL) were added to a reaction flask, and the mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and dried to obtain crude compound 11-2 (1.7 g), which was directly used in the next reaction. LCMS (m / z): 265.0 [M+1] + .

[0271] Step 2: Synthesis of compound 11-3

[0272] Compound 11-2 (1.7 g, crude) was dissolved in a mixture of dichloromethane (40 mL) and a catalytic amount of DMF. Oxaloyl chloride (962 mg, 7.58 mmol) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour until the solid was completely dissolved. The reaction solution was concentrated and dried. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-14%) to give compound 11-3 (820 mg, two-step yield: 65.3%). LCMS (m / z): 284.0, 286.0 [M+1] + .

[0273] Step 3: Synthesis of compound 11-4

[0274] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of dichloromethane (3 mL) and triethylamine (47.3 mg, 0.47 mmol). Compound 11-3 (53 mg, 0.19 mmol) was added under ice bath conditions, and the reaction was stirred at room temperature for 1.5 hours. Water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-8.5%) to give compound 11-4 (120 mg, yield: 86.6%). LCMS (m / z): 888.2 [M+1] + .

[0275] Step 4: Synthesis of Compound 11

[0276] Compound 11-4 (120 mg) was dissolved in a mixed solution of water (6 mL) and TFA (4 mL), and the mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 0-7.5%) to give a white solid compound 11 (55 mg, yield: 58.1%).

[0277] 1 H NMR (400MHz, MeOD) δ8.39(s,1H),8.18-8.05(m,2H),7.85(s,1H),7.51(d,J=8.3Hz,1H),7.43-7.32(m,4H),5.60(d,J=9 .4Hz,1H),5.18(s,2H),4.18(d,J=10.7Hz,2H),3.93(s,2H),3.50(s,2H),2.30(d,J=9.4Hz,1H); LCMS(m / z):700.2[M+1] + .

[0278] Example 12: Synthesis of N-(((4R / 4S,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide (compound 12)

[0279] Compound 11 (14 mg, 0.02 mmol), 10% Pd / C (3 mg), and methanol (2 mL) were added to a reaction flask. Hydrogen was then introduced to replace the hydrogen gas, and the mixture was stirred for 3 hours under hydrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and dried to give a white solid, compound 12 (10.5 mg, yield: 92.8%).

[0280] 1 H NMR (400MHz, MeOD) δ8.17-8.07(m,2H),7.86(s,1H),7.52(d,J=8.4Hz,1H),5.52(d,J=9.4Hz,1H),4.17 (d,J=13.8Hz,2H),3.99(s,2H),3.48(d,J=18.5Hz,2H),2.25(d,J=9.3Hz,1H); LCMS(m / z):566.1[M+1] + .

[0281] Example 13: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((1H-pyrrolo[2,3-b]pyridine-3-sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 13)

[0282] Step 1: Synthesis of Compound 13-2

[0283] Compound B3 (100 mg, 0.16 mmol) was dissolved in dichloromethane (4 mL), and then triethylamine (47.3 mg, 0.47 mmol) was added. Compound 13-1 (44.4 mg, 0.20 mmol) was added under ice bath conditions, and the reaction was stirred at room temperature for 1.5 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-85%) to give compound 13-2 (120 mg, yield: 93.7%). LCMS (m / z): 821.2 [M+1] + .

[0284] Step 2: Synthesis of Compound 13

[0285] Compound 13-2 (120 mg, 0.15 mmol) was dissolved in a mixed solution of water (8 mL) and trifluoroacetic acid (6 mL), and the mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated and dried, and the crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-9%), and then lyophilized to give a white solid compound 13 (40 mg, yield: 43.3%).

[0286] 1 H NMR (400MHz, MeOD) δ8.41-8.33(m,2H),8.02(d,J=3.2Hz,1H),7.41-7.22(m,6H),5.53(d,J=9.4Hz,1H),5.0 8(s,2H),4.12(s,2H),3.88(s,2H),3.58-3.39(m,2H),2.20(dd,J=17.5,8.7Hz,1H); LCMS(m / z):633.2[M+1] + .

[0287] Example 14: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide (compound 14)

[0288] Compound 13 (35 mg, 0.06 mmol), methanol (6 mL), and 10% Pd / C (6 mg) were added to a reaction flask. Hydrogen was then displaced, and the mixture was stirred for 3 hours under hydrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and dried to give a white solid, compound 14 (18 mg, yield: 65.2%).

[0289] 1 H NMR(400MHz,MeOD)δ8.40-8.33(m,2H),8.02(s,1H),7.34-7.27(m,1H),5.50(d,J=9.3Hz,1H),4.1 6(dd,J=16.2,10.6Hz,2H),3.97(s,2H),3.44(s,2H),2.23(d,J=9.4,1H); LCMS(m / z):499.2[M+1] + .

[0290] Example 15: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((6-methyl-1H-indole)-3-sulfonamido)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-imino)benzyl formate (compound 15)

[0291] Step 1: Synthesis of Compound 15-2

[0292] Compound 15-1 (900 mg, 6.86 mmol), pyridine sulfur trioxide (1.68 g, 10.6 mmol), and anhydrous pyridine (5 mL) were added to a reaction flask, and the mixture was stirred at 130 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by reversed-phase column chromatography (methanol / acetic acid aqueous solution = 0.5%) to give a grayish-white solid compound 15-2 (1.3 g, yield: 65.5%). LCMS (m / z): 211.0 [M+1] + .

[0293] Step 2: Synthesis of Compound 15-3

[0294] Compound 15-2 (500 mg, 1.73 mmol) was dissolved in a mixed solution of N,N-dimethylformamide (14.6 mg, 0.20 mmol) and dichloromethane (5 mL), and oxalyl chloride (450 mg, 3.0 mmol) was added dropwise. The reaction was carried out under nitrogen protection and stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 10%-15%) to give a grayish-white solid compound 15-3 (325 mg, yield: 81.9%). LCMS (m / z): 230.0, 232.0 [M+1] + .

[0295] Step 3: Synthesis of Compound 15-4

[0296] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (35.2 mg, 0.46 mmol) and dichloromethane (5 mL), and then compound 15-3 (42.9 mg, 0.19 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was complete, water (5 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a grayish-white solid compound 15-4 (120 mg, yield: 92.2%). LCMS (m / z): 834.3 [M+1] + .

[0297] Step 4: Synthesis of Compound 15

[0298] Compound 15-4 (120 mg, 0.14 mmol) was dissolved in a mixed solution of water (4 mL) and trifluoroacetic acid (8 mL), and the reaction was carried out under nitrogen protection and at 60 °C with stirring for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 5%-8%) to give a white solid compound 15 (24.3 mg, yield: 26.1%).

[0299] 1H NMR (400MHz, MeOD) δ7.79(d,J=2.5Hz,1H),7.44-7.33(m,6H),7.29(s,1H),7.07(d,J=8.0Hz,1H),5.65(d,J=9.4Hz,1H),5. 26(s,2H),4.22(s,1H),4.16(s,1H),3.94(s,2H),3.45(s,2H),2.45(s,3H),2.36(d,J=9.4Hz,1H); LCMS(m / z):646.2[M+1] + .

[0300] Example 16: Synthesis of 6-methyl-N-((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 16)

[0301] Compound 15 (6 mg, 0.01 mmol), 10% palladium on carbon (2 mg), and methanol (5 mL) were added to a reaction flask. Hydrogen was purged three times, and the mixture was stirred for 8 hours under hydrogen protection and at room temperature. After the reaction was complete, the mixture was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and then lyophilized to give a grayish-white solid, compound 16 (4.2 mg, yield: 88.4%).

[0302] 1 H NMR (400MHz, MeOD) δ7.84(s,1H),7.78(d,J=8.3Hz,1H),7.34(s,1H),7.11(d,J=7.4Hz,1H),5.52(d,J=9.5Hz, 1H),4.22-4.11(m,2H),4.01(s,2H),3.42(s,2H),2.46(s,3H),2.23(d,J=7.0Hz,1H); LCMS(m / z):512.1[M+1] + .

[0303] Example 17: Synthesis of 6-hydroxy-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 17)

[0304] Step 1: Synthesis of Compound 17-2

[0305] Compound 17-1 (0.50 g, 2.24 mmol), pyridine sulfur trioxide (0.53 g, 3.36 mmol), and pyridine (5 mL) were added to a reaction flask, and the mixture was stirred at 130 °C for 5 hours. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and dried to obtain crude compound 17-2 (2.6 g), which was used directly in the next reaction. LCMS (m / z): 303.1 [M+1] + .

[0306] Step 2: Synthesis of Compound 17-3

[0307] Compound 17-2 (0.8 g, crude) was dissolved in a mixture of dichloromethane (5 mL) and a catalytic amount of DMF. Oxaloyl chloride (0.42 g, 3.3 mmol) was added dropwise under nitrogen protection. After the addition was complete, the reaction mixture was stirred at 15 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 0-7.8%) to give compound 17-3 (150 mg, two-step yield: 67.6%). LCMS (m / z): 322.1, 324.1 [M+1] + .

[0308] Step 3: Synthesis of Compound 17-4

[0309] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (50 mg, 0.63 mmol) and dichloromethane (5 mL). Compound 17-3 (60 mg, 0.19 mmol) was added under stirring, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, water (5 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-35%) to give compound 17-4 (120 mg, yield: 83%). LCMS (m / z): 926.3 [M+1] + .

[0310] Step 4: Synthesis of Compound 17-5

[0311] Compound 17-4 (120 mg, 0.13 mmol) was dissolved in a mixed solution of water (5 mL) and trifluoroacetic acid (5 mL), and the mixture was stirred at 60 °C for 24 hours. After the reaction was complete, the solution was directly concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-7.0%) to give compound 17-5 (22 mg, yield: 22.9%). LCMS (m / z): 738.2 [M+1] + .

[0312] Step 5: Synthesis of Compound 17

[0313] Compound 17-5 (18 mg, 0.02 mmol), 10% Pd / C (10 mg), and methanol (5 mL) were added to a reaction flask. Hydrogen was purged, and the mixture was stirred for 3 hours under hydrogen protection. The reaction was monitored by HPLC until the starting material was completely reacted. Palladium on carbon was removed by filtration, and the filter cake was washed with methanol. The filtrate was concentrated and dried to give compound 17 (5 mg, yield: 39.9%).

[0314] 1 H NMR (400MHz, MeOD) δ7.77-7.69(m,2H),6.91(d,J=2.0Hz,1H),6.82(dd,J=8.7,2.0Hz,1H),5.54(d,J=9. 4Hz,1H),4.18(s,2H),3.93(d,J=6.7Hz,2H),3.46(s,2H),2.26(d,J=9.6Hz,1H); LCMS(m / z):514.1[M+1] + .

[0315] Example 18: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((1H-indole-6-sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 18)

[0316] Step 1: Synthesis of Compound 18-2

[0317] Compound 18-1 (1 g, 5.10 mmol) and dichloromethane (10 mL) were added to a reaction flask, followed by DMAP (124.6 mg, 1.02 mmol) and Boc2O (1.23 g, 5.61 mmol). After the addition was complete, the reaction was continued for 2 hours. Thin-layer chromatography (TLC) (PE / EA = 3:1) was used to monitor the reaction until the starting material was completely reacted. The reaction solution was then concentrated and dried. The crude product was purified by column chromatography (EA / PE = 0–4%) to give a pale yellow liquid compound 18-2 (1.4 g, yield: 92%).

[0318] Step 2: Synthesis of Compound 18-3

[0319] Compound 18-2 (950 mg, 3.21 mmol), benzyl mercaptan (478 mg, 3.85 mmol), Pd2(dba)3 (73.5 mg, 0.08 mmol), Xantphos (92.9 mg, 0.16 mmol), and DIPEA (1.25 g, 9.63 mmol) were added to dioxane (10 mL), and nitrogen was purged. The mixture was stirred at 100 °C for 16 hours. TLC (100% petroleum ether) was used to monitor the reaction until the starting material was completely reacted. The reaction solution was concentrated and dried. The crude product was purified by column chromatography (EA / PE = 0.1%) to give a white, low-melting-point solid compound 18-3 (950 mg, yield: 87.2%).

[0320] 1 H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 7.56 (d, J = 3.6Hz, 1H), 7.43 (d, J = 8.1Hz, 1H) ,7.32-7.17(m,6H),6.52(d,J=3.6Hz,1H),4.16(s,2H),1.67(d,J=7.6Hz,9H).

[0321] Step 3: Synthesis of compound 18-4

[0322] Compound 18-3 (300 mg, 0.88 mmol) was dissolved in glacial acetic acid (9 mL) and water (2.3 mL). NCS (354 mg, 2.65 mmol) was added in portions under ice bath conditions, and the mixture was allowed to rise naturally to room temperature with stirring overnight. TLC (PE / EA = 10:1) confirmed that both the starting material and intermediates had reacted completely. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and the green leaves were concentrated and dried. The crude product was purified by column chromatography (EA / PE = 0.4%) to give a low-melting-point white solid, compound 18-4 (248 mg, yield: 88.9%).

[0323] 1 H NMR (400MHz, CDCl3) δ8.90 (s, 1H), 7.94-7.85 (m, 2H), 7.76 (d, J = 8.4Hz, 1H), 6.71 (d, J = 3.6Hz, 1H), 1.71 (d, J = 6.8Hz, 9H).

[0324] Step 4: Synthesis of Compound 18-5

[0325] Compound B3 (100 mg, 0.16 mmol) was dissolved in dichloromethane (6 mL), and triethylamine (47.3 mg, 0.47 mmol) was added. Compound 18-4 (59 mg, 0.19 mmol) was then added under ice bath conditions, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0.28%) to give compound 18-5 (122 mg, yield: 85%). LCMS (m / z): 920.3 [M+1] + .

[0326] Step 5: Synthesis of Compound 18

[0327] Compound 18-5 (122 mg, 0.13 mmol) was dissolved in a mixed solution of water (8 mL) and trifluoroacetic acid (6 mL), and the mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated and dried, and the crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-8%), and then lyophilized to give a white solid compound 18 (13 mg, yield: 15.5%).

[0328] 1H NMR(400MHz,MeOD)δ8.41(d,J=4.7Hz,1H),7.99(s,1H),7.73(d,J=8.4Hz,1H ),7.54(dd,J=8.4,1.5Hz,1H),7.45-7.35(m,5H),6.58(d,J=2.8Hz,1H),5.6 7(d,J=9.4Hz,1H),5.29(s,2H),4.23(d,J=5.4Hz,1H),4.17(s,1H),3.96(d, J=10.1Hz,2H),3.44(s,2H),2.38(d,J=10.7Hz,1H); LCMS(m / z):632.2[M+1] + .

[0329] Example 19: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-6-sulfonamide (compound 19)

[0330] Compound 18 (12 mg, 0.02 mmol), methanol (3 mL), and 10% Pd / C (3 mg) were added to a reaction flask. Hydrogen was substituted, and the mixture was stirred for 3 hours under hydrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and dried. The crude product was purified by high performance liquid chromatography to obtain a white solid compound 19 (8.5 mg, yield: 89.9%).

[0331] 1 H NMR(400MHz,MeOD)δ7.99(s,1H),7.73(d,J=8.4Hz,1H),7.57-7.44(m,2H),6.58(d,J=3.1Hz,1H),5.51(d, J=9.4Hz,1H),4.15(d,J=15.0Hz,2H),3.98(s,2H),3.39(s,2H),2.27-2.21(m,1H); LCMS(m / z):498.1[M+1] + .

[0332] Example 20: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((1H-indole-4-sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 20)

[0333] Step 1: Synthesis of Compound 20-2

[0334] Compound 20-1 (1 g, 5.10 mmol) and dichloromethane (10 mL) were added to a reaction flask, followed by DMAP (124.6 mg, 1.02 mmol) and Boc2O (1.23 g, 5.61 mmol). After the addition was complete, the mixture was stirred for 1.5 hours. TLC (PE / EA = 10:1) was used to monitor the reaction until the starting material was completely reacted. 5% citric acid aqueous solution (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to give crude compound 20-2 (1.57 g, yield: 100%).

[0335] Step 2: Synthesis of compound 20-3

[0336] Compound 20-2 (600 mg, 2.03 mmol), benzyl mercaptan (301.9 mg, 2.43 mmol), Pd2(dba)3 (37.1 mg, 0.04 mmol), Xantphos (46.9 mg, 0.08 mmol), and DIPEA (785.5 mg, 6.08 mmol) were added to dioxane (10 mL), the mixture was purged with nitrogen, and the reaction was stirred at 100 °C for 16 hours under nitrogen protection. TLC (100% petroleum ether) was used to monitor the reaction until the reactants were fully reacted. The reaction solution was concentrated and dried, and the crude product was purified by column chromatography (EA / PE = 0-2.5%) to give a pale yellow oily compound 20-3 (708 mg, yield: 100%).

[0337] Step 3: Synthesis of compound 20-4

[0338] Compound 20-3 (300 mg, 0.88 mmol) was dissolved in a mixture of glacial acetic acid (9 mL) and water (2.3 mL). NCS (354 mg, 2.65 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was allowed to rise to room temperature and stirred overnight. TLC (PE / EA = 10:1) was used to monitor the reaction until both the starting material and intermediate were completely reacted. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by column chromatography (EA / PE = 0.28%) to give a white solid compound 20-4 (240 mg, yield: 86%).

[0339] 1 H NMR (400MHz, CDCl3) δ8.62(d,J=8.3Hz,1H),7.97(d,J=7.4Hz,1H),7.88(d,J=3 .7Hz, 1H), 7.50 (t, J = 8.1Hz, 1H), 7.19 (d, J = 3.7Hz, 1H), 1.71 (d, J = 8.7Hz, 9H).

[0340] Step 4: Synthesis of compound 20-5

[0341] Compound B3 (100 mg, 0.16 mmol) and DMAP (10 mg, 0.08 mmol) were dissolved in dichloromethane (6 mL), and triethylamine (47.3 mg, 0.47 mmol) was added. Compound 20-4 (59 mg, 0.19 mmol) was then added under ice bath conditions, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0.28%) to give compound 20-5 (117 mg, yield: 81.5%). LCMS (m / z): 920.3 [M+1] + .

[0342] Step 5: Synthesis of Compound 20

[0343] Compound 20-5 (117 mg, 0.13 mmol) was dissolved in a mixed solution of water (8 mL) and trifluoroacetic acid (6 mL), and the mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated and dried, and the crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-7.5%), and then lyophilized to give compound 20 (31 mg, yield: 38.6%) as a white solid.

[0344] 1 H NMR (400MHz, MeOD) δ7.69(d,J=8.1Hz,1H),7.64(d,J=6.9Hz,1H),7.46(d,J=3.1Hz,1H),7.41-7.22(m,6H),6.97(d,J=2.8Hz,1H), 5.55(d,J=9.2Hz,1H),5.09(d,J=7.9Hz,2H),4.14(s,2H),3.89(s,2H),3.40(s,2H),2.24(d,J=9.5Hz,1H); LCMS(m / z):632.2[M+1] + .

[0345] Example 21: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-4-sulfonamide (compound 21)

[0346] Compound 20 (25 mg, 0.04 mmol), methanol (4 mL), and 10% Pd / C (3 mg) were added to a reaction flask. Hydrogen was substituted, and the mixture was stirred for 3 hours under hydrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and dried. The crude product was purified by high-performance liquid chromatography to obtain a white solid compound 21 (2.65 mg, yield: 13.5%).

[0347] 1 H NMR (400MHz, MeOD) δ7.69(d,J=8.2Hz,1H),7.64(d,J=7.5Hz,1H),7.46(d,J=3.2Hz,1H),7.26(t,J=7.8Hz,1H),6.97(d,J =3.2Hz,1H),5.51(d,J=9.1Hz,1H),4.12(s,2H),3.91(s,2H),3.39(s,2H),2.23(d,J=9.4Hz,1H); LCMS(m / z):498.1[M+1] + .

[0348] Example 22: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((1H-indole-5-sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 22)

[0349] Step 1: Synthesis of compound 22-2

[0350] Compound 22-1 (1 g, 5.10 mmol) and dichloromethane (10 mL) were added to a reaction flask, followed by DMAP (124.6 mg, 1.02 mmol) and Boc₂O (1.23 g, 5.61 mmol). After the addition was complete, the mixture was stirred for 2 hours. TLC (PE / EA = 10:1) was used to monitor the reaction until the starting material was completely reacted. 5% citric acid aqueous solution (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to give a white solid, compound 22-2 (1.51 g, yield: 100%).

[0351] Step 2: Synthesis of compound 22-3

[0352] Compound 22-2 (600 mg, 2.03 mmol), benzyl mercaptan (301.9 mg, 2.43 mmol), Pd2(dba)3 (37.1 mg, 0.04 mmol), Xantphos (46.9 mg, 0.08 mmol), and DIPEA (785.5 mg, 6.08 mmol) were added to dioxane (10 mL), the mixture was purged with nitrogen, and the reaction was stirred at 115 °C for 48 hours under nitrogen protection. TLC (100% petroleum ether) was used to monitor the reaction until the reactants were fully reacted. The reaction solution was concentrated and dried, and the crude product was purified by column chromatography (EA / PE = 0-2.5%) to give a pale yellow oily compound 22-3 (500 mg, yield: 72.7%).

[0353] 1H NMR (400MHz, CDCl3) δ8.05(d,J=8.2Hz,1H),7.60(d,J=3.6Hz,1H),7.55(d,J=1.6Hz,1H),7.3 3(dd,J=8.6,1.8Hz,1H),7.29-7.21(m,5H),6.50(d,J=3.7Hz,1H),4.12(s,2H),1.69(s,9H).

[0354] Step 3: Synthesis of compound 22-4

[0355] Compound 22-3 (483 mg, 1.42 mmol) was dissolved in a mixture of glacial acetic acid (14.5 mL) and water (3.5 mL). NCS (570 mg, 4.27 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was allowed to rise to room temperature and stirred overnight. TLC (PE / EA = 10:1) was used to monitor the reaction until both the starting material and intermediate were completely reacted. Water (70 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by column chromatography (EA / PE = 0.22%) to give a white solid, compound 22-4 (364 mg, yield: 81%).

