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 thereof, and the use thereof as a pan sodium ion channel blocker.

Description

Tetrodotoxin derivative compounds and their use as sodium channel blockers Technical Field

[0001] The present invention relates to a compound having an inhibitory effect on multiple sodium ion channels or a pharmaceutically acceptable derivative thereof and a pharmaceutical composition thereof, as well as use of the compound as a pan-sodium ion channel blocker. Background Art

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

[0003] Tetrodotoxin has a local irritating effect on the intestines. Once absorbed, it rapidly acts on nerve endings and nerve centers, selectively and with high affinity, blocking sodium ion channels on nerve excitatory membranes. This impedes nerve conduction, causing nerve paralysis and death. Clinically, tetrodotoxin is used for analgesia, local anesthesia, sedation, antispasmodics, blood pressure reduction, and antiarrhythmic effects. However, its strong toxicity limits its use.

[0004] Voltage-gated sodium channels (VGSCs) are a type of microporous transmembrane glycoprotein widely distributed on the membranes of excitable cells such as neurons. +Voltage-gated sodium channels are the primary ion channels required for neuronal excitability and normal electrophysiological function. Voltage-gated sodium channels are composed of an α subunit and multiple β subunits. The α subunit is the primary functional unit, with nine subtypes (Nav1.1 to Nav1.9) identified. It consists of four highly similar homologous domains surrounding a central core, forming the central pore of the ion channel. Each domain has six α-helical transmembrane segments (S1-S6). The amino acid sequence of S4 is highly conserved and is considered the voltage sensor of voltage-gated sodium channels. The β subunit, of which there are four subtypes (β1-β4), assists in the localization and stability of the α subunit on the membrane and is involved in regulating its voltage sensitivity and inactivation. Voltage-gated sodium channels in different animal species share extensive homology, but also exhibit significant differences. Sodium channels are classified based on their sensitivity to tetrodotoxin (TTX) blockade as TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). TTX-R type sodium ion channels include Nav1.5, Nav1.8 and Nav1.9, and the rest are TTX-S type sodium ion channels. Nav1.7 is a transmembrane protein encoded by SCN9A, which is specifically expressed in peripheral sensory nerve endings and sympathetic ganglion neurons, and is mainly expressed on large-diameter dorsal root ganglion (DRG) neurons and unmyelinated small-diameter DRG, that is, it is expressed on 85% of nociceptors, which shows that Nav1.7 plays a very critical role in pain conduction. Nav1.7 plays a core role in the conduction and maintenance of pain signals and has become a very important target for the development of analgesic drugs. The compounds in the present invention are structurally modified and optimized for tetrodotoxin, and the obtained tetrodotoxin derivatives have significant inhibitory activity against TTX-S type sodium ion channels (including Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7), and are pan-sodium ion channel blockers.

[0005] In the prior art, tetrodotoxin-based derivatives are primarily derived from isolation and extraction from nature. 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 reports of laboratory synthesis of some tetrodotoxin derivatives. For example, 11-Deoxytetrodotoxin (J.AM.CHEM.SOC.2002,124,7847-7852), 8,11-Dideoxytetrodotoxin (Chem.Eur.J.2004,10,452-462) and the like.

[0006] Summary of the Invention

[0007] The first aspect of the present invention provides a compound or a pharmaceutically acceptable derivative thereof, wherein the compound has a structure of formula (I):

[0008] in,

[0009] X is absent or selected from -(CH2) m -and wherein the -CH2- is optionally replaced by -O- or a carbonyl group or optionally replaced by at least one R X replace;

[0010] Y1 and Y2 are each independently selected from methylene, O, S and NH, wherein the methylene and NH are optionally replaced by at least one R X replace;

[0011] R1 and R3 are each independently selected from hydrogen, hydroxy, amino, cyano, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3- 8 cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0012] R2 is selected from hydrogen, hydroxy, amino, formyl, acetyl, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, -(C=O)OR 10 and -O(C=O)R 11 wherein the formyl, acetyl, alkyl, cycloalkyl and heterocyclic groups are optionally replaced by at least one R X replace;

[0013] Each R4 is independently selected from hydrogen, deuterium, hydroxyl, halogen, -OR 12 and C 1-8 alkyl;

[0014] or R3 and R4 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R X replace;

[0015] R5 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 13 ;

[0016] R6 is selected from hydroxy, thiol, amino, azido, halogen, cyano, C 1-12 Alkyl, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl, C 5-10 Heteroaryl, -(C=O)-R 14 , guanidine, urea, -(OCH2CH2) n -OH, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, guanidinyl and ureido groups are optionally replaced by at least one R X replace;

[0017] or R5 and R6 together with the atoms to which they are attached form a 3-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R X replace;

[0018] R7 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 Alkyl, -OC1-4 Alkyl, C 3-8 Cycloalkyl and C 3-8 Heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl groups are optionally substituted by at least one R X replace;

[0019] R8 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 15 ;

[0020] or R4 and R8 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by at least one R X replace;

[0021] R9 is selected from hydrogen, deuterium, tritium, hydroxyl, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 16 ;

[0022] R 10 and R 11 Each independently selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-20 Aryl, C 1-8 Alkyl-C 6-20 Aryl, C 5-20 Heteroaryl and C 1-8 Alkyl-C 5-20 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0023] Each R 12 、R 13 、R 14 、R 15 and R 16 Each independently selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 3-8 Cycloalkyl, C 1- 8-alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0024] R 6’ Selected from hydrogen, hydroxy, amino, cyano, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0025] R 6” Selected from hydroxyl, thiol, amino, halogen, C 1-12 Alkyl, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0026] Each R X independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1- 8 alkyl, C 2-8 Alkenyl, C 3-20 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl, C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the amino, formyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally replaced by at least one RY replace;

[0027] Each R Y independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, formyl, acetyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, C 3-8 Heterocyclic group, -OC 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, -OC 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl, -OC 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the formyl, acetyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by at least one halogen, hydroxyl or R Y1 replace;

[0028] Each R Y1 Independently selected from amino, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R Y2 replace;

[0029] Each R Y2 Independently selected from amino, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 heteroaryl;

[0030] When X is a methylene group and R1, R2 and R3 are simultaneously hydrogen, R4, R5, R6, R7, R8 and R9 are not simultaneously hydroxyl groups;

[0031] m is an integer selected from 0-6;

[0032] n is an integer selected from 1-12;

[0033] t is an integer selected from 0-4.

[0034] The second aspect of 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.

[0035] A third aspect of the present invention provides a method for treating a disease or condition related to a sodium ion channel, including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof or its pharmaceutical composition to an individual in need thereof, optionally in combination with another therapeutic agent. Accordingly, the present invention also provides the compound of formula (I) or its pharmaceutically acceptable derivative or its pharmaceutical composition for the preparation of a drug for treating a disease or condition related to a sodium ion channel, optionally in combination with another therapeutic agent. The present invention further provides a compound of formula (I) or its pharmaceutically acceptable derivative or its pharmaceutical composition, for treating a disease or condition related to a sodium ion channel, 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 related to the sodium ion channel include pain. In one embodiment, the pain comprises 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, dental pain, HIV-associated pain, acute pain, pain associated with multiple sclerosis (MS), familial rectal pain, fibromyalgia, or pain caused by depression, cardiovascular disease, neurogenic cystitis, ulcerative colitis, respiratory disease, psychiatric disease, peripheral nerve damage, 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, myasthenic syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related disorders, familial erythromelalgia, primary erythromelalgia, epilepsy, epileptic encephalopathy, focal and generalized tonic seizures, restless legs syndrome, cardiac arrhythmia, tachyarrhythmia, atrial fibrillation, or ventricular fibrillation.

[0036] Therefore, the present invention also provides a method for analgesia, including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof to an individual in need thereof, optionally in combination with another therapeutic agent. Accordingly, the present invention also provides the purposes of a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof in the preparation of a medicine 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.

[0037] A fourth aspect of the present invention provides a compound of formula (II) having the following structure:

[0038] wherein X and R6 are as defined herein for the compound of formula (I), and Pg1 and Pg2 are independently selected from acetyl, trityl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), cyclopentyloxycarbonyl and methyloxycarbonyl (Fmoc). BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 shows the inhibition results of the analgesic efficacy test in the acetic acid writhing pain model of ICR mice. Figure 1A shows the results of the analgesic efficacy test of compound TTX-S in the acetic acid writhing pain model of ICR mice; Figure 1B shows the results of the analgesic efficacy test of compound 73 in the acetic acid writhing pain model of ICR mice; Figure 1C shows the results of the analgesic efficacy test of compound 77 in the acetic acid writhing pain model of ICR mice; Figure 1D shows the results of the analgesic efficacy test of compound 199 in the acetic acid writhing pain model of ICR mice; Figure 1E shows the results of the analgesic efficacy test of compound 199-B in the acetic acid writhing pain model of ICR mice; Figure 1F shows the results of the analgesic efficacy test of compound 210 in the acetic acid writhing pain model of ICR mice.

[0040] FIG2 shows the results of analgesic efficacy inhibition test in the rat formalin-induced inflammatory pain model. Figure 2A shows the results of the analgesic efficacy test of compound TTX in the rat formalin-induced inflammatory pain model; Figure 2B shows the results of the analgesic efficacy test of compound 77 in the rat formalin-induced inflammatory pain model; Figure 2C shows the results of the analgesic efficacy test of compound 199 in the rat formalin-induced inflammatory pain model; Figure 2D shows the results of the analgesic efficacy test of compound 199-B in the rat formalin-induced inflammatory pain model; Figure 2E shows the results of the analgesic efficacy test of compound 189 in the rat formalin-induced inflammatory pain model; Figure 2F shows the results of the analgesic efficacy test of compound 223 in the rat formalin-induced inflammatory pain model; Figure 2G shows the results of the analgesic efficacy test of compound 206 in the rat formalin-induced inflammatory pain model; Figure 2H shows the results of the analgesic efficacy test of compound 209 in the rat formalin-induced inflammatory pain model. DETAILED DESCRIPTION

[0041] definition

[0042] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0043] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps, even though the additional unrecited elements or method steps are not necessarily present (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of.").

[0044] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0045] 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, and for example, 1 to 4 carbon atoms. For example, as used herein, the term "C 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), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). Accordingly, "alkoxy" refers to an alkyl group as described herein that is attached to the remainder of the molecule through an oxygen atom.

[0046] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond. In some embodiments, the alkenyl group has 2 to 8 carbon atoms, such as 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0047] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or condensed polycyclic hydrocarbon ring group, including but not limited to a monocyclic alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), a condensed cycloalkyl group, a bridged ring or a spirocyclic structure. In the present invention, the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl group are optionally substituted with oxo groups (i.e., forming C=O). The term "C 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3 to 20 ring-forming 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 ring-forming carbon atoms. The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms, for example, a cycloalkyl group having 3, 4, 5, 6, 7 or 8 ring carbon atoms, for example, C 3-6 Cycloalkyl, which may be a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a fused cycloalkyl, such as C 5-8 Condensed cycloalkyl or C 5-6 Fused cycloalkyl.

[0048] As used herein, the term "heterocyclyl" or "heterocycle" refers to an aliphatic monocyclic, fused polycyclic, bridged or spirocyclic group having 2 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, including but not limited to oxygen atoms, nitrogen atoms and sulfur atoms, the carbon atoms and heteroatoms on the heterocyclyl group are optionally substituted with oxo groups (e.g., to form C=O, S(=O) or S(=O)2), and the carbon atoms and heteroatoms on the heterocyclyl group may also be optionally substituted with nitrogen-containing groups (e.g., to form C=NH).

[0049] As used herein, the term “C 3-8 "Heterocyclyl" means a heterocyclyl containing 3-8 ring atoms, such as a heterocyclyl containing 3, 4, 5, 6, 7 or 8 ring atoms, including but not limited to a 3-8 membered heterocyclyl, a 3-7 membered heterocyclyl, a 4-8 membered heterocyclyl, a 4-7 membered heterocyclyl, a 5-6 membered heterocyclyl, a 3-6 membered heterocyclyl, a 4-7 membered nitrogen-containing heterocyclyl, a 4-7 membered oxygen-containing heterocyclyl, a 4-7 membered sulfur-containing heterocyclyl, a 5-6 membered nitrogen-containing heterocyclyl, a 5-6 membered oxygen-containing heterocyclyl, a 5-6 membered sulfur-containing heterocyclyl, etc., wherein each of the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" optionally further contains one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 3-8 membered heterocyclyls include but are not limited to oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (such as ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,

[0050] In the present invention, the heterocyclic group can form a parallel ring structure with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other group can be on any heterocyclic group or cycloalkyl group. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic and heterocyclic groups, heterocyclic and cycloalkyl groups, monoheterocyclic and monoheterocyclic groups, and monoheterocyclic and monocycloalkyl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and (mono) cycloalkyl groups, 3-7 membered (mono) heterocyclic groups and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0051] The term "aryl" may contain 6 to 20 carbon atoms (C6-20 aryl), for example 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, for example 6-14 carbon atoms (C 6-14 Aryl) or 6-10 carbon atoms (C 6-10 "Aryl" includes six-membered aromatic carbocyclic rings, such as phenyl; bicyclic rings containing at least one aromatic carbocyclic ring, such as naphthyl, indanyl, and 1,2,3,4-tetrahydroquinoline; and tricyclic rings containing at least one aromatic carbocyclic ring, such as fluorene. If an aryl substituent is bicyclic or tricyclic and at least one of the rings is non-aromatic, the linkage is considered to be through the aromatic ring. For example, aryl includes six-membered aromatic carbocyclic rings fused to a five- to seven-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, provided that the point of linkage is through the aromatic carbocyclic ring.

[0052] 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, in certain 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, wherein at least one heteroatom is 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, wherein at least one heteroatom is present in the aromatic ring. The term "C 5-20 "Heteroaryl" refers to a heteroaryl group containing 5 to 20 ring atoms, for example, 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, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl (e.g., ), triazolyl, triazinyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl and the like.

[0053] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0054] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced by a group selected from the designated group, provided that the normal valence of the designated atom in the current context is not exceeded and that the substitution results in a stable compound, e.g., two hydrogen atoms on the designated carbon atom are replaced by the designated group across a double bond. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0055] If a substituent is described as "optionally substituted with at least one" or "optionally substituted with one or more," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0056] If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent. The groups described herein may be optionally substituted with one or more substituents. Useful substituents include, but are not limited to, deuterium, tritium, hydroxyl, amino, cyano, sulfhydryl, azido, guanidino, ureido, halogen, alkyl, cycloalkyl, heterocyclyl, alkoxy, alkenyl, aryl, heteroaryl, and heterocyclyl, etc., as described herein.

[0057] As used herein, the term "at least one" or similar expressions "one or more" means 1 or more under reasonable conditions, for example, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0058] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0059] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0060] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a separate diastereomer. 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-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oxime can exist in the following tautomeric form equilibrium in solution:

[0061] It is to be understood that the scope of the present invention encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0062] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, 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, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0063] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0064] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate salts and meglumine salts.

[0065] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, which can be removed at an appropriate subsequent stage using methods known in the art.

[0066] "Protecting group" (Pg) refers to a substituent that blocks or protects a specific functional group by reacting with other functional groups on a compound. For example, an "amino protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality on the compound. Suitable amino protecting groups include acetyl, trityl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), cyclopentyloxycarbonyl, and methyloxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent that effectively blocks or protects the hydroxyl function. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent that effectively blocks or protects the carboxyl function. Commonly used carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonamido)ethyl, 2-(p-nitrophenylthio)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, and the like. For a general description and instructions for use of protecting groups, see reference: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0067] The term "pharmaceutically acceptable derivative" refers to a compound or pharmaceutically acceptable excipient in the form of a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, enantiomer, tautomer or isotope-labeled compound or a mixture thereof. "Pharmaceutically acceptable salts" include but are not limited to salts made with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases can be selected from, for example: aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc salts. Further, pharmaceutically acceptable salts of inorganic bases can be selected from ammonium, calcium, magnesium, potassium, sodium salts. One or more crystal structures may exist in the solid salt, and it may also exist in the form of a hydrate. Salts of pharmaceutically acceptable organic non-toxic bases can be selected from, for example, salts of primary, secondary and tertiary amines, substituted amines including 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, hydralazine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0068] The term "effective amount" refers to a dose of the target compound or its pharmaceutically acceptable derivative that can induce a biological or medical response in a tissue, system, animal or human that can be observed by researchers, veterinarians, clinicians or other clinical personnel.

[0069] The term "composition" includes any product comprising the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from the combination of these specified ingredients in the specified amounts. Pharmaceutical compositions include any product comprising the active ingredient and an inert carrier, as well as any product resulting directly or indirectly from the combination, compounding, or aggregation of two or more ingredients, or from the decomposition of one or more ingredients, or from any other type of reaction or interaction of one or more ingredients.

[0070] The term "pharmaceutically acceptable" means compatible with the other ingredients of the formulation and not unacceptably harmful to the user.

[0071] The term "subject" refers to an individual suffering from a disease, condition, or the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of the class mammals: 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, and the like. In one embodiment, the mammal is a human.

[0072] The term "treating" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, arresting the development of the disease or symptom, alleviating the disease or symptom, promoting remission of the disease or symptom, or causing the cessation of symptoms of the disease or symptom and extending to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the patient taking the composition to prevent the risk of a certain disease, or taking it when the patient develops one or more physiological signs of a disease, although the disease has not yet been diagnosed.

[0073] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0074] As used herein, the term "therapeutic window" refers to the range of drug dosage or concentration within which a drug is effective in treating a disease without producing unacceptable toxic effects.

[0075] Compounds of the present invention

[0076] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable derivative thereof, wherein the compound has the structure of Formula (I):

[0077] in,

[0078] X is absent or selected from -(CH2) m -and wherein the -CH2- is optionally replaced by -O- or a carbonyl group or optionally replaced by at least one R X replace;

[0079] Y1 and Y2 are each independently selected from methylene, O, S and NH, wherein the methylene and NH are optionally replaced by at least one R X replace;

[0080] R1 and R3 are each independently selected from hydrogen, hydroxy, amino, cyano, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3- 8 cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0081] R2 is selected from hydrogen, hydroxy, amino, formyl, acetyl, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, -(C=O)OR 10 and -O(C=O)R 11 wherein the formyl, acetyl, alkyl, cycloalkyl and heterocyclic groups are optionally replaced by at least one R X replace;

[0082] Each R4 is independently selected from hydrogen, deuterium, hydroxyl, halogen, -OR 12 and C 1-8 alkyl;

[0083] or R3 and R4 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R X replace;

[0084] R5 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 13 ;

[0085] R6 is selected from hydroxy, thiol, amino, azido, halogen, cyano, C 1-12 Alkyl, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl, C 5-10 Heteroaryl, -(C=O)-R 14 , guanidine, urea, -(OCH2CH2) n -OH, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, guanidinyl and ureido groups are optionally replaced by at least one R X replace;

[0086] or R5 and R6 together with the atoms to which they are attached form a 3-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R X replace;

[0087] R7 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-8 Cycloalkyl and C 3-8 Heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl groups are optionally substituted by at least one R X replace;

[0088] R8 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 15 ;

[0089] or R4 and R8 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by at least one R X replace;

[0090] R9 is selected from hydrogen, deuterium, tritium, hydroxyl, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 16 ;

[0091] R 10 and R 11 Each independently selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8Heterocyclic group, C 6-20 Aryl, C 1-8 Alkyl-C 6-20 Aryl, C 5-20 Heteroaryl and C 1-8 Alkyl-C 5-20 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0092] Each R 12 、R 13 、R 14 、R 15 and R 16 Each independently selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 3-8 Cycloalkyl, C 1- 8-alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0093] R 6’ Selected from hydrogen, hydroxy, amino, cyano, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0094] R 6” Selected from hydroxyl, thiol, amino, halogen, C 1-12 Alkyl, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0095] Each R X independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1- 8 alkyl, C 2-8 Alkenyl, C 3-20 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl, C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the amino, formyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally replaced by at least one R Y replace;

[0096] Each R Y independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, formyl, acetyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, C 3-8 Heterocyclic group, -OC 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, -OC 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl, -OC 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the formyl, acetyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by at least one halogen, hydroxyl or R Y1 replace;

[0097] Each R Y1 Independently selected from amino, C1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R Y2 replace;

[0098] Each R Y2 Independently selected from amino, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 heteroaryl;

[0099] When X is a methylene group and R1, R2 and R3 are simultaneously hydrogen, R4, R5, R6, R7, R8 and R9 are not simultaneously hydroxyl groups;

[0100] m is an integer selected from 0-6;

[0101] n is an integer selected from 1-12;

[0102] t is an integer selected from 0-4.