[0356] 1 H NMR (400MHz, CDCl3) δ 8.39 (d, J = 8.9 Hz, 1H), 8.30 (d, J = 1.9 Hz, 1H), 7.98 (dd, J = 8.9, 2.0 Hz, 1H), 7.79 (d, J = 3.7 Hz, 1H), 6.74 (d, J = 3.7 Hz, 1H), 1.70 (s, 9H).

[0357] Step 4: Synthesis of compound 22-5

[0358] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (50 mg, 0.63 mmol) and dichloromethane (5 mL). Compound 22-4 (59 mg, 0.19 mmol) was added under stirring, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-35%) to give white compound 22-5 (120 mg, 83.6%). LCMS (m / z): 920.3 [M+1] + .

[0359] Step 5: Synthesis of Compound 22

[0360] Compound 22-5 (120 mg, 0.13 mmol) was dissolved in a mixed solution of water (5 mL) and trifluoroacetic acid (5 mL), and the mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the mixture was directly concentrated and dried. The crude product was subjected to normal phase column chromatography (methanol / dichloromethane = 0-7%) to give compound 22 (20 mg, yield: 24.3%).

[0361] 1 H NMR (400MHz, MeOD) δ8.17(d,J=1.5Hz,1H),7.64(dd,J=8.6,1.8Hz,1H),7.55(d,J=8.6Hz,1H),7.42(d,J=3.2Hz,1H),7.40-7.29(m,5H),6.6 3(d,J=3.2Hz,1H),5.57(d,J=9.1Hz,1H),5.11(s,2H),4.15(s,2H),3.90(s,2H),3.42(s,2H),2.26(d,J=9.3Hz,1H); LCMS(m / z):632.2[M+1] + .

[0362] Example 23: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-5-sulfonamide (compound 23)

[0363] Compound 22 (8 mg, 0.01 mmol), 10% Pd / C (8 mg), and methanol (5 mL) were added to a reaction flask. Hydrogen was purged, and the mixture was stirred for 3 hours under hydrogen protection. HPLC monitoring was performed until the reactants were fully reacted. The reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated and dried to give a white solid, compound 23 (5 mg, yield: 79.4%).

[0364] 1 H NMR (400MHz, MeOD) δ8.18(d,J=1.4Hz,1H),7.64(dd,J=8.6,1.8Hz,1H),7.55(d,J=8.6Hz,1H),7.42(d,J=3.2Hz,1H),6.63(d,J=4.7 ,1H),5.51(d,J=9.4Hz,1H),4.16(d,J=12.6Hz,2H),4.07-3.83(m,2H),3.39(s,2H),2.24(d,J=9.4Hz,1H); LCMS(m / z):498.1[M+1] + .

[0365] Example 24: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((1H-indole-7-sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 24)

[0366] Step 1: Synthesis of Compound 24-2

[0367] Add compound 24-1 (500 mg, 2.55 mmol) and dichloromethane (10 mL) to the reaction flask, then add...

[0368] Compound 24-2 (680 mg, 2.30 mmol), benzyl mercaptan (342.2 mg, 2.76 mmol), Pd2(dba)3 (84.1 mg, 0.09 mmol), Xantphos (106.3 mg, 0.18 mmol), and DIPEA (890.2 mg, 6.89 mmol) were added to dioxane (10 mL), nitrogen was purged, and the mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was monitored by TLC (PE / EA = 10:1) until the starting material was completely reacted. The reaction solution was concentrated and dried, and the crude product was purified by column chromatography (EA / PE = 0–2.6%) to give a pale yellow solid compound 24-3 (631 mg, yield: 81%).

[0369] Step 3: Synthesis of compound 24-4

[0370] Compound 24-3 (300 mg, 0.88 mmol) was dissolved in a mixture of glacial acetic acid (9 mL) and water (2.2 mL). NCS (354 mg, 2.65 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was allowed to rise to room temperature and stirred overnight. TLC (PE / EA = 10:1) was used to monitor the reaction until most of the starting materials and intermediates had reacted completely. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by column chromatography (EA / PE = 0.25%) to give a white solid, compound 24-4 (110 mg, yield: 39.4%).

[0371] 1 H NMR (400MHz, CDCl3) δ8.09 (d, J = 8.0 Hz, 1H), 7.90 (dd, J = 7.7, 0.7 Hz, 1H), 7.55 (d, J = 3.6 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 1.67 (s, 9H).

[0372] Step 4: Synthesis of Compound 24-5

[0373] Compound B3 (100 mg, 0.16 mmol) was dissolved in a mixed solution of pyridine (35.2 mg, 0.46 mmol) and dichloromethane (5 mL), and then compound 24-4 (59.1 mg, 0.19 mmol) was added. The reaction was carried out under nitrogen atmosphere with stirring at room temperature for 3 hours. After the reaction was complete, water (5 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a grayish-white solid compound 24-5 (123 mg, yield: 85.7%). LCMS (m / z): 920.3 [M+1] + .

[0374] Step 5: Synthesis of Compound 24

[0375] Compound 24-5 (120 mg, 0.13 mmol) was dissolved in a mixed solution of water (4 mL) and trifluoroacetic acid (4 mL), and the mixture was stirred at 60 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 5%-8%) to give compound 24 (12.2 mg, yield: 14.8%) as a white solid.

[0376] 1 H NMR (400MHz, MeOD) δ7.85(d,J=7.9Hz,1H),7.65(d,J=7.3Hz,1H),7.41(d,J=3.2Hz,1H),7.39-7.28(m,5H),7.19(t,J=7.7Hz,1H),6.62(d ,J=3.2Hz,1H),5.55(d,J=9.0Hz,1H),5.09(s,2H),4.14(s,2H),3.89(s,2H),3.44(s,2H),2.23(d,J=9.3Hz,1H); LCMS(m / z):632.2[M+1] + .

[0377] Example 25: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-7-sulfonamide (compound 25)

[0378] Compound 24 (9 mg, 0.01 mmol), methanol (2 mL), and 10% Pd / C (1 mg) were added to a reaction flask. Hydrogen was purged three times, and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, palladium on carbon was removed by filtration. The filter cake was washed several times with methanol, and the filtrate was concentrated, dried, and then lyophilized to give a grayish-white solid, compound 25 (5.7 mg, yield: 80.4%).

[0379] 1 H NMR (400MHz, MeOD) δ7.88(d,J=7.9Hz,1H),7.66(d,J=7.5Hz,1H),7.48-7.41(m,1H),7.21(td,J=7.8,2.8Hz,1H),6.64(dd,J=3.2,1.8Hz ,1H),5.35(d,J=4.7Hz,1H),4.16(d,J=7.1Hz,2H),3.94-3.88(m,2H),3.50-3.42(m,2H),2.21(d,J=7.3Hz,1H); LCMS(m / z):498.1[M+1] + .

[0380] Example 26: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((1H-pyrrolo[2,3-c]pyridine-3-sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 26)

[0381] Step 1: Synthesis of Compound 26-2

[0382] Compound 26-1 (400 mg, 3.39 mmol), pyridine sulfur trioxide (808.4 mg, 5.08 mmol), and pyridine (8 mL) were added to a reaction flask, and the mixture was heated under reflux for 10 hours. The reaction solution was concentrated and dried to obtain crude compound 26-2 (1.2 g, yield: 100%), which was used directly in the next reaction step. LCMS (m / z): 199.0 [M+1] + .

[0383] Step 2: Synthesis of compound 26-3

[0384] The crude compound 26-2 (1.6 g, 5.08 mmol) was dissolved in a mixture of dichloroethane (30 mL) and a catalytic amount of DMF. Oxaloyl chloride (2.58 g, 20.32 mmol) was added dropwise under nitrogen protection and stirring. After the addition was complete, the mixture was stirred at room temperature for 30 minutes, during which bubbles were generated. The reaction system was heated to 55 °C and stirred for 16 hours. LC-MS monitoring continued until most of the starting material had reacted completely. The reaction solution was concentrated and dried to obtain the crude compound 26-3 (1.4 g, yield: 100%), which was used directly in the next reaction. LC-MS (m / z): 217.0, 219 [M+1] + .

[0385] Step 3: Synthesis of compound 26-4

[0386] The crude compound 26-3 (700 mg, 2.54 mmol) was dissolved in dichloromethane (15 mL), and DMAP (67.6 mg, 0.55 mmol) and pyridine (754.5 mg, 3.46 mmol) were added. Boc₂O (754.5 mg, 3.46 mmol) was then added dropwise under stirring. After the addition was complete, the mixture was stirred overnight at room temperature. LC-MS was monitored until the starting material was almost completely consumed. The reaction mixture was filtered, the filtrate was concentrated and dried, and the crude product was purified by rapid column chromatography (EA / PE = 0-25%) to give a white solid compound 26-4 (46 mg, yield: 5.7%).

[0387] Step 4: Synthesis of compound 26-5

[0388] Compound B3 (85 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), and pyridine (32 mg, 0.40 mmol) was added. Compound 26-4 (50 mg, 0.16 mmol) was then added under ice bath conditions, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 26-5 (85 mg, yield: 69.6%). LCMS (m / z): 921.3 [M+1] + .

[0389] Step 5: Synthesis of Compound 26

[0390] Compound 26-5 (85 mg, 0.09 mmol) was dissolved in a mixed solution of water (4 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated and dried, and the crude product was purified by reversed-phase column chromatography (0.1% HOAc in H2O / MeOH = 0-5%) to give a white solid compound 26 (15 mg, yield: 25.7%).

[0391] 1 H NMR (400MHz, MeOD) δ8.82(s,1H),8.27(d,J=5.7Hz,1H),8.15(s,1H),7.97(d,J=5.6Hz,1H),7.45-7.23(m,5H),5.56(d,J= 9.4Hz,1H),5.13(s,2H),4.13(d,J=16.1Hz,2H),3.89(s,2H),3.48(s,2H),2.26(d,J=9.5Hz,1H); LCMS(m / z):633.2[M+1] + .

[0392] Example 27: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonamide (compound 27)

[0393] Compound 26 (10 mg, 0.02 mmol), 10% Pd / C (2 mg), and methanol (4 mL) were added to a reaction flask, and hydrogen gas was substituted. The mixture was stirred for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and dried. The crude product was purified by high performance liquid chromatography to obtain a white solid compound 27 (6 mg, yield: 76.1%).

[0394] 1 H NMR (400MHz, MeOD) δ8.74(s,1H),8.18(d,J=5.7Hz,1H),8.07(s,1H),7.90(d,J=5.5Hz,1H),5.41(d,J=9.3Hz,1H) ,4.13-3.96(m,2H),3.79(dd,J=7.1,4.5Hz,2H),3.48-3.31(m,2H),2.12(d,J=8.7Hz,1H); LCMS(m / z):499.1[M+1] + .

[0395] Example 28: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((7-fluoro-1H-indole)-3-sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 28)

[0396] Step 1: Synthesis of compound 28-2

[0397] Compound 28-1 (500 mg, 3.70 mmol), pyridine sulfur trioxide (883 mg, 5.55 mmol), and pyridine (5 mL) were added to a reaction flask, and the mixture was stirred at 130 °C for 5 hours. After the reaction was complete, the reaction solution was concentrated and dried to obtain crude compound 28-2 (1.6 g, yield: 100%), which was directly used in the next reaction. LCMS (m / z): 216.0 [M+1] + .

[0398] Step 2: Synthesis of compound 28-3

[0399] Compound 28-2 (1.6 g, 3.70 mmol) was dissolved in a mixed solution of DMF (68 mg, 0.51 mmol) and dichloromethane (15 mL). Oxaloyl chloride (971 mg, 7.65 mmol) was added dropwise under nitrogen protection and at 0 °C. After the addition was complete, the mixture was stirred at 15 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-22%) to give compound 28-3 (700 mg, yield: 80.9%). LCMS (m / z): 234.0, 236.0 [M+1] + .

[0400] Step 3: Synthesis of compound 28-4

[0401] Compound B3 (85 mg, 0.13 mmol) was dissolved in a mixed solution of pyridine (53 mg, 0.67 mmol) and dichloromethane (5 mL). Compound 28-3 (37.1 mg, 0.16 mmol) was added under ice bath conditions. The reaction was stirred at approximately 15 °C for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 28-4 (80 mg, yield: 71%). LCMS (m / z): 838.2 [M+1] + .

[0402] Step 4: Synthesis of Compound 28

[0403] Compound 28-4 (80 mg, 0.10 mmol) was dissolved in a mixed solution of water (4 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at 60 °C for 24 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0-9.8%) to give compound 28 (15.0 mg, yield: 24.2%).

[0404] 1 H NMR(400MHz,MeOD)δ7.90(d,J=3.7Hz,1H),7.73(d,J=8.0Hz,1H),7.39-7.24(m,5H),7.18(td,J=8.0,4.7Hz,1H),7.02(dd,J=11.3,7.9 Hz,1H),5.52(d,J=9.4Hz,1H),5.05(s,2H),4.12(s,2H),3.88(s,2H),3.52-3.38(m,2H),2.21(d,J=9.5Hz,1H); LCMS(m / z):650.2[M+1] + .

[0405] Example 29: Synthesis of 7-fluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 29)

[0406] Compound 28 (10.0 mg, 0.02 mmol), 10% Pd / C (5 mg), and methanol (10 mL) were added to a reaction flask. Hydrogen was purged, and the mixture was stirred at 25 °C for 4 hours under hydrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried, and then lyophilized to give a white solid, compound 29 (3 mg, yield: 37.8%).

[0407] 1 H NMR (400MHz, MeOD) δ7.81(d,J=3.1Hz,1H),7.63(d,J=8.1Hz,1H),7.09(td,J=8.0,4.7Hz,1H),6.93(dd,J=11.2,7.9H z,1H),5.42(d,J=9.2Hz,1H),4.03(s,2H),3.81(s,2H),3.43-3.27(m,2H),2.17-2.11(m,1H); LCMS(m / z):516.1[M+1] + .

[0408] Example 30: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((1H-pyrrolo[3,2-b]pyridine-3-sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 30)

[0409] Step 1: Synthesis of Compound 30-2

[0410] Compound 30-1 (2.6 g, 22.01 mmol), pyridine sulfur trioxide (5.2 g, 32.67 mmol), and pyridine (30 mL) were added to a reaction flask and stirred at 130 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction system was concentrated to remove pyridine, yielding a residue. Water (50 mL) was added to the residue, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was discarded, and the aqueous phase was allowed to stand for 18 hours to precipitate crystals. The crystals were filtered and dried to give a gray solid compound 30-2 (4.1 g, yield: 67.2%).

[0411] Step 2: Synthesis of compound 30-3

[0412] Compound 30-2 (4.0 g, 14.42 mmol) was dissolved in 1,2-dichloroethane (10 mL), and DMF (0.26 g, 3.56 mmol) was added. The mixture was stirred for 10 minutes under nitrogen protection at room temperature. Then, oxalyl chloride (3.81 g, 30 mmol) was added, and the reaction mixture was heated to 60 °C and stirred for 18 hours. After the reaction was complete, the reaction solution was concentrated to remove the solvent, yielding a gray solid, crude compound 30-3 (4.3 g, yield >100%), which was used directly in the next reaction. LCMS (m / z): 217.0, 219.0 [M+1] + .

[0413] Step 3: Synthesis of compound 30-4

[0414] Compound 30-3 (300 mg, 1.38 mmol) was dissolved in dichloromethane (5 mL), and pyridine (220 mg, 2.78 mmol) and DMAP (34.2 mg, 0.28 mmol) were added. The mixture was stirred at room temperature for 10 minutes, then Boc₂O (358 mg, 1.64 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was purified by Prep-TLC to give a white solid compound 30-4 (42 mg, yield: 9.6%). LCMS (m / z): 317.0, 319.0 [M+1] + .

[0415] Step 4: Synthesis of compound 30-5

[0416] Compound B3 (80 mg, 0.125 mmol) was dissolved in a mixed solution of pyridine (35.2 mg, 0.45 mmol) and dichloromethane (5 mL). Compound 30-4 (42 mg, 0.13 mmol) was added under nitrogen protection and stirring, and the reaction was stirred at 25 °C for 3 hours. After the reaction was complete, water (5 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phases were combined, concentrated, and dried. The residue was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5-30%) to give a grayish-white solid, compound 30-5 (91 mg, yield: 79.1%). LCMS (m / z): 921.3 [M+1] + .

[0417] Step 5: Synthesis of Compound 30

[0418] Compound 30-5 (91 mg, 0.099 mmol) was dissolved in a mixed solution of water (1.5 mL) and TFA (3 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was purified by reversed-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5%-8%) to give a white solid compound 30 (6.1 mg, yield: 9.6%).

[0419] 1 H NMR(400MHz,MeOD)δ8.49(d,J=4.7Hz,1H),8.14(s,1H),8.03-7.91(m,1H),7.39-7.28(m,6H),5.53(d,J=9.4Hz,1H),5 .09(s,2H),4.13(d,J=19.6Hz,2H),3.88(s,2H),3.57(d,J=3.8Hz,2H),2.25(d,J=9.3Hz,1H); LCMS(m / z):633.2[M+1] + .

[0420] Example 31: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-sulfonamide (compound 31)

[0421] Compound 30 (5 mg, 0.008 mmol) and methanol (2 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (1 mg). The mixture was then purged with hydrogen three times, and the reaction was stirred at 25 °C for 8 hours. After the reaction was complete, Pd / C was removed by filtration, and the filtrate was concentrated, dried, and then lyophilized to give a grayish-white solid, compound 31 (3.2 mg, yield: 82.1%).

[0422] 1 H NMR(400MHz,D2O)δ8.37(dd,J=4.8,1.3Hz,1H),8.11(s,1H),7.96-7.90(m,1H),7.29(dd,J=8.4,4.8Hz,1H),5.28(d, J=9.4Hz,1H),4.20-3.94(m,2H),3.92-3.72(m,2H),3.48-3.34(m,2H),2.15(d,J=9.7Hz,1H); LCMS(m / z):499.1[M+1] + .

[0423] Example 32: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((methanesulfonyl)carbamoyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 32)

[0424] Step 1: Synthesis of compound 32-2

[0425] Compound B1 (80 mg, 0.122 mmol), methanesulfonamide (14 mg, 0.147 mmol), DMAP (7.5 mg, 0.061 mmol), HATU (56 mg, 0.147 mmol), and triethylamine (37 mg, 0.366 mmol) were dissolved in DMF (3 mL) and reacted with stirring at 50 °C for 16 hours. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography to give a yellow solid compound 32-2 (110 mg, impure, containing some condensing agent). LCMS (m / z): 733.2 [M+1] + .

[0426] Step 2: Synthesis of Compound 32

[0427] Compound 32-1 (110 mg crude) was dissolved in a mixed solution of trifluoroacetic acid (4 mL) and water (5 mL), and the reaction was stirred at 60 °C for 18 hours. HPLC monitoring was maintained until the reaction was complete. The reaction solution was cooled to room temperature and concentrated and dried. The crude product was purified by reversed-phase column chromatography and then lyophilized to give a white solid compound 32 (16 mg, two-step yield: 24.1%).

[0428] 1 H NMR(400MHz,MeOD)δ7.43-7.31(m,5H),5.65(s,1H),5.23(s,2H),4.72-4.65(m,1H),4.5 2-4.44(m,2H),4.28(s,1H),3.06(s,3H),2.31(d,J=9.2Hz,1H); LCMS(m / z):545.1[M+1] + .

[0429] Example 33: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-imino-N-(methanesulfonyl)decahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-carboxamide (compound 33)

[0430] Compound 32 (12 mg, 0.022 mmol) was dissolved in methanol (4 mL), and 10% Pd / C (3 mg) was added. Hydrogen gas was purged three times, and the reaction was stirred at room temperature for 3 hours. HPLC monitoring was performed until the reaction was complete. The mixture was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and then lyophilized to give a white solid, compound 33 (7 mg, yield: 77%).

[0431] 1 H NMR(400MHz,D2O)δ5.49(d,J=9.8Hz,1H),4.61-4.37(m,2H),4.22(s,1H),3.93(s,1H),3.08(s,3H),2.26(s,1H); LCMS(m / z):411.1[M+1] + .

[0432] Example 34: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-imino-N-(benzenesulfonyl)decahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-carboxamide (compound 34)

[0433] Step 1: Synthesis of Compound 34-1

[0434] Compound B1 (100 mg, 0.153 mmol), phenylsulfonamide (29 mg, 0.184 mmol), DMAP (9.3 mg, 0.0765 mmol), HATU (70 mg, 0.184 mmol), and triethylamine (46 mg, 0.459 mmol) were dissolved in DMF (4 mL) and reacted at 55 °C with stirring for 5 hours. HPLC monitoring continued until the reaction was complete. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography to give a yellow solid compound 34-1 (65 mg, impure, containing some condensing agent). LCMS (m / z): 795.2 [M+1] + .

[0435] Step 2: Synthesis of compound 34-2

[0436] Compound 34-1 (65 mg crude) was dissolved in a mixed solution of trifluoroacetic acid (3 mL) and water (4 mL), and the reaction was stirred at 60 °C for 18 hours. HPLC monitoring continued until the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and dried. The crude product was purified by Prep-HPLC and lyophilized to give compound 34-2 (1.15 mg, yield: 1.2%) as a white solid. LCMS (m / z): 607.1 [M+1] + .

[0437] Step 3: Synthesis of Compound 34

[0438] Compound 34-2 (1.15 mg, 0.0019 mmol) was dissolved in methanol (1 mL), and 10% Pd / C (1 mg) was added. Hydrogen gas was purged three times, and the reaction was stirred at room temperature for 3 hours. HPLC monitoring was performed until the reaction was complete. The mixture was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and then lyophilized to give a white solid, compound 34 (0.84 mg, yield: 93%).

[0439] 1 H NMR (400 MHz, D2O) δ7.88 (d, J=7.6 Hz,2H),7.71-7.46(m,3H),5.48(s,1H),3.97-3.88(m,1H),3.60-3.40(m,2H),3.12(s,1H),2.24-2.17(m,1H); LCMS(m / z):473.1[M+1] + .

[0440] Example 35: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((3-tert-butylphenyl)sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 35)

[0441] Step 1: Synthesis of Compound 35-1

[0442] Compound B3 (80 mg, 0.125 mmol) and dichloromethane (5 mL) were added to a reaction flask, followed by pyridine (36.8 mg, 0.465 mmol), and then 3-tert-butylbenzenesulfonyl chloride (31.7 mg, 0.136 mmol). The reaction was stirred for 3 hours under nitrogen protection and at approximately 25°C. HPLC monitoring was maintained until the reaction was complete. Water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and dried. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a grayish-white solid compound 35-1 (91 mg, yield: 87%). LCMS (m / z): 837.3 [M+1] + .

[0443] Step 2: Synthesis of Compound 35

[0444] Compound 35-1 (91.0 mg, 0.11 mmol) was dissolved in a mixed solution of water (2 mL) and trifluoroacetic acid (3 mL), and the reaction was stirred at 60 °C for 16 hours under nitrogen protection. HPLC monitoring was maintained until the reaction was complete. The reaction solution was concentrated and dried, and the crude product was purified by reversed-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5-8%) to give a white solid compound 35 (21.2 mg, yield: 30%).

[0445] 1 H NMR (400 MHz, MeOD) δ7.94 (s, 1H), 7.71 (t, J = 6.7 Hz, 2H), 7.51 (t, J = 7.8 Hz,1H),7.40-7.23(m,5H),5.56-5.48(m,1H),5.05(s,2H),4.23-4.07(m,2H),4.00(d,J=19.0H z,2H),3.42(d,J=4.5Hz,2H),2.24-2.18(m,1H),1.37(d,J=3.6Hz,9H); LCMS(m / z):649.2[M+1] + .

[0446] Example 36: Synthesis of 3-(tert-butyl)-N-[(4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl]benzenesulfonamide (compound 36)

[0447] Compound 35 (10 mg, 0.015 mmol) and methanol (4 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (1 mg). Hydrogen gas was purged three times, and the mixture was stirred at 25 °C for 8 hours. HPLC monitoring was maintained until the reaction was complete. Pd / C was removed by filtration, and the filtrate was concentrated, dried, and then lyophilized to give a grayish-white solid, compound 36 (5.2 mg, yield: 65.6%). LCMS (m / z): 515.2 [M+1] + .

[0448] Example 37: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((2,3,4-trifluorophenyl)sulfonylamino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 37)

[0449] Step 1: Synthesis of Compound 37-1

[0450] Compound B3 (80 mg, 0.125 mmol) and dichloromethane (5 mL) were added to a reaction flask and stirred at room temperature for 10 minutes. Pyridine (19.75 mg, 0.25 mmol) was added, followed by dropwise addition of 2,3,4-trifluorobenzenesulfonyl chloride (31.9 mg, 0.138 mmol). The reaction was stirred at room temperature for 30 minutes. HPLC monitoring was maintained until the reaction was complete. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The residue was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 0-35%) to give compound 37-1 (100 mg, yield: 96%). LCMS (m / z): 835.2 [M+1] + .

[0451] Step 2: Synthesis of Compound 37

[0452] Compound 37-1 (100 mg, 0.12 mmol) was dissolved in a mixed solution of water (10 mL) and trifluoroacetic acid (5 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 20 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was concentrated and dried, and the residue was purified by rapid column chromatography (methanol / dichloromethane = 0-5%) to give compound 37 (30 mg, yield: 38.7%).

[0453] 1H NMR(400MHz,MeOD)δ7.74(dd,J=13.1,6.6Hz,1H),7.41-7.23(m,6H),5.52(d,J=9.1Hz,1H),5.0 6(s,2H),4.11(s,2H),3.87(s,2H),3.59(s,2H),2.18(d,J=9.7Hz,1H); LCMS(m / z):647.1[M+1] + .

[0454] Example 38: Synthesis of 2,3,4-trifluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 38)

[0455] Compound 37 (25 mg, 0.039 mmol) and methanol (10 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (25 mg). Hydrogen gas was then introduced to displace the reaction mixture, and the reaction was continued for approximately 3 hours. HPLC monitoring was maintained until the reaction was complete. The reaction mixture was filtered through a funnel lined with diatomaceous earth and washed with 0.05 Maq. AcOH. The filtrate was concentrated and dried. The crude compound was slurried with 10 mL of diethyl ether, filtered, and the filter cake was concentrated to remove the solvent, yielding compound 38 (10 mg, yield: 50.5%).

[0456] 1 H NMR (400MHz, MeOD) δ7.74(dd,J=13.0,6.4Hz,1H),7.31(dd,J=12.5,5.5Hz,1H),5.50(d,J=9.4Hz,1H),4.17 -4.06(m,2H),3.97(d,J=18.4Hz,2H),3.58(d,J=8.6Hz,2H),2.20(d,J=9.4Hz,1H); LCMS(m / z):513.1[M+1] + .

[0457] Example 39: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((2,4,6-trifluorophenyl)sulfonylamino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 39)

[0458] Step 1: Synthesis of Compound 39-1

[0459] Compound B3 (80 mg, 0.125 mmol) and DMAP (7.6 mg, 0.0625 mmol) were dissolved in dichloromethane (4 mL), and pyridine (30 mg, 0.375 mmol) was added. Under ice bath conditions, 2,4,6-trifluorobenzenesulfonyl chloride (34.5 mg, 0.15 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. HPLC monitoring was maintained until the reaction was complete. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 2), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by wet column chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to give compound 39-1 (82 mg, yield: 79%). LCMS (m / z): 835.2 [M+1] + .

[0460] Step 2: Synthesis of Compound 39

[0461] Compound 39-1 (82 mg, 0.098 mmol) was dissolved in a mixed solution of water (8 mL) and trifluoroacetic acid (6 mL), and the reaction was stirred at 60 °C for 16 hours. HPLC monitoring was maintained until the reaction was complete. The reaction system was concentrated and dried, and the crude product was purified by flash column chromatography and then lyophilized to give a white solid compound 39 (34 mg, yield: 53.5%).

[0462] 1 H NMR (400MHz, MeOD) δ7.39-7.24(m,5H),7.06(t,J=9.1Hz,2H),5.53(d,J=9.3Hz,1H),5.06 (s,2H),4.11(s,2H),3.89(s,2H),3.68(s,2H),2.22-2.15(m,1H); LCMS(m / z):647.1[M+1] + .

[0463] Example 40: Synthesis of 2,4,6-trifluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 40)

[0464] Compound 39 (30 mg, 0.0464 mmol) was dissolved in methanol (5 mL), and palladium hydroxide / carbon (5 mg) was added. Hydrogen gas was purged three times, and the mixture was stirred for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and dried to give a white solid compound 40 (22 mg, yield: 92.5%).

[0465] 1 H NMR(400MHz,MeOD)δ7.16-6.99(m,2H),5.51(d,J=9.3Hz,1H),4.13(d,J=11.5Hz ,2H),3.97(s,2H),3.72-3.58(m,2H),2.24-2.18(m,1H); LCMS(m / z):513.1[M+1] + .

[0466] Example 41: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((2,4-difluorophenyl)sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 41)

[0467] Step 1: Synthesis of Compound 41-1

[0468] Compound B3 (80 mg, 0.125 mmol) and dichloromethane (5 mL) were added to a reaction flask and stirred at room temperature for 10 min. Pyridine (19.75 mg, 0.25 mmol) was added, followed by dropwise addition of 2,4-difluorobenzenesulfonyl chloride (31.9 mg, 0.15 mmol). The mixture was stirred at room temperature for 30 min. HPLC monitoring was maintained until the reaction was complete. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The residue (100 mg) was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 0-35%) to give compound 41-1 (83 mg, yield: 81.4%). LCMS (m / z): 817.2 [M+1] + .

[0469] Step 2: Synthesis of Compound 41

[0470] Compound 41-1 (81.6 mg, 0.10 mmol) was dissolved in a mixed solution of water (10 mL) and trifluoroacetic acid (5 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 20 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was concentrated and dried, and the residue was subjected to rapid column chromatography (methanol / dichloromethane = 0-5%) to give compound 41 (20 mg, yield: 31.8%).

[0471] 1 H NMR (400MHz, MeOD) δ8.04-7.91(m,1H),7.42-7.25(m,5H),7.21(t,J=10.8Hz,1H),7.14(t,J=8.8Hz,1H),5.55(d, J=9.0Hz,1H),5.09(s,2H),4.13(s,2H),3.89(s,2H),3.57(s,2H),2.22(d,J=9.6Hz,1H); LCMS(m / z):629.1[M+1] + .

[0472] Example 42: Synthesis of 2,4-difluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 42)

[0473] Compound 41 (18 mg, 0.0286 mmol) and methanol (10 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (20 mg, 0.010 mmol). Hydrogen gas was then introduced to displace the reaction mixture, and the reaction proceeded for approximately 3 hours. HPLC monitoring was maintained until the reaction proceeded completely. The reaction mixture was filtered through a funnel lined with diatomaceous earth and washed with 0.05 M acetic acid aqueous solution. The filtrate was concentrated and dried. The crude compound was stirred and slurried with methyl tert-butyl ether (10 mL), filtered, and the filter cake was collected and dried to give compound 42 (11 mg, yield: 77.7%).

[0474] 1 H NMR (400MHz, MeOD) δ8.09-7.85(m,1H),7.25-7.19(m,1H),7.15(t,J=8.4Hz,1H),5.50(d,J=9.4Hz,1H),4 .20-4.08(m,2H),4.06-3.90(m,2H),3.54(d,J=6.3Hz,2H),2.22(d,J=9.4Hz,1H); LCMS(m / z):495.1[M+1]+ .

[0475] Example 43: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((2,5-difluorophenyl)sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 43)

[0476] Step 1: Synthesis of Compound 43-1

[0477] Compound B3 (80 mg, 0.125 mmol) and dichloromethane (5 mL) were added to a reaction flask and stirred at room temperature for 10 minutes. Pyridine (19.75 mg, 0.25 mmol) was then added, followed by dropwise addition of 2,5-difluorobenzenesulfonyl chloride (31.9 mg, 0.15 mmol). The mixture was stirred at room temperature for 30 minutes. HPLC monitoring was maintained until the reaction was complete. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The residue was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 0-35%) to give compound 43-1 (70 mg, yield: 68.6%). LCMS (m / z): 817.2 [M+1] + .

[0478] Step 2: Synthesis of Compound 43

[0479] Compound 43-1 (70 mg, 0.086 mmol) was dissolved in a mixed solution of water (10 mL) and trifluoroacetic acid (5 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 20 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was concentrated and dried, and the residue was purified by rapid column chromatography (eluent: methanol / dichloromethane = 0-5%) to give a white solid, compound 43 (18.6 mg, yield: 34.5%).

[0480] 1H NMR(400MHz,MeOD)δ7.67-7.60(m,1H),7.47-7.20(m,7H),5.53(d,J=9.4Hz,1H),5.06(s,2H), 4.12(s,2H),3.89(s,2H),3.58(d,J=9.3Hz,2H),2.19(d,J=9.6Hz,1H); LCMS(m / z):629.1[M+1] + .

[0481] Example 44: Synthesis of 2,5-difluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 44)

[0482] Compound 43 (18 mg, 0.029 mmol) and methanol (10 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (18 mg). Hydrogen gas was then introduced to displace the reaction mixture, and the reaction proceeded under hydrogen purging for approximately 3 hours. HPLC monitoring was maintained until the reaction was complete. The reaction mixture was filtered through a funnel lined with diatomaceous earth and washed with 0.05 Maq. AcOH. The filtrate was concentrated and dried. The crude compound was slurried with methyl tert-butyl ether (10 mL), filtered, and the filtrate was concentrated to remove the solvent. The filtrate was then lyophilized to give compound 44 (10 mg, yield: 70.6%) as a white solid.

[0483] 1 H NMR (400MHz, MeOD) δ7.68-7.62(m,1H),7.47-7.38(m,2H),5.52(d,J=9.4Hz,1H),4.15(d,J=3 .7Hz,2H),3.92(d,J=6.9Hz,2H),3.62(s,2H),2.22(d,J=9.5Hz,1H); LCMS(m / z):495.1[M+1] + .

[0484] Example 45: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((3,5-difluorophenyl)sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 45)

[0485] Step 1: Synthesis of Compound 45-1

[0486] Compound B3 (80 mg, 0.125 mmol) and dichloromethane (5 mL) were added to a reaction flask, followed by pyridine (36.8 mg, 0.46 mmol), and then 3,5-difluorobenzenesulfonyl chloride (29.0 mg, 0.137 mmol) was added dropwise. The reaction was stirred for 3 hours under nitrogen protection and at 25 °C. HPLC monitoring was maintained until the reaction was complete. Water (5 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 5-30%) to give a grayish-white solid compound 45-1 (86 mg, yield: 84.3%). LCMS (m / z): 817.2 [M+1] + .

[0487] Step 2: Synthesis of Compound 45

[0488] Compound 45-1 (85.0 mg, 0.104 mmol) was dissolved in a mixed solution of water (2 mL) and trifluoroacetic acid (3 mL), and the reaction was stirred at 60 °C for 16 hours under nitrogen protection. HPLC monitoring was maintained until the reaction was complete. The reaction solution was concentrated and dried, and the crude product was purified by reversed-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5-8%) to give a white solid compound 45 (18.2 mg, yield: 27.8%).

[0489] 1 H NMR (400MHz, MeOD) δ7.53(d,J=4.6Hz,2H),7.43-7.23(m,6H),5.54(d,J=9.2Hz,1H),5.07(d,J=3.7Hz ,2H),4.11(s,2H),3.91(s,J=17.1Hz,2H),3.52(s,2H),2.21(d,J=9.8Hz,1H); LCMS(m / z):629.1[M+1] + .

[0490] Example 46: Synthesis of 3,5-difluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 46)

[0491] Compound 45 (10 mg, 0.016 mmol) and methanol (4 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (1 mg). The mixture was purged with hydrogen three times, and the reaction was stirred at 25 °C for 8 hours. HPLC monitoring was performed until the reaction was complete. Pd / C was removed by filtration, and the filtrate was concentrated, dried, and then lyophilized to give a grayish-white solid, compound 46 (6.4 mg, yield: 81.3%).

[0492] HNMR LCMS (m / z): 495.1 [M+1] + .

[0493] Example 47: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((2,6-difluorophenyl)sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 47)

[0494] Step 1: Synthesis of Compound 47-1

[0495] Compound B3 (70 mg, 0.109 mmol), pyridine (26 mg, 0.327 mmol), and DMAP (7 mg, 0.0545 mmol) were dissolved in dichloromethane (6 mL). 2,6-Difluorobenzenesulfonyl chloride (28 mg, 0.13 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 1.5 hours. HPLC monitoring continued until the reaction was complete. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic fractions were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by wet rapid column chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to give compound 47-1 (80 mg, yield: 90%). LCMS (m / z): 817.2 [M+1] + .

[0496] Step 2: Synthesis of Compound 47

[0497] Compound 47-1 (80 mg, 0.098 mmol) was dissolved in a mixed solution of trifluoroacetic acid (3 mL) and water (4 mL), and the reaction was stirred at 60 °C for 18 hours. HPLC monitoring was maintained until the reaction was complete. The reaction solution was cooled to room temperature and concentrated and dried. The crude product was purified by rapid column chromatography and then lyophilized to give compound 47-1 (20 mg, yield: 33%) as a white solid.

[0498] 1 H NMR (400MHz, MeOD) δ7.72-7.58(m,1H),7.41-7.22(m,5H),7.22(s,2H),5.53(d,J=9.3Hz,1H),5. 06(s,2H),4.14(s,2H),3.90(s,2H),3.67(s,2H),2.20(d,J=8.7Hz,1H); LCMS(m / z):629.1[M+1] + .

[0499] Example 48: Synthesis of 2,6-difluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 48)

[0500] Compound 47 (20 mg, 0.0318 mmol) was dissolved in methanol (8 mL), and Pd(OH)₂ / C (5 mg) was added. Hydrogen gas was purged three times, and the reaction was stirred at room temperature for 3 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and then lyophilized to give a white solid, compound 48 (14 mg, yield: 89%).

[0501] 1 H NMR (400MHz, MeOD) δ7.64(s,1H),7.16(t,J=8.9Hz,2H),5.51(d,J=9.0Hz,1H),4.15( d,J=6.6Hz,2H),3.98(s,2H),3.64(s,2H),2.21-2.18(m,1H); LCMS(m / z):495.1[M+1] + .

[0502] Example 49: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((4-cyclopropylphenyl)sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 49)

[0503] Step 1: Synthesis of Compound 49-2

[0504] Compound 49-1 (200 mg, 1.015 mmol), benzyl mercaptan (151 mg, 1.218 mmol), Pd2(dba)3 (46 mg, 0.051 mmol), Xantphos (59 mg, 0.102 mmol), and diisopropylethylamine (399 mg, 3.045 mmol) were dissolved in dioxane (10 mL). The mixture was purged with nitrogen and stirred at 100 °C for 5 hours under nitrogen protection. The mixture was then cooled to room temperature, and water (30 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography to give a pale yellow solid compound 49-2 (210 mg, yield: 86%).

[0505] Step 2: Synthesis of Compound 49-3

[0506] Compound 49-2 (50 mg, 0.207 mmol) was dissolved in a mixture of HOAc (1 mL) and water (1 mL). NCS (83 mg, 0.621 mmol) was added in portions under ice bath conditions. After the addition was complete, the reaction mixture was stirred under ice bath conditions for 2 hours. Water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by Prep-TLC to give compound 49-3 (32 mg, 71% yield).

[0507] 1 H NMR (400MHz, CDCl3) δ7.90 (d, J = 8.6 Hz, 2H), 7.24 (dd, J = 14.0, 5.5 Hz, 2H), 2.06-1.96 (m, 1H), 1.21-1.12 (m, 2H), 0.89-0.81 (m, 2H).

[0508] Step 3: Synthesis of compound 49-4

[0509] Compound B3 (22 mg, 0.034 mmol), pyridine (8 mg, 0.102 mmol), and DMAP (2.1 mg, 0.017 mmol) were dissolved in dichloromethane (2 mL). Compound 49-3 (11 mg, 0.051 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic fractions were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 0-55%) to give compound 49-4 (25 mg, yield: 89%). LCMS (m / z): 821.3 [M+1] + .

[0510] Step 4: Synthesis of Compound 49

[0511] Compound 49-4 (80 mg, 0.0975 mmol) was dissolved in a mixed solution of trifluoroacetic acid (6 mL) and water (8 mL), and stirred at 60 °C for 18 hours. HPLC monitoring was maintained until the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and dried. The crude product was purified by rapid column chromatography and then lyophilized to give compound 49 (10 mg, yield: 16.2%) as a white solid.

[0512] 1 H NMR(400MHz,MeOD)δ7.76(d,J=8.4Hz,2H),7.40-7.21(m,7H),5.53(d,J=9.4Hz,1H),5.06(s,2H),4.13(s,2H),3.89(s,2H),3.45 (d,J=21.4Hz,2H),2.20(dd,J=8.3,4.6Hz,1H),2.05-1.97(m,1H),1.14-1.02(m,2H),0.84-0.73(m,2H); LCMS(m / z):633.2[M+1] + .

[0513] Example 50: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-4-propylbenzenesulfonamide (compound 50)

[0514] Compound 49 (10 mg, 0.0158 mmol) was dissolved in methanol (2 mL), and 10% Pd / C (2 mg) was added. Hydrogen gas was purged three times, and the reaction was stirred at room temperature for 3 hours. HPLC monitoring was performed until the reaction was complete. The mixture was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and then lyophilized to give compound 50 (7 mg, yield: 89%) as a white solid.

[0515] 1 H NMR (400MHz, MeOD) δ7.81(d,J=8.3Hz,2H),7.41(d,J=8.3Hz,2H),5.52(d,J=9.4Hz,1H),4.15(d,J=16.0Hz,2H),3.99(d,J=12.1H z,2H),3.43(s,2H),2.73-2.67(m,2H),2.23(d,J=13.4Hz,1H),1.72-1.66(m,2H),0.97(t,J=7.3Hz,3H); LCMS(m / z):501.2[M+1] + .

[0516] Example 51: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((4-chlorophenyl)sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 51)

[0517] Step 1: Synthesis of Compound 51-1

[0518] Compound B3 (70 mg, 0.109 mmol), pyridine (26 mg, 0.327 mmol), and DMAP (6.7 mg, 0.055 mmol) were dissolved in dichloromethane (8 mL). 4-Chlorobenzenesulfonyl chloride (35 mg, 0.164 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. HPLC monitoring continued until the reaction was complete. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic fractions were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to give compound 51-1 (95 mg, yield >100%, containing residual pyridine). LCMS (m / z): 815.2 [M+1] + .

[0519] Step 2: Synthesis of Compound 51

[0520] Compound 51-1 (95 mg, 0.109 mmol) was dissolved in a mixed solution of trifluoroacetic acid (4.5 mL) and water (6 mL), and the reaction was stirred at 60 °C for 18 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was cooled to room temperature, concentrated to dryness, and the crude product was purified by rapid column chromatography and then lyophilized to give compound 51 (22 mg, yield: 32.2%) as a white solid.

[0521] 1 H NMR (400MHz, MeOD) δ7.92-7.86(m,2H),7.60(d,J=8.7Hz,2H),7.33(m,5H),5.55(d,J=9.1Hz,1H),5.08(d,J=5.8H z,2H),4.12(s,2H),3.89(s,2H),3.53-3.44(m,2H),2.24-2.20(d,J=11.3Hz,1H); LCMS(m / z):627.1,629.1[M+1] + .

[0522] Example 52: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((3-cyclopropylphenyl)sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 52)

[0523] Step 1: Synthesis of Compound 52-1

[0524] Compound B3 (70 mg, 0.109 mmol), pyridine (26 mg, 0.327 mmol), and DMAP (6.7 mg, 0.055 mmol) were dissolved in dichloromethane (8 mL). 3-Cyclopropylbenzenesulfonyl chloride (35.5 mg, 0.164 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. HPLC monitoring continued until the reaction was complete. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to give compound 52-1 (84 mg, yield: 93%). LCMS (m / z): 821.3 [M+1] + .

[0525] Step 2: Synthesis of Compound 52

[0526] Compound 52-1 (84 mg, 0.102 mmol) was dissolved in a mixed solution of trifluoroacetic acid (4.5 mL) and water (6 mL), and the reaction was stirred at 60 °C for 18 hours. HPLC monitoring was maintained until the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and dried. The crude product was purified by rapid column chromatography and then lyophilized to give compound 52 (17 mg, 26% yield) as a white solid.