[0103] In some embodiments, X is absent or selected from methylene, carbonyl, and In a specific embodiment, X is absent. It will be understood by those skilled in the art that the absence of X indicates that R6 is directly attached to the remainder of the molecule. In a specific embodiment, X is a methylene group. In a specific embodiment, X is a carbonyl group. In one embodiment, X is a methylene group further supported by an R X In one embodiment, X is methylene, which is further substituted by one R X Substituted, the R X In a specific embodiment, X is methylene, which is further supported by an R X Substituted, the R X For fluorine.

[0104] In some embodiments, Y1 is methylene. In some embodiments, Y1 is O. In some embodiments, Y1 is S. In some embodiments, Y1 is NH.

[0105] In some embodiments, Y2 is methylene. In some embodiments, Y2 is O. In some embodiments, Y2 is S. In some embodiments, Y2 is NH.

[0106] In a specific embodiment, R1 is hydrogen. In a specific embodiment, R1 is hydroxy. In a specific embodiment, R1 is amino. In a specific embodiment, R1 is cyano.

[0107] In some embodiments, R2 is selected from hydrogen, hydroxy, amino, formyl, acetyl, and -(C=O)OR 10 In some embodiments, R2 is selected from hydrogen, acetyl, and -(C=O)OR 10 In a specific embodiment, R2 is hydrogen. In a specific embodiment, R2 is hydroxy. In a specific embodiment, R2 is amino. In a specific embodiment, R2 is formyl. In a specific embodiment, R2 is acetyl. In a specific embodiment, R2 is -(C=O)OR 10 , where R 10 In a specific embodiment, R2 is -(C=O)OR 10 , where R 10 It is cyclopentyl.

[0108] In some embodiments, R3 is selected from hydrogen, hydroxy, amino, cyano, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl and C 1-8 Alkyl-C 6-10 Aryl, wherein the alkyl, cycloalkyl and aryl groups are optionally substituted by at least one R X In some embodiments, R3 is selected from hydrogen, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl and C 1-8 Alkyl-C 6-10 Aryl, wherein the alkyl, cycloalkyl and aryl groups are optionally substituted by at least one R X In some embodiments, R3 is selected from hydrogen, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl and C 1-8 Alkyl-C 6- 10 Aryl, wherein the alkyl, cycloalkyl and aryl groups are optionally substituted by at least one R X Substituted, where R XIn one embodiment, R3 is hydrogen. In one embodiment, R3 is methyl. In one embodiment, R3 is ethyl. In one embodiment, R3 is isopropyl. In one embodiment, R3 is In a specific embodiment, R3 is In a specific embodiment, R3 is In a specific embodiment, R3 is In a specific embodiment, R3 is In a specific embodiment, R3 is In a specific embodiment, R3 is In a specific embodiment, R3 is hydroxy. In a specific embodiment, R3 is amino. In a specific embodiment, R3 is cyano.

[0109] In some embodiments, R4 is selected from hydrogen, deuterium, and hydroxyl. In a specific embodiment, R4 is hydrogen. In a specific embodiment, R4 is deuterium. In a specific embodiment, R4 is hydroxyl.

[0110] In some embodiments, R3 and R4 together with the atoms to which they are attached form a six-membered heterocyclic ring. In some embodiments, the heterocyclic ring formed by R3 and R4 together with the atoms to which they are attached is selected from In a specific embodiment, R3 and R4 together with the atoms to which they are attached form a heterocyclic ring that is In a specific embodiment, R3 and R4 together with the atoms to which they are attached form a heterocyclic ring that is

[0111] In a specific embodiment, R5 is hydroxy. In a specific embodiment, R5 is hydrogen. In a specific embodiment, R5 is deuterium.

[0112] In one embodiment, R5 is halogen. In a specific embodiment, R5 is fluorine.

[0113] In one embodiment, R5 is -OR 13 In a specific embodiment, R5 is methoxy. In a specific embodiment, R5 is

[0114] In some embodiments, R6 is selected from hydroxy, thiol, amino, azido, halogen, cyano, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8 Heterocyclic group, C 5-10 Heteroaryl, guanidino, ureido and wherein the amino, alkyl, heterocyclyl, heteroaryl, guanidinyl and ureido groups are optionally replaced by at least one R X In some embodiments, R6 is selected from hydroxy, thiol, amino, azido, halogen, cyano, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8 Heterocyclic group, C 5-10 Heteroaryl, guanidino, ureido and wherein the amino, alkyl, heterocyclyl, heteroaryl, guanidinyl and ureido groups are optionally replaced by at least one R X Substituted, where R X Selected from hydrogen, halogen, hydroxy, carboxyl, amino, C 1-8 Alkyl, C 1-8 Alkyl-C 6-10 Aryl, C 3-20 Cycloalkyl, C 3-8 Heterocyclic and C 5-10 In some embodiments, R X Selected from halogen, hydroxy, amino, formyl, C 1-8 Alkyl, C 3-20 Cycloalkyl, C 1-8 Alkyl-C 6-10 Aryl, C 3-8 Heterocyclic groups and wherein the amino, formyl, alkyl, cycloalkyl and heterocyclic groups are optionally replaced by at least one R Y In other embodiments, R Y Selected from halogen, hydroxy, carboxyl, formyl, acetyl and C 1-8 Alkyl, wherein the formyl group is optionally replaced by a hydroxyl group or R Y1 In some other embodiments, R Y1 is selected from amino groups, said amino group being optionally replaced by R Y2 In some embodiments, R Y2 Selected from C 1-8 alkyl.

[0115] In some embodiments, R6 is Among them, R 6’ In some embodiments, R6 is selected from hydrogen and methyl. Among them, R 6” Selected from C 1-12 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted by at least one R X In other embodiments, R X Selected from halogen, C1-8 Alkyl, -OC 1-8 Alkyl, C 3-20 Cycloalkyl and C 6-10 Aryl, wherein the alkyl, cycloalkyl and aryl groups are optionally substituted by at least one R Y In some other embodiments, R Y is halogen, and the halogen is fluorine.

[0116] In some embodiments, R6 is selected from hydroxy, halogen, cyano, amino, azido, methoxy, methylamino, tert-butyl, propenyl, guanidino, ureido,

[0117] In some preferred embodiments, R6 is selected from hydroxy, amino, methoxy, methylamino, guanidine, urea,

[0118] In some more preferred embodiments, R6 is selected from hydroxy, amino, methylamino, guanidine, urea,

[0119] In a specific embodiment, R6 is hydroxy. In some embodiments, R6 is selected from halogen. In some embodiments, R6 is fluorine. In some embodiments, R6 is cyano. In some embodiments, R6 is azido. In a specific embodiment, R6 is amino. In a specific embodiment, R6 is methoxy. In a specific embodiment, R6 is methylamino. In a specific embodiment, R6 is tert-butyl. In a specific embodiment, R6 is propenyl. In a specific embodiment, R6 is guanidinyl. In a specific embodiment, R6 is ureido. In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is In a specific embodiment, R6 is

[0120] In some embodiments, R5 and R6 together with the atoms to which they are attached form a 3-12 membered heterocyclic ring. In a specific embodiment, the heterocyclic ring formed by R5 and R6 together with the atoms to which they are attached is selected from ethylene oxide, In a specific embodiment, R5 and R6 together with the atoms to which they are attached form a heterocycle that is ethylene oxide. In a specific embodiment, R5 and R6 together with the atoms to which they are attached form a heterocycle that is In a specific embodiment, R5 and R6 together with the atoms to which they are attached form a heterocyclic ring that is In a specific embodiment, R5 and R6 together with the atoms to which they are attached form a heterocyclic ring that is In a specific embodiment, R5 and R6 together with the atoms to which they are attached form a heterocyclic ring that is In a specific embodiment, R5 and R6 together with the atoms to which they are attached form a heterocyclic ring that is

[0121] In some embodiments, R7 is selected from hydrogen, hydroxy, C 1-8 Alkyl and -OC 1-8 Alkyl, wherein the alkyl group is optionally substituted by at least one R X In one embodiment, R7 is hydrogen. In one embodiment, R7 is hydroxy. In one embodiment, R7 is methoxy. In one embodiment, R7 is trifluoromethoxy. R7 is difluoromethoxy. In one embodiment, R7 is methyl. In one embodiment, R7 is trifluoromethyl. In one embodiment, R7 is difluoromethyl.

[0122] In a specific embodiment, R8 is hydroxy.

[0123] In some embodiments, R4 and R8, together with the atoms to which they are attached, form a heterocyclic ring having the following structure:

[0124] wherein X, Y1, Y2, R1, R2, R3, R5, R6, R7 and R9 are as defined herein for formula (I), and t' is an integer selected from 0-3, for example, t' is 0, 1, 2 or 3.

[0125] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable derivative thereof provided by the present invention, R4 and R8 together with the atoms to which they are attached form a heterocyclic ring having the following structure:

[0126] wherein X, R1, R2, R3, R5, R6, R7 and R9 are as defined herein for formula (I).

[0127] In some embodiments, R9 is selected from hydrogen, deuterium, hydroxyl and -OR 16 In a specific embodiment, R9 is hydrogen. In a specific embodiment, R9 is deuterium. In a specific embodiment, R9 is hydroxy. In a specific embodiment, R9 is methoxy. In a specific embodiment, R9 is

[0128] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

[0129] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12.

[0130] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0131] The present invention covers any combination of the above embodiments.

[0132] In some embodiments, compounds of the present invention include, but are not limited to:

[0133] In some preferred embodiments, the compounds of the present invention include the following structure:

[0134] In some more preferred embodiments, the compounds of the present invention include the following structure:

[0135] Pharmaceutical compositions, preparations and treatment methods of the present invention

[0136] 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.

[0137] In some embodiments, the pharmaceutical composition can be administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0138] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by any suitable route.

[0139] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0140] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0141] The amount of a compound of the invention administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician.

[0142] In some embodiments, the pharmaceutical composition of the present invention may also include one or more additional therapeutic agents (e.g., other drugs for use with sodium ion channels). In some embodiments, the therapeutic methods of the present invention may also include administering one or more additional therapeutic agents (e.g., other drugs for use with sodium ion channels).

[0143] Synthesis method of compound of formula (I)

[0144] The present invention provides a compound of formula (II) having the following structure:

[0145] wherein X and R6 are as defined herein for formula (I), and Pg1 and Pg2 are independently selected from acetyl, trityl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), cyclopentyloxycarbonyl and methyloxycarbonyl (Fmoc).

[0146] In some embodiments, X in the compound of formula (II) is a carbonyl group. In some embodiments, R6 in the compound of formula (II) is a hydroxyl group. In other embodiments, R6 in the compound of formula (II) is hydrogen. In some embodiments, X in the compound of formula (II) is a methylene group. In some embodiments, R6 in the compound of formula (II) is an amino group. In some embodiments, Pg1 in the compound of formula (II) is a benzyloxycarbonyl (Cbz). In some embodiments, Pg2 in the compound of formula (II) is a benzyloxycarbonyl (Cbz).

[0147] In some embodiments, the compound of formula (II) is

[0148] In some embodiments, the compound of formula (II) is

[0149] In some embodiments, the compound of formula (II) is

[0150] In some embodiments, the compound of formula (II) 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, which comprises using the compound of formula (II); or relates to the use of the compound of formula (II) in the preparation of the compound of formula (I) or a pharmaceutically acceptable derivative thereof.

[0151] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable derivative thereof can be synthesized by the following route:

[0152] wherein R represents any suitable group in the corresponding position herein.

[0153] In some specific embodiments, the synthesis of the compound of formula (I) or a pharmaceutically acceptable derivative thereof comprises the following intermediate synthesis steps:

[0154] In other specific embodiments, the synthesis of the compound of formula (I) or its pharmaceutically acceptable derivatives includes the following intermediate synthesis steps:

[0155] In a specific embodiment, the synthesis of the compound of formula (I) or a pharmaceutically acceptable derivative thereof comprises the following intermediate synthesis steps:

[0156] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable derivative thereof can be synthesized by the following route:

[0157] wherein R represents any suitable group in the corresponding position herein.

[0158] In other embodiments, the compound of formula (I) or a pharmaceutically acceptable derivative thereof can be synthesized by the following route:

[0159] wherein R represents any suitable group in the corresponding position herein.

[0160] In some other embodiments, the compound of formula (I) or a pharmaceutically acceptable derivative thereof can be synthesized by the following route:

[0161] Wherein, R represents any suitable group corresponding to the position herein.

[0162] Exemplary embodiments

[0163] Embodiment 1: In one embodiment, the present invention provides a compound or a pharmaceutically acceptable derivative thereof, wherein the compound has a structure of formula (I):

[0164] in,

[0165] X does not exist or is -(CH2) m -, wherein the -CH2- is optionally replaced by -O- or a carbonyl group or optionally replaced by at least one R X replace;

[0166] Y1 and Y2 are each independently selected from methylene, O, S and NH, wherein the methylene and NH are optionally replaced by at least one R X replace;

[0167] R1 and R3 are each independently selected from hydrogen, hydroxy, amino, cyano, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3- 8 cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0168] R2 is selected from hydrogen, hydroxy, amino, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, -(C=O)OR 10 and -O(C=O)R 11 wherein the alkyl, cycloalkyl and heterocyclyl groups are optionally replaced by at least one R X replace;

[0169] Each R4 is independently selected from hydrogen, deuterium, hydroxyl, halogen, -OR 12 and C 1-8 alkyl;

[0170] or R3 and R4 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R X replace;

[0171] R5 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 13 ;

[0172] R6 is selected from hydroxy, thiol, amino, azido, halogen, cyano, C 1-12 Alkyl, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl, C 5-10 Heteroaryl, -(C=O)-R 14 , guanidine, urea and -(OCH2CH2) n -OH, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, guanidino and ureido are optionally replaced by at least one R X replace;

[0173] or R5 and R6 together with the atoms to which they are attached form a 3-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R X replace;

[0174] R7 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-8 Cycloalkyl and C 3-8 Heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl groups are optionally substituted by at least one RX replace;

[0175] R8 is a hydroxyl group;

[0176] or R4 and R8 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by at least one R X replace;

[0177] R9 is selected from hydrogen, deuterium, tritium, hydroxyl, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 15 ;

[0178] R 10 and R 11 Each independently selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0179] R 12 、R 13 、R 14 and R 15 Each independently selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace;

[0180] Each R X independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 3-8 Cycloalkyl, C 1-8Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the amino, formyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R Y replace;

[0181] Each R Y Independently selected from hydrogen, halogen, hydroxyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, C 3-8 Heterocyclic group, -OC 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, -OC 6-10 Aryl, C 1- 8-alkyl-C 6-10 Aryl, C 5-10 Heteroaryl, -OC 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with at least one halogen or hydroxyl group;

[0182] When X is a methylene group and R1, R2 and R3 are simultaneously hydrogen, R4, R5, R6, R7, R8 and R9 are not simultaneously hydroxyl groups;

[0183] m is an integer selected from 0-6;

[0184] n is an integer selected from 1-12;

[0185] t is an integer selected from 0-4.

[0186] Embodiment 2: In one embodiment, in the compound of Embodiment 1 or a pharmaceutically acceptable derivative thereof, X is selected from methylene and carbonyl.

[0187] Embodiment 3: In one embodiment, in the compound of Embodiment 1 or Embodiment 2 or a pharmaceutically acceptable derivative thereof, R1 is hydrogen.

[0188] Embodiment 4: In one embodiment, in the compound of any one of Embodiments 1-3 or a pharmaceutically acceptable derivative thereof, R2 is selected from hydrogen and -(C=O)OR 10 .

[0189] Embodiment 5: In one embodiment, in the compound of embodiment 4 or a pharmaceutically acceptable derivative thereof, the R 10 It is benzyl.

[0190] Embodiment 6: In one embodiment, in the compound of any one of Embodiments 1-5 or a pharmaceutically acceptable derivative thereof, R3 is selected from hydrogen, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl and C 1-8 Alkyl-C 6-10 Aryl, wherein the alkyl, cycloalkyl and aryl groups are optionally substituted by at least one R X replace.

[0191] Embodiment 7: In one embodiment, in the compound of embodiment 6 or a pharmaceutically acceptable derivative thereof, the R X Selected from hydroxyl and carboxyl.

[0192] Embodiment 8: In one embodiment, in the compound of embodiment 6 or a pharmaceutically acceptable derivative thereof, R3 is selected from hydrogen, methyl, ethyl, isopropyl,

[0193] Embodiment 9: In one embodiment, in the compound according to any one of Embodiments 1 to 8 or a pharmaceutically acceptable derivative thereof, R4 is selected from hydrogen, deuterium and hydroxyl.

[0194] Embodiment 10: In one embodiment, in the compound of any one of Embodiments 1-9 or a pharmaceutically acceptable derivative thereof, R3 and R4 together with the atoms to which they are attached form a six-membered heterocyclic ring.

[0195] Embodiment 11: In one embodiment, in the compound of embodiment 10 or a pharmaceutically acceptable derivative thereof, the heterocyclic ring formed by R3 and R4 together with the atoms to which they are attached is selected from

[0196] Embodiment 12: In one embodiment, in the compound according to any one of Embodiments 1 to 11 or a pharmaceutically acceptable derivative thereof, R5 is hydroxyl.

[0197] Embodiment 13: In one embodiment, in the compound of any one of Embodiments 1-12 or a pharmaceutically acceptable derivative thereof, R6 is selected from hydroxyl, amino, -OC 1-12 Alkyl and C 3-8 Heterocyclyl, wherein the amino, alkyl and heterocyclyl groups are optionally replaced by at least one R X replace.

[0198] Embodiment 14: In one embodiment, in the compound of Embodiment 13 or a pharmaceutically acceptable derivative thereof, the R X Selected from hydroxyl, -C 1-8 Alkyl, C 1-8 Alkyl-C 6-10 Aryl.

[0199] Embodiment 15: In one embodiment, in the compound of embodiment 13 or a pharmaceutically acceptable derivative thereof, R6 is selected from hydroxyl, amino, methoxy, methylamino,

[0200] Embodiment 16: In one embodiment, in the compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable derivative thereof, R7 is hydroxyl.

[0201] Embodiment 17: In one embodiment, in the compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable derivative thereof, R8 is hydroxyl.

[0202] Embodiment 18: In one embodiment, in the compound of any one of Embodiments 1-17 or a pharmaceutically acceptable derivative thereof, R4 and R8 together with the atoms to which they are attached form a heterocyclic ring having the following structure:

[0203] wherein X, Y1, Y2, R1, R2, R3, R5, R6, R7 and R9 are as defined in any one of Embodiments 1-17, and t' is an integer selected from 0-3.

[0204] Embodiment 19: In one embodiment, in the compound of any one of Embodiments 1-18 or a pharmaceutically acceptable derivative thereof, R4 and R8 together with the atoms to which they are attached form a heterocyclic ring having the following structure:

[0205] wherein X, R1, R2, R3, R5, R6, R7 and R9 are as defined in any one of Embodiments 1-18.

[0206] Embodiment 20: In one embodiment, the compound or a pharmaceutically acceptable derivative thereof has the following structure:

[0207] Embodiment 21: In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1-20 or a pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable carriers.

[0208] Embodiment 22: In one embodiment, the present invention provides use of the compound described in any one of Embodiments 1-20 or a pharmaceutically acceptable derivative thereof, or the pharmaceutical composition described in Embodiment 21, in the preparation of a medicament for treating diseases or conditions associated with sodium ion channels or for analgesia.

[0209] Embodiment 23: In one embodiment, the present invention provides a compound having the structure of formula (II):

[0210] in,

[0211] X, R6 are as defined in any one of embodiments 1-20,

[0212] Pg1 and Pg2 are independently selected from acetyl, trityl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and methyloxycarbonyl (Fmoc).