[0527] 1 H NMR(400MHz,MeOD)δ7.66(dd,J=7.8,1.1Hz,1H),7.60(d,J=1.7Hz,1H),7.4 4(t,J=7.8Hz,1H),7.39-7.27(m,6H),5.54(d,J=9.1Hz,1H),5.07(d,J=3.1H z,2H),4.13(s,2H),3.89(s,2H),3.53-3.38(m,2H),2.26-2.17(m,1H),2.06 -1.99(m,1H),1.08-1.02(m,2H),0.80-0.74(m,2H); LCMS(m / z):633.2[M+1] + .

[0528] Example 53: Synthesis of N-((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-3-propylbenzenesulfonamide (compound 53)

[0529] Compound 52 (12 mg, 0.019 mmol) was dissolved in methanol (3 mL), and 10% Pd / C (2 mg) was added to replace the hydrogen gas three times. The reaction was stirred at room temperature for 3 hours. HPLC monitoring was performed until the reaction was complete. The mixture was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and then lyophilized to give compound 53 (8 mg, yield: 84%) as a white solid.

[0530] 1H NMR (400MHz, MeOD) δ7.71(dd,J=6.5,3.9Hz,2H),7.55-7.40(m,2H),5.51(d,J=9.4Hz,1H),4.14(d,J=16.3Hz,2H),3.97(s,2H) ,3.41(t,J=8.0Hz,2H),2.74-2.66(m,2H),2.22(t,J=7.3Hz,1H),1.76-1.62(m,2H),1.02-0.93(m,3H); LCMS(m / z):501.2[M+1] + .

[0531] Example 54: Methyl 3-(N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-2-(((benzyloxy)carbonyl)imino)-4,6,9,10,11-pentahydroxydecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)sulfonylamino)benzoate (compound) Synthesis of Compound 54) and 3-(N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-2-(((benzyloxycarbonyl)imino)-4,6,9,10,11-pentahydroxydecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)sulfonamide)benzoic acid (compound 55)

[0532] Step 1: Synthesis of Compound 54-1

[0533] Compound B3 (85 mg, 0.133 mmol) and dichloromethane (5 mL) were added to a reaction flask and stirred at room temperature for 10 minutes. Pyridine (21 mg, 0.265 mmol) was then added, followed by dropwise addition of methyl 3-chlorosulfonylbenzoate (37.4 mg, 0.159 mmol). The reaction mixture was then stirred at room temperature for 30 minutes. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 0-35%) to give compound 54-1 (77 mg, yield: 69.2%). LCMS (m / z): 839.2 [M+1] + .

[0534] Step 2: Synthesis of Compounds 54 and 55

[0535] Compound 54-1 (77 mg, 0.092 mmol) was dissolved in a mixed solution of water (10 mL) and trifluoroacetic acid (10 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 20 hours. HPLC monitoring was maintained until the reactants were completely reacted. The reaction solution was concentrated and dried, and the residue was purified by Prep-HPLC to give a white solid compound 54 (12 mg, yield: 20.1%) and compound 55 (8.5 mg, yield: 14.6%), with an overall yield of 34.7%.

[0536] Compound 54:

[0537] 1 H NMR (400MHz, MeOD) δ8.52(t,J=1.6Hz,1H),8.26(d,J=7.9Hz,1H),8.20-8.09(m,1H),7.72(t,J=7.9Hz,1H),7.47-7.26(m,5H),5.61(d,J=9.1H z,1H),5.19(s,2H),4.15(d,J=21.6Hz,2H),3.96(s,3H),3.92(s,2H),3.56-3.43(m,2H),2.32(dd,J=16.6,8.3Hz,1H); LCMS(m / z):651.2[M+1] + .

[0538] Compound 55:

[0539] 1 H NMR (400MHz, MeOD) δ8.50(s,1H),8.24(d,J=7.7Hz,1H),8.08(d,J=8.3Hz,1H),7.67(t,J=7.8Hz,1H),7.46-7.31(m,5H),5.65( d,J=9.3Hz,1H),5.26(s,2H),4.24-4.10(m,2H),3.94(s,2H),3.52-3.44(m,2H),2.35(d,J=9.4Hz,1H); LCMS(m / z):637.1[M+1] + .

[0540] Example 55: Synthesis of methyl 3-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)sulfonamide)benzoate (compound 56)

[0541] Compound 54 (10 mg, 0.0154 mmol) was dissolved in methanol (3 mL), and 10% Pd / C (2 mg) was added. Hydrogen gas was purged three times, and the reaction was stirred at room temperature for 3 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and then lyophilized to give a white solid compound 56 (7 mg, yield: 88%).

[0542] 1 H NMR(400MHz,MeOD)δ8.51(dd,J=6.4,4.8Hz,1H),8.34-8.20(m,1H),8.08-8.19(m,1H),7.72(dd,J=9.7,5.9Hz,1H),5. 50(d,J=9.2Hz,1H),4.24-4.06(m,2H),3.96(s,5H),3.54-3.39(m,2H),2.23(d,J=9.4Hz,1H); LCMS(m / z):517.5[M+1] + .

[0543] Example 56: Synthesis of 3-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)sulfonamide)benzoic acid (compound 57)

[0544] Compound 55 (8 mg, 0.0126 mmol) was dissolved in methanol (3 mL), and 10% Pd / C (2 mg) was added. Hydrogen was purged three times, and the reaction was stirred at room temperature for 3 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and then lyophilized to give a white solid compound 57 (5 mg, yield: 79%).

[0545] 1 H NMR (400MHz, MeOD) δ8.39(s,1H),8.13(d,J=7.7Hz,1H),7.95(d,J=7.9Hz,1H),7.56(t,J=7.8Hz,1H),5.42(d,J=9.3Hz ,1H),4.05(dd,J=5.4,3.9Hz,2H),3.82(d,J=7.8Hz,2H),3.46-3.34(m,2H),2.18-2.07(m,1H); LCMS(m / z):503.1[M+1] + .

[0546] Example 57: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((3-ethoxyphenyl)sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-iminooxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 58)

[0547] Step 1: Synthesis of Compound 58-2

[0548] Compound 58-1 (800 mg, 4.0 mmol), benzyl mercaptan (595.2 mg, 4.8 mmol), Pd2(dba)3 (366.2 mg, 0.4 mmol), Xantphos (462.4 mg, 0.8 mmol), and diisopropylethylamine (1.03 g, 8.0 mmol) were added to 1,4-dioxane (8 mL), the mixture was purged with nitrogen, and the mixture was stirred at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 0-3%) to give a grayish-white solid compound 58-2 (900 mg, yield: 92.2%).

[0549] Step 2: Synthesis of Compound 58-3

[0550] Compound 58-2 (800 mg, 3.27 mmol) was dissolved in acetonitrile (6 mL), and water (3 mL) and glacial acetic acid (2 mL) were added. NCS (1.42 g, 9.8 mmol) was added in portions at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 0-5%) to give a colorless liquid compound 58-3 (380 mg, yield: 52.7%).

[0551] Step 3: Synthesis of compound 58-4

[0552] Compound B3 (80 mg, 0.125 mmol) was dissolved in a mixed solution of pyridine (36.8 mg, 0.46 mmol) and dichloromethane (5 mL), and then compound 58-3 (30.1 mg, 0.137 mmol) was added. The reaction was carried out under nitrogen protection and stirred at 25 °C for 3 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a grayish-white solid compound 58-4 (86 mg, yield: 82.7%). LCMS (m / z): 825.3 [M+1] + .

[0553] Step 4: Synthesis of Compound 58

[0554] Compound 58-4 (85.0 mg, 0.10 mmol) was dissolved in a mixed solution of trifluoroacetic acid (3 mL) and water (2 mL), and the reaction was stirred at 60 °C for 16 hours under nitrogen protection. HPLC monitoring was maintained until the reaction was complete. The reaction solution was concentrated and dried, and the crude product was purified by reversed-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5%-8%) to give a white solid compound 58 (20.1 mg, yield: 30.5%).

[0555] 1 H NMR(400MHz,MeOD)δ7.58(t,J=8.0Hz,1H),7.51(dd,J=6.7,1.6Hz,1H),7.48-7.33(m,6H),7.31-7.25(m,1H),5.50(d,J=9.4Hz,1H),5 .09(s,2H),4.32-4.09(m,4H),4.09-3.80(m,2H),3.58-3.40(m,2H),2.26(d,J=9.6Hz,1H),1.48-1.36(m,3H); LCMS(m / z):637.2[M+1] + .

[0556] Example 58: Synthesis of 3-ethoxy-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 59)

[0557] Compound 58 (10 mg, 0.016 mmol) and methanol (4 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (1 mg). Hydrogen gas was purged three times, and the mixture was stirred at 25 °C for 4 hours. HPLC monitoring was maintained until the reaction was complete. Pd / C was removed by filtration, and the filtrate was concentrated, dried, and then lyophilized to give a white solid, compound 59 (6.2 mg, yield: 79.4%).

[0558] LCMS(m / z): 503.2 [M+1] + .

[0559] Example 59: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((3-(methanesulfonyl)phenyl)sulfonamido)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 60)

[0560] Step 1: Synthesis of Compound 60-1

[0561] Compound B3 (80 mg, 0.125 mmol) was dissolved in a mixed solution of pyridine (36.8 mg, 0.46 mmol) and dichloromethane (5 mL). 3-(methanesulfonyl)benzenesulfonyl chloride (34.6 mg, 0.137 mmol) was added, and the mixture was stirred at 25 °C for 3 hours under nitrogen protection. HPLC monitoring was maintained until the reaction was complete. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a grayish-white solid compound 60-1 (92 mg, yield: 85.1%). LCMS (m / z): 859.2 [M+1] + .

[0562] Step 2: Synthesis of Compound 60

[0563] Compound 60-1 (92.0 mg, 0.11 mmol) was dissolved in a mixed solution of trifluoroacetic acid (3 mL) and water (2 mL), and the reaction was stirred at 60 °C for 16 hours under nitrogen protection. HPLC monitoring was maintained until the reaction was complete. The reaction solution was concentrated and dried, and the crude product was purified by reversed-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5%-8%) to give a white solid compound 60 (22.4 mg, yield: 31.2%).

[0564] 1 H NMR(400MHz,MeOD)δ8.45(t,J=1.6Hz,1H),8.27-8.13(m,2H),7.85(t,J=7.9Hz,1H),7.39-7.24(m,5H),5.48(d,J=9.4Hz,1H),5.06(s,2H),4.0 8(s,1H),3.99(s,1H),3.85(s,1H),3.76(s,1H),3.63-3.52(m,2H),3.2 0(d,J=2.1Hz,3H),2.17(dd,J=10.0,4.9Hz,1H); LCMS(m / z):671.1[M+1] + .

[0565] Example 60: Synthesis of 3-(methanesulfonyl)-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 61)

[0566] Compound 60 (10 mg, 0.015 mmol) and methanol (4 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (1 mg). Hydrogen gas was purged three times, and the mixture was stirred at 25 °C for 4 hours. HPLC monitoring was maintained until the reaction was complete. The reaction solution was filtered to remove Pd / C, and the filtrate was concentrated, dried, and then lyophilized to give a white solid, compound 61 (6.5 mg, yield: 81.2%).

[0567] 1 H NMR (400MHz, MeOD) δ8.47-8.41(m,1H),8.32-8.27(m,1H),8.27-8.24(m,1H),7.98-7.91(m,1H),5.48(d,J=9.4Hz,1H),4. 21-4.05(m,2H),4.01-3.83(m,2H),3.58-3.47(m,2H),3.31-3.29(m,3H),2.23(d,J=10.1Hz,1H); LCMS(m / z):537.1[M+1] + .

[0568] Example 61: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-isopropylphenyl)sulfonamido)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 62)

[0569] Step 1: Synthesis of Compound 62-1

[0570] Compound B3 (80 mg, 0.125 mmol) was dissolved in a mixed solution of pyridine (36.8 mg, 0.46 mmol) and dichloromethane (5 mL). 3-Isopropylbenzenesulfonyl chloride (29.8 mg, 0.137 mmol) was added, and the mixture was stirred at 25 °C for 3 hours under nitrogen protection. HPLC monitoring was maintained until the reaction was complete. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a grayish-white solid compound 62-1 (90 mg, yield: 87.3%). LCMS (m / z): 823.3 [M+1] + .

[0571] Step 2: Synthesis of Compound 62

[0572] Compound 62-1 (90 mg, 0.11 mmol) was dissolved in a mixed solution of trifluoroacetic acid (3 mL) and water (2 mL), and the reaction was stirred at 60 °C for 16 hours under nitrogen protection. HPLC monitoring was performed until the reaction was complete. The reaction solution was concentrated and dried, and the crude product was purified by reversed-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5%-8%) to give a white solid compound 62 (20 mg, yield: 28.2%).

[0573] 1 H NMR(400MHz,MeOD)δ7.78(s,1H),7.73-7.69(m,1H),7.56-7.47(m,2H),7.39-7.24(m,5H),5.53(d,J=9.4Hz,1H),5.06(s,2H),4.1 3(s,2H),3.89(s,2H),3.52-3.40(m,2H),3.07-2.97(m,1H),2.22(d,J=7.3Hz,1H),1.30(d,J=12.8Hz,6H); LCMS(m / z):635.2[M+1]+ .

[0574] Example 62: Synthesis of 3-isopropyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 63)

[0575] Compound 62 (10 mg, 0.016 mmol) and methanol (4 mL) were added to a reaction flask, followed by the addition of 10% Pd / C (1 mg). Hydrogen gas was purged three times, and the mixture was stirred at 25 °C for 4 hours. HPLC monitoring was maintained until the reaction was complete. The reaction solution was filtered to remove Pd / C, and the filtrate was concentrated, dried, and then lyophilized to give a white solid, compound 63 (5.2 mg, yield: 66.7%).

[0576] 1 H NMR(400MHz,MeOD)δ7.68(s,1H),7.63(d,J=7.0Hz,1H),7.48-7.40(m,2H),5.42(d,J=9.1Hz,1H),4.12-4.02(m,2H),3.95- 3.86(m,2H),3.36-3.30(m,2H),2.98-2.88(m,1H),2.12(dd,J=16.9,9.4Hz,1H),1.25-1.14(m,6H); LCMS(m / z):501.2[M+1] + .

[0577] Example 63: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(((3-ethylphenyl)sulfonylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 64)

[0578] Step 1: Synthesis of Compound 64-1

[0579] Compound B3 (80 mg, 0.125 mmol) was dissolved in a mixed solution of pyridine (36.8 mg, 0.46 mmol) and dichloromethane (5 mL), and 3-ethylbenzenesulfonyl chloride (27.9 mg, 0.137 mmol) was added. The mixture was stirred at 25 °C for 3 hours under nitrogen protection. HPLC monitoring was maintained until the reaction was complete. Water (5 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a grayish-white solid compound 64-1 (92 mg, yield: 90.2%). LCMS (m / z): 809.3 [M+1] + .

[0580] Step 2: Synthesis of Compound 64

[0581] Compound 64-1 (92 mg, 0.11 mmol) was dissolved in a mixed solution of trifluoroacetic acid (3 mL) and water (2 mL), and the reaction was stirred at 60 °C for 16 hours under nitrogen protection. HPLC monitoring was maintained until the reaction was complete. The reaction solution was concentrated and dried, and the crude product was purified by reversed-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5%-8%) to give a white solid compound 64 (20 mg, yield: 28.3%).

[0582] 1 H NMR(400MHz,MeOD)δ7.75(s,1H),7.73-7.69(m,1H),7.49(d,J=4.7Hz,2H),7.39-7.26(m,5H),5.54(d,J=9.1Hz,1H),5.06(s,2H),4.1 3(s,2H),3.89(s,2H),3.51-3.41(m,2H),2.75(q,J=7.6Hz,2H),2.22(d,J=8.3Hz,1H),1.28(t,J=7.6Hz,3H); LCMS(m / z):621.2[M+1] + .

[0583] Example 64: Synthesis of 3-ethyl-N-[(4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl]methyl]benzenesulfonamide (compound 65)

[0584] Compound 64 (10 mg, 0.016 mmol) was dissolved in methanol (4 mL), and 10% Pd / C (1 mg) was added. Hydrogen gas was purged three times, and the mixture was stirred at 25 °C for 4 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was filtered to remove Pd / C, and the filtrate was concentrated, dried, and then lyophilized to give a grayish-white solid, compound 65 (5.2 mg, yield: 66.2%).

[0585] 1 H NMR (400MHz, MeOD) δ7.78-7.66(m,2H),7.59-7.49(m,2H),5.52(d,J=9.4Hz,1H),4.22-4.10(m,2H),4.02-3.84 (m,2H),3.53-3.40(m,2H),2.82-2.72(m,2H),2.24(d,J=9.2Hz,1H),1.32-1.24(m,3H); LCMS(m / z):487.1[M+1] + .

[0586] Example 65: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((1H-indazole-3-sulfonamido)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 66)

[0587] Step 1: Synthesis of Compound 66-2

[0588] Compound 66-1 (1 g, 7.71 mmol) was dissolved in H₂O (6 mL) and concentrated hydrochloric acid (6 mL). The mixture was stirred at room temperature for 30 minutes until the solid was completely dissolved. The solution was then cooled to -5°C, and sodium nitrite (0.622 g, 9.0 mmol) was added dropwise, maintaining the temperature below 0°C throughout the process. After the addition was complete, the mixture was stirred for another 30 minutes to obtain the prepared solution. In another reaction flask, glacial acetic acid (15 mL) was added, and sulfur dioxide gas was continuously bubbled through the solution in an ice-water bath for approximately 30 minutes. Then, copper chloride (0.38 g, 2.253 mmol) was added, followed by the previously prepared solution, maintaining the temperature below 0°C. After the addition was complete, the mixture was stirred at 0°C for another 30 minutes, then naturally heated to 10°C and reacted for 1 hour. LC-MS monitoring was performed until the target product was formed. Add water (50 mL) to the reaction solution, extract with ethyl acetate (40 mL x 3), combine the organic phases and wash with water (50 mL x 2), then wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate and dry the filtrate, and purify the crude product by rapid column chromatography (ethyl acetate / petroleum ether = 0-30%) to give white compound 66-2 (500 mg, yield: 30.7%).

[0589] 1 H NMR (400MHz, CDCl3) δ11.70 (s, 1H), 8.15 (d, J = 8.3Hz, 1H), 7.78 (d, J = 8.6Hz, 1H), 7.67-7.58 (m, 1H), 7.54-7.46 (m, 1H); LCMS (m / z): 217.0, 219.0 [M+1] + .

[0590] Step 2: Synthesis of Compound 66-3

[0591] Compound B3 (100 mg, 0.16 mmol) was dissolved in dichloromethane (6 mL), and pyridine (57 mg, 0.72 mmol) was added. Compound 66-2 (40.5 mg, 0.19 mmol) was then added under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-40%) to give compound 66-3 (110 mg, yield: 85.9%). LCMS (m / z): 821.2 [M+1] + .

[0592] Step 3: Synthesis of Compound 66

[0593] Compound 66-3 (110 mg, 0.13 mmol) was dissolved in water (6 mL) and trifluoroacetic acid (4 mL), heated to 60 °C, and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 0-11.2%) to give a white solid compound 66 (26 mg, yield: 30.7%).

[0594] 1 H NMR (400MHz, MeOD) δ8.07(d,J=8.3Hz,1H),7.64(d,J=8.5Hz,1H),7.51(t,J=7.3Hz,1H),7.43-7.30(m,6H),5.63(d,J=9.4H z,1H),5.21(s,2H),4.19(d,J=12.0Hz,2H),4.01-3.88(m,2H),3.67(m,2H),2.34(d,J=9.4Hz,1H); LCMS(m / z):633.2[M+1] + .

[0595] Example 66: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indazole-3-sulfonamide (compound 67)

[0596] Compound 66 (20 mg, 0.032 mmol) was dissolved in methanol (5 mL), and 10% palladium on carbon (4 mg) was added. After purging with hydrogen three times, the mixture was stirred for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and dried. The crude product was purified by high performance liquid chromatography to obtain a white solid compound 67 (12 mg, yield: 76%).

[0597] 1 H NMR (400MHz, MeOD) δ8.10(d,J=8.3Hz,1H),7.67(d,J=8.5Hz,1H),7.53(t,J=7.7Hz,1H),7.42-7.31(m,1H),5.55(d,J=9. 4Hz,1H),4.25-4.09(m,2H),3.94(d,J=7.8Hz,2H),3.71(d,J=13.0Hz,2H),2.27(d,J=9.3Hz,1H); LCMS(m / z):499.3[M+1] + .

[0598] Example 67: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(2,4,5-trifluorophenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 68)

[0599] Step 1: Synthesis of Compound 68-1

[0600] Compound B3 (80 mg, 0.125 mmol) was dissolved in dichloromethane (5 mL), pyridine (36.8 mg, 0.47 mmol) was added, followed by compound 68-1 (30.1 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a white solid compound 68-2 (86 mg, yield: 82.5%). LCMS (m / z): 835.5 [M+1] + .

[0601] Step 2: Synthesis of Compound 68

[0602] Compound 68-2 (85 mg, 0.10 mmol) was dissolved in a mixed solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and at 60 °C with stirring for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 5%-8%) to give a white solid compound 68 (20.1 mg, yield: 30.4%).

[0603] 1 H NMR(400MHz,MeOD)δ7.85(dd,J=15.7,9.1Hz,1H),7.53-7.29(m,6H),5.65(d,J=9.4Hz,1H),5.28(s,2H),4.2 1-4.09(m,2H),3.95-3.85(d,J=9.8Hz,2H),3.65-3.59(m,2H),2.33(d,J=9.4Hz,1H); LCMS(m / z):647.3[M+1] + .

[0604] Example 68: Synthesis of 2,4,5-trifluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 69)

[0605] Compound 68 (10 mg, 0.015 mmol) dissolved in methanol (4 mL) was added to a reaction flask, followed by the addition of 10% Pd / C (1 mg) to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and then lyophilized to give a white solid compound 69 (6.2 mg, yield: 78.2%).

[0606] 1 H NMR(400MHz,MeOD)δ7.85(dd,J=15.9,8.9Hz,1H),7.89-7.81(m,1H),5.51(d,J=9.4Hz,2H),4.15- 4.07(m,2H),3.91-3.85(m,2H),3.64-3.57(m,2H),2.20(d,J=5.1Hz,1H); LCMS(m / z):513.2[M+1] + .