[0213] Embodiment 24: In one embodiment, the compound of Embodiment 23 has the following structure: Beneficial effects

[0214] The compound of formula (I) provided by the present invention or its pharmaceutically acceptable derivative has excellent blocking effect on sodium ion channel. Meanwhile, compared to tetrodotoxin, the compound of formula (I) provided by the present invention or its pharmaceutically acceptable derivative can be synthesized in large quantities by the mode of chemical synthesis, is easy to obtain, has more excellent analgesic intensity and better treatment window, has broader application prospect. The compound of the present invention or its pharmaceutically acceptable derivative also has better toxicological properties (such as toxicity is lower) and selectivity to sodium ion channel subtypes, can avoid the effect on the sodium ion channel hNav1.5 that may cause heart disease, so as to have better drug safety when having the same or comparable therapeutic effect.

[0215] Example

[0216] Synthesis Preparation Example

[0217] Unless otherwise specified, the reagents and solvents used in the synthesis were provided by domestic manufacturers and were used without further purification.

[0218] Synthesis of intermediates:

[0219] Intermediate Synthesis Example 1: Synthesis of Benzyl (Z)-((Methylamino)(methylthio)methylene)carbamate A1

[0220] Compound A1-1 (4.00 g, 38.40 mmol), dichloromethane (50 mL), and triethylamine (8.70 g, 85.98 mmol) were added to a reaction flask. Under nitrogen, the temperature was lowered to 0°C, and benzyl chloroformate (8.60 g, 50.41 mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined and concentrated to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 10%-15%) to obtain compound A1 (0.80 g, yield: 9%). LCMS (m / z): 239.1 [M+1] + .

[0221] Intermediate Synthesis Example 2: Synthesis of Benzyl (E)-((Ethylamino)(methylthio)methylene)carbamate A2

[0222] Step 1: Synthesis of 1-(tert-butyl)-3-ethylthiourea (A2-2)

[0223] To a solution of ethylamine (0.78 g, 17.30 mmol) in DCM (40 mL) at 0°C was added tert-butyl isothiocyanate (2.00 g, 17.36 mmol). The reaction was stirred at room temperature for 3 hours, and the mixture was concentrated to afford compound A2-2 (2.50 g, 90% yield) as a white solid, which was used directly in the next reaction. LCMS (m / z): 161.1 [M+1] + .

[0224] Step 2: Synthesis of 1-ethylthiourea (A2-3)

[0225] Concentrated hydrochloric acid (15 mL) and compound A2-2 (2.50 g, 15.60 mmol) were added to the reaction flask, heated to 100°C, and stirred for 1 hour. The reaction mixture was concentrated to obtain a crude product of compound A2-3 (2.50 g, 100% yield) as a pale yellow oil. LCMS (m / z): 105.0 [M+1] + .

[0226] Step 3: Synthesis of ethylcarbamoylthiomethyl ester (A2-4)

[0227] Compound A2-3 (2.50 g, 15.60 mmol, crude) and methanol (10 mL) were added to a reaction flask. Methyl iodide (2 mL, 32.13 mmol) was added dropwise at room temperature and stirred for 16 hours. The reaction mixture was concentrated to obtain a crude product of Compound A2-4 (2.50 g, 100% yield) as a pale yellow oil. LCMS (m / z): 119.1 [M+1] + .

[0228] Step 4: Synthesis of Compound A2

[0229] To a reaction flask, crude compound A2-4 (2.50 g, 15.60 mmol), dichloromethane (40 mL), and triethylamine (8.48 g, 83.80 mmol) were added. Under nitrogen, the temperature was lowered to 0°C, and benzyl chloroformate (5.30 g, 31.07 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were concentrated to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 10%-100%) to obtain compound A2 (2.40 g, three-step reaction yield: 61%) as a yellow solid. LCMS (m / z): 253.1 [M+1] + .

[0230] Intermediate Synthesis Example 3: Synthesis of Benzyl (E)-((Cyclopropylamino)(methylthio)methylene)carbamate (A3)

[0231] The synthesis of compound A3 was carried out using cyclopropylamine as the starting material. The first two steps of synthesizing compound A3-3 were carried out according to the synthesis method of compound A2. The third step of synthesizing compound A3 was carried out using a one-pot method.

[0232] Step 3: Synthesis of Compound A3

[0233] Compound A3-3 (2.50 g, 21.52 mmol) and tetrahydrofuran (30 mL) were added to a reaction flask. Methyl iodide (3.67 g, 25.86 mmol) and sodium bicarbonate (9.05 g, 107.73 mmol) were added with stirring. The mixture was allowed to react at room temperature overnight under nitrogen. The reaction solution was then cooled to 0°C, and benzyl chloroformate (4.40 g, 25.79 mmol) was added. The reaction was allowed to react at room temperature for 3 hours. Water (200 mL) was then added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 25%-67%) to obtain Compound A3 (3.50 g, yield: 62%) as a white solid. LCMS (m / z): 265.1 [M+1] + .

[0234] Intermediate Synthesis Example 4: Synthesis of Benzyl (E)-((Isopropylamino)(methylthio)methylene)carbamate (A4)

[0235] The synthesis of compound A4 was carried out using isopropylamine as the starting material. The synthesis method was similar to that of compound A3. LCMS (m / z): 267.1 [M+1] + .

[0236] Intermediate Synthesis Example 5: Synthesis of Benzyl (E)-(((cyclobutylmethyl)amino)(methylthio)methylene)carbamate (A5)

[0237] The synthesis of compound A5 was carried out using cyclobutylmethylamine as the starting material. The synthesis method was similar to that of compound A3. LCMS (m / z): 293.1 [M+1] + .

[0238] Intermediate Synthesis Example 6: Synthesis of Benzyl (E)-((Cyclobutylamino)(methylthio)methylene)carbamate (A6)

[0239] Step 1: Synthesis of compound A6-2

[0240] Sodium thiocyanate (1.25 g, 15.42 mmol) and acetonitrile (10 mL) were added to a reaction flask, cooled to 0°C, and benzyl chloroformate (2.34 g, 13.72 mmol) was added dropwise. After the addition was complete, the temperature was raised to 50°C and the mixture was stirred for 10 minutes. Cyclobutylamine (1.00 g, 14.06 mol) was then added. After the addition was complete, the mixture was stirred at 50°C for 10 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by flash column chromatography to obtain Compound A6-2 (360 mg, 10% yield) as an off-white solid.

[0241] 1 H NMR (400MHz, DMSO) δ11.09 (s, 1H), 9.89 (d, J = 6.6Hz, 1H), 7.48-7.26 (m, 5H), 5.19 (s, 2H), 4.67 -4.52(m,1H),2.43-2.25(m,2H),2.06-1.88(m,2H),1.81-1.63(m,2H); LCMS(m / z):265.1[M+1] + .

[0242] Step 2: Synthesis of 1-cyclobutylthiourea (A6-3)

[0243] Compound A6-2 (360 mg, 1.36 mmol), methanol (3 mL), and water (3 mL) were added to a reaction flask. Sodium hydroxide (0.55 g, 13.68 mmol) was added with stirring and the reaction was stirred at room temperature for 1 hour. 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to approximately 6. The reaction solution was then concentrated to obtain crude compound A6-3 (250 mg, yield >100%). LCMS (m / z): 131.1 [M+1] + .

[0244] Step 3: Synthesis of cyclobutylcarbamoylthiomethyl ester (A6-4)

[0245] Compound A6-3 (1.50 g, 8.75 mmol, crude) and methanol (20 mL) were added to a reaction flask. Methyl iodide (1.86 g, 13.10 mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain crude compound A6-4 (2.00 g, yield >100%) as a yellow oil. LCMS (m / z): 145.1 [M+1] + .

[0246] Step 4: Synthesis of Compound A6

[0247] To a reaction flask, crude compound A6-4 (2.00 g, 8.75 mmol) and dichloromethane (40 mL) were added, followed by triethylamine (5.60 g, 55.34 mmol). Under nitrogen, the mixture was cooled to 0°C and benzyl chloroformate (3.50 g, 20.52 mmol) was added dropwise. After completion of the addition, the mixture was stirred at room temperature for 16 hours. The reaction solution was then diluted with water (100 mL) and extracted with dichloromethane (100 mL x 3). The organic phases were combined and concentrated to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 10%-20%) to obtain compound A6 (1.20 g, yield: 49%) as a yellow solid.

[0248] 1 H NMR (400MHz, DMSO) δ10.19-9.03(m,1H),7.38(d,J=3.9Hz,5H),5.05(s,2H),4.21(t,J=56.1Hz,1H),2.38 (s,3H),2.23(d,J=23.6Hz,2H),2.11-1.96(m,2H),1.67(dd,J=20.0,13.5Hz,2H); LCMS(m / z):279.1[M+1] + .

[0249] Intermediate Synthesis Example 7: Synthesis of Benzyl (E)-(((Cyclopropylmethyl)amino)(methylthio)methylene)carbamate (A7)

[0250] Compound A7 was synthesized using cyclopropylmethylamine as the starting material, with reference to the synthesis of compound A6. LCMS (m / z): 279.1 [M+1] + .

[0251] Intermediate Synthesis Example 8: Synthesis of tert-butyl (E)-((benzylamino)(methylthio)methylene)carbamate (A8)

[0252] Compound A8 uses benzylamine as the starting material, and the first three steps of synthesizing compound A8-4 are performed by referring to the synthesis method of compound A2.

[0253] Step 4: Synthesis of tert-butyl (E)-((benzylamino)(methylthio)methylene)carbamate (A8)

[0254] To a reaction flask, crude compound A8-4 (2.10 g, 11.60 mmol) and dichloromethane (40 mL) were added. 4-Dimethylaminopyridine (130 mg, 1.06 mmol) and triethylamine (3.50 g, 34.59 mmol) were added with stirring. The temperature was lowered to 0°C, and di-tert-butyl dicarbonate (3.00 g, 13.75 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. The reaction solution was then diluted with water (40 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 20%) to obtain compound A8 (1.70 g, yield: 52%) as a white solid. LCMS (m / z): 281.1 [M+1] + .

[0255] Intermediate Synthesis Example 9: Synthesis of (E)-(10,10-dimethyl-9,9-diphenyl-8-oxo-2-thia-4-azepine-9-dodec-3-ylidene)carbamic acid benzyl ester (A9)

[0256] Compound A9 uses 3-aminopropanol as the starting material, and the first three steps of synthesizing compound A9-4 are performed by referring to the synthesis method of compound A2.

[0257] Step 4: Synthesis of (3-((tert-butyldiphenylsilyl)oxy)propyl)carbamoyl imidothiomethyl ester (A9-5)

[0258] Compound A9-4 (1.6 g, 10.79 mmol) and tetrahydrofuran (20 mL) were added to a reaction flask. Under nitrogen, triethylamine (3.27 g, 32.32 mmol) and tert-butyldiphenylsilyl chloride (5.92 g, 21.54 mmol) were added and stirred at room temperature for 16 hours. The reaction was then quenched with water (80 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 15%-50%) to obtain compound A9-5 (1.2 g, yield: 29%). LCMS (m / z): 387.2 [M+1] + .

[0259] Step 5: Synthesis of benzyl (E)-(10,10-dimethyl-9,9-diphenyl-8-oxo-2-thia-4-aza-9-dodec-3-ylidene)carbamate (A9)

[0260] Compound A9-5 (1.20 g, 3.10 mmol) and dichloromethane (20 mL) were added to a reaction flask, followed by triethylamine (0.94 g, 9.29 mmol). The temperature was lowered to 0°C, and benzyl chloroformate (0.64 g, 3.76 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 15%-30%) to obtain Compound A9 (1.00 g, yield: 62%) as a white solid. LCMS (m / z): 521.2 [M+H] + .

[0261] Intermediate Synthesis Example 10: Synthesis of Methyl (E)-3-(Benzyloxy)carbonyl)imino)(methylthio)methyl)amino)propionate (A10)

[0262] Compound A10 was synthesized using tert-butyl 3-aminopropionate as the starting material, following the synthesis method of Compound A2. LCMS (m / z): 311.1 [M+1] + .

[0263] Intermediate Synthesis Example 11: 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]dioxetane[4,5-e]isobenzofuran-4-carboxylic acid (B1)

[0264] The starting materials S8 and TTX-42 can be prepared by referring to the method of patent application CN 113956266 A, the entire content of which is incorporated herein by reference.

[0265] 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]dioxacyclo[4,5-e]isobenzofuran-4-carboxylic acid (B1)

[0266] To a reaction flask, add TTX-42 (160 mg, 0.25 mmol), acetonitrile (2 mL), 2,2,6,6-tetramethylpiperidinyl oxide (7 mg, 0.04 mmol), and 7% potassium dihydrogen phosphate aqueous solution (2 mL). Heat to 40°C, then add 7.5% sodium hypochlorite solution (0.1 mL) and sodium chlorite (45.22 mg, 0.50 mmol) over approximately 10 minutes. Continue stirring at 40°C overnight. Cool the reaction mixture to room temperature, add saturated sodium bicarbonate aqueous solution (1 mL) and sodium sulfite aqueous solution (1 mL), and extract with ethyl acetate (5 mL x 3). Combine the organic phases and concentrate to obtain the crude product. The crude product is purified by flash column chromatography (methanol / dichloromethane = 10%) to afford Compound B1 (100 mg, yield: 61%).

[0267] 1 H 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] + .

[0268] Intermediate Synthesis Example 12: 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]dioxacyclo[4,5-e]isobenzofuran-4-carbaldehyde (B2)

[0269] Add anhydrous dichloromethane (2 mL) to a 10 mL reaction flask, replace the atmosphere with nitrogen three times, add oxalyl chloride (30 mg, 0.23 mmol), lower the temperature to -78°C, and add dimethyl sulfoxide (37 mg, 0.47 mmol) dropwise. Stir the reaction for 30 minutes after addition. Then add a solution of TTX-42 (100 mg, 0.16 mmol) in dichloromethane (0.5 mL) dropwise. Stir the reaction at -78°C for 25 minutes after addition. Then add triethylamine (79 mg, 0.78 mmol) dropwise. After addition, allow the reaction to proceed at room temperature for 2 hours. Complete reaction of the starting material was monitored by HPLC. Add water (10 mL) to the reaction solution, extract with dichloromethane (10 mL x 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 0-60%) to give compound B2 (52 mg, yield: 51%) as a white solid.

[0270] 1 H 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] + .

[0271] Intermediate Synthesis Example 13: 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]dioxacyclo[4,5-e]isobenzofuran-4-methylamine (B3)

[0272] 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]dioxacyclo[4,5-e]isobenzofuran-4-carbaldehyde oxime (B2-1)

[0273] 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, and sodium acetate (134.60 mg, 1.64 mmol) was added under ice-bath conditions. After the addition was complete, the reaction solution was warmed to room temperature and reacted for 48 hours. HPLC was used to monitor until the reaction of the starting materials was complete. The reaction solution was concentrated and dried to obtain a residue. Ethyl acetate (30 mL) was added to the residue, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated and dried to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound B2-1 (666 mg, yield: 93%) as a white solid.

[0274] 1 H 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] + .

[0275] Step 2: Synthesis of Compound B3

[0276] 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. The reaction solution was cooled to -45°C under nitrogen protection, and sodium borohydride (100 mg) was then added. The mixture was stirred until the reaction initiated (the reaction solution darkened in color and a large amount of bubbles were generated). The remaining sodium borohydride (187 mg) was then added in batches. After the addition was complete, the reaction was continued for 30 minutes. HPLC was used to monitor the reaction until the reaction of the raw materials was complete. Acetic acid (2 mL) was added to the reaction solution, the cooling bath was removed, and the solution was stirred until the color turned light green. Dichloromethane (20 mL) was then added, and saturated sodium bicarbonate solution was slowly added to pH = 8. The filter cake was slurried with dichloromethane / methanol (10 / 1, 30 mL x 2) and filtered. The combined filtrates were separated, and the aqueous phase was extracted with dichloromethane / methanol (10 / 1, 20 mL x 2). All organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by flash column chromatography (MeOH / DCM = 0-10%) to obtain Compound B3 (558 mg, yield: 67.4%) as a white solid.

[0277] 1 H 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] + .

[0278] Synthesis of target compound:

[0279] The synthesis of the target compound is carried out according to the following synthetic routes 1, 2, 3 or 4:

[0280] Synthesis route 1:

[0281] Synthesis route 2:

[0282] Synthesis route three:

[0283] Synthesis Route 4:

[0284] Wherein, R represents any suitable group corresponding to the position herein.

[0285] Example 1: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 1) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 2)

[0286] TTX-39 (850 mg, 1.25 mmol), water (12 mL), and trifluoroacetic acid (12 mL) were added to a reaction flask. Under nitrogen, the mixture was heated to 60°C and allowed to react overnight. HPLC analysis confirmed the complete reaction of the starting material, and the reaction solution was concentrated to obtain a residue. The residue was purified by flash column chromatography (methanol / dichloromethane = 0-10%) to afford compound 1 (368 mg, yield: 65%) and compound 2 (150 mg, yield: 28%) as white solids, for a total yield of 93%.

[0287] Compound 1:

[0288] 1 H NMR (400MHz, MeOD) δ7.45-7.33 (m, 5H), 5.69 (t, J = 8.7Hz, 1H), 5.29 (s, 2H), 4.24 (d, J = 7. 9Hz, 1H), 4.18 (s, 1H), 4.06-3.95 (m, 4H), 2.40 (d, J = 9.4Hz, 1H); LCMS (m / z): 454.1[M+1] + .

[0289] Compound 2:

[0290] 1H NMR (400MHz, MeOD) δ7.42-7.31(m,5H),5.40(s,1H),5.18(s,2H),4.54(d,J=2.0Hz,1H),4.49(s,1H),4.21(dd,J=2.8, 1.4Hz,1H),4.05(s,1H),3.97(d,J=11.5Hz,1H),3.91(d,J=11.5Hz,1H),2.81(d,J=2.8Hz,1H); LCMS(m / z):436.1[M+1] + .

[0291] Example 2: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (Compound 3)

[0292] Compound 2 (30 mg, 0.07 mmol), methanol (6 mL), and 10% palladium on carbon (5 mg) were added to a reaction flask. The atmosphere was replaced with hydrogen three times, and hydrogenation was performed under a hydrogen balloon at 25°C with stirring for 3 hours. The reaction was monitored for completeness by HPLC. The reaction mixture was filtered, the filter cake was washed with methanol (200 mL), and the filtrate was concentrated to afford compound 3 (8 mg, yield: 38%) as a white solid.

[0293] 1 H NMR(400MHz,D2O)δ5.36(s,1H),4.46(d,J=2.1Hz,1H),4.42(s,1H),4.19(s,1H),4.01(s,1H) ,3.81(d,J=7.2Hz,1H),3.76(d,J=12.2Hz,1H),2.78(d,J=2.9Hz,1H); LCMS(m / z):302.1[M+1] + .

[0294] Example 3: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(hydroxymethyl)-2-iminooctahydro-5,9-epoxy-7,10aR methyleneoxy[4,5-d]pyrimidine-4-d-6,9,10,11(10H)-tetrol (Compound 4)

[0295] Step 1: Synthesis of benzyl ((4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, Z)-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene-4-d)carbamate (Compound 4-1)

[0296] Compound 1 (100 mg, 0.22 mmol), anhydrous deuterated acetonitrile (3 mL), and deuterated acetic acid (2.5 mL) were added to a reaction flask. Sodium deuterated cyanoborohydride (73 mg, 1.1 mmol) was added with stirring and allowed to react at 50°C for 8 hours. HPLC analysis indicated incomplete reaction. Additional sodium deuterated cyanoborohydride (73 mg, 1.1 mmol) was added and the reaction continued for approximately 48 hours, leaving approximately 20% of the starting material remaining. The reaction solution was concentrated to a residue, which was slurried with diethyl ether (15 mL). The acetic acid was removed by filtration, and the filter cake was collected and purified by HPLC (Welch Xtimate C18 × 30 mm × 150 mm, 10 μm; flow rate: 30 mL / min (0.1% NH4OAc, ACN)) to afford compound 4-1 (39 mg, 40% yield).

[0297] 1 H NMR (400MHz, MeOD) δ7.45-7.30 (m, 5H), 5.18 (s, 2H), 4.44-3.73 (m, 7H), 2.50 (d, J = 12.4Hz, 1H); HRMS (ESI+): C 19 H 22 DN3O9([M+H] + ):Calculated value: 439.15; measured value: 439.21.

[0298] Step 2: Synthesis of compound 4

[0299] The product was synthesized according to the method of Example 2 to obtain white solid compound 4 (26 mg, yield: 88%).