[0607] Example 69: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(2,3-difluorophenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 70)

[0608] Step 1: Synthesis of Compound 70-2

[0609] Compound B3 (80 mg, 0.125 mmol) was dissolved in dichloromethane (5 mL), pyridine (36.8 mg, 0.47 mmol) was added, followed by compound 70-1 (30.1 mg, 0.14 mmol). The mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 70-2 (82 mg, yield: 80.4%). LCMS (m / z): 817.3 [M+1]+ .

[0610] Step 2: Synthesis of Compound 70

[0611] Compound 70-2 (80 mg, 0.098 mmol) was dissolved in a mixed solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 5%-8%) to give a white solid compound 70 (15 mg, yield: 24.4%).

[0612] 1 H NMR(400MHz,MeOD)δ7.69(dd,J=7.8,6.1Hz,1H),7.57(dd,J=16.0,8.3Hz,1H),7.40-7.25(m,6H),5.54(d,J =9.4Hz,1H),5.08(s,2H),4.12(s,2H),3.89(s,2H),3.59(s,2H),2.24-2.19(m,1H); LCMS(m / z):629.3[M+1] + .

[0613] Example 70: Synthesis of 2,3-difluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 71)

[0614] Compound 70 (10 mg, 0.016 mmol) was dissolved in methanol (4 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the reaction solution was filtered to remove Pd / C, the filtrate was concentrated and dried, and then lyophilized to give a grayish-white solid compound 71 (5.8 mg, yield: 73.7%).

[0615] 1 H NMR(400MHz,MeOD)δ7.70(dd,J=7.7,6.1Hz,1H),7.58(dd,J=16.5,8.1Hz,1H),7.39-7.31(m,1H),5.52( d,J=9.3Hz,1H),4.14(s,2H),3.91(s,2H),3.66-3.55(m,2H),2.24-2.17(m,1H); LCMS(m / z):495.2[M+1]+ .

[0616] Example 71: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(3-isopropoxyphenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 72)

[0617] Step 1: Synthesis of Compound 72-2

[0618] Compound B3 (80 mg, 0.125 mmol) was dissolved in dichloromethane (5 mL), pyridine (36.8 mg, 0.47 mmol) was added, followed by compound 72-1 (32.1 mg, 0.137 mmol). The mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 72-2 (90 mg, yield: 85.9%). LCMS (m / z): 838.5 [M+1] + .

[0619] Step 2: Synthesis of Compound 72

[0620] Compound 72-2 (85 mg, 0.101 mmol) was dissolved in a mixed solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 5%-8%) to give compound 72 (18.2 mg, yield: 27.6%) as a white solid.

[0621] 1 H NMR(400MHz,MeOD)δ7.49-7.41(m,2H),7.40-7.26(m,6H),7.17-7.13(m,1H),5.53(d,J=9.3Hz,1H),5.05(s,2H),4.73-4.6 5(m,1H),4.13(s,2H),3.89(s,2H),3.52-3.41(m,2H),2.21(d,J=9.7Hz,1H),1.34(d,J=6.1Hz,6H); LCMS(m / z):651.3[M+1] + .

[0622] Example 72: Synthesis of 3-isopropoxy-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 73)

[0623] Compound 72 (10 mg, 0.015 mmol) was dissolved in methanol (4 mL) and added to a reaction flask. 10% Pd / C (1 mg) was added to replace the hydrogen gas, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, Pd / C was removed by filtration, the filtrate was concentrated and dried, and then lyophilized to give a grayish-white solid compound 73 (6.2 mg, yield: 78.1%).

[0624] 1 H NMR (400MHz, CDCl3) δ7.53(t,J=8.0Hz,1H),7.45(d,J=7.9Hz,1H),7.40-7.35(m,1H),7.20(dd,J=8.2,1.7Hz,1H),5.49(d,J=9.5Hz,1H),4.75-4 .63(m,1H),4.19(d,J=11.3Hz,1H),4.13(s,1H),3.99(s,2H),3.43(s,2 H),2.25(d,J=9.5Hz,1H),1.34(d,J=6.0Hz,6H); LCMS(m / z):517.3[M+1] + .

[0625] Example 73 Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(3-fluoro-5-methoxyphenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 74)

[0626] Step 1: Synthesis of Compound 74-2

[0627] Compound 74-1 (800 mg, 3.9 mmol) was dissolved in a mixed solution of diisopropylethylamine (1.03 g, 8.0 mmol) and 1,4-dioxane (10 mL). Benzyl mercaptan (595.2 mg, 4.8 mmol), Pd2(dba)3 (366.2 mg, 0.4 mmol), and Xantphos (462.4 mg, 0.8 mmol) were added. The mixture was stirred at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 74-2 (900 mg, yield: 92.9%).

[0628] Step 2: Synthesis of Compound 74-3

[0629] Compound 74-2 (800 mg, 3.22 mmol) was dissolved in a mixed solution of acetonitrile (6 mL), water (3 mL), and acetic acid (2 mL). The solution was cooled to 0 °C, and NCS (1.42 g, 10.63 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a colorless liquid compound 74-3 (240 mg, yield: 33.0%).

[0630] Step 3: Synthesis of compound 74-4

[0631] Compound B3 (80 mg, 0.125 mmol) was dissolved in a mixed solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL), and then compound 74-3 (30.6 mg, 0.136 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 74-4 (90 mg, yield: 87.0%). LCMS (m / z): 829.2 [M+1] + .

[0632] Step 4: Synthesis of Compound 74

[0633] Compound 74-4 (85 mg, 0.103 mmol) was dissolved in a mixed solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and at 60 °C with stirring for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 5%-8%) to give a white solid compound 74 (21.2 mg, yield: 32.3%).

[0634] 1 H NMR(400MHz,MeOD)δ7.39-7.25(m,6H),7.24-7.20(m,1H),7.02-6.93(m,1H),5.53(d,J=9.0Hz,1H), 5.05(s,2H),4.18-4.06(s,2H),3.88(s,5H),3.48(s,2H),2.23-2.18(m,1H); LCMS(m / z):641.3[M+1] + .

[0635] Example 74: Synthesis of 3-fluoro-5-methoxy-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 75)

[0636] Compound 74 (10 mg, 0.016 mmol) was dissolved in methanol (4 mL), 10% Pd / C (1 mg) was added, and the mixture was purged with hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, Pd / C was removed by filtration, the filtrate was concentrated and dried, and then lyophilized to give a grayish-white solid compound 75 (5.2 mg, yield: 65.7%).

[0637] 1 H NMR(400MHz,MeOD)δ7.28(s,1H),7.24-7.20(m,1H),7.02-6.92(m,1H),5.52(d,J=9.5Hz,1H),4.14(d ,J=8.3Hz,2H),3.97-3.84(m,5H),3.53-3.44(m,2H),2.23(d,J=10.4Hz,1H); LCMS(m / z):507.2[M+1] + .

[0638] Example 75: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(2-tert-butylphenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxy-octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 76)

[0639] Step 1: Synthesis of Compound 76-2

[0640] Compound 76-1 (1.5 g, 10.05 mmol) was slowly added to a solution of water (10 mL) and concentrated sulfuric acid (3.15 g, 32.16 mmol). A large amount of white solid precipitated, and the reaction was continued with stirring for 30 minutes. The reaction system was cooled to -5 °C, and a sodium nitrite (0.87 g, 12.57 mmol) / water (2 mL) solution was added dropwise. After the addition was complete, the reaction was continued for 20 minutes to prepare a diazonium solution. In another reaction flask, potassium iodide (5.11 g, 30.75 mmol) and water (6 mL) were added, and the reaction system was cooled to 0 °C. The above diazonium solution was added dropwise. After the addition was complete, the reaction system was maintained at 0-10 °C and the reaction was continued for 2 hours. Then, water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (25 mL x 2). The organic phases were combined. The mixture was then washed successively with sodium sulfite aqueous solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (petroleum ether = 100%) to give a pale yellow oily compound 76-2 (800 mg, yield: 30.7%).

[0641] 1 H NMR (400MHz, CDCl3) δ8.00 (dd, J=7.8, 1.4Hz, 1H), 7.43 (dd, J=8.0, 1.7Hz, 1H), 7.31-7.26 (m, 1H), 6.85-6.77 (m, 1H), 1.53 (s, 9H).

[0642] Step 2: Synthesis of Compound 76-3

[0643] Compound 76-1 (800 mg, 3.08 mmol) was dissolved in 1,4-dioxane (10 mL), and benzyl mercaptan (458.4 mg, 3.69 mmol), Pd2(dba)3 (56.4 mg, 0.062 mmol), Xantphos (71.3 mg, 0.123 mmol), and diisopropylethylamine (1.20 g, 9.24 mmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 16 hours under nitrogen protection. The reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-2%) to give a light brown oily compound 76-3 (364 mg, yield: 40%).

[0644] Step 3: Synthesis of Compound 76-4

[0645] Compound 76-3 (317 mg, 1.24 mmol) was dissolved in a mixed solution of acetonitrile (5 mL), acetic acid (1 mL), and water (1 mL). NCS (743.2 mg, 5.57 mmol) was added in portions under ice bath cooling. After the addition was complete, the reaction mixture was allowed to rise naturally to room temperature and reacted for 16 hours at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-1.5%) to give a white solid, compound 76-4 (150 mg, yield: 52.1%).

[0646] Step 4: Synthesis of Compound 76-5

[0647] Compound B3 (90 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), DMAP (8.6 mg, 0.07 mmol) and pyridine (33.4 mg, 0.42 mmol) were added, followed by compound 76-4 (49 mg, 0.21 mmol). The mixture was stirred for 1 hour. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined. The mixture was then washed successively with citric acid aqueous solution, saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative TLC to give compound 76-5 (75 mg, yield: 64%). LCMS (m / z): 837.3 [M+1] + .

[0648] Step 5: Synthesis of Compound 76

[0649] Compound 76-5 (75 mg, 0.09 mmol) was dissolved in a solution of trifluoroacetic acid (3 mL) and water (4 mL). The reaction system was heated to 60 °C and stirred for 24 hours. The reaction solution was concentrated and dried, and the crude product was purified by preparative liquid chromatography to give a white solid compound 76 (11.4 mg, yield: 19.6%).

[0650] 1 H NMR (400MHz, MeOD) δ7.97(d,J=8.0Hz,1H),7.75(d,J=8.1Hz,1H),7.56-7.49(m,1H),7.44-7.24(m,6H),5.57(d,J=9.0Hz,1H ),5.10(s,2H),4.18(s,2H),3.93(d,J=15.5Hz,2H),3.57(s,2H),2.26(d,J=9.4Hz,1H),1.58(s,9H); LCMS(m / z):649.2[M+1] + .

[0651] Example 76: Synthesis of 2-(tert-butyl)-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 77)

[0652] Compound 76 (8 mg, 0.0123) was dissolved in methanol (1.5 mL), and 10% Pd / C (3 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 77 (5.5 mg, yield: 86.6%).

[0653] 1 H NMR(400MHz,MeOD)δ7.97(dd,J=8.0,1.4Hz,1H),7.78-7.72(m,1H),7.57-7.49(m,1H),7.44-7.35(m,1H),5.53(d,J=9 .4Hz,1H),4.18(d,J=8.8Hz,2H),4.03(s,2H),3.55(s,2H),2.26(d,J=9.3Hz,1H),1.58(s,9H); LCMS(m / z):515.2[M+1] + .

[0654] Example 77: Synthesis of 2-tert-butyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 78)

[0655] Step 1: Synthesis of Compound 78-2

[0656] Compound 78-1 (1 g, 5.0 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen atmosphere and cooled to approximately -75 °C. 2.5 M n-butyllithium (2.2 mL, 5.5 mmol) was added dropwise, and the reaction was stirred for 30 minutes after the addition was complete. Then, sulfonyl chloride (0.742 g, 5.5 mmol) / tetrahydrofuran (1 mL) was added dropwise, and the reaction was stirred for 1 hour after the addition was complete. The reaction mixture was quenched in ice water, extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-20%) to give the oily compound 78-2 (350 mg, yield: 31.9%), which was directly used in the next reaction. LCMS (m / z): 220.1 [M+1] + .

[0657] Step 2: Synthesis of Compound 78-3

[0658] Compound B3 (90 mg, 0.14 mmol) was dissolved in a mixture of pyridine (44.3 mg, 0.56 mmol) and dichloromethane (8 mL). Compound 74-2 (61.7 mg, 0.28 mmol) was added under ice bath conditions, and the reaction mixture was stirred at room temperature for 16 hours after the addition was complete. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-60%) to give white compound 78-3 (75 mg, yield: 65%). LCMS (m / z): 824.3 [M+1] + .

[0659] Step 3: Synthesis of Compound 78

[0660] Compound 78-3 (75 mg, 0.09 mmol) was dissolved in a solution of trifluoroacetic acid (2 mL) and water (3 mL). The reaction system was heated to 60 °C and reacted for 24 hours. The reaction solution was concentrated and dried, and the crude product was purified by preparative liquid chromatography to give a white solid compound 78 (23 mg, yield: 39.7%).

[0661] 1 H NMR (400MHz, MeOD) δ7.45-7.29(m,6H),7.22-7.12(m,2H),6.97(dd,J=8.4,2.1Hz,1H),5.61(d,J=9.4Hz,1H),5.18(s,2 H),4.17(d,J=15.2Hz,2H),3.92(s,2H),3.51-3.37(m,2H),3.01(s,6H),2.30(d,J=9.7Hz,1H); LCMS(m / z):636.2[M+1] + .

[0662] Example 78: Synthesis of 3-dimethylamino-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 79)

[0663] Compound 78 (20 mg, 0.031 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, 0.5% aqueous acetic acid (5 mL) was added to the reaction system, and the mixture was stirred for another 15 minutes. The catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 79 (3.5 mg, yield: 22.2%).

[0664] 1 H NMR (400MHz, MeOD) δ7.46-7.32(m,1H),7.26-7.11(m,2H),6.99(dd,J=8.4,2.5Hz,1H),5.51(d,J=9.4Hz,1H ),4.21-4.09(m,2H),4.00(s,2H),3.41(s,2H),3.00(s,6H),2.22(t,J=9.9Hz,1H); LCMS(m / z):502.2[M+1] + .

[0665] Example 79: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-[(2,3,6-trifluorophenyl)sulfonamidomethyl]-octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 80)

[0666] Step 1: Synthesis of Compound 80-2

[0667] Compound B3 (60 mg, 0.094 mmol) was dissolved in a solution of pyridine (22 mg, 0.278 mmol) and dichloromethane (4 mL). Compound 80-1 (26 mg, 0.113 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-35%) to give compound 80-2 (55 mg, yield: 70%). LCMS (m / z): 835.3 [M+1] + .

[0668] Step 2: Synthesis of Compound 80

[0669] Compound 80-2 (55 mg, 0.066 mmol) was dissolved in a solution of trifluoroacetic acid (3 mL) and water (4 mL). The reaction system was heated to 60 °C and stirred for 18 hours, then cooled to room temperature. The reaction solution was concentrated and dried, and the crude product was purified by normal-phase column chromatography to give a white solid compound 80 (15 mg, yield: 35.2%).

[0670] 1 H NMR(400MHz,MeOD)δ7.54-7.45(m,2H),7.42-7.30(m,5H),5.60(d,J=9.1Hz,1H),5.19(s,2H),4.1 4(d,J=16.7Hz,2H),3.91(s,2H),3.71-3.57(m,2H),2.27(d,J=9.5Hz,1H); LCMS(m / z):647.1[M+1] + .

[0671] Example 80: Synthesis of 2,3,6-trifluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 81)

[0672] Compound 80 (13 mg, 0.02 mmol) was dissolved in methanol (2 mL), and 20% palladium hydroxide / carbon (3 mg) was added to displace hydrogen gas. The mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, and the filter cake was washed with methanol. The filtrate was concentrated, dried, and lyophilized to give a white solid, compound 81 (8.5 mg, yield: 82.5%).

[0673] 1 H NMR(400MHz,MeOD)δ7.61-7.39(m,2H),5.50(d,J=9.4Hz,1H),4.12(d,J=15.8Hz,2 H),3.95(s,2H),3.69-3.52(m,2H),2.20(d,J=9.4Hz,1H); LCMS(m / z):513.2[M+1] + .

[0674] Example 81: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(1-methyl-1H-pyrazole-4-sulfonamido)methyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 82)

[0675] Step 1: Synthesis of Compound 82-2

[0676] Compound B3 (90 mg, 0.14 mmol) was dissolved in a solution of pyridine (45 mg, 0.57 mmol) and dichloromethane (4 mL), and then compound 82-1 (38 mg, 0.21 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-45%) to obtain compound 82-2 (95 mg, yield: 86.2%). LCMS (m / z): 785.3 [M+1] + .

[0677] Step 2: Synthesis of Compound 82

[0678] Compound 82-2 (95 mg, 0.121 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction system was heated to 60 °C and stirred for 18 hours. The reaction system was then cooled to room temperature, concentrated and dried, and the crude product was purified by high performance liquid chromatography to obtain a white solid compound 82 (29 mg, yield: 40.2%).

[0679] 1 H NMR (400MHz, MeOD) δ8.12(s,1H),7.80(d,J=0.5Hz,1H),7.46-7.25(m,5H),5.58(d,J=9.3Hz,1H),5.14(s,2H),4. 14(d,J=16.8Hz,2H),3.94(s,3H),3.91(s,2H),3.58-3.43(m,2H),2.27(d,J=9.3Hz,1H); LCMS(m / z):597.1[M+1] + .

[0680] Example 82: Synthesis of 1-methyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-pyrazole-4-sulfonamide (compound 83)

[0681] Compound 82 (22 mg, 0.037 mmol) was dissolved in methanol (3 mL), and 10% palladium hydroxide / carbon (3 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 83 (17 mg, yield: 99%).

[0682] 1 H NMR(400MHz,MeOD)δ8.12(s,1H),7.80(d,J=0.6Hz,1H),5.51(d,J=9.4Hz,1H),4.20-4.09(m,2 H),4.07-3.95(m,2H),3.94(s,3H),3.48(s,2H),2.23(d,J=9.4Hz,1H); LCMS(m / z):463.3[M+1] + .

[0683] Example 83: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(1H-pyrazole-4-sulfonamido)methyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 84)

[0684] Step 1: Synthesis of Compound 84-2

[0685] Compound B3 (92 mg, 0.144 mmol) was dissolved in a solution of pyridine (34 mg, 0.46 mmol) and dichloromethane (3 mL). Compound 84-1 (36 mg, 0.216 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography to give compound 84-2 (78 mg, yield: 70.5%). LCMS (m / z): 771.3 [M+1] + .

[0686] Step 2: Synthesis of Compound 84

[0687] Compound 84-2 (78 mg, 0.10 mmol) was dissolved in a solution of trifluoroacetic acid (3 mL) and water (4 mL). The reaction system was heated to 60 °C and stirred for 18 hours. The reaction system was cooled to room temperature, concentrated and dried. The crude product was purified by normal-phase column chromatography, concentrated and lyophilized to give a white solid compound 84 (29 mg, yield: 49.2%).

[0688] 1 H NMR(400MHz,MeOD)δ8.04(s,2H),7.43-7.23(m,5H),5.59(d,J=9.6Hz,1H),5.15(s,2H),4.16(d ,J=11.6Hz,2H),3.92(s,2H),3.65-3.41(m,2H),2.28(d,J=9.5Hz,1H); LCMS(m / z):583.1[M+1] + .

[0689] Example 84: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-pyrazole-4-sulfonamide (compound 85)

[0690] Compound 84 (27 mg, 0.046 mmol) was dissolved in methanol (3 mL), and 10% palladium hydroxide / carbon (3 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 85 (20 mg, yield: 96.2%).

[0691] 1 H NMR(400MHz,MeOD)δ8.04(s,2H),5.52(d,J=10.0Hz,1H),4.21-4.10(m,2H),3 .94(s,2H),3.51-3.43(m,2H),2.24(d,J=9.5Hz,1H); LCMS(m / z):449.2[M+1] + .

[0692] Example 85: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(5-carbamoylpyridin-3-sulfonamido)methyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 86)

[0693] Step 1: Synthesis of Compound 86-2

[0694] Compound 86-1 (200 mg, 1.0 mmol), benzyl mercaptan (151 mg, 1.22 mmol), Pd2(dba)3 (46 mg, 0.051 mmol), and Xantphos (59 mg, 0.102 mmol) were dissolved in a solution of diisopropylethylamine (399 mg, 3.09 mmol) and 1,4-dioxane (10 mL). The mixture was purged with nitrogen and stirred at 100 °C for 5 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography to give compound 86-2 (210 mg, yield: 86%).

[0695] Step 2: Synthesis of Compound 86-3

[0696] Compound 86-2 (160 mg, 0.66 mmol) was dissolved in a mixed solution of acetonitrile (1.5 mL), acetic acid (1.5 mL), and water (1.5 mL). NCS (436 mg, 3.27 mmol) was added in portions under ice bath cooling. After the addition was complete, the reaction mixture was stirred for 5 hours under ice bath conditions. After the reaction was complete, the reaction solution was directly freeze-dried to obtain crude compound 86-3 (510 mg), which was used directly in the next reaction step.

[0697] Step 3: Synthesis of Compound 86-4

[0698] Compound B3 (90 mg, 0.14 mmol) was dissolved in a solution of pyridine (33 mg, 0.42 mmol) and dichloromethane (3 mL). Compound 86-3 (46 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give compound 86-4 (85 mg, yield: 73.3%). LCMS (m / z): 825.3 [M+1] + .

[0699] Step 4: Synthesis of Compound 86

[0700] Compound 86-4 (85 mg, 0.103 mmol) was dissolved in a solution of trifluoroacetic acid (3 mL) and water (4.5 mL), and the mixture was stirred at 60 °C for 18 hours. The reaction system was cooled to room temperature, and then the reaction solution was concentrated and dried. The crude product was purified by reverse-phase column chromatography to give a white solid compound 86 (8 mg, yield: 12.2%).

[0701] 1 H NMR (400MHz, MeOD) δ9.19 (s, 1H), 9.17 (d, J = 2.1Hz, 1H), 8.69 (d, J = 2.0Hz, 1H), 7.39-7.23 (m, 5H), 5.51 (d, J = 9.4Hz, 1H),5.06(s,2H),4.07(d,J=22.2Hz,2H),3.96-3.74(m,2H),3.60(s,2H),2.22-2.15(m,1H); LCMS(m / z):637.2[M+1] + .

[0702] Example 86: Synthesis of 5-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)aminosulfonyl)nicotinamide (compound 87)

[0703] Compound 86 (6.5 mg, 0.01 mmol) was dissolved in methanol (3 mL), and 10% palladium hydroxide / carbon (3 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, the filter cake was washed with methanol, and then the filtrate was concentrated, dried, and lyophilized to give a white solid, compound 87 (4.5 mg, yield: 87.7%).

[0704] 1 H NMR(400MHz,MeOD)δ9.18(dd,J=12.4,2.1Hz,2H),8.69(t,J=2.1Hz,1H),5.49(d,J=7.8Hz,1H),4 .13(s,2H),4.02-3.89(m,2H),3.63-3.51(m,2H),2.20(d,J=7.9Hz,1H); LCMS(m / z):503.2[M+1] + .

[0705] Example 87: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(5-cyanopyridin-3-sulfonamido)methyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 88)

[0706] Step 1: Synthesis of Compound 88-2

[0707] Compound 88-1 (200 mg, 1.09 mmol), benzyl mercaptan (151 mg, 1.22 mmol), Pd2(dba)3 (46 mg, 0.051 mmol), and Xantphos (59 mg, 0.102 mmol) were dissolved in a solution of diisopropylethylamine (399 mg, 3.09 mmol) and 1,4-dioxane (10 mL). The mixture was purged with nitrogen and stirred at 100 °C for 5 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was purified by normal-phase column chromatography to give compound 88-2 (210 mg, yield: 84.9%).

[0708] Step 2: Synthesis of Compound 88-3

[0709] Compound 88-2 (500 mg, 2.21 mmol) was dissolved in a solution of acetonitrile (3 mL), acetic acid (3 mL), and water (3 mL). NCS (1.47 g, 11.01 mmol) was added in portions under ice bath cooling. After the addition was completed, the mixture was stirred under ice bath conditions for 5 hours. The reaction solution was then freeze-dried. The crude product was purified by normal phase column chromatography to obtain compound 88-3 (270 mg, yield: 60.3%).

[0710] Step 3: Synthesis of Compound 88-4

[0711] Compound B3 (90 mg, 0.14 mmol) was dissolved in a solution of pyridine (45 mg, 0.57 mmol) and dichloromethane (4 mL), and then compound 88-3 (43 mg, 0.212 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography to give compound 88-4 (82 mg, yield: 72.6%). LCMS (m / z): 807.3 [M+1] + .

[0712] Step 4: Synthesis of Compound 88

[0713] Compound 88-4 (82 mg, 0.102 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL), and the mixture was stirred at 60 °C for 18 hours. The reaction system was cooled to room temperature, and then the reaction solution was concentrated and dried. The crude product was purified by preparative liquid chromatography to give a white solid compound 88 (13.6 mg, yield: 21.6%).

[0714] 1 H NMR (400MHz, MeOD) δ9.24(d,J=2.2Hz,1H),9.10(d,J=1.9Hz,1H),8.64(t,J=2.0Hz,1H),7.45-7.22(m,5H),5.52(d,J=9.3Hz,1H),5.0 9(s,2H),4.06(d,J=27.1Hz,2H),3.84(d,J=29.7Hz,2H),3.66-3.53(d,J=10.3Hz,2H),2.18(d,J=7.7Hz,1H); LCMS(m / z):619.1[M+1] + .

[0715] Example 88: Synthesis of 3-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-2-((benzyloxy)carbonyl)imino)-4,6,9,10,11-pentahydroxydecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)aminosulfonyl)benzenesulfonic acid (compound 89)

[0716] Step 1: Synthesis of Compound 89-2

[0717] Compound B3 (78 mg, 0.122 mmol) was dissolved in a solution of pyridine (39 mg, 0.493 mmol) and dichloromethane (3 mL), and then compound 89-1 (47 mg, 0.183 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0.8%) to give a colorless oily compound 89-2 (55 mg, yield: 52.5%). LCMS (m / z): 861.4 [M+1] + .

[0718] Step 2: Synthesis of Compound 89

[0719] Compound 89-2 (55 mg, 0.064 mmol) was dissolved in a solution of trifluoroacetic acid (3 mL) and water (4 mL), and the mixture was stirred at 60 °C for 18 hours. The reaction solution was cooled to room temperature, concentrated, and dried to obtain the crude product. The crude product was purified by preparative liquid chromatography to give a white solid compound 89 (2 mg, yield: 4.65%).

[0720] 1 H NMR (400MHz, MeOD) δ8.33(s,1H),8.05(d,J=7.7Hz,1H),7.97(d,J=8.5Hz,1H),7.65(t,J=7.9Hz,1H),7.46-7.26(m,5H),5.61(d ,J=9.2Hz,1H),5.17(s,2H),4.15(d,J=17.3Hz,2H),3.92(s,2H),3.49-3.47(m,2H),2.22-2.15(m,1H); LCMS(m / z):673.4[M+1] + .

[0721] Example 89: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(4-methanesulfonylphenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 90)

[0722] Step 1: Synthesis of Compound 90-2

[0723] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 90-1 (34.6 mg, 0.136 mmol) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a white solid compound 90-2 (65 mg, yield: 60.6%). LCMS (m / z): 859.5 [M+1] + .

[0724] Step 2: Synthesis of Compound 90

[0725] Compound 90-2 (65 mg, 0.076 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL). Under nitrogen protection, the mixture was heated to 60 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 0%–10%) to give a white solid compound 90 (14.5 mg, yield: 28.6%).

[0726] 1 H NMR (400MHz, MeOD) δ8.15 (s, 4H), 7.41-7.22 (m, 5H), 5.52 (d, J = 9.4Hz, 1H), 5.08 (d, J = 6.0Hz, 2H), 4.08 (d, J = 23.7Hz,2H),3.85(d,J=17.4Hz,2H),3.54(s,2H),3.18(s,3H),2.20(d,J=7.5Hz,1H); LCMS(m / z):671.1[M+1] + .

[0727] Example 90: Synthesis of 4-methanesulfonyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 91)

[0728] Compound 90 (10 mg, 0.015 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to displace hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid, compound 91 (5.2 mg, yield: 65.0%). LCMS (m / z): 537.4 [M+1] + .

[0729] Example 91: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-[(2,3,5-trifluorophenyl)sulfonamidomethyl]-octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 92)

[0730] Step 1: Synthesis of Compound 92-2

[0731] Compound 92-1 (840 mg, 3.98 mmol), benzyl mercaptan (595.2 mg, 4.79 mmol), Pd2(dba)3 (366.2 mg, 0.4 mmol), and Xantphos (462.4 mg, 0.8 mmol) were dissolved in a solution of diisopropylethylamine (1.03 g, 7.97 mmol) and 1,4-dioxane (10 mL). The mixture was purged with nitrogen and stirred at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 92-2 (900 mg, yield: 88.9%).

[0732] Step 2: Synthesis of Compound 92-3

[0733] Compound 92-2 (830 mg, 3.26 mmol) was dissolved in a solution of acetonitrile (10 mL), water (3 mL), and acetic acid (2 mL). The reaction system was cooled to 0 °C, and NCS (1.42 g, 10.63 mmol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a colorless liquid compound 92-3 (380 mg, yield: 50.5%).

[0734] Step 3: Synthesis of compound 92-4

[0735] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL), and then compound 92-4 (31.5 mg, 0.137 mmol) was added. The mixture was stirred for 3 hours under nitrogen protection at room temperature. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a grayish-white solid compound 92-4 (65 mg, yield: 62.4%). LCMS (m / z): 835.5 [M+1] + .

[0736] Step 4: Synthesis of Compound 92

[0737] Compound 92-4 (65 mg, 0.078 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 5%-8%) to give a white solid compound 92 (19.1 mg, yield: 37.9%).

[0738] 1 H NMR(400MHz,MeOD)δ7.53-7.45(m,2H),7.39-7.26(m,5H),5.54(d,J=9.6Hz,1H),5.09(s,2 H),4.12(s,2H),3.89(s,2H),3.61(s,2H),2.20(d,J=10.0Hz,1H); LCMS(m / z):647.3[M+1] + .

[0739] Example 92: Synthesis of 2,3,5-trifluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 93)

[0740] Compound 92 (10 mg, 0.015 mmol) was dissolved in methanol (5 mL), and 10% Pd(OH)2 / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 93 (5.8 mg, yield: 73.1%).

[0741] 1 H NMR(400MHz,MeOD)δ7.56-7.38(m,2H),5.48(d,J=9.4Hz,1H),4.19-4.06(m,2H),3 .97(d,J=10.6Hz,2H),3.59(s,2H),2.19(d,J=9.4Hz,1H); LCMS(m / z):513.2[M+1] + .

[0742] Example 93: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(4-fluoro-3-methanesulfonylphenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxy-octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 94)

[0743] Step 1: Synthesis of Compound 94-2

[0744] Chlorosulfonic acid (3.1 g, 26.6 mmol) was dissolved in dichloromethane (5 mL), and compound 94-1 (1.58 g, 9.07 mmol) was added dropwise under ice bath cooling. After the addition was complete, the mixture was stirred at room temperature for 3 hours. After the reaction was complete, ice water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal phase column chromatography (petroleum ether = 100%) to give a yellow oily compound 94-2 (1.4 g, yield: 56.7%).

[0745] Step 2: Synthesis of Compound 94-3

[0746] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 94-2 (37.1 mg, 0.136 mmol) was added, and the mixture was stirred at room temperature under nitrogen protection for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a white solid, compound 94-3 (75.2 mg, yield: 68.7%). LCMS (m / z): 877.3 [M+1] + .

[0747] Step 3: Synthesis of Compound 94

[0748] Compound 94-3 (75 mg, 0.086 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 94 (17.5 mg, yield: 29.7%).

[0749] 1 H NMR (400MHz, MeOD) δ8.44(dd,J=6.4,2.3Hz,1H),8.30-8.24(m,1H),7.59(t,J=9.2Hz,1H),7.43-7.28(m,5H),5.56(d,J=9.5Hz,1H ),5.18(s,2H),4.18-3.96(m,2H),3.85(d,J=32.5Hz,2H),3.57(s,2H),3.32(s,3H)2.25(d,J=9.4Hz,1H); LCMS(m / z):689.1[M+1] + .

[0750] Example 94: Synthesis of 4-fluoro-3-methanesulfonyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 95)

[0751] Compound 94 (10 mg, 0.015 mmol) was dissolved in methanol (5 mL), and 10% Pd(OH)2 / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 95 (6.3 mg, yield: 78.3%).

[0752] 1 H NMR(400MHz,MeOD)δ8.40(dd,J=6.2,2.3Hz,1H),8.35-8.27(m,1H),7.66(t,J=9.2Hz,1H),5.46(d,J=9.4Hz,1H), 4.20-4.02(m,2H),3.93(s,2H),3.52(d,J=7.1Hz,2H),3.38(s,3H),2.20(d,J=9.4Hz,1H); LCMS(m / z):555.2[M+1] + .

[0753] Example 95: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(3-aminosulfonylphenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxetane[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 96)

[0754] Step 1: Synthesis of Compound 96-3

[0755] Compound 96-1 (944 mg, 4.0 mmol), benzyl mercaptan (595.2 mg, 4.8 mmol), Pd2(dba)3 (366.2 mg, 0.4 mmol), and Xantphos (462.4 mg, 0.8 mmol) were dissolved in a solution of diisopropylethylamine (1.03 g, 8.0 mmol) and 1,4-dioxane (10 mL). The mixture was purged with nitrogen and stirred at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a white solid, compound 96-3 (990 mg, yield: 88.6%). LCMS (m / z): 280.1 [M+1] + .

[0756] Step 2: Synthesis of Compound 96-4

[0757] Compound 96-3 (912 mg, 3.26 mmol) was dissolved in a solution of acetonitrile (6 mL), water (3 mL), and acetic acid (2 mL). The reaction system was cooled to 0 °C, and NCS (1.42 g, 9.8 mmol) was added in portions. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a colorless liquid compound 96-4 (430 mg, yield: 51.5%).

[0758] Step 3: Synthesis of Compound 96-5

[0759] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 96-4 (34.9 mg, 0.136 mmol) was added, and the mixture was stirred at room temperature under nitrogen protection for 3 hours. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 96-5 (82 mg, yield: 76.4%). LCMS (m / z): 860.8 [M+1] + .

[0760] Step 4: Synthesis of Compound 96

[0761] Compound 96-5 (80 mg, 0.093 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 96 (21.3 mg, yield: 34.1%).

[0762] 1 H NMR (400MHz, MeOD) δ8.41(t,J=1.6Hz,1H),8.15-8.07(m,2H),7.76(t,J=7.9Hz,1H),7.40-7.25(m,5H),5.52(d,J=9.3Hz, 1H),5.10(s,2H),4.08(d,J=36.6Hz,2H),3.86(d,J=13.9Hz,2H),3.55(s,2H),2.24-2.18(m,1H); LCMS(m / z):672.1[M+1] + .

[0763] Example 96: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1,3-benzenedisulfonamide (compound 97)

[0764] Compound 96 (10 mg, 0.015 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 97 (6.5 mg, yield: 81.3%).

[0765] 1 H NMR(400MHz,MeOD)δ8.36(s,1H),8.16(t,J=7.8Hz,2H),7.84(t,J=7.9Hz,1H),5.46(d,J=9.4Hz,1H),4.2 2-4.04(m,2H),3.95(d,J=20.5Hz,2H),3.56-3.48(m,2H),2.22(d,J=9.4Hz,1H); LCMS(m / z):538.5[M+1] + .

[0766] Example 97: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(1-methyl-1H-imidazol-4-sulfonamido)methyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxetane[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 98)

[0767] Step 1: Synthesis of Compound 98-2

[0768] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 98-1 (24.6 mg, 0.136 mmol) was added, and the mixture was stirred at room temperature under nitrogen protection for 3 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and dried to obtain a crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a grayish-white solid compound 98-2 (91 mg, yield: 92.9%). LCMS (m / z): 785.3 [M+1] + .

[0769] Step 2: Synthesis of Compound 98

[0770] Compound 98-2 (90 mg, 0.115 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 7%-10%) to give a white solid compound 98 (20 mg, yield: 29.2%).

[0771] 1 H NMR (400MHz, MeOD) δ7.75(s,1H),7.69(s,1H),7.41-7.25(m,5H),5.55(d,J=9.5Hz,1H),5.11(s,2H),4.12(d,J =28.9Hz,2H),3.88(d,J=16.2Hz,2H),3.78(s,3H),3.61(s,2H),2.25(d,J=9.5Hz,1H); LCMS(m / z):597.2[M+1] + .

[0772] Example 98: Synthesis of 1-methyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-imidazolium-4-sulfonamide (compound 99)

[0773] Compound 98 (10 mg, 0.017 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added. The mixture was then replaced with hydrogen gas and stirred at room temperature for 8 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 99 (3.5 mg, yield: 45.2%).

[0774] 1 H NMR (400MHz, MeOD) δ7.80 (s, 1H), 7.77 (s, 1H), 5.51 (d, J = 9.2Hz, 1H), 4.27-4.11 (m, 2H) ,3.99(s,2H),3.81(s,3H),3.56(s,2H),2.27(d,J=9.4Hz,1H); LCMS(m / z):463.4[M+1] + .

[0775] Example 99: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(perfluorophenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxetaneocteno[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 100)

[0776] Step 1: Synthesis of Compound 100-2

[0777] Compound B3 (80 mg, 0.125 mmol) was dissolved in pyridine (30 mg, 0.379 mmol) and dichloromethane (6 mL). Compound 100-1 (50 mg, 0.188 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography to give compound 100-2 (75 mg, yield: 69%). LCMS (m / z): 871.2 [M+1] + .

[0778] Step 2: Synthesis of Compound 100

[0779] Compound 100-2 (75 mg, 0.086 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction system was heated to 60 °C and stirred for 18 hours. The reaction system was then cooled to room temperature and concentrated to remove the solvent. The crude product was purified by normal-phase column chromatography to give a white solid compound 100 (29 mg, yield: 49.3%).

[0780] 1 H NMR(400MHz,MeOD)δ7.49-7.29(m,5H),5.64(d,J=9.4Hz,1H),5.28(s,2H),4.17(s,1H),4.07(s ,1H),3.91(d,J=13.1Hz,2H),3.82-3.67(m,2H),2.26(d,J=9.4Hz,1H); LCMS(m / z):683.3[M+1] + .

[0781] Example 100: Synthesis of 2,3,4,5,6-pentafluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 101)

[0782] A solution of compound 100 (15 mg, 0.022 mmol) and methanol (4 mL) was mixed with 10% palladium hydroxide / carbon (3 mg) to replace the hydrogen gas, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, the filter cake was washed with methanol, the filtrate was concentrated, dried, and lyophilized to give a white solid compound 101 (10 mg, yield: 83%).

[0783] 1 H NMR(400MHz,MeOD)δ5.48(d,J=9.1Hz,1H),4.07(d,J=24.0Hz,2H),3.88(s,2H),3.72(s,2H),2.21-2.14(m,1H); LCMS(m / z):549.3[M+1] + .

[0784] Example 101: Synthesis of 2,3,5,6-tetrafluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 102)

[0785] Step 1: Synthesis of Compound 102-2

[0786] Compound 102-1 (1 g, 6.66 mmol) was dissolved in chlorosulfonic acid (15 mL), and the reaction mixture was heated to 100 °C for 5 hours. The reaction mixture was cooled to room temperature, and then the reaction solution was slowly quenched in ice water. Extraction was performed with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give a brown oily compound 102-2 (160 mg, 10% yield).

[0787] Step 2: Synthesis of Compound 102-3

[0788] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (39.5 mg, 0.5 mmol) and dichloromethane (5 mL), and then compound 102-2 (47 mg, 0.188 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give compound 102-3 (60 mg, yield: 56.3%). LCMS (m / z): 853.3 [M+1] + .

[0789] Step 3: Synthesis of Compound 102-4

[0790] Compound 102-3 (60 mg, 0.07 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction system was heated to 60 °C and stirred for 18 hours. The reaction system was cooled to room temperature and concentrated and dried. The crude product was purified by normal phase column chromatography to give a white solid compound 102-4 (16 mg, yield: 34.2%).

[0791] 1 HNMR(400MHz,MeOD)δ7.77-7.63(m,1H),7.36-7.28(m,5H),5.52-5.45(m,1H),5.04(s,2H),4.19- 3.95(m,2H),3.93-3.77(m,2H),3.72-3.51(m,2H),2.19(d,J=7.4Hz,1H); LCMS(m / z):665.3[M+1] + .

[0792] Step 4: Synthesis of Compound 102

[0793] Compound 102-4 (15 mg, 0.023 mmol) was dissolved in methanol (4 mL), and 10% palladium hydroxide / carbon (3 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 102 (9 mg, yield: 75.2%).

[0794] 1H NMR (400MHz, MeOD) δ7.67-7.55(m,1H),5.41(d,J=9.3Hz,1H),4.03(s,2H),3.80(s,2H),3.64(s,2H),2.08(d,J=8.7Hz,1H); LCMS(m / z):531.3[M+1] + .

[0795] Example 102: Synthesis of ((4S,4aS,5S,6R,7R,9R,10S,10aS,11R,E)-6-[(3-((((4R,4aR,5R,6S,7R,9R,10S,10aS,11R,E)-2-((benzyloxy)carbonyl)imino)-4,6,9,10,11-pentahydroxy-decahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)aminosulfonyl)phenyl)sulfonamide methyl]-4,6,9,10,11-pentahydroxy-octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (compound 103)

[0796] Step 1: Synthesis of Compound 103-2

[0797] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL), and then compound 103-1 (17.2 mg, 0.063 mmol) was added. The mixture was stirred for 1 hour under nitrogen protection at room temperature. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a white solid compound 103-2 (92 mg, yield: 99%). LCMS (m / z): 1483.3 [M+1] + .

[0798] Step 2: Synthesis of Compound 103

[0799] Compound 103-2 (92 mg, 0.062 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was stirred for 16 hours under nitrogen protection and at 60 °C. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 103 (7.6 mg, yield: 11.1%).

[0800] 1 H NMR(400MHz,MeOD)δ8.40(s,1H),8.15(dd,J=7.9,1.8Hz,2H),7.80(t,J=7.9Hz,1H),7.46-7.27(m,10H),5.59(d,J=9.6Hz,2H), 5.18(s,4H),4.14(d,J=21.4Hz,4H),3.91(d,J=13.2Hz,4H),3.70-3.47(m,4H),2.29(d,J=9.1Hz,2H); LCMS(m / z):1107.4[M+1] + .

[0801] Example 103: N1-(((4R,4aR,5R,6S,7R,9R,10S,10aS,11R)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-N 3 Synthesis of -(((4S,4aS,5S,6R,7R,9R,10S,10aS,11R)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1,3-benzenedisulfonamide (compound 104)

[0802] Compound 104 (5 mg, 0.0045 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the reaction system was filtered to remove the catalyst, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 104 (3.2 mg, yield: 84.4%).

[0803] 1 H NMR(400MHz,MeOD)δ7.79-7.67(m,4H),5.52(d,J=9.4Hz,2H),4.11(d,J=29.3Hz,4H),3 .92(d,J=5.7Hz,4H),3.53-3.48(m,4H),2.19(d,J=9.6Hz,2H); LCMS(m / z):837.3[M-1] - .

[0804] Example 104: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(3,4,5-trifluorophenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxy-octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 105)

[0805] Step 1: Synthesis of Compound 105-2

[0806] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 105-1 (31.5 mg, 0.137 mmol) was added, and the mixture was stirred for 1 hour under nitrogen protection at room temperature. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 105-2 (85 mg, yield: 81.6%). LCMS (m / z): 835.2 [M+1] + .

[0807] Step 2: Synthesis of Compound 105

[0808] Compound 105-2 (85 mg, 0.102 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 105 (12 mg, yield: 18.2%).

[0809] 1 H NMR (400MHz, MeOD) δ7.72(t,J=6.7Hz,2H),7.41-7.23(m,5H),5.52(d,J=9.4Hz,1H),5.06(s,2H),4.09( d,J=13.7Hz,2H),3.86(d,J=17.8Hz,2H),3.59-3.45(m,2H),2.22-2.16(m,1H); LCMS(m / z):647.3[M+1] + .