[0300] 1 H NMR (400MHz, D2O) δ4.11 (d, J = 1.3Hz, 1H), 3.96 (s, 1H), 3.93 (s, 1H), 3.90-3. 87(m,2H),3.74(d,J=14.9Hz,1H),3.67(d,J=8.7Hz,1H),2.49-2.36(m,1H).

[0301] 13C NMR (4% CD3COOD / 96% D2O, 100 MHz) δ 154.5 (C), 108.6 (C), 79.9 (CH), 77.0 (CH), 74.7 (CH), 73.0 (CH), 71.9 (CH), 70.5 (C), 69.3 (CH), 62.8 (C), 55.4 (CH); HRMS (ESI+): calculated value C 11 H 16 DN3O7([M+H] + ):305.11, measured value:305.21.

[0302] Example 4: Synthesis of benzyl ((4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, Z)-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 5)

[0303] Compound 1 (500 mg, 1.10 mmol), acetonitrile (10 mL), and glacial acetic acid (10 mL) were added to a reaction flask. Sodium cyanoborohydride (0.69 g, 11.00 mmol) was added portionwise with stirring. The mixture was allowed to react at 50°C for 16 hours. Most of the solvent was concentrated, and the residue was subjected to preparative isolation to obtain Compound 5 (135 mg, 28% yield) as a colorless oil.

[0304] 1 H NMR (400MHz, MeOD) δ7.44-7.25 (m, 5H), 5.15 (s, 2H), 4.29-3.74 (m, 7H), 3.29-3.24 (m, 1H), 2.48 (d, J = 6.6Hz, 1H); LCMS (m / z): 438.1 [M+1] + .

[0305] Example 5: Synthesis of (4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(hydroxymethyl)-2-iminotetrahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetrol (Compound 6)

[0306] The product was synthesized according to the method of Example 2 to obtain white solid compound 6 (30 mg, yield: 100%).

[0307] 1H NMR(400MHz,D2O)δ4.17(s,1H),4.02(s,1H),3.98(s,1H),3.93(d,J=4.4Hz,2H),3.92(s, 1H),3.77(t,J=11.8Hz,1H),3.32-3.28(m,1H),2.52-2.46(m,1H); LCMS(m / z):304.1[M+1] + .

[0308] Example 6: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)-3-methyloctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 7) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(hydroxymethyl)-3-methyloctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 8)

[0309] Step 1: Synthesis of compound S8-A1

[0310] Compound A1 (0.62 g, 2.60 mmol), anhydrous acetonitrile (40 mL), S8 (0.80 g, 2.15 mmol), and triethylamine (1.09 g, 10.77 mmol) were added to a reaction flask. Under nitrogen protection, the mixture was cooled to 0°C and silver trifluoromethanesulfonate (1.1 g, 4.31 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 10%-25%) to obtain compound S8-A1 (0.50 g, yield: 41%) as an off-white solid. LCMS (m / z): 562.2 [M+1] + .

[0311] Step 2: Synthesis of Compounds 7 and 8

[0312] The white solid compound 7 (170 mg, yield: 36%) and the white solid compound 8 (130 mg, yield: 29%) were synthesized according to the method of Example 1, with a total yield of 65%.

[0313] Compound 7:

[0314] 1 H NMR (400MHz, MeOD) δ7.54-7.20(m,5H),5.35-5.11(m,3H),4.19(t,J=7.2Hz,1H),4.14(d,J=5.5Hz,1H ),4.05-3.98(m,2H),3.98-3.91(m,2H),3.12-3.04(m,3H),2.50-2.37(m,1H); LCMS(m / z):468.2[M+1] + .

[0315] Compound 8:

[0316] 1 H NMR (400MHz, MeOD) δ7.48-7.17(m,5H),5.30(s,1H),5.10(s,2H),4.47(d,J=1.9Hz,1H),4.38(s,1H),4.16(d,J=1.3Hz,1H ),4.00(s,1H),3.96(d,J=11.4Hz,1H),3.90(d,J=11.4Hz,1H),3.05(s,3H),2.73(d,J=3.0Hz,1H); LCMS(m / z):450.1[M+1] + .

[0317] Example 7: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(hydroxymethyl)-2-imino-3-methyloctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 9)

[0318] The product was synthesized according to the method of Example 2 to obtain compound 9 (9.0 mg, yield: 90%) as a white solid. 1 H NMR(400MHz,MeOD)δ5.55-5.05(m,1H),4.11-4.06(m,1H),4.06-3.98(m,1H) ,3.97-3.82(m,4H),2.91(s,3H),2.36-2.12(m,1H); LCMS(m / z):334.1[M+1] + .

[0319] Example 8: Synthesis of benzyl ((4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, E)-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)-3-methyloctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 10)

[0320] The product was synthesized according to the method of Example 4 to obtain compound 10 (19.5 mg, yield: 12%) as a white solid. 1 HNMR(400MHz,MeOD)δ7.39-7.31(m,5H),5.09(s,2H),4.40(s,1H),4.22-4.08(m,2H),3.97(s,2H),3.74(q,J=11 .6Hz,1H),3.55-3.47(m,1H),3.11(d,J=12.6Hz,1H),3.04(s,3H),2.51(d,J=6.7Hz,1H); LCMS(m / z):452.2[M+1] + .

[0321] Example 9: Synthesis of (4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(hydroxymethyl)-2-imino-3-methyloctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetrol (Compound 11)

[0322] The compound was synthesized according to the method of Example 2 to obtain compound 11 (12.0 mg, yield: 88%) as a white solid. 1 HNMR(400MHz,MeOD)δ4.12(s,1H),4.04(s,2H),3.99(d,J=7.8Hz,2H),3.86-3.80(m,1 H),3.78(d,J=4.8Hz,1H),3.62-3.50(m,1H),3.09(d,J=6.5Hz,3H),2.63(s,1H); LCMS (m / z):318.1[M+1] + .

[0323] Example 10: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-9-(hydroxymethyl)-2-imino-3-methyloctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (Compound 12)

[0324] The compound 12 was synthesized according to the method of Example 2 to obtain compound 12 (16 mg, yield: 91%) as a white solid. 1 H NMR(400MHz,MeOD)δ5.36(s,1H),4.48(d,J=1.9Hz,1H),4.37(s,1H),4.17(s,1H),4.01(s,1H),3.97( d,J=11.4Hz,1H),3.90(d,J=11.4Hz,1H),3.12(s,3H),2.80(d,J=2.9Hz,1H); LCMS(m / z):316.1[M+1] + .

[0325] Example 11: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-3-ethyl-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 13) and ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-3-ethyl-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(methantriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 14)

[0326] Step 1: Synthesis of compound S8-A2

[0327] The compound S8-A1 in Example 6 was synthesized to obtain an off-white solid compound S8-A2 (0.75 g, yield: 48%). LCMS (m / z): 576.3 [M+1] + .

[0328] Step 2: Synthesis of Compounds 13 and 14

[0329] The white solid compound 13 (360 mg, yield: 58%) and the white solid compound 14 (120 mg, 20%) were synthesized according to the method of Example 1, with a total yield of 78%.

[0330] Compound 13:

[0331] 1H NMR(400MHz,MeOD)δ7.42-7.21(m,5H),5.35(d,J=9.3Hz,1H),5.11(s,2H),4.39(s, br,1H),4.14(s,1H),4.01(s,2H),3.94-3.64(m,3H),3.53-3.44(m,1H),2.34(d,J= 9.3Hz, 1H), 1.10 (t, J=6.7Hz, 3H); LCMS (m / z): 482.2[M+1] + .

[0332] Compound 14:

[0333] 1 H NMR (400MHz, MeOD) δ7.46-7.14(m,5H),5.37(s,1H),5.12(d,J=12.7Hz,2H),4.46(d,J=1.9Hz,1H),4.38(s,1H),4.18(s,1H), 4.03-3.87(m,3H),3.75-3.62(m,1H),3.44-3.34(m,1H),2.66(d,J=2.8Hz,1H),1.15(t,J=7.1Hz,3H); LCMS(m / z):464.2[M+1] + .

[0334] Example 12: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-ethyl-6-(hydroxymethyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 15)

[0335] The white solid compound 15 (16 mg, yield: 77%) was synthesized according to the method of Example 2. LCMS (m / z): 348.2 [M+1] + .

[0336] Example 13: Synthesis of benzyl ((4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, E)-3-ethyl-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 16)

[0337] The product was synthesized according to the method of Example 4 to obtain white solid compound 16 (24 mg, yield: 12%). 1H NMR(400MHz,MeOD)δ7.41-7.23(m,5H),5.10(s,2H),4.14(s,br,3H),4.05-3.79(m,4H),3.77-3.67(m,1H),3.4 3-3.32(m,1H),3.20-3.05(m,1H),2.47(dd,J=12.6,5.4Hz,1H),1.11(t,J=7.1Hz,3H); LCMS(m / z):466.2[M+1] + .

[0338] Example 14: Synthesis of (4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-ethyl-6-(hydroxymethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetrol (Compound 17)

[0339] The product was synthesized according to the method of Example 2 to obtain white solid compound 17 (12 mg, yield: 72%). 1 H NMR(400MHz,D2O)δ4.08(s,1H),3.91(s,4H),3.84(d,J=8.8Hz,2H),3.47-3.32(m,1H) ,3.30-3.16(m,2H),2.47(dd,J=12.6,6.3Hz,1H),1.10(s,3H); LCMS(m / z):332.1[M+1] + .

[0340] Example 15: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-3-ethyl-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-6,9,11(5aH)-triol (Compound 18)

[0341] The product was synthesized according to the method of Example 2 to obtain white solid compound 18 (13 mg, yield: 99%).

[0342] 1H NMR(400MHz,D2O)δ5.44(s,1H),4.46(d,J=1.9Hz,1H),4.27(s,1H),4.13(s,1H),3.98-3.93(m,2H),3.8 6(d,J=12.1Hz,1H),3.49-3.37(m,2H),2.78(d,J=2.9Hz,1H),1.23-1.14(m,3H); LCMS(m / z):330.1[M+1] + .

[0343] Example 16: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-3-cyclobutyl-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 19) and ((4S, Synthesis of benzyl (5aS,6S,8R,9S,10S,11S,11aR,12R,E)-3-cyclobutyl-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 20)

[0344] Step 1: Synthesis of compound S8-A6

[0345] The compound S8-A1 in Example 6 was synthesized to obtain an off-white solid compound S8-A6 (380 mg, yield: 66%). LCMS (m / z): 602.3 [M+1] + .

[0346] Step 2: Synthesis of Compounds 19 and 20

[0347] The white solid compound 19 (160 mg, yield: 50%) and the white solid compound 20 (65 mg, yield: 21%) were synthesized according to the method of Example 1, with a total yield of 71%.

[0348] Compound 19:

[0349] 1HNMR(400MHz,MeOD)δ7.49-7.32(m,5H),5.62(s,1H),5.31(s,2H),4.66-4.36(m,1H),4.31-4.18(m,2H),4.09(s,1H),4.02(s, 2H),4.00-3.95(m,1H),2.49(d,J=9.2Hz,1H),2.47-2.31(m,3H),2.14-1.94(m,1H),1.82-1.61(m,2H); LCMS(m / z):508.2[M+1] + .

[0350] Compound 20:

[0351] 1 H NMR (400MHz, MeOD) δ7.43-7.24(m,5H),5.75(s,1H),5.11(s,2H),4.97-4.94(m,1H),4.46(d,J=2.0Hz,1H),4.37(s,1H),4.23(s,1H),4.01( s,1H),3.98(d,J=11.5Hz,1H),3.91(d,J=11.5Hz,1H),2.62(d,J=2.9Hz,1H),2.28-2.07(m,4H),1.77-1.57(m,2H); LCMS(m / z):490.2[M+1] + .

[0352] Example 17: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-cyclobutyl-6-(hydroxymethyl)-2-iminooctanehydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 21)

[0353] The white solid compound 21 (28 mg, yield: 68%) was obtained by referring to the method of Example 2. LCMS (m / z): 374.2 [M+1] + .

[0354] Example 18: Synthesis of benzyl ((4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, E)-3-cyclobutyl-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 22)

[0355] The product was synthesized according to the method of Example 4 to obtain white solid compound 22 (11 mg, yield: 8%).

[0356] 1 H NMR(400MHz,MeOD)δ7.44-7.22(m,5H),5.22-5.12(m,1H),5.10(s,2H),4.57(s,2H),4.12-3.87(m,4H),3.81(s,1H),3 .47-3.32(m,1H),2.48-2.30(m,1H),2.28-2.15(m,2H),2.12-2.00(m,2H),1.72-1.57(m,2H); LCMS(m / z):492.2[M+1] + .

[0357] Example 19: Synthesis of (4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-cyclobutyl-6-(hydroxymethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetrol (Compound 23)

[0358] The product was synthesized according to the method of Example 2 to obtain white solid compound 23 (7.0 mg, yield: 89%).

[0359] 1 H NMR(400MHz,D2O)δ4.24-4.13(m,1H),4.12(s,1H),4.00-3.94(m,2H),3.94-3.88(m,3H),3.84(t,J=12.1Hz,1H),3.4 0(dd,J=11.5,6.3Hz,1H),2.44(dd,J=12.5,6.3Hz,1H),2.34-2.07(m,4H),1.74-1.56(m,2H); LCMS(m / z):358.2[M+1] + .

[0360] Example 20: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-3-cyclobutyl-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-6,9,11(5aH)-triol (Compound 24)

[0361] The product was synthesized according to the method of Example 2 to obtain white solid compound 24 (45 mg, yield: 100%).

[0362] 1 H NMR(400MHz,D2O)δ5.94(s,1H),4.65(d,J=1.8Hz,1H),4.57(s,1H),4.41(s,1H),4.35-4.25(m,1H),4.20(s,1H),4.07( d,J=12.2Hz,1H),4.00(s,1H),2.99(d,J=3.0Hz,1H),2.33(d,J=10.3Hz,4H),1.89-1.74(m,2H); LCMS(m / z):356.1[M+1] + .

[0363] Example 21: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-3-(cyclopropylmethyl)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 25) and ((4S, Synthesis of benzyl (5aS,6S,8R,9S,10S,11S,11aR,12R,E)-3-(cyclopropylmethyl)-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 26)

[0364] Step 1: Synthesis of compound S8-A7

[0365] The compound S8-A1 in Example 6 was synthesized to obtain an off-white solid compound S8-A7 (0.80 g, yield: 49%). LCMS (m / z): 602.3 [M+1] + .

[0366] Step 2: Synthesis of Compounds 25 and 26

[0367] The white solid compound 25 (295 mg, yield: 44%) and the white solid compound 26 (280 mg, yield: 43%) were synthesized according to the method of Example 1, with a total yield of 87%.

[0368] Compound 25:

[0369] 1H NMR(400MHz,MeOD)δ7.49-7.27(m,5H),5.71-5.62(m,1H),5.26(d,J=9.8Hz,2H),4.2 1(d,J=1.5Hz,1H),4.16(s,1H),4.08-3.91(m,4H),3.86-3.72(m,1H),3.43-3.34(m, 1H),2.47-2.37(m,1H),1.16-1.03(m,1H),0.61-0.44(m,2H),0.42-0.34(m,1H),0.28-0.19(m,1H); LCMS(m / z):508.2[M+1] + .

[0370] Compound 26:

[0371] 1 H NMR (400MHz, MeOD) δ7.47-7.20 (m, 5H), 5.45 (s, 1H), 5.11 (s, 2H), 4.48 (d, J = 2.1Hz, 1H), 4. 39(s,1H),4.18(dd,J=3.0,1.6Hz,1H),4.01(t,J=1.8Hz,1H),3.97(d,J=11.4Hz,1H),3.90 (d,J=11.5Hz,1H),3.43(dd,J=14.4,7.0Hz,1H),3.34(dd,J=12.3,4.8Hz,1H),2.69(d,J=2 .6Hz,1H),1.16-0.99(m,1H),0.59-0.44(m,2H),0.36-0.22(m,2H); LCMS(m / z):490.2[M+1] + .

[0372] Example 22: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-(cyclopropylmethyl)-6-(hydroxymethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 27)

[0373] The product was synthesized according to the method of Example 2 to obtain white solid compound 27 (25 mg, yield: 74%). 1H NMR(400MHz,D2O)δ5.44(d,J=9.6Hz,1H),4.24(s,1H),4.13(s,2H),3.97(d,J=12.1Hz,2H),3.92-3.84(m,1H),3.12- 2.96(m,2H),2.28(d,J=9.5Hz,1H),1.10-0.89(m,1H),0.59-0.42(m,2H),0.23-0.13(m,2H); LCMS(m / z):374.2[M+1] + .

[0374] Example 23: Synthesis of benzyl ((4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, E)-3-(cyclopropylmethyl)-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 28)

[0375] The compound 28 was synthesized according to the method of Example 4 to obtain compound 28 (14 mg, yield: 12%).

[0376] 1 H NMR(400MHz,MeOD)δ7.52-7.20(m,5H),5.10(s,2H),4.52-4.07(m,3H),4.04-3.88(m,3H),3.83-3.57(m,2H),3.29- 3.14(m,2H),2.52-2.39(m,1H),1.16-0.87(m,1H),0.56-0.42(m,2H),0.25(d,J=4.4Hz,2H); LCMS(m / z):492.2[M+1] + .

[0377] Example 24: Synthesis of (4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-(cyclopropylmethyl)-6-(hydroxymethyl)-2-iminoheptahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetrol (Compound 29)

[0378] The product was synthesized according to the method of Example 2 to obtain white solid compound 29 (10 mg, yield: 93%).

[0379] 1H NMR(400MHz,D2O)δ4.12-4.02(m,2H),4.00-3.90(m,3H),3.86(d,J=6.1Hz,2H),3.44-3.30(m,2H),3.13-3.00(m,1 H),2.49(dd,J=12.6,6.2Hz,1H),1.09-0.94(m,1H),0.58-0.44(m,2H),0.31-0.15(m,2H); LCMS(m / z):358.2[M+1] + .

[0380] Example 25: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-3-(cyclopropylmethyl)-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-6,9,11(5aH)-triol (Compound 30)

[0381] The product was synthesized according to the method of Example 2 to obtain compound 30 (30 mg, yield: 84%) as a white solid.

[0382] 1 H NMR(400MHz,D2O)δ5.52(s,1H),4.47(d,J=2.1Hz,1H),4.31(s,1H),4.21- 4.11(m,1H),3.98(t,J=1.8Hz,1H),3.94(d,J=12.1Hz,1H),3.85(d,J=12.1 Hz,1H),3.38-3.30(m,1H),3.26-3.16(m,1H),2.81(d,J=2.9Hz,1H),1.12- 0.95(m,1H),0.62-0.48(m,2H),0.35-0.18(m,2H); LCMS(m / z):356.1[M+1] + .

[0383] Example 26: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-3-cyclopropyl-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 31) and ((4S, Synthesis of benzyl (5aS,6S,8R,9S,10S,11S,11aR,12R,E)-3-cyclopropyl-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 32)

[0384] Step 1: Synthesis of compound S8-A3

[0385] The compound S8-A1 in Example 6 was synthesized to obtain a white solid compound S8-A3 (0.90 g, yield: 57%). LCMS (m / z): 588.3 [M+1] + .

[0386] Step 2: Synthesis of Compound 31 and Compound 32

[0387] The synthesis was carried out according to the method of Example 1 to obtain white foamy solid compound 31 (1.35 g, yield: 71%) and compound 32 (200 mg, yield: 11%), with a total yield of 88%.

[0388] Compound 31:

[0389] 1 H NMR (400MHz, MeOD) δ7.41-7.27(m,5H),5.43-5.30(m,3H),4.25(d,J=1.4Hz,1H),4.12(s,1H),4.06-4.00(m,2H),4.00-3.94(m ,2H),2.89-2.73(m,1H),2.52(d,J=8Hz,1H),1.17-1.08(m,1H),1.07-0.95(m,2H),0.86-0.72(m,1H); LCMS(m / z):494.2[M+1] + .

[0390] Compound 32:

[0391] LCMS (m / z): 476.2 [M+1] + .

[0392] Example 27: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-cyclopropyl-6-(hydroxymethyl)-2-iminooctanehydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 33)

[0393] The product was synthesized according to the method of Example 2 to obtain white solid compound 33 (14 mg, yield: 97%).

[0394] 1 H NMR(400MHz,D2O)δ5.52(s,1H),4.44(d,J=2.1Hz,1H),4.36(s,1H),4.19(s,1H),4.00(s,1H),3.83(s,1H),3.52( s,1H),2.76(d,J=2.7Hz,1H),2.7-2.66(m,1H),0.87(d,J=6.6Hz,2H),0.79-0.72(m,2H); LCMS(m / z):360.1[M+1] + .

[0395] Example 28: Synthesis of benzyl ((4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, E)-3-cyclopropyl-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 34)

[0396] The product was synthesized according to the method of Example 4 to obtain compound 34 (52 mg, yield: 54%) as a white solid.

[0397] 1 H NMR(400MHz,MeOD)δ7.44-7.23(m,5H),5.13(s,2H),4.59(s,br,1H),4.23-3.76(m,6H),3.14(s,br,1H),2. 84-2.73(m,1H),2.43(dd,J=12.5,5.5Hz,1H),0.88-0.71(m,3H),0.69-0.61(m,1H); LCMS(m / z):478.2[M+1] + .

[0398] Example 29: Synthesis of (4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-cyclopropyl-6-(hydroxymethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetrol (Compound 35)

[0399] The product was synthesized according to the method of Example 2 to obtain compound 35 (25 mg, yield: 91%) as a white solid.

[0400] 1 H NMR(400MHz,D2O)δ4.15(s,1H),4.00(s,1H),3.97(s,1H),3.94(s,2H),3.88(s,1H),3.80(d,J=11.9Hz,1H),3.37(dd,J=11.5,6.5H z,1H),2.73(s,1H),2.54(dd,J=12.3,6.4Hz,1H),0.89(dd,J=14.1,6.5Hz,3H),0.76(dd,J=7.4,4.1Hz,1H); LCMS(m / z):344.1[M+1] + .

[0401] Example 30: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-3-cyclopropyl-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-6,9,11(5aH)-triol (Compound 36)

[0402] The product was synthesized according to the method of Example 2 to obtain white solid compound 36 (152 mg, yield: 100%).

[0403] 1 H NMR(400MHz,D2O)δ4.15(s,1H),4.00(s,1H),3.97(s,1H),3.94(s,2H),3.88(s,1H),3.80(d,J=11.9Hz,1H),2. 73(s,1H),2.54(dd,J=12.3,6.4Hz,1H),0.95-0.85(m,3H),0.76(dd,J=7.4,4.1Hz,1H); LCMS(m / z):342.1[M+1] + .

[0404] Example 31: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)-3-isopropyloctahydro-5,9-epoxy-7,10-methyloxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 37) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(hydroxymethyl)-3-isopropyloctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 38)

[0405] Step 1: Synthesis of compound S8-A4

[0406] The compound S8-A1 was synthesized according to the method of Example 6 to obtain a white foamy solid compound S8-A4 (0.91 g, yield: 57%). LCMS (m / z): 590.3 [M+1] + .

[0407] Step 2: Synthesis of Compound 37 and Compound 38

[0408] The synthesis was carried out according to the method of Example 1 to obtain white foamy solid compound 37 (330 mg, yield: 46%) and white foamy solid compound 38 (17 mg, yield: 2%), with a total yield of 48%.

[0409] Compound 37:

[0410] 1 H NMR(400MHz,MeOD)δ7.52-7.28(m,5H),5.79(s,1H),5.30(s,2H),4.59(d,J =2.1Hz,1H),4.52(s,1H),4.39-4.31(m,1H),4.30-4.27(m,1H),4.07(t,J= 1.8Hz,1H),3.98(d,J=11.5Hz,1H),3.92(d,J=11.5Hz,1H),2.82(d,J=2.9H z,1H),1.35(d,J=6.6Hz,3H),1.25(d,J=6.7Hz,3H); LCMS(m / z):496.2[M+1] + .

[0411] Compound 38:

[0412] LCMS (m / z): 478.2 [M+1] + .

[0413] Example 32: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(hydroxymethyl)-2-imino-3-isopropyloctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 39)

[0414] The product was synthesized according to the method of Example 2 to obtain compound 39 (9.8 mg, yield: 90%) as a white solid.

[0415] 1 H NMR (400 MHz, D2O) δ 5.74 (s, 1H), 4.54 (d, J = 1.7 Hz, 1H), 4.47 (s, 1H), 4.31 (s, 1H), 4.09 (s, 1H), 4.03-3.97 (m, 1H), 3.96-3.91 (m, 1H), 3.85 (d, J = 12.2 Hz, 1H), 2.85 (d, J = 2.6 Hz, 1H), 1.27 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H); HRMS (ESI+): calculated value: C 14 H 23 O8N3([M+H] + ):362.15,measurement value:361.35.

[0416] Example 33: Synthesis of benzyl ((4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, E)-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)-3-isopropyloctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 40)

[0417] The product was synthesized according to the method of Example 4 to obtain white solid compound 40 (17.8 mg, yield: 19%). LCMS (m / z): 480.2 [M+1] + .

[0418] Example 34: Synthesis of (4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(hydroxymethyl)-2-imino-3-isopropyloctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetrol (Compound 41)

[0419] The product was synthesized according to the method of Example 2 to obtain compound 41 (10 mg, yield: 93%) as a white solid.

[0420] 1 H NMR (400 MHz, D2O) δ 4.47 (d, J = 35.1 Hz, 1H), 4.21 (d, J = 61.5 Hz, 1H), 4.04-3.96 (m, 2H), 3.95-3.85 (d, J = 17.8 Hz, 2H), 3.83-3.60 (m, 2H), 3.37-3.21 (m, 1H), 2.48 (dd, J = 12.1, 6.0 Hz, 1H), 1.15 (t, J = 5.8 Hz, 6H); HRMS (ESI+): calculated value: C 22 H 29 O 10 N3([M+H] + ):346.15,measurement value:346.16.

[0421] Example 35: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-9-(hydroxymethyl)-2-imino-3-isopropyloctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-6,9,11(5aH)-triol (Compound 42)

[0422] The product was synthesized according to the method of Example 2 to obtain white solid compound 42 (10 mg, yield: 93%).

[0423] 1 H NMR(400MHz,D2O)δ5.74(s,1H),4.54(d,J=1.8Hz,1H),4.46(s,1H),4.30(s,1H),4.09(s,1H),4.03-3.96(m,1H),3.93(d,J=12 .3Hz,1H),3.85(d,J=12.2Hz,1H),2.85(d,J=2.6Hz,1H),1.27(d,J=6.6Hz,3H),1.18(d,J=6.7Hz,3H); LCMS(m / z):344.1[M+1] + .

[0424] Example 36: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)-3-(3-hydroxypropyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)benzylcarbamate (Compound 43), ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(hydroxymethyl)- 1H-(4-(2-hydroxy-3-methyl-1-oxo-4-oxo-2H,11H-9,13-epoxy-7a,11-methyleneoxy)benzyl)-3-(3-hydroxypropyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiaza-2(1H)-ylidene)carbamate (Compound 44), ((7aR,8S,9S,11S,12S,13R,13aR,13bR,15S,E)-8,9,12,15-tetrahydroxy-12-(hydroxymethyl)octahydro-2H,11H-9,13-epoxy-7a,11-methyleneoxy[4',5':4, Synthesis of benzyl (7aR,8S,9S,11S,12S,13R,13aR,15S,E)-8,9,12,15-tetrahydroxy-12-(hydroxymethyl)octahydro-2H,11H-9,13-epoxy-7a,11-methyleneoxy[4',5':4,5]pyrimidinyl[6,1-b][1,3]oxazin-6(7H)-ylidene)carbamate (Compound 46)

[0425] Step 1: Synthesis of Compound S8-A9-a and Compound S8-A9-b

[0426] The reaction mixture was synthesized by referring to the method of compound S8-A1 in Example 6 to obtain a mixture of white solid compounds S8-A9-a and S8-A9-b (0.70 g, 43%).

[0427] Compound S8-A9-a: LCMS (m / z): 606.3 [M+H] + .

[0428] Compound S8-A9-b: LCMS (m / z): 844.4 [M+H] + .

[0429] Step 2: Synthesis of Compound 43, Compound 44, Compound 45 and Compound 46

[0430] According to the method of Example 1, white solid compound 43 (30 mg, yield: 7%), compound 44 (25 mg, yield: 5%), compound 45 (8 mg, yield: 2%) and compound 46 (25 mg, yield: 5%) were obtained, with a total yield of 19%.

[0431] Compound 43:

[0432] 1 H NMR(400MHz,MeOD)δ7.38-7.27(m,5H),5.42-5.28(d,1H),5.08(s,2H),4.57(s,br,1H),4.15(d,J=8.4Hz,2H),4.04-3.91(m,3H ),3.75-3.69(m,2H),3.59-3.53(m,2H),2.68(d,J=4.8Hz,1H),2.36(d,J=9.6Hz,1H),1.84-1.75(m,2H); LCMS(m / z):512.2[M+H] + .

[0433] Compound 44:

[0434] 1 H NMR(400MHz,MeOD)δ7.32-7.13(m,5H),5.27(s,1H),5.00(s,2H),4.47(s ,1H),4.39(d,J=2.0Hz,1H),4.31(s,1H),4.09(s,1H),3.92(s,1H),3.84( dd,J=27.0,11.5Hz,2H),3.67-3.58(m,1H),3.52-3.44(m,2H),3.44-3.33 (m,1H),2.61(d,J=2.8Hz,1H),1.72-1.61(m,2H); LCMS(m / z):494.2[M+H] + .

[0435] Compound 45:

[0436] 1H NMR (400MHz, MeOD) δ7.43-7.23(m,5H),5.09(s,2H),5.04(d,J=7.2Hz,1H),4.56(s,1H),4.32-4.08(m,3H),4.07-3.92(m, 3H),3.93-3.66(m,2H),3.15-2.96(m,1H),2.83(s,1H),1.98-1.74(m,1H),1.55(d,J=13.8Hz,1H); LCMS(m / z):494.2[M+H] + .

[0437] Compound 46:

[0438] 1 H NMR (400MHz, MeOD) δ7.46-7.19 (m, 5H), 5.16 (d, J = 9.5Hz, 1H), 5.09 (s, 2H), 4.7 7(d,J=14.0Hz,1H),4.56(s,1H),4.46-4.24(m,1H),4.17-3.95(m,4H),3.90(d ,J=9.2Hz,1H),3.70(d,J=11.6Hz,1H),2.85(t,J=13.1Hz,1H),2.45(d,J=9.4H z,1H),1.86(q,J=12.6Hz,1H),1.58(d,J=13.3Hz,1H); LCMS(m / z):494.2[M+H] + .

[0439] Example 37: Synthesis of (7aR,8S,9S,11S,12S,13R,13aR,13bR,15S)-12-(hydroxymethyl)-6-iminodihydro-2H,11H-9,13-epoxy-7a,11-methyleneoxy[4',5':4,5]pyrimido[6,1-b][1,3]oxazine-8,9,12,15(8H)-tetrol (Compound 47)

[0440] The product was synthesized according to the method of Example 2 to obtain white solid compound 47 (11 mg, yield: 100%).

[0441] 1H NMR(400MHz,D2O)δ5.01(d,J=20.2Hz,1H),4.25(dd,J=26.7,13.3Hz,1H),4.09(dd,J=5.4,1.6Hz,2H),4.04-3.91(m,4H),3.84( s,1H),3.56(s,1H),3.46-3.36(m,1H),2.76(d,J=5.5Hz,1H),1.99-1.83(m,1H),1.67(d,J=14.2Hz,1H); LCMS(m / z):360.1[M+1] + .

[0442] Example 38: Synthesis of (7aR,8S,9S,11S,12S,13R,13aR,15S)-12-(hydroxymethyl)-6-iminodihydro-2H,11H-9,13-epoxy-7a,11-methyleneoxy[4',5':4,5]pyrimido[6,1-b][1,3]oxazine-8,9,12,15(8H)-tetrol (Compound 48)

[0443] The product was synthesized according to the method of Example 2 to obtain white solid compound 48 (11 mg, yield: 100%).

[0444] 1 H NMR(400MHz,D2O)δ5.11(d,J=9.5Hz,1H),4.16(s,1H),4.07(dd,J=11.4Hz,J=4.2Hz,1H),4.01-3.89(m,5H),3.81(d,J=11.9Hz ,1H),3.78(s,1H),3.30-3.20(m,1H),2.40(d,J=9.4Hz,1H),2.01-1.81(m,1H),1.73(d,J=13.8Hz,1H); LCMS(m / z):360.1[M+1] + .

[0445] Example 39: 3-((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-2-(((benzyloxy)carbonyl)imino)-4,6,9,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-3(4H)-yl)propanoic acid (Compound 49) and ((7aR,8S,9 Synthesis of benzyl (S,11S,12S,13R,13aR,13bR,15S,E)-8,9,12,15-tetrahydroxy-12-(hydroxymethyl)-2-oxooctahydro-2H,11H-9,13-epoxy-7a,11-methyleneoxy[4',5':4,5]pyrimidinyl[6,1-b][1,3]oxazin-6(7H)-ylidene)carbamate (Compound 50)

[0446] Step 1: Synthesis of compound S8-A10

[0447] The compound S8-A1 was synthesized according to the method of Example 6 to obtain a white solid compound S8-A10 (300 mg, yield: 29%). LCMS (m / z): 634.3 [M+1] + .

[0448] Step 2: Synthesis of Compounds 49 and 50

[0449] The white solid compound 49 (25.3 mg, yield: 10%) and the compound 50 (65 mg, yield: 27%) were synthesized according to the method of Example 1.

[0450] Compound 49:

[0451] 1 H NMR (400MHz, MeOD) δ7.43-7.25(m,5H),5.38(t,J=9.1Hz,1H),5.18(t,J=9.5Hz,2H),4.40-4.10(m,2H),4.06-3.9 5(m,2H),3.95-3.65(m,4H),2.76-2.67(m,1H),2.65-2.55(m,1H),2.41(d,J=9.5Hz,1H); LCMS(m / z):526.2[M+1] + .

[0452] Compound 50:

[0453] 1H NMR(400MHz,MeOD)δ7.43-7.23(m,5H),5.47(s,1H),5.12(s,2H),4.46(d,J=2.1Hz, 1H), 4.37 (s, 1H), 4.17 (dd, J = 2.9, 1.5Hz, 1H), 4.00 (t, J = 1.7Hz, 1H), 3.95 (d, J = 11. 5Hz,1H),3.90(d,J=11.5Hz,1H),3.85-3.76(m,1H),3.71-3.61(m,1H),2.68(d,J=2 .9Hz,1H),2.62(dd,J=15.4,7.7Hz,1H),2.56-2.46(m,1H); LCMS(m / z):508.2[M+1] + .

[0454] Example 40: Synthesis of (7aR,8S,9S,11S,12S,13R,13aR,13bR,15S)-8,9,12,15-tetrahydroxy-12-(hydroxymethyl)-6-iminododecahydro-2H,11H-9,13-epoxy-7a,11-methyleneoxy[4',5':4,5]pyrimidinyl[6,1-b][1,3]oxazin-2-one (Compound 51)

[0455] The product was synthesized according to the method of Example 2 to obtain compound 51 (15 mg, yield: 67%) as a white solid.

[0456] 1 H NMR(400MHz,D2O)δ5.50(s,1H),4.52(d,J=2.1Hz,1H),4.45(s,1H),4.27(s,1H),4.08(s,1H),3.91(d,J=12.2Hz, 1H),3.84(d,J=12.2Hz,1H),3.71-3.55(m,2H),2.87(d,J=2.9Hz,1H),2.51-2.42(m,2H); LCMS(m / z):374.1[M+1] + .

[0457] Example 41: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-3-(cyclobutylmethyl)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 52) and ((4S, Synthesis of benzyl (5aS,6S,8R,9S,10S,11S,11aR,12R,E)-3-(cyclobutylmethyl)-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 53)

[0458] Step 1: Synthesis of compound S8-A5

[0459] Compound S8-A1 was synthesized according to the method of Example 6 to obtain compound S8-A5 (923 mg, yield: 55.7%) as a white foamy solid. LCMS (m / z): 616.3 [M+1] +

[0460] Step 2: Synthesis of Compound 52 and Compound 53

[0461] The white solid compound 52 (300 mg, yield: 39%) and the white solid compound 53 (90 mg, yield: 12%) were synthesized according to the method of Example 1, with a total yield of 51%.

[0462] Compound 52:

[0463] 1 H NMR(400MHz,MeOD)δ7.51-7.29(m,5H),5.47(dd,J=17.2,9.7Hz,1H),5.28(d,J =10.0Hz,2H),4.51-4.31(m,1H),4.20(d,J=1.5Hz,1H),4.16(s,1H),4.06-3.9 5(m,3H),3.91-3.72(m,1H),3.66-3.56(m,1H),2.74(dd,J=14.8,7.3Hz,1H),2 .46-2.36(m,1H),2.17-1.98(m,2H),1.95-1.69(m,4H); LCMS(m / z):522.2[M+1] + .

[0464] Compound 53:

[0465] 1 H NMR(400MHz,MeOD)δ7.47-7.25(m,5H),5.35(s,1H),5.14(s,2H),4.48(d,J=2.1H z,1H),4.39(s,1H),4.18(dd,J=3.0,1.5Hz,1H),4.02(t,J=1.8Hz,1H),3.95(dd, J=27.9,11.4Hz,2H),3.60(dd,J=14.0,7.5Hz,1H),3.48(dd,J=14.0,7.3Hz,1H), 2.69-2.59(m,2H),2.10-1.98(m,2H),1.96-1.71(m,4H); LCMS(m / z):504.2[M+1] + .

[0466] Example 42: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-3-(cyclobutylmethyl)-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-6,9,11(5aH)-triol (Compound 54)

[0467] The synthesis was carried out according to the method of Example 2 to obtain an off-white solid compound 54 (9 mg, yield: 55.8%).

[0468] 1 H NMR(400MHz,D2O)δ5.41(s,1H),4.44(s,1H),4.26(s,1H),4.11(s,1H),4.01-3.77(m,3H),3.41(d ,J=6.0Hz,2H),2.73(s,1H),2.58(s,1H),1.99(s,2H),1.88-1.55(m,4H); LCMS(m / z):370.2[M+1] + .

[0469] Example 43: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-(cyclobutylmethyl)-6-(hydroxymethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 55)

[0470] The synthesis was carried out according to the method of Example 2 to obtain an off-white solid compound 55 (35 mg, yield: 47.1%).

[0471] 1 H NMR(400MHz,D2O)δ5.44(d,J=8.6Hz,1H),4.35-3.70(m,6H),3.18(d,J=5.5Hz,2H),2.49(d,J=6 .6Hz,1H),2.31(dd,J=29.5,9.2Hz,1H),1.99(s,2H),1.86-1.56(m,4H); LCMS(m / z):388.2[M+1] + .

[0472] Example 44: Synthesis of (4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-(cyclobutylmethyl)-6-(hydroxymethyl)-2-iminooctanhydro-5,9-epoxy-7,10-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetrol (Compound 56)

[0473] Step 1: Synthesis of benzyl ((4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, E)-3-(cyclobutylmethyl)-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 56-1)

[0474] The compound 56-1 was synthesized according to the method of Example 4 to obtain a white foamy solid compound (50 mg, yield: 51.1%). LCMS (m / z): 506.2 [M+1] + .

[0475] Step 2: Synthesis of compound 56

[0476] The synthesis was carried out according to the method of Example 2 to obtain an off-white solid compound 56 (18 mg, yield: 76.6%).

[0477] 1 H NMR(400MHz,D2O)δ4.20-3.70(m,6H),3.55-3.41(m,1H),3.28-3.08(m,2H),2.56(d,J=66.2Hz,3H),2.09-1.59(m,6H); LCMS(m / z):372.2[M+1] + .

[0478] Example 45: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-3-benzyl-6-(hydroxymethyl)-2-iminooctanhydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 57) and (4S, 5aS, 6S, 8R, 9S, 10S, 11S, 11aR, 12R)-3-benzyl-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (Compound 58)

[0479] Step 1: Synthesis of compound S8-A8

[0480] The compound S8-A1 in Example 6 was synthesized to obtain an off-white solid compound S8-A8 (0.84 g, yield: 61%). LCMS (m / z): 604.3 [M+1] + .