[0810] Example 105: Synthesis of 3,4,5-trifluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 106)

[0811] Compound 105 (8 mg, 0.012 mmol) was dissolved in methanol (5 mL), and 10% Pd(OH)₂ / C (1 mg) was added to displace hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid, compound 106 (5.2 mg, yield: 82%). LCMS (m / z): 512.9 [M+1] + .

[0812] Example 106: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(2,3,4,5-tetrafluorophenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxy-octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 107)

[0813] Step 1: Synthesis of Compound 107-2

[0814] Compound 107-1 (0.5 g, 3.33 mmol) was dissolved in chlorosulfonic acid (10 mL), and the reaction system was heated to 100 °C and reacted for 5 hours. The reaction system was then cooled to room temperature, and the reaction solution was slowly quenched in ice water. Extraction was performed with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give a brown oily compound 107-2 (110 mg, yield 13.3%).

[0815] Step 2: Synthesis of Compound 107-3

[0816] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (39.5 mg, 0.5 mmol) and dichloromethane (4 mL). Compound 107-2 (42 mg, 0.169 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give compound 107-3 (55 mg, yield: 51.6%). LCMS (m / z): 853.3 [M+1] + .

[0817] Step 3: Synthesis of Compound 107

[0818] Compound 107-3 (55 mg, 0.064 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction system was heated to 60 °C and stirred for 18 hours. The reaction system was cooled to room temperature, concentrated and dried. The crude product was purified by normal-phase column chromatography to give a white solid compound 107 (15 mg, yield: 35%).

[0819] 1 H NMR (400MHz, MeOD) δ7.70 (s, 1H), 7.45-7.35 (m, 5H), 5.64 (d, J = 9.3Hz, 1H), 5.27 (s, 2H), 4.18 (s, 1H) ),4.09(s,1H),3.91(d,J=15.1Hz,2H),3.65(s,2H),2.30(d,J=9.3Hz,1H); LCMS(m / z):665.3[M+1] + .

[0820] Example 107: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-[(2,3,4,6-tetrafluorophenyl)sulfonamidomethyl]-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxetaneocteno[4,5-d]pyrimidine-2(1H)-ylidene)carbamate (compound 108)

[0821] Step 1: Synthesis of Compound 108-2

[0822] Compound 108-1 (500 mg, 3.33 mmol) was dissolved in chlorosulfonic acid (4 mL). The reaction system was heated to 100 °C and stirred for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and then the reaction system was slowly quenched in ice water. The mixture was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product (650 mg, yield: 78.5%), which was used directly in the next step of the reaction.

[0823] Step 2: Synthesis of Compound 108-3

[0824] Compound B3 (85 mg, 0.133 mmol) was dissolved in a solution of pyridine (42 mg, 0.531 mmol) and dichloromethane (4 mL). Compound 108-2 (49.7 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give a colorless oily compound 108-3 (96 mg, yield: 84.9%). LCMS (m / z): 853.4 [M+1] + .

[0825] Step 3: Synthesis of Compound 108

[0826] Compound 108-3 (96 mg, 0.113 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction system was heated to 60 °C and stirred for 18 hours. The reaction system was cooled to room temperature, concentrated, and dried to obtain the crude product. The crude product was purified by preparative liquid chromatography to give a white solid compound 108 (17 mg, yield: 22.7%).

[0827] 1 H NMR (400MHz, MeOD) δ7.40-7.26 (m, 6H), 5.54 (d, J = 9.3Hz, 1H), 5.21 (s, 2H), 4.12 ( s,2H),3.90(s,2H),3.73(s,2H),2.18(d,J=13.1Hz,1H); LCMS(m / z):665.4[M+1] + .

[0828] Example 108: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1,4-benzenedisulfonamide (compound 109)

[0829] Step 1: Synthesis of Compound 109-2

[0830] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 109-1 (34.9 mg, 0.136 mmol) was added, and the mixture was stirred at room temperature under nitrogen protection for 1 hour. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a white solid compound 109-2 (85 mg, yield: 79.1%). LCMS (m / z): 860.3 [M+1] + .

[0831] Step 2: Synthesis of Compound 109-3

[0832] Compound 109-2 (85 mg, 0.099 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 109-3 (24 mg, yield: 36.1%).

[0833] 1 H NMR(400MHz,MeOD)δ8.12-8.01(m,4H),7.39-7.25(m,5H),5.53(d,J=9.4Hz,1 H),5.07(s,2H),4.10(d,J=16.2Hz,2H),3.88(s,2H),3.59-3.43(m,2H),2.24 -2.17(m,1H); LCMS(m / z):672.3[M+1] + .

[0834] Step 3: Synthesis of Compound 109

[0835] Compound 109-3 (24 mg, 0.036 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 109 (15.0 mg, yield: 78.1%).

[0836] 1 H NMR(400MHz,MeOD)δ8.11-8.02(m,4H),5.50(d,J=9.4Hz,1H),4.12(d,J=24.8Hz,2H) ,4.03-3.90(m,2H),3.51-3.46(m,2H),2.22(d,J=9.4Hz,1H); LCMS(m / z):538.4[M+1] + .

[0837] Example 109: Synthesis of 4-fluoro-2-methyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 110)

[0838] Step 1: Synthesis of Compound 110-2

[0839] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (40.5 mg, 0.512 mmol) and dichloromethane (4 mL). Compound 110-1 (40 mg, 0.192 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to give a colorless oily compound 110-2 (95 mg, yield: 93.6%). LCMS (m / z): 813.4 [M+1] + .

[0840] Step 2: Synthesis of Compound 110-3

[0841] Compound 110-2 (95 mg, 0.117 mmol) was dissolved in a solution of trifluoroacetic acid (3 mL) and water (4 mL). The reaction system was heated to 60 °C and stirred for 18 hours. The reaction system was cooled to room temperature, and then the reaction solution was concentrated and dried. The crude product was purified by normal phase column chromatography to give a white solid compound 110-3 (55 mg, yield: 75.3%).

[0842] 1 H NMR(400MHz,MeOD)δ7.90(dd,J=8.8,5.7Hz,1H),7.41-7.22(m,5H),7.10-6.96(m,2H),5.54(d,J=9.5Hz,1H),5.16(s,2H),4.08( d,J=33.4Hz,2H),3.84(d,J=5.5Hz,2H),3.40(dd,J=4.7,3.0Hz,2H),2.57(s,3H),2.25(d,J=9.5Hz,1H); LCMS(m / z):625.4[M+1] + .

[0843] Step 3: Synthesis of Compound 110

[0844] Compound 110-3 (55 mg, 0.088 mmol) was dissolved in methanol (6 mL), and 10% palladium hydroxide / carbon (8 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 7 hours. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 110 (38.9 mg, yield: 90%).

[0845] 1 H NMR (400MHz, MeOD) δ7.89(dd,J=8.8,5.7Hz,1H),7.07(dd,J=9.6,2.4Hz,1H),7.00(td,J=8.4,2.5Hz,1H),5.41(d,J=9.4Hz,1 H),4.03(d,J=18.2Hz,2H),3.80(s,2H),3.46-3.30(m,2H),2.57(s,3H),2.11(dd,J=16.3,8.8Hz,1H); LCMS(m / z):491.3[M+1] + .

[0846] Example 110: Synthesis of 4-fluoro-3-methyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 111)

[0847] Step 1: Synthesis of Compound 111-2

[0848] Chlorosulfonic acid (3.1 g, 26.6 mmol) was dissolved in dichloromethane (5 mL). Compound 111-1 (1.0 g, 9.08 mmol) was added dropwise under ice bath cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, ice water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (petroleum ether = 100%) to give a yellow oily compound 111-2 (1.1 g, yield: 58.1%).

[0849] 1 H NMR (400MHz, CDCl3) δ8.04-7.83 (m, 2H), 7.23 (t, J = 8.7Hz, 1H), 2.40 (d, J = 2.0Hz, 3H).

[0850] Step 2: Synthesis of compound 111-3

[0851] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 111-2 (27.5 mg, 0.132 mmol) was added, and the mixture was stirred for 1 hour under nitrogen protection at room temperature. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a white solid compound 111-3 (90 mg, yield: 88.7%). LCMS (m / z): 813.3 [M+1] + .

[0852] Step 3: Synthesis of compound 111-4

[0853] Compound 111-3 (90 mg, 0.111 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the mixture was stirred at 60 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 111-4 (25 mg, yield: 36.1%).

[0854] 1 H NMR (400MHz, MeOD) δ7.82(dd,J=7.0,2.3Hz,1H),7.78-7.72(m,1H),7.40-7.20(m,6H),5.54(d,J=9.3Hz,1H),5.07(d,J= 3.1Hz,2H),4.11(s,2H),3.89(s,2H),3.48(s,2H),2.35(d,J=1.6Hz,3H),2.22(d,J=8.4Hz,1H); LCMS(m / z):625.3[M+1] + .

[0855] Step 4: Synthesis of Compound 111

[0856] Compound 111-4 (25 mg, 0.04 mmol) was dissolved in methanol (5 mL), and 10% Pd(OH)2 / C (2 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 111 (14 mg, yield: 71.3%).

[0857] 1 H NMR (400MHz, MeOD) δ7.82(dd,J=7.1,1.9Hz,1H),7.79-7.73(m,1H),7.24(t,J=9.0Hz,1H),5.51(d,J=9.4Hz,1H),4.13( d,J=21.0Hz,2H),3.92(s,2H),3.52-3.37(m,2H),2.35(d,J=1.7Hz,3H),2.23(d,J=9.2Hz,1H); LCMS(m / z):491.4[M+1] + .

[0858] Example 111: Synthesis of 2-chloro-4-fluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 112)

[0859] Step 1: Synthesis of Compound 112-2

[0860] Compound B3 (88 mg, 0.137 mmol) was dissolved in a solution of pyridine (43.4 mg, 0.55 mmol) and dichloromethane (3 mL). Compound 112-1 (47 mg, 0.205 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was then added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-25%) to give a colorless oily compound 112-2 (93 mg, yield: 81.3%). LCMS (m / z): 833.3, 835.3 [M+1] + .

[0861] Step 2: Synthesis of Compound 112-3

[0862] Compound 112-2 (93 mg, 0.112 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction mixture was heated to 60 °C and stirred for 18 hours. The reaction mixture was then cooled to room temperature, concentrated, and dried. The crude product was purified by normal-phase column chromatography to give a white solid compound 112-3 (44 mg, yield: 61.1%). LCMS (m / z): 645.4, 647.4 [M+1] + .

[0863] Step 3: Synthesis of Compound 112

[0864] Compound 112-3 (30 mg, 0.047 mmol) was dissolved in a solution of triethylamine (80 mg, 0.79 mmol), triethylsilane (1 mL), and dichloromethane (3 mL). Palladium dichloride (6 mg) was added, and the mixture was purged with nitrogen. The mixture was stirred at room temperature for 18 hours. The reaction solution was then filtered, the filter cake was washed with methanol, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by preparative liquid chromatography to give a white solid compound 112 (5.5 mg, yield: 23.1%).

[0865] 1 HNMR(400MHz,MeOD)δ8.16(dd,J=8.9,5.9Hz,1H),7.50(dd,J=8.5,2.5Hz,1H),7.34-7.22(m,1H),5.52(d,J=9.5Hz, 1H),4.15(d,J=12.7Hz,2H),3.97(s,2H),3.56-3.49(m,2H),2.23(d,J=10.4Hz,1H); LCMS(m / z):511.4,513.4[M+1] + .

[0866] Example 112: Synthesis of 2-chloro-3-fluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 113)

[0867] Step 1: Synthesis of Compound 113-2

[0868] Compound B3 (86 mg, 0.134 mmol) was dissolved in a solution of pyridine (40.3 mg, 0.51 mmol) and dichloromethane (6 mL). Compound 113-1 (46 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic fractions were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to give a colorless oily compound 113-2 (96 mg, yield: 85.8%). LCMS (m / z): 833.3, 835.3 [M+1] + .

[0869] Step 2: Synthesis of compound 113-3

[0870] Compound 113-2 (96 mg, 0.115 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction mixture was heated to 60 °C and stirred for 18 hours. The reaction mixture was then cooled to room temperature, concentrated, and dried. The crude product was purified by normal-phase column chromatography to give a white solid compound 113-3 (52 mg, yield: 70%). LCMS (m / z): 645.3, 647.3 [M+1] + .

[0871] Step 3: Synthesis of Compound 113

[0872] Compound 113-3 (52 mg, 0.081 mmol) was dissolved in a solution of triethylamine (80 mg, 0.79 mmol), triethylsilane (1 mL), and dichloromethane (4 mL). Palladium dichloride (5 mg) was added, nitrogen was purged, and the mixture was stirred at room temperature for 18 hours under nitrogen protection. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by preparative liquid chromatography and lyophilized to give a white solid compound 113 (4.94 mg, yield 12%).

[0873] 1 H NMR (400MHz, MeOD) δ8.00-7.91(m,1H),7.61-7.49(m,2H),5.52(d,J=9.2Hz,1H),4.15(d,J =10.9Hz,2H),3.99(s,2H),3.55(s,2H),2.23(d,J=5.4,1H); LCMS(m / z):511.3,513.1[M+1] + .

[0874] Example 113: Synthesis of 3-fluoro-4-methyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 114)

[0875] Step 1: Synthesis of Compound 114-2

[0876] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 114-1 (28.4 mg, 0.137 mmol) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 114-2 (90 mg, yield: 88.7%). LCMS (m / z): 813.3 [M+1] + .

[0877] Step 2: Synthesis of Compound 114-3

[0878] Compound 114-2 (90 mg, 0.111 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 114-3 (25 mg, yield: 36.1%). LCMS (m / z): 625.3 [M+1] + .

[0879] Step 3: Synthesis of Compound 114

[0880] Compound 114-3 (25 mg, 0.04 mmol) was dissolved in methanol (5 mL), and 10% Pd(OH)2 / C (2 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 114 (18 mg, yield: 91.7%).

[0881] 1 H NMR (400MHz, MeOD) δ7.66-7.58(m,2H),7.49(t,J=7.6Hz,1H),5.53(d,J=9.4Hz,1H),4.22-4.11(m,2H) ,3.99(s,2H),3.48-3.42(m,2H),2.38(d,J=1.7Hz,3H),2.25(d,J=9.4Hz,1H); LCMS(m / z):491.5[M+1] + .

[0882] Example 114: Synthesis of 3-chloro-2-fluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (compound 115)

[0883] Step 1: Synthesis of Compound 115-2

[0884] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 115-1 (31.2 mg, 0.136 mmol) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a grayish-white solid compound 115-2 (85 mg, yield: 81.7%). LCMS (m / z): 833.2 [M+1] + .

[0885] Step 2: Synthesis of Compound 115-3

[0886] Compound 115-2 (85 mg, 0.102 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (10 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 115-3 (32 mg, yield: 49.6%). LCMS (m / z): 645.3 [M+1] + .

[0887] Step 3: Synthesis of Compound 115

[0888]

[0889] Compound 115-3 (26 mg, 0.04 mmol) was dissolved in a solution of triethylamine (30 mg, 0.30 mmol), triethylsilane (80 mg, 0.69 mmol), and dichloromethane (15 mL). Palladium dichloride (5 mg) was added, and the atmosphere was purged with nitrogen. The mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by reverse-phase column chromatography and lyophilized to give a white solid compound 115 (4.94 mg, yield: 24%).

[0890] 1H NMR (400MHz, MeOD) δ7.75(t,J=6.3Hz,1H),7.67(t,J=7.4Hz,1H),7.25(t,J=7.5Hz,1H),5.41(d,J=9.0Hz,1 H),4.04(d,J=15.2Hz,2H),3.88(s,2H),3.48(s,2H),2.10(d,J=7.4Hz,1H); LCMS(m / z):511.1,513.1[M+1] + .

[0891] Example 115: Synthesis of 5-methyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)pyridine-3-sulfonamide (compound 116)

[0892] Step 1: Synthesis of Compound 116-2

[0893] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 116-1 (26.2 mg, 0.137 mmol) was added, and the mixture was stirred at room temperature under nitrogen protection for 1 hour. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 116-2 (92 mg, yield: 92.6%). LCMS (m / z): 796.2 [M+1] + .

[0894] Step 2: Synthesis of Compound 116-3

[0895] Compound 116-2 (90 mg, 0.113 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 116-3 (17.5 mg, yield: 25.5%). LCMS (m / z): 608.3 [M+1] + .

[0896] Step 3: Synthesis of Compound 116

[0897] Compound 116-3 (15 mg, 0.025 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 116 (11 mg, yield: 94.1%).

[0898] 1 H NMR (400MHz, MeOD) δ8.85(d,J=1.9Hz,1H),8.64(d,J=1.3Hz,1H),8.16(s,1H),5.52(d,J=9.4Hz,1H),4.15(dd,J=16 .1,10.9Hz,2H),3.98(d,J=26.0Hz,2H),3.56-3.50(m,2H),2.49(s,3H),2.26-2.20(m,1H); LCMS(m / z):474.5[M+1] + .

[0899] Example 116: Synthesis of 6-chloro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indole-3-sulfonamide (compound 117)

[0900] Step 1: Synthesis of Compound 117-2

[0901] Compound 117-1 (1 g, 6.60 mmol) was dissolved in a solution of pyridine (15 mL) and pyridine sulfur trioxide (1.58 g, 9.93 mmol). After the addition was complete, the reaction system was heated to 130 °C and stirred for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated, and dried to obtain crude compound 117-2 (2.1 g), which was directly used in the next reaction. LCMS (m / z): 231.9, 233.9 [M+1] + .

[0902] Step 2: Synthesis of Compound 117-3

[0903] 2.1 g of crude compound 117-2 was dissolved in 20 mL of dichloromethane, and a catalytic amount of N,N-dimethylformamide was added. The reaction mixture was cooled in an ice bath, and 1.67 g (13.16 mmol) of oxaloyl chloride was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 117-3 (650 mg, two-step yield: 39.4%).

[0904] Step 3: Synthesis of Compound 117-4

[0905] Compound B3 (86 mg, 0.134 mmol) was dissolved in a solution of pyridine (40.3 mg, 0.51 mmol) and dichloromethane (6 mL). Compound 117-3 (50 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to give a colorless oily compound 117-4 (50 mg, yield: 43.6%). LCMS (m / z): 854.3 [M+1] + .

[0906] Step 4: Synthesis of Compound 117-5

[0907] Compound 117-4 (50 mg, 0.059 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction mixture was heated to 60 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, concentrated, and dried. The crude product was purified by normal-phase column chromatography to give a white solid compound 117-5 (24 mg, yield: 61.6%). LCMS (m / z): 666.3 [M+1] + .

[0908] Step 5: Synthesis of Compound 117

[0909] Compound 117-5 (24 mg, 0.036 mmol) was dissolved in a solution of triethylamine (60 mg, 0.59 mmol), tert-butyldimethylsilane (1 mL), and dichloromethane (4 mL). Palladium acetate (5 mg) was added, nitrogen was purged, and the mixture was stirred at room temperature for 18 hours under nitrogen protection. The reaction solution was filtered, the filter cake was washed with methanol, the filtrate was concentrated and dried, and the crude product was purified by preparative liquid chromatography to give a white solid compound 117 (1.05 mg, yield: 5.5%). LCMS (m / z): 532.3, 534.3 [M+1] + .

[0910] Example 117: Synthesis of N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-6-(trifluoromethyl)-1H-indazole-3-sulfonamide (compound 118)

[0911] Step 1: Synthesis of Compound 118-2

[0912] Compound 118-1 (1.0 g, 5.29 mmol) was dissolved in ethanol (10 mL). Hydrazine hydrate (740 mg, 11.83 mmol) was added to the reaction system. The reaction system was heated to 95 °C under nitrogen protection and stirred for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-56%) to give compound 118-2 (1.0 g, yield: 94.3%), an off-white solid.

[0913] 1 H NMR (400MHz, DMSO) δ11.85(s,1H),7.92(d,J=8.4Hz,1H),7.59(s,1H),7.18(dd,J=8.4,1.2Hz,1H),5.60(s,2H); LCMS(m / z):202.1[M+1] + .

[0914] Step 2: Synthesis of Compound 118-3

[0915] Compound 118-3 (1.0 g, 4.97 mmol) was dissolved in a solution of concentrated hydrochloric acid (6 mL) and water (6 mL), and the reaction was stirred at room temperature for 0.5 hours. The reaction system was cooled to -5 °C, and sodium nitrite (563 mg, 8.16 mmol) / water (3 mL) was added dropwise. After the addition was complete, the reaction was stirred at approximately -5 °C for 0.5 hours to prepare a diazonium salt solution. Acetic acid (15 mL) was added to another reaction flask, which was cooled in an ice bath, and SO2 gas was bubbled through it for about 0.5 hours. CuCl2 (273 mg, 2.03 mmol) was then added. The reaction system was cooled to -5 °C, and the diazonium salt solution prepared above was added dropwise. After the addition was complete, the reaction was stirred at the same low temperature for 0.5 hours, and then the reaction system was warmed to room temperature and stirred for 1 hour. After the reaction was complete, ice water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-29%) to give a white solid compound 118-3 (300 mg, yield: 21.2%). LCMS (m / z): 283.3 [M-1] - .

[0916] Step 3: Synthesis of compound 118-4

[0917] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 118-3 (38.7 mg, 0.137 mmol) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 118-4 (50 mg, yield: 45.0%). LCMS (m / z): 889.1 [M+1] + .

[0918] Step 4: Synthesis of compound 118-5

[0919] Compound 118-5 (50 mg, 0.056 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (10 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by normal phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 118-5 (11.9 mg, yield: 30.2%).

[0920] 1 H NMR (400MHz, MeOD) δ8.29(d,J=8.8Hz,1H),8.03(s,1H),7.60(d,J=8.7Hz,1H),7.43-7.29(m,5H),5.60(d,J=9.0Hz ,1H),5.15(s,2H),4.19(s,2H),3.94(d,J=9.5Hz,2H),3.71(s,2H),2.29(d,J=9.3Hz,1H); LCMS(m / z):701.3[M+1] + .