[0481] Step 2: Synthesis of Compound 57 and Compound 58

[0482] According to the method of Example 1, compound 57 (13 mg, yield: 2%) and compound 58 (79 mg, yield: 15%) were obtained as white solids with a total yield of 15%.

[0483] Compound 57:

[0484] LCMS (m / z): 410.2 [M+1] + .

[0485] Compound 58

[0486] 1 H NMR(400MHz,MeOD)δ7.48-7.29(m,5H),5.39(s,1H),4.54(s,1H),4.50-4.38(m,3H ), 4.22 (s, 1H), 4.06 (s, 1H), 3.96 (dd, J = 26.9, 11.5Hz, 2H), 2.77 (d, J = 2.6Hz, 1H).

[0487] LCMS (m / z): 392.1 [M+1] + .

[0488] Example 46: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(methoxymethyl)octahydro-5,9-epoxy-7,10-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 59) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(methoxymethyl)octahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 60)

[0489] Step 1: Synthesis of compound 59-1

[0490] To a 50 mL single-necked flask, add TTX-42 (250 mg, 0.39 mmol) and anhydrous dichloromethane (8 mL). Under nitrogen, cool to approximately 0°C, add 1,8-bis(methylaminonaphthalene) (251 mg, 1.17 mmol), and then trimethyloxonium tetrafluoroborate (115 mg, 0.78 mmol). After addition, warm to room temperature and stir overnight. HPLC analysis confirmed that most of the starting materials had reacted completely. Add saturated sodium bicarbonate solution (15 mL) to the reaction mixture, extract with dichloromethane (15 mL x 3). Combine the organic phases, wash twice with 0.25 M dilute hydrochloric acid (10 mL x 2), wash once with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. The crude product was purified by prep-TLC (developing solvent: petroleum ether / ethyl acetate = 3:1) to obtain compound 59-1 as a light yellow oil (167 mg, yield: 65.3%).

[0491] 1 H NMR (400MHz, CDCl3) δ11.60(s,1H),8.94(s,1H),7.43-7.28(m,10H),5.28-5.09(m,5H),4.71(s,1H),4.63(s,1H),4.63 4.51-4.32(m,1H),4.21-4.01(m,1H),3.94(s,1H),3.84(d,J=9.8Hz,1H),3.75(s,1H),3.68(d,J=10 .0Hz,1H),3.50(s,3H),3.29(s,2H),2.07(s,1H),1.41(s,3H),1.25(m,3H); LCMS(m / z):656.2[M+1] + .

[0492] Step 2: Synthesis of Compounds 59 and 60

[0493] The white solid compound 59 (38.4 mg, yield: 33%) and the white solid compound 60 (23.7 mg, yield: 21%) were synthesized according to the method of Example 1. The total yield was 54%.

[0494] Compound 59:

[0495] 1 H NMR(400MHz,MeOD)δ7.43-7.21(m,5H),5.54(d,J=9.4Hz,1H),5.05(s,2H),4 .51-3.66(m,6H),3.44(s,3H),2.22(d,J=9.4Hz,1H); LCMS(m / z):468.2[M+1] + .

[0496] Compound 60:

[0497] 1 H NMR(400MHz,MeOD)δ7.40-7.20(m,5H),5.27(s,1H),5.07(s,2H),4.47(d,J=1.9Hz,1H),4.42(s,1H),4.17(s,1H),4 .01(s,1H),3.84(d,J=9.7Hz,1H),3.75(d,J=9.7Hz,1H),3.44(s,3H),2.68(d,J=2.8Hz,1H); LCMS(m / z):450.1[M+1] + .

[0498] Example 47: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-2-imino-6-(methoxymethyl)octahydro-5,9-epoxy-7,10-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 61)

[0499] Synthesize according to the method of Example 2. After the reaction is complete, filter the reaction solution, collect the filter cake, add deionized water (30 mL) and 2.5% acetic acid aqueous solution (5 mL), stir at room temperature for 1 hour, and filter. Repeat this operation once. Combine all the filtrates and concentrate to obtain a crude product. Add two drops of methanol to the crude product to dissolve all the products, then add methyl tert-butyl ether (10 mL), stir for 30 minutes, let stand, and suck out the supernatant. Then add methyl tert-butyl ether (10 mL) again, stir for 30 minutes, let stand, and suck out the supernatant. The residue is concentrated to obtain an off-white solid compound 61 acetate (12.5 mg, yield: 98%).

[0500] 1 H NMR(400MHz,CD3OD+D2O+CD3COOD)δ5.40(d,J=9.2Hz,1H),4.32-3.98(m,2H),3.88-3 .47(m,4H),3.32(s,3H),2.12(d,J=9.3Hz,1H),1.86(s,3H); LCMS(m / z):334.1[M+1] + .

[0501] Example 48: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-2-Imino-9-(methoxymethyl)octahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (Compound 62)

[0502] The method of Example 47 was used to synthesize Compound 62 acetate (12 mg, yield: 96%) as an off-white solid.

[0503] 1 H NMR(400MHz,D2O+CD3COOD)δ5.45(s,1H),4.54(d,J=2.2Hz,1H),4.50(s, 1H),4.28(dd,J=2.9,1.6Hz,1H),4.10(t,J=1.8Hz,1H),3.84(d,J=10.8Hz,1H),3.75(d, J=10.8Hz,1H),3.39(s,3H),2.87(d,J=2.8Hz,1H),1.95(s,3H); LCMS(m / z):316.1[M+1] + .

[0504] Example 49: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-((benzylamino)methyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 63) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-9-((benzylamino)methyl)-6,9,11-trihydroxyoctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 64)

[0505] Step 1: Synthesis of compound 63-1

[0506] To a reaction flask, B2 (490 mg, 0.77 mmol, crude), dimethyl sulfoxide (8 mL), benzylamine (123 mg, 1.15 mmol), potassium acetate (432 mg, 4.41 mmol), and acetic acid (0.54 g, 9.04 mmol) were added. Sodium triacetylborohydride (1.83 g, 8.66 mmol) was added with stirring. Under nitrogen, the temperature was raised to 55°C and the reaction was allowed to proceed for 3 hours. HPLC analysis confirmed complete reaction. The reaction solution was cooled to room temperature, and water (40 mL) was added to the reaction solution, resulting in the precipitation of a large amount of light yellow solid. Stirring was continued for 30 minutes, and the mixture was filtered. The filter cake was washed with water (10 mL x 2). The filter cake was collected, dissolved in ethyl acetate (15 mL), washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue (440 mg). The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1-2:1, then changed to dichloromethane / methanol = 40:1-10:1) to give a crude product (220 mg) with a purity of approximately 70% as determined by HPLC. Prep-TLC (developing solvent: dichloromethane / methanol = 25:1) gave compound 63-1 (120 mg, yield: 21.3%) as a light yellow foamy solid.

[0507] 1H NMR(400MHz, CDCl3)δ11.59(s,1H),8.90(s,1H),7.43-7.31(m,15H),5.26- 5.17(m,4H),5.17-5.13(m,2H),5.11(d,J=2.1Hz,1H),4.61-4.56(m,2H),4 .32(d,J=8.2Hz,1H),3.94-3.85(m,3H),3.26(s,3H),3.18(d,J=12.6Hz,1H ),2.94(d,J=12.6Hz,1H),1.37(s,3H),1.22(s,3H); LCMS(m / z):731.3[M+1] + .

[0508] Step 2: Synthesis of Compound 63 and Compound 64

[0509] The white solid compound 63 (7.1 mg, yield: 8.3%) and the white solid compound 64 (1.8 mg, yield: 2.2%) were synthesized according to the method of Example 1, with a total yield of 10.5%.

[0510] Compound 63:

[0511] 1 H NMR (400MHz, MeOD) δ7.41-7.22(m,10H),5.53(d,J=9.5Hz,1H),5.05(d,J=3.6Hz,2 H),4.24-3.94(m,4H),3.93-3.85(m,2H),3.22-3.09(m,2H),2.20(dd,J=16.7,8.8 Hz,1H); LCMS(m / z):543.2[M+1] + .

[0512] Compound 64:

[0513] 1 H NMR (400MHz, MeOD) δ7.41-7.21(m,10H),5.27(s,1H),5.07(s,2H),4.46(d,J=2.1Hz,1H),4.42(s,1H),4.15(dd,J=3.0 ,1.6Hz,1H),4.03(d,J=1.7Hz,1H),3.86(s,2H),3.11(q,J=12.7Hz,2H),2.69(d,J=2.9Hz,1H); LCMS(m / z):525.2[M+1] + .

[0514] Example 50: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-hydroxyazetidin-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 65) and ((4S,5 Synthesis of benzyl (aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3-hydroxyazetidin-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 174)

[0515] Step 1: Synthesis of compound 65-1

[0516] Synthesize compound 63-1 according to the method of Example 49. After the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2). The filter cake was collected and dried to obtain compound 65-1 as a white solid (160 mg, yield: 86%). LCMS (m / z): 697.3 [M+1] + .

[0517] Step 2: Synthesis of Compound 65 and Compound 174

[0518] The white solid compound 65 (58.8 mg, yield: 21.2%) and compound 174 (11.9 mg, yield: 4.5%) were synthesized according to the method of Example 1, with a total yield of 25.7%.

[0519] Compound 65: 1 H NMR(400MHz,MeOD)δ7.49-7.31(m,5H),5.76-5.63(m,1H),5.29(s,2H),4.68(s,1H),4.54(s,2H),4.24(s,1H),4.1 6(s,2H),4.09(s,br,1H),4.03-3.90(m,3H),3.85(d,J=13.2Hz,1H),2.37(d,J=9.1Hz,1H); LCMS(m / z):509.2[M+1] + .

[0520] Compound 174: 1H NMR (400MHz, MeOD) δ7.39-7.19(m,5H),5.26(s,1H),5.07(s,2H),4.45(d,J=2.1Hz,1H),4.41(s,1H),4.36(t,J=6.2Hz,1 H),4.08(dd,J=2.9,1.5Hz,1H),3.94(s,1H),3.78-3.70(m,2H),3.09(d,J=6.0Hz,2H),3.06(d,J=4.3Hz,1H),2.97(d,J= 13.3Hz, 1H), 2.67 (d, J=3.0Hz, 1H); LCMS (m / z): 491.2[M+1] + .

[0521] Example 51: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-((3-hydroxyazetidin-1-yl)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 66)

[0522] The product was synthesized according to the method of Example 2 to obtain white solid compound 66 (17 mg, yield: 68%).

[0523] 1 H NMR(400MHz,D2O)δ5.40(d,J=9.5Hz,1H),4.66(s,1H),4.55-4.44(m,2H),4.23(d,J=11.2H z,1H),4.17-3.90(m,5H),3.88-3.67(m,2H),2.27(d,J=9.4Hz,1H); LCMS(m / z):375.1[M+1] + .

[0524] Example 52: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-2-(((benzyloxy)carbonyl)imino)-4,6,9,10,11-pentahydroxydecahydro-5,9-epoxy-7,10-methyleneoxy[4,5-d]pyrimidine-6-carboxylic acid (Compound 67) and (4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-2-(((benzyloxy)carbonyl)imino)-6,9,11-trihydroxydecahydro-4,8,11a-(methantriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxadiazepine-9-carboxylic acid (Compound 68)

[0525] The white solid compound 67 (14.7 mg, yield: 21%) and the white solid compound 68 (25.0 mg, yield: 37%) were synthesized according to the method of Example 1, with a total yield of 58%.

[0526] Compound 67:

[0527] 1 H NMR (400MHz, MeOD) δ7.50-7.22 (m, 5H), 5.60 (s, 1H), 5.15 (s, 2H), 4.34 (m, 4H), 2.25 (d, J = 9.2Hz, 1H); LCMS (m / z): 468.1 [M+1] + .

[0528] Compound 68:

[0529] 1 H NMR (400MHz, MeOD) δ7.46-7.20 (m, 5H), 5.32 (s, 1H), 5.09 (s, 2H), 4.59-4.33 (m, 4H), 2.72 (d, J = 3.0Hz, 1H); LCMS (m / z): 450.1[M+1] + .

[0530] Example 53: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodihydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-carboxylic acid (Compound 69)

[0531] The product was synthesized according to the method of Example 2 to obtain compound 69 (8.1 mg, yield: 77%) as a white solid.

[0532] 1 H NMR(400MHz,D2O)δ5.44(d,J=9.5Hz,1H),4.44(d,J=66.7Hz,2H),4.02(dd,J=61.4,49.6Hz,2H),2.22(d,J=9.0Hz,1H); LCMS(m / z):334.1[M+1] + .

[0533] Example 54: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-iminodecahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-9-carboxylic acid (Compound 70)

[0534] The product was synthesized according to the method of Example 2 to obtain compound 70 (12.0 mg, yield: 69%) as a white solid.

[0535] 1 H NMR (400MHz, D2O) δ5.45 (s, 1H), 4.54 (s, 1H), 4.52-4.42 (m, 3H), 2.84 (d, J = 2.7Hz, 1H); LCMS (m / z): 316.1[M+1] + .

[0536] Example 55: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-carbamoyl-46,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 71) and ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-9-carbamoyl-6,9,11-trihydroxyoctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 72)

[0537] Step 1: Synthesis of compound 71-1

[0538] B1 (200 mg, 0.31 mmol) and dichloromethane (3 mL) were added to a reaction flask. Ammonium chloride (20.0 mg, 0.37 mmol), triethylamine (94.0 mg, 0.93 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (143 mg, 0.38 mmol) were added with stirring. After the addition was complete, the reaction was stirred at room temperature for 16 hours. HPLC analysis confirmed complete reaction of the starting materials. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 50%) to obtain Compound 71-1 (195 mg, yield: 96%) as an oily liquid. LCMS (m / z): 655.2 [M+1] + .

[0539] Step 2: Synthesis of Compound 71 and Compound 72

[0540] The white solid compound 71 (12 mg, yield: 9%) and the white solid compound 72 (16 mg, yield: 12%) were synthesized according to the method of Example 1, with a total yield of 21%.

[0541] Compound 71:

[0542] 1 H NMR(400MHz,MeOD)δ7.43-7.22(m,5H),5.57(d,J=9.5Hz,1H),5.07(s,2H),4.34(d,J =28.3Hz,1H),4.16(d,J=35.0Hz,3H),2.29(d,J=9.3Hz,1H); LCMS(m / z):467.1[M+1] + .

[0543] Compound 72:

[0544] 1 H NMR(400MHz,MeOD)δ7.43-7.21(m,5H),5.31(s,1H),5.07(s,2H),4.53-4.45(m,2H),4 .31(dd,J=3.0,1.6Hz,1H),4.17(s,1H),2.77(d,J=3.0Hz,1H); LCMS(m / z):449.1[M+1] + .

[0545] Example 56: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminodihydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-carboxamide (Compound 73)

[0546] The product was synthesized according to the method of Example 2 to obtain white solid compound 73 (4 mg, yield: 60%).

[0547] 1 H NMR(400MHz,D2O)δ5.44(d,J=9.4Hz,1H),4.51(s,1H),4.32(s,1H),4.24(s,1H),3.92(s,1H),2.30(d,J=9.4Hz,1H); LCMS(m / z):333.1[M+1] + .

[0548] Example 57: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-iminodecahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-9-carboxamide (Compound 74)

[0549] The product was synthesized according to the method of Example 2 to obtain compound 74 (5 mg, yield: 80%) as a white solid.

[0550] 1 H NMR (400MHz, D2O) δ5.40 (s, 1H), 4.50 (d, J = 2.2Hz, 1H), 4.48 (s, 1H), 4.45 (dd, J = 3.1, 1.8Hz, 1H), 4.34 (t, J = 1.9Hz, 1H), 2.87 (d, J = 3.0Hz, 1H).

[0551] Example 58: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(methylcarbamoyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 75) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(methylcarbamoyl)octahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)carbamate (Compound 76)

[0552] Step 1: Synthesis of compound 75-1

[0553] The oily liquid compound 75-1 (200 mg, yield: 96%) was synthesized by referring to the method of compound 71-1 in Example 55. LCMS (m / z): 669.2 [M+1] + .

[0554] Step 2: Synthesis of Compound 75 and Compound 76

[0555] The white solid compound 75 (33 mg, yield: 23%) and the white solid compound 76 (21 mg, yield: 15%) were synthesized according to the method of Example 1, with a total yield of 38%.

[0556] Compound 75:

[0557] 1 H NMR(400MHz,MeOD)δ7.41-7.27(m,5H),5.58(d,J=9.4Hz,1H),5.09(s,2H),4.32(s,1H),4 .21(s,1H),4.18-3.99(m,2H),2.87(s,3H),2.30(d,J=9.4Hz,1H); LCMS(m / z):481.2[M+1] + .

[0558] Compound 76:

[0559] 1H NMR(400MHz,MeOD)δ7.41-7.23(m,5H),5.30(s,1H),5.07(s,2H),4.52-4.46(m,2H),4.31(dd ,J=3.0,1.5Hz,1H),4.17(s,1H),2.87(s,3H),2.77(d,J=2.9Hz,1H); LCMS(m / z):463.1[M+1] + .

[0560] Example 59: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-imino-N-methyldecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-carboxamide (Compound 77)

[0561] The product was synthesized according to the method of Example 2 to obtain compound 77 (15 mg, yield: 72%) as a white solid.

[0562] 1 H NMR(400MHz,D2O)δ5.62(d,J=9.5Hz,1H),4.63(s,1H),4.50(s,1H),4.43(s, 1H), 4.16 (s, 1H), 2.97 (s, 3H), 2.48 (d, J = 9.4Hz, 1H); LCMS (m / z): 347.1[M+1] + .

[0563] Example 60: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-imino-N-methyldecahydro-4,8,11a-(methanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]diazepine-9-carboxamide (Compound 78)

[0564] The product was synthesized according to the method of Example 2 to obtain white solid Compound 78 (10 mg, yield: 61%).

[0565] 1 H NMR(400MHz,D2O)δ5.59(s,1H),4.70(d,J=2.2Hz,1H),4.64(s,1H),4.58(dd,J=3.0, 1.7Hz,1H),4.47(s,1H),3.05(d,J=3.0Hz,1H),2.93(s,3H); LCMS(m / z):329.1[M+1] + .

[0566] Example 61: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(dimethylcarbamoyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 79) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-9-(dimethylcarbamoyl)-6,9,11-trihydroxyoctahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)carbamate (Compound 80)

[0567] Step 1: Synthesis of compound 79-1

[0568] The compound 71-1 in Example 55 was synthesized to obtain an off-white solid compound 79-1 (200 mg, yield: 95%). LCMS (m / z): 683.3 [M+1] + .

[0569] Step 2: Synthesis of Compound 79 and Compound 80

[0570] The white solid compound 79 (24 mg, yield: 17%) and compound 80 (16 mg, yield: 12%) were synthesized according to the method of Example 1, with a total yield of 29%.

[0571] Compound 79:

[0572] 1 H NMR (400MHz, MeOD) δ7.42-7.22(m,5H),5.58(d,J=9.5Hz,1H),5.05(s,2H),4.64(d,J=42.6Hz,1H),4.45(s,1 H),4.17(dd,J=103.5,50.7Hz,2H),3.41(s,3H),3.01(s,3H),2.26(d,J=9.5Hz,1H); LCMS(m / z):495.2[M+1] + .

[0573] Compound 80:

[0574] 1H NMR(400MHz,MeOD)δ7.43-7.23(m,5H),5.31(s,1H),5.07(s,2H),4.77(s,1H),4.52(s,1 H),4.49-4.43(m,2H),3.30-2.85(m,6H),2.76(d,J=2.8Hz,1H); LCMS(m / z):477.2[M+1] + .

[0575] Example 62: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-imino-N,N-dimethyldecahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-carboxamide (Compound 81)

[0576] The product was synthesized according to the method of Example 2 to obtain compound 81 (15 mg, yield: 100%) as a white solid.

[0577] 1 H NMR(400MHz,D2O)δ5.45(t,J=8.1Hz,1H),4.64(s,1H),4.50(s,1H),4.24(d,J=8.3Hz,1H),3.91( d,J=7.2Hz,1H),3.33-3.16(m,3H),2.92(s,3H),2.32(t,J=13.6Hz,1H); LCMS(m / z):361.1[M+1] + .

[0578] Example 63: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-imino-N,N-dimethyldecahydro-4,8,11a-(methanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]diazepine-9-carboxamide (Compound 82)

[0579] The product was synthesized according to the method of Example 2 to obtain white solid Compound 82 (8 mg, yield: 100%).

[0580] 1H NMR(400MHz,D2O)δ5.45(t,J=8.1Hz,1H),4.64(s,1H),4.50(s,1H),4.24(d,J=8.3Hz,1H),3.91( d,J=7.2Hz,1H),3.33-3.16(m,3H),2.92(s,3H),2.32(t,J=13.6Hz,1H); LCMS(m / z):343.1[M+1] + .

[0581] Example 64: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(pyrrolidine-1-carbonyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 83) and benzyl (4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(pyrrolidine-1-carbonyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 84)

[0582] Step 1: Synthesis of compound 83-1

[0583] The compound 71-1 in Example 55 was synthesized to obtain a light yellow oily compound 83-1 (150 mg, yield: 69%).

[0584] Step 2: Synthesis of Compound 83 and Compound 84

[0585] The white solid compound 83 (6.8 mg, yield: 6%) and the white solid compound 84 (15.0 mg, yield: 14%) were synthesized according to the method of Example 1, with a total yield of 20%.

[0586] Compound 83:

[0587] 1H NMR(400MHz,MeOD)δ7.39-7.25(m,5H),5.31(s,1H),5.07(s,2H),4.77(s,1H),4.56(s,1H),4.49-4.41(m,2H),4.03-3.9 0(m,1H),3.67(d,J=10.3Hz,1H),3.51(t,J=6.5Hz,2H),2.73(d,J=2.7Hz,1H),1.99-1.81(m,4H); LCMS(m / z):503.2[M+1] + .

[0588] Compound 84:

[0589] 1 H NMR (400MHz, MeOD) δ7.39-7.24(m,5H),5.58(d,J=9.3Hz,1H),5.06(s,2H),4.76(s,1H),4.47(s,1H),4.31(d,J=28.0 Hz,1H),4.14(s,1H),3.86(s,1H),3.79(s,1H),3.53(s,2H),2.25(s,1H),2.01-1.80(m,4H); LCMS(m / z):521.2[M+1] + .

[0590] Example 65: Benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(piperidine-1-carbonyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Chemical Synthesis of Compound 85 / Compound 86) and piperidin-1-yl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-iminodecahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]diazepin-9-yl)methanone (Compound 87)

[0591] Step 1: Synthesis of compound 85-1

[0592] Compound 85-1 was synthesized by referring to the method of compound 71-1 in Example 55 to obtain an oily compound (215 mg, yield: 95%). LCMS (m / z): 723.3 [M+1] + .

[0593] Step 2: Synthesis of Compound 85 / Compound 86 and Compound 87

[0594] Synthesized according to the method of Example 1, two stereoisomers, in which the chiral carbon in the reaction formula is in R or S conformation, were obtained as white solid compound 85 (31 mg, yield: 21%) and white solid compound 86 (16 mg, yield: 10%). White solid compound 87 (16 mg, yield: 15%) was also obtained at the same time, with a total yield of 46%.

[0595] Compound 85:

[0596] 1 H NMR(400MHz,MeOD)δ7.41-7.25(m,5H),5.32(s,1H),5.08(s,2H),4.69(s,1H),4.48(s,2H),4.45(s,1H) ,3.84-3.60(m,4H),2.77(d,J=2.7Hz,1H),1.76-1.65(m,2H),1.64-1.54(m,4H); LCMS(m / z):517.2[M+1] + .

[0597] Compound 86:

[0598] 1 H NMR (400MHz, MeOD) δ7.41-7.22(m,5H),5.40(d,J=3.6Hz,1H),5.06(s,2H),4.61(s,1H),4.48(d,J=1.6Hz,1H),4.28(d,J=3.5Hz,1H),3.96(d d,J=47.3,13.2Hz,2H),3.39(d,J=15.3Hz,1H),3.17(dd,J=21.6,12.0Hz,1H),2.90-2.82(m,1H),1.78-1.44(m,6H); LCMS(m / z):517.2[M+1] + .

[0599] Compound 87:

[0600] 1 H NMR(400MHz,D2O)δ5.43(s,1H),4.57(d,J=1.9Hz,1H),4.51(s,1H),4.48(s,1H),3.8 0-3.32(m,5H),2.92(d,J=2.2Hz,1H),1.55(d,J=35.9Hz,6H).LCMS(m / z):383.2[M+1] + .

[0601] Example 66: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(aminomethyl)-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 88)

[0602] The product was synthesized according to the method of Example 2 to obtain white solid Compound 88 (21 mg, yield: 93%).

[0603] 1 H NMR(400MHz,D2O)δ5.45-5.39(m,1H),4.29-4.22(m,1H),4.17(s,1H),4.07(d,J=12.9Hz,1H),3.9 3(dd,J=14.4,9.7Hz,1H),3.58-3.36(m,2H),2.27(dd,J=9.4,4.4Hz,1H); LCMS(m / z):319.1[M+1] + .

[0604] Example 67: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((methylamino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 89) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((methylamino)methyl)octahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 90)

[0605] Step 1: Synthesis of compound 89-1

[0606] Synthesize compound 63-1 according to the method of Example 49. After the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2). The filter cake was collected and dried to obtain compound 89-1 (150 mg, yield: 92%) as a white solid. LCMS (m / z): 655.3 [M+1] + .

[0607] Step 2: Synthesis of Compound 89 and Compound 90

[0608] The white solid compound 89 (77 mg, yield: 72%) and the white solid compound 90 (5.2 mg, yield: 5%) were synthesized according to the method of Example 1, with a total yield of 77%.

[0609] Compound 89:

[0610] 1 H NMR(400MHz,MeOD)δ7.52-7.35(m,5H),5.73(d,J=9.4Hz,1H),5.33(s,2H),4.30(dd,J =8.5,7.1Hz,2H),4.06(s,2H),3.66(s,2H),2.82(d,J=3.1Hz,3H),2.50-2.36(m,1H). LCMS(m / z):467.2[M+1] + .

[0611] Compound 90:

[0612] 1 H NMR (400MHz, MeOD) δ7.34(d,J=11.6Hz,5H),5.28(s,1H),5.07(s,2H),4.47(d,J=2.0Hz,1H),4.43(s,1H ), 4.15 (d, J = 1.3Hz, 1H), 4.02 (s, 1H), 3.15 (dd, J = 27.7, 12.7Hz, 2H), 2.70 (d, J = 3.3Hz, 1H), 2.53 (s, 3H). LCMS(m / z):449.2[M+1] + .

[0613] Example 68: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((methylamino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 91)

[0614] The product was synthesized according to the method of Example 2 to obtain compound 91 (31 mg, yield: 79%) as a white solid.

[0615] 1H NMR (400MHz, D2O) δ5.46 (dd, J=14.6, 5.7Hz, 1H), 4.33-4.21 (m, 2H), 4.15 (s, 1H), 4.09-3. 97(m,1H),3.66-3.51(m,2H),2.78(s,3H),2.33(t,J=9.6Hz,1H); LCMS(m / z):333.1[M+1] + .

[0616] Example 69: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((dimethylamino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 92)

[0617] Step 1: Synthesis of compound 92-1

[0618] Synthesize compound 63-1 according to the method of Example 49. After the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2). The filter cake was collected and dried to obtain compound 92-1 as a white solid (175 mg, yield: 100%). LCMS (m / z): 669.3 [M+1] + .

[0619] Step 2: Synthesis of compound 92

[0620] The product was synthesized according to the method of Example 1 to obtain compound 92 (33 mg, yield: 27.5%) as a white solid.

[0621] 1 H NMR (400MHz, MeOD) δ7.48-7.32(m,5H),5.69(d,J=9.4Hz,1H),5.27(s,2H),4.26(d,J=18.4Hz,2 H),4.06(s,2H),3.88-3.62(m,2H),3.00(s,6H),2.40(d,J=9.4Hz,1H); LCMS(m / z):481.2[M+1] + .

[0622] Example 70: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((dimethylamino)methyl)-2-iminooctanoate-5,9-epoxy-7,10a-methanooxep[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 93)

[0623] The product was synthesized according to the method of Example 2 to obtain compound 93 (12 mg, yield: 68%) as a white solid.

[0624] 1 H NMR(400MHz,D2O)δ5.63(d,J=9.2Hz,1H),4.45(s,2H),4.30(s,1H),4.12(s,1H),4 .02-3.90(m,2H),2.52(d,J=9.7Hz,1H),2.23-2.14(m,6H); LCMS(m / z):347.2[M+1] + .

[0625] Example 71: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((cyclopropylamino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 94)

[0626] Step 1: Synthesis of compound 94-1

[0627] Synthesize compound 63-1 according to the method of Example 49. After the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2). The filter cake was collected and dried to obtain compound 94-1 as a white solid (95 mg, yield: 85%). LCMS (m / z): 681.3 [M+1] + .

[0628] Step 2: Synthesis of compound 94

[0629] The product was synthesized according to the method of Example 1 to obtain compound 94 (7 mg, yield: 10%) as a white solid.

[0630] 1H NMR(400MHz,MeOD)δ7.40-7.23(m,5H),5.52(d,J=9.4Hz,1H),5.05(s,2H),4.25-3.75(m,4H), 3.23(s,2H),2.33-2.16(m,2H),0.53-0.44(m,2H),0.42-0.34(m,2H).LCMS(m / z):493.2[M+1] + .

[0631] Example 72: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((3-hydroxycyclobutyl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 95)

[0632] Step 1: Synthesis of compound 95-1

[0633] Synthesize compound 63-1 according to the method described in Example 49. After completion of the reaction, cool the reaction mixture to room temperature, add it to water (30 mL), extract with ethyl acetate (15 mL x 3), and wash with saturated sodium chloride (20 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue is purified by flash column chromatography (dichloromethane / methanol = 0%-8%) to obtain 95-1 as a white solid (125 mg, yield: 62.5%). LCMS (m / z): 711.3 [M+1] + .

[0634] Step 2: Synthesis of compound 95

[0635] The product was synthesized according to the method of Example 1 to obtain compound 95 (15 mg, yield: 16.3%) as a white solid.

[0636] 1 H NMR(400MHz,MeOD)δ7.47-7.40(m,5H),5.73(d,J=9.4Hz,1H),5.32(s,2H),4.58-4.45(m 1H),4.29(s,2H),4.17-3.94(m,3H),3.56(s,2H),2.82-2.73(m,1H),2. 61-2.55(m,1H),2.45-2.36(m,2H),2.21(m,1H).LCMS(m / z):523.2[M+1] + .

[0637] Example 73: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((3-hydroxycyclobutyl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 96)

[0638] The product was synthesized according to the method of Example 2 to obtain compound 96 (5.2 mg, yield: 67.2%) as a white solid.

[0639] 1 H NMR(400MHz,D2O)δ5.44(d,J=9.4Hz,1H),4.32-4.21(m,2H),4.17-3.91(m,3H),3.57-3.35(m ,3H),2.80-2.69(m,1H),2.60-2.53(m,1H),2.42-2.29(m,2H),2.11(dd,J=20.1,9.1Hz,1H). LCMS(m / z):389.2[M+1] + .

[0640] Example 74: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2-(((1H)-ylidene)carbamic acid benzyl ester octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)alanine (Compound 97)

[0641] Step 1: Synthesis of Compound 97-1

[0642] To a reaction flask, B2 (200 mg, 0.31 mmol), 2-aminopropionamide hydrochloride (77.9 mg, 0.63 mmol), KOAc (176.5 mg, 1.80 mmol), and anhydrous DMSO (5.0 mL) were added dropwise. AcOH (221.2 mg, 3.69 mmol) was added dropwise. The reaction mixture was heated at 60°C for 1 hour. Sodium cyanoborohydride (112 mg, 1.76 mmol) was added portionwise to the reaction mixture, and the reaction was continued at 60°C for 1 hour. The reaction was monitored for completion by HPLC. The reaction mixture was cooled to room temperature, and ice water (30 mL) was added dropwise to the reaction mixture. 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, and concentrated to obtain a residue. The residue was purified by flash column chromatography (methanol / dichloromethane = 0-8%) to obtain white solid compound 97-1 (128 mg, yield: 57.5%). LCMS (m / z): 712.3 [M+1] + .

[0643] Step 2: Synthesis of compound 97

[0644] Synthesized according to the method of Example 1, compound 97-1 (123 mg, 0.17 mmol) was added as the starting material, and the crude product was purified by prep-HPLC (A: 0.1% AcOH, B: MeOH = 0-8%) to obtain compound 97 (10 mg, yield: 13.6%) as a white solid. LCMS (m / z): 525.2 [M+1] + .

[0645] Example 75: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11(10H)-pentahydroxy-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)alanine (Compound 98)

[0646] The product was synthesized according to the method of Example 2 to obtain white solid compound 98 (5.0 mg, yield: 67.1%). LCMS (m / z): 391.1 [M+1] + .

[0647] Example 76: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(azetidin-1-ylmethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 99)

[0648] Step 1: Synthesis of Compound 99-1

[0649] Synthesize compound 63-1 according to the method of Example 49. After the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2). The filter cake was collected and dried to obtain compound 99-1 (200 mg, yield: 94%) as a white solid. LCMS (m / z): 681.3 [M+1] + .

[0650] Step 2: Synthesis of Compound 99

[0651] The product was synthesized according to the method of Example 1 to obtain compound 99 (33 mg, yield: 23%) as a white solid.

[0652] 1 H NMR(400MHz,MeOD)δ7.53-7.28(m,5H),5.71(d,J=8.9Hz,1H),5.32(s,2H),4.44-4.23(m, 5H),4.20-3.57(m,6H),3.31-3.25(m,1H),2.40(d,J=9.4Hz,1H).LCMS(m / z):493.2[M+1] + .

[0653] Example 77: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(azetidin-1-ylmethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 100)

[0654] The product was synthesized according to the method of Example 2 to obtain compound 100 (17 mg, yield: 78%) as a white solid.

[0655] 1 H NMR(400MHz,D2O)δ5.46(d,J=9.4Hz,1H),4.44-4.23(m,4H),4.04-3.76(m,3H),3.74-3.4 2(m,2H),2.72-2.57(m,1H),2.50-2.35(m,1H),2.13-1.97(m,2H).LCMS(m / z):359.2[M+1] + .

[0656] Example 78: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-fluoroazetidin-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 101) and ((4S, Synthesis of benzyl (5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3-fluoroazetidin-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 102)

[0657] Step 1: Synthesis of compound 101-1

[0658] Referring to the synthesis method of compound 97-1 in Example 74, material B2 (200 mg, 0.31 mmol) was added to obtain compound 101-1 (210 mg, yield: 96.3%). LCMS (m / z): 699.3 [M+1] + .

[0659] Step 2: Synthesis of Compound 101 and Compound 102

[0660] The synthesis was carried out according to the method of Example 1, and compound 101-1 (210 mg, 0.30 mmol) was added to obtain compound 101 (25 mg, 16.3%) and compound 102 (5 mg, 3.4%).

[0661] Compound 101:

[0662] 1 H NMR(400MHz,MeOD)δ7.46-7.26(m,5H),5.62(d,J=9.4Hz,1H),5.29-5.15(m,2.5H),5.12-5.05(m,0.5H) ,4.30-3.82(m,6H),3.59-3.46(m,2H),3.29-3.07(m,2H),2.31(d,J=9.1Hz,1H); LCMS(m / z):511.2[M+1] + .

[0663] Compound 102:

[0664] 1H NMR(400MHz,MeOD)δ7.50-7.19(m,5H),5.27(s,1H),5.22-5.16(m,0.5H),5.09-5 .01(m,2.5H),4.45(d,J=2.0Hz,1H),4.41(s,1H),4.10(d,J=1.3Hz,1H),3.95(s,1 H),3.82-3.69(m,2H),3.39(dd,J=9.4,4.6Hz,1H),3.36-3.32(m,1H),3.11(d,J=1 3.3Hz,1H),3.00(d,J=13.3Hz,1H),2.67(d,J=3.0Hz,1H); LCMS(m / z):493.2[M+1] + .

[0665] Example 79: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((3-fluoroazetidin-1-yl)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 103)

[0666] The synthesis was carried out according to the method of Example 2, and compound 101 (15 mg, 0.03 mmol) was added to obtain compound 103 (10 mg, yield: 90.4%).

[0667] 1 H NMR(400MHz,D2O)δ5.63-5.28(m,2H),4.67-4.42(m,4H),4.33-4.13(m,2H),4.09-3.68(m,4H),2.30(d,J=9.5Hz,1H); LCMS(m / z):377.1[M+1] + .

[0668] Example 80: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-hydroxypyrrolidin-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 104) and ((4S, Synthesis of benzyl (5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3-hydroxypyrrolidin-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 105)

[0669] Step 1: Synthesis of compound 104-1

[0670] Synthesize compound 63-1 according to the method of Example 49. After the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2). The filter cake was collected and dried to obtain compound 104-1 (145 mg, yield: 87%) as a white solid. LCMS (m / z): 711.3 [M+1] + .

[0671] Step 2: Synthesis of Compounds 104 and 105

[0672] The white solid compound 104 (33 mg, yield: 31%) and the compound 105 (3 mg, yield: 3%) were synthesized according to the method of Example 1.

[0673] Compound 104:

[0674] 1 H NMR (400MHz, MeOD) δ7.57-7.23(m,5H),5.69(d,J=7.3Hz,1H),5.29(s,2H),4.59(s,1H),4.29(s,1H),4.23(s,1H),3.97(d,J=42.4Hz,2H),3. 87-3.76(m,1H),3.63(t,J=5.0Hz,3H),3.56-3.39(m,2H),2.41(d,J=9.2Hz,1H),2.20(d,J=26.9Hz,1H),2.11(s,1H); LCMS(m / z):523.2[M+1] + .

[0675] Compound 105:

[0676] LCMS (m / z): 505.2 [M+1] + .

[0677] Example 81: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((3-hydroxypyrrolidin-1-yl)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 106)

[0678] The product was synthesized according to the method of Example 2 to obtain compound 106 (13 mg, yield: 87%) as a white solid.

[0679] 1 H NMR(400MHz,D2O)δ5.46(d,J=9.4Hz,1H),4.66(s,2H),4.29(d,J=6.6Hz,2H),4.13(s,1H),4.05-3.91(m,2 H),3.89-3.75(m,2H),3.63-3.35(m,2H),2.35(d,J=9.4Hz,2H),2.16-2.03(m,1H); LCMS(m / z):389.2[M+1] + .

[0680] Example 82: ((4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S, E)-4, 6, 9, 10, 11- Synthesis of benzyl pentahydroxy-6-((3-fluoropyrrolidin-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 107) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3-fluoropyrrolidin-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 108)

[0681] Step 1: Synthesis of Compound 107-1

[0682] Compound B2 (200 mg, 0.31 mmol) was dissolved in dimethyl sulfoxide (3 mL), and 3-fluoropyrrolidine hydrochloride (59 mg, 0.47 mmol), glacial acetic acid (221.79 mg, 3.69 mmol), and potassium acetate (176.6 mg, 1.8 mmol) were added. The mixture was heated to 60°C and stirred for 1 hour under nitrogen. Sodium cyanoborohydride (222.1 mg, 3.537 mmol) was then added portionwise and allowed to react for 30 minutes. HPLC monitoring was used until the reaction was complete. The reaction system was cooled to room temperature, and then ice water (50 mL) was added. The mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a residue of approximately 230 mg. The residue was purified by flash column chromatography (MeOH / DCM = 0-5%) to afford compound 107-1 (200 mg, yield: 89.9%).

[0683] Step 2: Synthesis of Compounds 107 and 108

[0684] Compound 107-1 (200 mg, 0.28 mmol) was added to a reaction flask, followed by water (10 mL) and TFA (10 mL). The mixture was heated to 60°C and stirred under nitrogen for 18 hours. The reaction solution was concentrated to dryness, and the residue was purified by flash column chromatography (MeOH / DCM = 0-5%) to afford compound 107 (30 mg, yield: 20.4%) and compound 108 (6 mg, yield: 4%), for a total yield of 24.4%.