[0921] Step 5: Synthesis of Compound 118

[0922] Compound 118-5 (10 mg, 0.014 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, 0.5% acetic acid aqueous solution (5 mL) was added, and the mixture was stirred for 10 minutes. The catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 118 (6.5 mg, yield: 80.3%).

[0923] 1 H NMR(400MHz,MeOD)δ8.23(d,J=8.7Hz,1H),8.10(s,1H),7.57(d,J=8.7Hz,1H),5.52(d,J=9.5Hz,1H), 4.26-4.16(m,2H),4.04(d,J=13.1Hz,2H),3.64(s,2H),2.28(d,J=9.4Hz,1H); LCMS(m / z):567.5[M+1] + .

[0924] Example 118: Synthesis of 6-fluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indazole-3-sulfonamide (compound 119)

[0925] Step 1: Synthesis of Compound 119-2

[0926] Compound 119-1 (739 mg, 4.89 mmol) was dissolved in a solution of concentrated hydrochloric acid (6 mL) and water (6 mL), and the reaction was stirred at room temperature for 0.5 hours. The reaction system was then cooled to -5°C, and sodium nitrite (563 mg, 8.16 mmol) / water (2 mL) was added dropwise. After the addition was complete, the reaction was stirred at low temperature for another 0.5 hours to prepare a diazonium salt solution. Acetic acid (15 mL) was added to another reaction flask, which was cooled in an ice bath, and SO2 gas was bubbled through it for approximately 0.5 hours. CuCl2 (273 mg, 2.03 mmol) was then added, and the temperature was lowered to -5°C. The diazonium salt solution prepared above was then added dropwise. After the addition was complete, the reaction was stirred at low temperature for another 0.5 hours, then raised to room temperature and stirred for another hour. After the reaction was complete, ice water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-29%) to give a white solid compound 119-2 (230 mg, yield: 20.1%). LCMS (m / z): 233.1 [M-1] - .

[0927] Step 2: Synthesis of Compound 119-3

[0928] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 119-2 (32.1 mg, 0.137 mmol) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 119-3 (85 mg, yield: 81.2%). LCMS (m / z): 839.3 [M+1] + .

[0929] Step 3: Synthesis of Compound 119-4

[0930] Compound 119-3 (85 mg, 0.101 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 119-4 (15 mg, yield: 22.8%). LCMS (m / z): 651.3 [M+1]+ .

[0931] Step 5: Synthesis of Compound 119

[0932] Compound 119-4 (15 mg, 0.023 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, 0.5% acetic acid aqueous solution (5 mL) was added, and the mixture was stirred for another 10 minutes. The catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid compound 119 (6.5 mg, yield: 54.6%).

[0933] 1 H NMR (400MHz, CD3OD) δ8.07 (dd, J=9.0, 5.1Hz, 1H), 7.38 (dd, J=9.1, 1.9Hz, 1H), 7.25-7.19 (m, 1H), 5.53 (d,J=9.4Hz,1H),4.19(s,2H),3.97(s,2H),3.66(s,2H),2.26(d,J=9.0Hz,1H); LCMS(m / z):517.5[M+1] + .

[0934] Example 119: Synthesis of 6-chloro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indazole-3-sulfonamide (compound 120)

[0935] Step 1: Synthesis of Compound 120-2

[0936] Compound 120-1 (1.5 g, 9.64 mmol) was dissolved in ethanol (15 mL), and 80% hydrazine hydrate (3 mL) was added. The reaction mixture was heated to 80 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, concentrated, and dried to obtain a crude product. Petroleum ether was added to the crude product to form a slurry, which was then filtered. The filter cake was collected and dried to give a yellow solid compound 120-2 (1.6 g, 99% yield). LCMS (m / z): 168.4 [M+1] + .

[0937] Step 2: Synthesis of Compound 120-3

[0938] Compound 120-3 (1 g, 5.97 mmol) was dissolved in a solution of hydrochloric acid (6 mL) and water (6 mL). The reaction system was cooled to 0-5 °C in an ice bath, and sodium nitrite (1.03 g, 14.93 mmol) / water (4 mL) was added dropwise. After the addition was complete, the reaction was stirred at low temperature for 1 hour to prepare a diazonium salt solution. Acetic acid (8 mL) was added to another reaction flask, which was cooled in an ice-water bath, and SO2 gas was introduced. After continuous bubbling for about 30 minutes, copper chloride (241 mg, 1.79 mmol) was added, followed by the diazonium salt solution prepared above. After stirring for half an hour, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give a yellow solid compound 120-3 (420 mg, yield: 28%).

[0939] Step 3: Synthesis of Compound 120-4

[0940] Compound B3 (86 mg, 0.134 mmol) was dissolved in a solution of pyridine (42.3 mg, 0.53 mmol) and dichloromethane (2 mL). Compound 120-3 (50 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-48%) to give a colorless oily compound 120-4 (90 mg, yield: 78.4%). LCMS (m / z): 855.4 [M+1] + .

[0941] Step 4: Synthesis of Compound 120-5

[0942] Compound 120-4 (90 mg, 0.105 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL). The reaction mixture was heated to 60 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, concentrated, and dried. The crude product was purified by normal-phase column chromatography to give a white solid compound 120-5 (44 mg, yield: 62.7%). LCMS (m / z): 667.4, 669.1 [M+1] + .

[0943] Step 5: Synthesis of Compound 120

[0944] Compound 120-5 (40 mg, 0.06 mmol) was dissolved in a solution of triethylamine (100 mg, 0.99 mmol), triethylsilane (90 mg, 0.77 mmol), and dichloromethane (8 mL). Palladium chloride (5 mg) was added, and the atmosphere was purged with nitrogen. The mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated and dried. The crude product was purified by preparative liquid chromatography to give a white solid compound 120 (1.32 mg, yield: 4.13%).

[0945] 1 H NMR (400MHz, CD3OD) δ8.05(d,J=8.7Hz,1H),7.71(d,J=1.2Hz,1H),7.34(dd,J=8.8,1.7Hz,1H),5.54(d, J=10.1Hz,1H),4.20(s,2H),4.07-3.91(m,2H),3.66(s,2H),2.24-2.19(m,1H); LCMS(m / z):533.3[M+1] + .

[0946] Example 120: Synthesis of 6-methyl-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1H-indazole-3-sulfonamide (compound 121)

[0947] Step 1: Synthesis of Compound 121-2

[0948] Compound 121-1 (1.0 g, 7.40 mmol) was dissolved in a solution of ethanol (10 mL) and 80% hydrazine hydrate (740 mg, 11.83 mmol). The reaction system was heated to 95 °C and stirred for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-56%) to give a white solid compound 121-2 (1.0 g, yield: 91.7%). LCMS (m / z): 148.3 [M+1] + .

[0949] Step 2: Synthesis of compound 121-3

[0950] Compound 121-2 (720 mg, 4.89 mmol) was added to a solution of concentrated hydrochloric acid (6 mL) and water (6 mL), and the mixture was stirred at room temperature for 0.5 hours. The reaction system was then cooled to -5°C, and sodium nitrite (563 mg, 8.16 mmol) / water (2 mL) was added dropwise. The mixture was stirred at low temperature for 0.5 hours to prepare a diazonium salt solution. In another reaction flask, acetic acid (15 mL) was added, the flask was cooled in an ice bath, and SO2 gas was bubbled through it for about 0.5 hours. CuCl2 (273 mg, 2.03 mmol) was then added, and the mixture was cooled to -5°C. The diazonium salt solution prepared above was then added dropwise. After the addition was complete, the mixture was stirred at low temperature for another 0.5 hours, and then the reaction system was brought to room temperature and stirred for 1 hour. After the reaction was complete, ice water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-29%) to give a white solid compound 121-3 (150 mg, yield: 13.3%). LCMS (m / z): 229.1 [M-1] - .

[0951] Step 3: Synthesis of compound 121-4

[0952] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL). Compound 121-3 (31.3 mg, 0.136 mmol) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, water (15 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give a white solid compound 121-4 (85 mg, yield: 81.5%). LCMS (m / z): 835.3 [M+1] + .

[0953] Step 4: Synthesis of Compound 121-5

[0954] Compound 121-4 (85 mg, 0.102 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (10 mL), and the mixture was stirred for 16 hours under nitrogen protection and at 60 °C. After the reaction was complete, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 121-5 (20.4 mg, yield: 31.0%).

[0955] 1 H NMR (400MHz, MeOD) δ7.83(d,J=8.4Hz,1H),7.31(s,1H),7.29-7.15(m,5H),7.08(dd,J=8.5,0.9Hz,1H),5.45(d,J=9.3H z,1H),4.98(s,2H),4.06(s,2H),3.81(s,2H),3.55(s,2H),2.41(s,3H),2.15(d,J=9.5Hz,1H); LCMS(m / z):647.3[M+1] + .

[0956] Step 5: Synthesis of Compound 121

[0957] Compound 121-5 (15 mg, 0.023 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (1 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, 0.5% aqueous acetic acid (5 mL) was added, and the mixture was stirred for another 10 minutes. The catalyst was removed by filtration, and the filtrate was concentrated, dried, and lyophilized to give a white solid, compound 121 (11.0 mg, yield: 92.5%).

[0958] 1 H NMR (400MHz, MeOD) δ7.93(d,J=8.6Hz,1H),7.50(s,1H),7.25(d,J=8.5Hz,1H),5.52(d,J=9.4Hz,1H),4.2 1(d,J=23.5Hz,2H),4.02(s,2H),3.61(s,2H),2.53(s,3H),2.28(d,J=9.6Hz,1H); LCMS(m / z):513.5[M+1] + .

[0959] Example 121: N1-methyl-N 4 Synthesis of -(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1,4-benzenedisulfonamide (compound 122)

[0960] Step 1: Synthesis of Compound 122-2

[0961] Compound 122-1 (1 g, 4.0 mmol), benzyl mercaptan (744 mg, 6.0 mmol), Pd2(dba)3 (109 mg, 0.12 mmol), and Xantphos (46 mg, 0.08 mmol) were dissolved in a solution of diisopropylethylamine (1.55 g, 12 mmol) and 1,4-dioxane (15 mL). The mixture was purged with nitrogen, heated to 100 °C, and stirred for 3 hours. The mixture was then cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give compound 122-2 (1.04 g, yield: 88.7%) as a yellow solid. LCMS (m / z): 294.4 [M+1] + .

[0962] Step 2: Synthesis of Compound 122-3

[0963] Compound 122-2 (400 mg, 1.70 mmol) was dissolved in a solution of acetonitrile (3 mL), acetic acid (3 mL), and water (3 mL). Under ice bath cooling, NCS (911 mg, 6.82 mmol) was added in portions. After the addition was complete, the mixture was stirred under ice bath conditions for 4 hours. After the reaction was complete, water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography to give a colorless oily compound 122-3 (210 mg, yield: 45.7%).

[0964] Step 3: Synthesis of compound 122-4

[0965] Compound B3 (90 mg, 0.14 mmol) was dissolved in a solution of pyridine (44.5 mg, 0.56 mmol) and dichloromethane (3 mL), and then compound 122-3 (57 mg, 0.21 mmol) was added. The mixture was stirred at room temperature for 2.5 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-48%) to give a colorless oily compound 122-4 (85 mg, yield: 69.2%). LCMS (m / z): 874.4 [M+1] + .

[0966] Step 4: Synthesis of Compound 122-5

[0967] Compound 122-4 (85 mg, 0.097 mmol) was dissolved in a solution of trifluoroacetic acid (4.5 mL) and water (6 mL), and the mixture was heated to 60 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, concentrated, and dried to obtain the crude product. The crude product was purified by normal-phase column chromatography to give a white solid compound 122-5 (50 mg, yield: 75%). LCMS (m / z): 686.4 [M+1] + .

[0968] Step 5: Synthesis of Compound 122

[0969] Compound 122-5 (50 mg, 0.073 mmol) was dissolved in methanol (6 mL), and 10% palladium hydroxide / carbon (5 mg) was added to replace the hydrogen gas. The mixture was stirred at room temperature for 6 hours, filtered, and the filter cake was washed with methanol. The filtrate was concentrated and dried to obtain the crude product. The crude product was purified by preparative liquid chromatography to give a white solid compound 122 (3.01 mg, yield: 7.5%).

[0970] 1 H NMR (400MHz, CD3OD) δ8.15-8.10(m,2H),8.04(d,J=8.7Hz,2H),5.53(d,J=9.4Hz,1H),4.14(d,J=1 3.4Hz,2H),3.92(s,2H),3.55(s,2H),2.60(s,3H),2.22(d,J=7.2Hz,1H); LCMS(m / z):552.2[M+1] + .

[0971] Example 122: N1,N1-dimethyl-N 4 Synthesis of -(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)-1,4-benzenedisulfonamide (compound 123)

[0972] Step 1: Synthesis of Compound 123-2

[0973] Compound 123-1 (1.05 g, 4.0 mmol), benzyl mercaptan (595.2 mg, 4.8 mmol), Pd2(dba)3 (366.2 mg, 0.4 mmol), and Xantphos (462.4 mg, 0.8 mmol) were dissolved in a solution of diisopropylethylamine (1.03 g, 8.0 mmol) and 1,4-dioxane. The reaction mixture was stirred at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%–30%) to give compound 123-2 (990 mg, yield: 81.0%) as an off-white solid. LCMS (m / z): 308.1 [M+1] + .

[0974] Step 2: Synthesis of Compound 123-3

[0975] Compound 123-2 (1 g, 3.25 mmol) was dissolved in acetonitrile (6 mL), and water (3 mL) and acetic acid (2 mL) were added. The reaction system was cooled to 0 °C, and NCS (1.42 g, 10.63 mmol) was added in portions. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a colorless liquid compound 123-3 (430 mg, yield: 46.6%).

[0976] Step 3: Synthesis of Compound 123-4

[0977] Compound B3 (80 mg, 0.125 mmol) was dissolved in a solution of pyridine (36.8 mg, 0.47 mmol) and dichloromethane (5 mL), and then compound 123-3 (38.7 mg, 0.136 mmol) was added. The reaction was carried out under nitrogen protection and stirred at room temperature for 3 hours. After the reaction was complete, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, concentrated, and dried. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to give a white solid compound 123-4 (85 mg, yield: 76.7%). LCMS (m / z): 888.5 [M+1] + .

[0978] Step 4: Synthesis of Compound 123-5

[0979] Compound 123-4 (85 mg, 0.096 mmol) was dissolved in a solution of trifluoroacetic acid (6 mL) and water (4 mL), and the reaction was carried out under nitrogen protection and stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and dried. The crude product was purified by normal-phase column chromatography (methanol / dichloromethane = 8%-10%) to give a white solid compound 123-5 (21.3 mg, yield: 31.8%). LCMS (m / z): 700.3 [M+1] + .

[0980] Step 5: Synthesis of Compound 123

[0981] Compound 123-5 (21 mg, 0.03 mmol) was dissolved i...

Claims

1. A compound having the structure of Formula (I): ###0001### or a pharmaceutically acceptable derivative thereof. ​ wherein, X is selected from -(CH2) m - and carbonyl, wherein the -CH2- is optionally substituted with at least one R X substituent; R1is selected from the group consisting of hydrogen, -(C=0)OR3, and -0(C=0)R4; R2is selected from the group consisting of amino, guanidino, ureido and wherein said amino, guanidino and urea groups are optionally substituted with at least one R X substituted; R3and R4are each independently selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, three- to eight-membered heterocyclyl, C 6-20 aryl, C 1-8 alkyl-C 6-20 aryl, five- to twenty-membered heteroaryl, and C 1-8 alkyl-five- to twenty-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with at least one R X substituent; R5is selected from the group consisting of hydrogen, hydroxyl, and cyano; R6is selected from the group consisting of hydroxy, thiol, C 1-12 alkyl, -O-C 1-12 alkyl, C 3-8 cycloalkyl, three- to eight-membered heterocyclyl, C 6- 10 aryl and five- to ten-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with at least one R X substituent; or R5and R6together with the atoms to which they are attached form a five- to twelve-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R X substituted; Each R X Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1- 8-alkyl, C 3-20 cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, C 1-8 Alkyl-ternary to octahedral heterocyclic groups, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aromatic, penta- to deca-aryl, C 1-8 Alkyl-penta-to-deca-aryl, wherein said carboxyl, amino, formyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with at least one R Y substituent; R7is selected from the group consisting of hydroxy, thiol, amino, C 1-12 alkyl, -O-C 1-12 alkyl, C 3-8 cycloalkyl, three- to eight-membered heterocyclyl, C 6-10 aryl and five- to ten-membered heteroaryl, wherein the amino, alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with at least one R Y substituent; Each R Y Independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, formyl, acetyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, ternary to octahedral heterocyclic groups, -O-ternary to octahedral heterocyclic groups, C 1- 8-alkyl-ternary to octahedral heterocyclic groups, C 6-10 Aryl, -OC 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, penta- to deca-aryl, -O- penta- to deca-aryl, C 1-8 Alkyl-penta-to-deca-aryl and wherein said amino, formyl, acetyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, C 1-8 alkyl, -O-C 1-8 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl; m is an integer selected from 1-6; with the proviso that the compound of formula (I) is not a compound of the following structure:

2. The compound of claim 1 or a pharmaceutically acceptable derivative thereof, wherein, X is methylene, formula (I) has the structure of formula (II): wherein, R1is as defined in claim 1 ; R6is selected from the following structures:

3. The compound of claim 1 or a pharmaceutically acceptable derivative thereof, wherein, X is methylene, formula (I) has the structure of formula (III): where, R1and R7are as defined in claim 1.

4. The compound of claim 1 or a pharmaceutically acceptable derivative thereof, wherein, X is carbonyl, Formula (I) has the structure of Formula (IV): where, R1and R6are as defined in claim 1.

5. The compound of claim 1 or a pharmaceutically acceptable derivative thereof, wherein R1is hydrogen or -(C=0)OR3.

6. The compound of claim 5 or a pharmaceutically acceptable derivative thereof, wherein R3is benzyl.

12. The compound of claim 7 or a pharmaceutically acceptable derivative thereof, wherein R5is hydrogen.

7. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein R2 is selected from the group consisting of ureido and wherein the ureido is optionally substituted with at least one R X .

8. The compound of claim 7, or a pharmaceutically acceptable derivative thereof, wherein the R X is 9. The compound of claim 8, or a pharmaceutically acceptable derivative thereof, wherein R7 is selected from the group consisting of hydroxy, amino, C 1-12 alkyl, C 3-8 cycloalkyl, three- to eight-membered heterocyclyl, C 6-10 aryl, and five- to ten-membered heteroaryl, wherein the amino, alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted with at least one R Y substituent.

10. The compound of claim 9, or a pharmaceutically acceptable derivative thereof, wherein the R Y selected from halogen, hydroxyl, amino, C 1-8 alkyl, -O-C 1-8 alkyl, wherein the alkyl is optionally substituted with at least one halogen.

11. The compound of claim 8 or 9, or a pharmaceutically acceptable derivative thereof, wherein R7 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 17. The compound of claim 1 or a pharmaceutically acceptable derivative thereof, wherein X is methylene or carbonyl.

13. The compound of claim 7, or a pharmaceutically acceptable derivative thereof, wherein R6 is selected from the group consisting of C 1-12 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, and a five- to ten-membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, and heteroaryl are optionally substituted with at least one R X substituent.

14. The compound of claim 13, or a pharmaceutically acceptable derivative thereof, wherein the R X is selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, formyl, C 1-8 alkyl, -O-C 1-8 alkyl, C 3-20 cycloalkyl, and heterocyclyl, wherein the carboxyl, formyl, alkyl, cycloalkyl, and heterocyclyl are optionally substituted with at least one R Y .

15. The compound of claim 14, or a pharmaceutically acceptable derivative thereof, wherein the R Y is selected from the group consisting of halogen, hydroxy, amino, C 1-8 alkyl, -O-C 1-8 alkyl.

16. The compound of any one of claims 13-15, or a pharmaceutically acceptable derivative thereof, wherein the R6 is selected from methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, Preferably, said R6is selected from More preferably, said R6is selected from 21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-20 or a pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable carriers.

18. The compound of claim 17, or a pharmaceutically acceptable derivative thereof, wherein X is methylene and R2 is selected from Preferably, X is methylene and R2is selected from 19. The compound of claim 17, or a pharmaceutically acceptable derivative thereof, wherein X is carbonyl and R2 is selected from Preferably, said X is carbonyl, said R2is selected from 20. A compound or pharmaceutically acceptable derivative thereof having the structure: preferably 22. Use of a compound of any one of claims 1-20 or a pharmaceutically acceptable derivative or the pharmaceutical composition of claim 18 in the manufacture of a medicament for treating a disease or condition associated with a sodium ion channel or for analgesia.

23. The use of claim 22, wherein, the disease or condition associated with a sodium ion channel comprises pain, including neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, labor pain, labor pain, chronic pain, persistent pain, peripherally-mediated pain, centrally-mediated pain, chronic headache, migraine, cluster, tension, phantom, dental, HIV-related pain, acute pain, multiple sclerosis (MS)-related pain, familial rectal pain, fibromyalgia, or pain resulting from a condition including depression, cardiovascular disease, neurogenic bladder, ulcerative colitis, respiratory disease, psychiatric disease, peripheral nerve injury, HIV treatment-induced neuropathy, thermosensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudohypoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythromelalgia, primary erythromelalgia, epilepsy, epileptic encephalopathy, partial and general tonic seizures, restless leg syndrome, cardiac arrhythmia, tachyarrhythmia, atrial or ventricular fibrillation; ​ The pain targeted by the analgesic needle includes neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, labor pain, labor pain, chronic pain, persistent pain, peripherally-mediated pain, centrally-mediated pain, chronic headache, migraine, cluster, tension, phantom limb pain, dental pain, HIV-related pain, acute pain, multiple sclerosis (MS)-related pain, familial rectal pain, fibromyalgia, or pain including that resulting from depression, cardiovascular disease, neurogenic bladder, ulcerative colitis, respiratory disease, psychiatric disease, peripheral nerve injury, HIV treatment-induced neuropathy, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, muscular rigidity, malignant hyperthermia, cystic fibrosis, pseudohypoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythromelalgia, primary erythromelalgia, epilepsy, epileptic encephalopathy, focal and generalized tonic seizures, restless leg syndrome, cardiac arrhythmia, tachyarrhythmia, atrial or ventricular fibrillation.

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