[0685] Compound 107:

[0686] 1 H NMR(400MHz,MeOD)δ7.51-7.21(m,5H),5.64(d,J=9.3Hz,1H),5.30-5.08(m,3H),4.32-3.82(m,4H),3 .30-2.98(m,5H),2.91-2.70(m,1H),2.35(d,J=9.4Hz,1H),2.28-2.01(m,2H); LCMS(m / z):525.2[M+1] + .

[0687] Compound 108:

[0688] LCMS (m / z): 507.2 [M+1] + .

[0689] Example 83: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((3-fluoropyrrolidin-1-yl)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 109)

[0690] Compound 107 (20 mg, 0.04 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (10 mg) was added. The hydrogen atmosphere was replaced three times. The reaction mixture was allowed to react for approximately 3 hours, and then monitored by HPLC until the reaction was complete. The reaction mixture was filtered, and the filter cake was rinsed with 0.05 M AcOH aqueous solution. The filtrate was concentrated to obtain the crude product, which was then slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the solvent was removed by aspiration. The residue was concentrated to dryness to obtain compound 109 (10 mg, yield: 67.1%).

[0691] Compound 109:

[0692] 1 H NMR(400MHz,D2O)δ5.60-5.38(m,2H),4.30(s,2H),4.13(s,1H),4.08-3.57(m,7H),2.51-2.29(m,3H); LCMS(m / z):391.4[M+1] + .

[0693] Example 84: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(morpholinomethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 110) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(morpholinomethyl)octahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 111)

[0694] Step 1: Synthesis of compound 110-1

[0695] Compound B2 (200 mg, 0.31 mmol), morpholine (54.5 mg, 0.63 mmol), potassium acetate (176.6 mg, 1.8 mmol), and dimethyl sulfoxide (8 mL) were added to a reaction flask, followed by acetic acid (221.8 mg, 3.69 mmol). The mixture was heated to 60°C and allowed to react for 2 hours. Sodium triacetylborohydride (749.6 mg, 3.54 mmol) was then added and the reaction continued for 1.5 hours. The mixture was then stirred at room temperature overnight. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by prep-TLC (developing solvent: DCM / MeOH = 30:1) to yield compound 110-1 (84 mg, 32.9% yield). LCMS (m / z): 711.3 [M+1]. + .

[0696] Step 2: Synthesis of Compounds 110 and 111

[0697] Compound 110-1 (84 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (2.5 mL) and water (2.5 mL), heated to 65°C, and allowed to react overnight. HPLC monitoring was performed until the reaction was complete. The reaction solution was concentrated to dryness and then purified by reverse-phase flash column chromatography (eluent: MeOH / 0.1% HOAc aqueous solution = 0-2%) to obtain compound 110 (22 mg, yield: 35.6%) and compound 111 (2.5 mg, yield: 4.2%), with a total yield of 39.8%.

[0698] Compound 110:

[0699] 1 H NMR(400MHz,MeOD)δ7.46-7.15(m,5H),5.56(d,J=7.4Hz,1H),5.11(s,2H),4.33-3.81(m,4H),3.69( t,J=4.5Hz,4H),3.05-2.85(m,2H),2.74-2.58(m,4H),2.27(d,J=9.5Hz,1H); LCMS(m / z):523.2[M+1] + .

[0700] Compound 111:

[0701] LCMS (m / z): 505.2 [M+1] + .

[0702] Example 85: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(morpholinomethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 112)

[0703] Compound 110 (9 mg, 0.02 mmol), MeOH (15 mL) and 10% Pd / C (3 mg) were added to a reaction flask, hydrogen was replaced 3 times, and then hydrogen balloon pressurized hydrogenation for 3 hours. HPLC monitoring was performed until the raw material reaction was complete, and then 0.2% aqueous acetic acid solution (5 mL) was added to the reaction solution, stirred for 30 minutes, filtered, and the filter cake was pulped twice with 0.2% aqueous acetic acid solution and filtered. The filtrates were combined, concentrated and dried, and then methanol (2 drops) was added to dissolve the solid, and methyl tert-butyl ether (10 mL) was added to precipitate a white solid. Stir for 15 minutes, let stand, and suck out the supernatant. The residue was concentrated and dried and then lyophilized to obtain the acetate salt of compound 112 (7.5 mg, yield: 96%).

[0704] 1 H NMR (400MHz, D2O) δ5.44 (d, J = 9.4Hz, 1H), 4.40-4.12 (m, 3H), 4.06-3.89 (m, 5H), 3.87-3. 71(m,2H),3.55-3.41(m,4H),2.34(d,J=9.4Hz,1H),2.02(s,3H); LCMS(m / z):389.2[M+1] + .

[0705] Example 86: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2-(((1H)-ylidene)carbamic acid benzyl ester octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)glycine (Compound 113)

[0706] Step 1: Synthesis of compound 113-1

[0707] Compound B2 (205 mg, 0.32 mmol), glycine hydrochloride (36 mg, 0.48 mmol), AcOH (227 mg, 3.78 mmol), and KOAc (180 mg, 1.84 mmol) were dissolved in DMSO (2.5 mL) and stirred at 60°C for 2 hours. Sodium cyanoborohydride (227 mg, 3.62 mmol) was then added to the reaction mixture in three batches. Stirring was continued at 60°C for two hours. After completion, the reaction was quenched with water and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed once with saturated brine, separated, and dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dryness under vacuum and purified by normal phase column chromatography (methanol / dichloromethane = 10%) to obtain compound 113-1 (145 mg, yield: 64.8%). LCMS (m / z): 698.3 [M+1] + .

[0708] Step 2: Synthesis of compound 113

[0709] Compound 113-1 (145 mg, 0.20 mmol) was added to a 1:1 solution of water and trifluoroacetic acid and stirred at 65°C for 17 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product, which was then purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid = 0-6.5%) to afford compound 113 (18 mg, yield: 17.0%).

[0710] 1 HNMR(400MHz,MeOD)δ7.38-7.26(m,5H),5.54(s,1H),5.07(s,2H),4.42-3.77(m,5H),3.67-3.43(m,3H),2.24(s,1H); LCMS(m / z):511.2[M+1] + .

[0711] Example 87: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11(10H)-pentahydroxy-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)glycine (Compound 114)

[0712] Compound 113 (10 mg, 0.02 mmol) and 10% Pd / C (5 mg) were added to MeOH (2 mL), the hydrogen atmosphere was replaced, and the reaction was stirred at 25°C for 4 hours. After completion of the reaction, 0.5% aqueous acetic acid was added, stirred for 0.5 hours, and then filtered. The filtrate was concentrated and dried to obtain compound 114 (9.03 mg, yield: 122%, purity: 74.00%). LCMS (m / z): 377.1 [M+1] + .

[0713] Example 88: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2(1H)-ylidene)carbamic acid benzyl ester octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)pyrrolidine-3-carboxylic acid (Compound 115)

[0714] Step 1: Synthesis of compound 115-1

[0715] Following the method for compound 63-1 in Example 49, compound B2 (190 mg, 0.30 mmol) was added. After the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2), collected, and dried to obtain compound 115-1 (175 mg, yield: 80%) as a white solid. LCMS (m / z): 738.3 [M+1] + .

[0716] Step 2: Synthesis of compound 115

[0717] The synthesis was carried out according to the method of Example 1, and compound 115-1 (175 mg, 0.24 mmol) was added to obtain white solid compound 115 (29 mg, yield: 22%).

[0718] 1 H NMR (400MHz, MeOD) δ7.50-7.35(m,5H),5.69(d,J=9.0Hz,1H),5.27(s,2H),4.28(d,J=16.8Hz,2H),4.13(s ,2H),3.93-3.64(m,3H),3.62-3.42(m,3H),3.24-3.13(m,1H),2.50-2.21(m,3H); LCMS(m / z):551.2[M+1] + .

[0719] Example 89: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11(10H)-pentahydroxy-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)pyrrolidine-3-carboxylic acid (Compound 116)

[0720] Synthesized according to the method of Example 2, compound 115 (11 mg, 0.01 mmol) was added to obtain white solid compound 116 (4.5 mg, yield: 54%). LCMS (m / z): 417.2 [M+1] + .

[0721] Example 90: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-aminopyrrolidin-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 117)

[0722] Step 1: Synthesis of compound 117-1

[0723] Compound B2 (200 mg, 0.31 mmol) was dissolved in dimethyl sulfoxide (3 mL), and 3-(Boc-amino)pyrrolidine hydrochloride (87.4 mg, 0.47 mmol), glacial acetic acid (221.8 mg, 3.69 mmol), and potassium acetate (176.6 mg, 1.8 mmol) were added. Under nitrogen, the mixture was heated to 60°C and stirred for 1 hour. Sodium cyanoborohydride (222.1 mg, 3.54 mmol) was then added portionwise and allowed to react for 30 minutes. HPLC monitoring was performed until the reaction was complete. The reaction solution was cooled to room temperature, then ice water (50 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a residue of approximately 230 mg. The residue was purified by flash column chromatography (MeOH / DCM=0-5%) to obtain compound 117-1 (240 mg, yield: 94.9%). LCMS (m / z): 810.4 [M+1] + .

[0724] Step 2: Synthesis of compound 117

[0725] Compound 117-1 (240 mg, 0.3 mmol) was added to a reaction flask, followed by water (15 mL) and TFA (7.5 mL). The mixture was heated to 60°C under nitrogen and allowed to react for 18 hours. The reaction solution was concentrated to dryness, and the resulting residue was purified by flash column chromatography (MeOH / DCM = 0-4%) to afford compound 117 (30 mg, yield: 19.5%). LCMS (m / z): 522.2 [M+1] + .

[0726] Example 91: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-((3-aminopyrrolidin-1-yl)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 118)

[0727] Compound 117 (30 mg, 0.06 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (30 mg) was added. The hydrogen atmosphere was replaced three times. After hydrogen was introduced into the reaction solution for approximately 3 hours, HPLC monitoring was performed until the reaction was complete. The reaction solution was filtered, and the filter cake was rinsed with 0.05 M aqueous acetic acid. The filtrate was concentrated to obtain the crude compound. The crude product was slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was aspirated. The residue was concentrated to dryness to obtain compound 118 (20 mg, yield: 89.8%).

[0728] 1 H NMR(400MHz,D2O)δ5.42(d,J=9.3Hz,1H),4.29-4.16(m,3H),4.10(s,1H),4.02-3.88(m,3H),3.82-3.62(m,3H) ),2.67-2.55(m,1H),2.31(d,J=9.1Hz,1H),2.24-2.15(m,1H),1.99(d,J=9.8Hz,1H); LCMS(m / z):388.2[M+1] + .

[0729] Example 92: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((R)-3-acetamidopyrrolidin-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 119)

[0730] Step 1: Synthesis of compound 119-1

[0731] Compound B2 (200 mg, 0.31 mmol), 3-acetamido-(s)-tetrahydropyrrole (77 mg, 0.47 mmol), AcOH (222 mg, 3.71 mmol), and KOAc (177 mg, 1.80 mmol) were dissolved in DMSO (4 mL) and stirred at 60°C for 2 hours. Sodium cyanoborohydride (197 mg, 3.13 mmol) was added to the reaction solution in three batches. After the addition was complete, the reaction was stirred at 60°C for another 2 hours. After completion, the reaction was quenched with water and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and the resulting residue was purified by flash column chromatography (methanol / dichloromethane = 0-3.5%) to obtain compound 119-1 (110 mg, yield: 46.8%). LCMS (m / z): 752.3 [M+1] + .

[0732] Step 2: Synthesis of compound 119-2

[0733] Compound 119-1 (110 mg, 0.14 mmol) was added to a 1:4 mixture of water and trifluoroacetic acid (20 mL) and stirred at 60°C for 17 hours. After completion of the reaction, the mixture was concentrated to dryness. The resulting crude product was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid = 0-4.5%) to afford compound 119-2 (15 mg, yield: 19.7%). LCMS (m / z): 522.2 [M+1] + .

[0734] Step 3: Synthesis of compound 119

[0735] Compound 119-2 (15 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2 mL), and acetic anhydride (3.5 mg, 0.03 mmol) was added. The mixture was stirred at 18°C ​​for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness, and the resulting residue was purified by Prep-HPLC to afford compound 119 (2.0 mg, yield: 12.3%).

[0736] 1H NMR (400MHz, MeOD) δ7.44-7.17(m,5H),5.53(d,J=9.4Hz,1H),5.06(s,2H),4.33-4.23(m,1H),4.20-4.06(m,2H),3.94(s,2H),3.17-3.05(m,2H ),3.04-2.96(m,1H),2.91(dd,J=9.8,6.7Hz,1H),2.73-2.59(m,2H),2. 30-2.15(m,2H),1.92(s,3H),1.71-1.58(m,1H); LCMS(m / z):564.2[M+1] + .

[0737] Example 93: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((2,2,2-trifluoroethylamino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 120)

[0738] Step 1: Synthesis of compound 120-1

[0739] Compound B2 (150 mg, 0.23 mmol), trifluoroethylamine hydrochloride (48 mg, 0.35 mmol), AcOH (163 mg, 2.71 mmol), and KOAc (130 mg, 1.32 mmol) were dissolved in DMSO (3 mL) and stirred at 60°C for 2 hours. Sodium cyanoborohydride (80 mg, 1.26 mmol) was added to the reaction solution in three batches. After the addition was complete, the reaction was stirred at 60°C for 2 hours. After completion of the reaction, ice water was added to quench the reaction, and a small amount of solid sodium chloride was added. A white solid precipitated from the solution. The reaction system was filtered, and the filter cake was rinsed twice with a small amount of ice water. The filter cake was concentrated and dried to obtain compound 120-1 (95 mg, yield: 56%) as a white solid. LCMS (m / z): 723.2 [M+1] + .

[0740] Step 2: Synthesis of compound 120

[0741] Compound 120-1 (95 mg, 0.13 mmol) was added to a mixture of water and trifluoroacetic acid (1:2) (15 mL) and stirred at 60°C for 17 hours. After completion, the reaction solution was concentrated to dryness, and the resulting residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid = 0-7%) to afford compound 120 (7.5 mg, yield: 10.7%).

[0742] 1 H NMR(400MHz,MeOD)δ7.46-7.20(m,5H),5.59(d,J=9.0Hz,1H),5.11(s,2H),4.62(s,1H),4.50-4.35(m, 1H),4.31-4.12(m,2H),3.95(s,2H),3.41-3.35(m,2H),2.26(d,J=9.4Hz,1H); LCMS(m / z):535.2[M+1] + .

[0743] Example 94: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((2,2,2-trifluoroethylamino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 121)

[0744] Compound 120 (5 mg, 0.01 mmol) and 10% Pd / C (2.5 mg) were added to methanol (5 mL). The hydrogen atmosphere was replaced and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, the mixture was filtered, the filtrate was concentrated to dryness, and the resulting residue was lyophilized to obtain compound 121 (1.62 mg, yield: 43%).

[0745] 1 H NMR (400MHz, D2O) δ5.44-5.39(m,1H),4.49-4.43(m,2H),4.23(s,1H),4.16-4.01(m,3H),3.47-3.39(m,2H),2.20(dd,J=54.7,9.4Hz,1H). LCMS(m / z):401.1[M+1] + .

[0746] Example 95: Synthesis of ((((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-benzyl 4,6,9,10,11-pentahydroxy-2-((1H)-ylidene)carbamate octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)amino)propionic acid (Compound 122)

[0747] Step 1: Synthesis of compound 122-1

[0748] Compound B2 (150 mg, 0.24 mmol) was dissolved in DMSO (3 mL), and 3-aminopropionamide hydrochloride (43.86 mg, 0.35 mmol), acetic acid (166.5 mg, 2.77 mmol), and potassium acetate (132.6 mg, 1.35 mmol) were added. The mixture was heated to 60°C under nitrogen for 1 hour. Sodium cyanoborohydride (83.4 mg, 1.33 mmol) was added portionwise, and the reaction was continued at 60°C for 30 minutes. HPLC monitoring was used until the reaction of the starting material was complete. The reaction solution was cooled to room temperature, and then ice water (20 mL) was added and stirred. A large amount of solid precipitated. The filter cake was collected by filtration and concentrated to dryness to obtain crude compound 122-1 (100 mg, yield: 60%), which was used directly in the next reaction.

[0749] Step 2: Synthesis of compound 122

[0750] Crude compound 122-1 (100 mg, 0.14 mmol) was added to a reaction flask, followed by water (10 mL) and TFA (5 mL). The mixture was heated to 60°C under nitrogen for 20 hours. The reaction solution was concentrated to dryness, and the residue was purified by flash column chromatography (MeOH / DCM = 0-3%) to obtain compound 122 (25 mg, yield: 34%).

[0751] 1 H NMR (400MHz, MeOD) δ7.40-7.33(m,5H),5.59(d,J=9.3Hz,1H),5.12(s,2H),4.27-4.15(m,2H),4. 12-3.95(m,2H),3.59(s,2H),3.24(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),2.27(d,J=9.3Hz,1H). LCMS(m / z):525.2[M+1] + .

[0752] Example 96: Synthesis of ((((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11(10H)-pentahydroxy-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)amino)propionic acid (Compound 123)

[0753] Compound 122 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), 10% Pd / C (20 mg) was added, hydrogen was replaced and the mixture was reacted under a hydrogen atmosphere for 3 hours. HPLC was used to monitor the reaction until the raw material reaction was complete. The reaction solution was filtered and the filter cake was rinsed with 0.05 M aqueous acetic acid. The filtrate was concentrated to obtain a crude compound, which was then slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was removed. The residue was concentrated and dried to obtain compound 123 (14 mg, yield: 94%).

[0754] 1 H NMR(400MHz,D2O)δ5.43(d,J=9.2Hz,1H),4.26(s,2H),4.09(s,1H),3.91(s,1H), 3.72-3.52(m,2H),3.34(t,J=6.4Hz,2H),2.69(t,J=6.4Hz,2H),2.31(d,J=9.4Hz, 1H); LCMS(m / z):391.1[M+1] + .

[0755] Example 97: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((2,2-difluoroethyl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 124)

[0756] Step 1: Synthesis of compound 124-1

[0757] Compound B2 (190 mg, 0.30 mmol), 2,2-difluoroethylamine (36.2 mg, 0.45 mmol), acetic acid (196 mg, 3.4 mmol), and potassium acetate (161.7 mg, 1.7 mmol) were dissolved in DMSO (4 mL) and heated to 60°C with stirring under nitrogen for 1 hour. Sodium triacetylborohydride (94.2 mg, 1.5 mmol) was added and stirring continued for 1 hour. After the reaction, the reaction system was cooled to room temperature and water (2 mL) was added. A white solid precipitated. After stirring for 5 minutes, the mixture was filtered to obtain an off-white solid, Compound 124-1 (200 mg, yield: 95.6%). LCMS (m / z): 705.3 [M+1] + .

[0758] Step 2: Synthesis of compound 124

[0759] Compound 124-1 (200 mg, 0.28 mmol) was dissolved in a 2:1 TFA:H₂O solution (4 mL) and stirred at 60°C under nitrogen for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5%-8%) to afford Compound 124 (25 mg, yield: 17.1%) as a white solid.

[0760] 1 H NMR(400MHz,MeOD)δ7.47-7.29(m,5H),6.13-5.77(m,1H),5.65(d,J=8.0Hz,1H),5.22(s,2H),4.60(s,1H),4.1 9(d,J=17.2Hz,2H),3.97(s,2H),3.27(s,1H),3.12-3.00(m,2H),2.33(d,J=9.0Hz,1H); LCMS(m / z):517.2[M+1] + .

[0761] Example 98: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((2,2-difluoroethyl)amino)methyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 125)

[0762] Compound 124 (7.0 mg, 0.013 mmol) was dissolved in methanol (2 mL), and 10% Pd / C (1 mg) was added. The hydrogen atmosphere was replaced three times, and the mixture was stirred at 25°C for 8 hours. After the reaction, 1% aqueous acetic acid was added, stirred for 5 minutes, and filtered. The filter cake was then rinsed three times with 1% aqueous acetic acid. The filtrate was concentrated to dryness and lyophilized to obtain Compound 125 (3.2 mg, yield: 61.8%) as an off-white solid.

[0763] 1 H NMR(400MHz,D2O)δ6.31(t,J=53.3Hz,1H),5.42(d,J=9.3Hz,1H),4.27(d,J=10.7Hz,2H),4.10(s ,1H),3.90(s,1H),3.74(s,2H),3.71-3.59(m,2H),2.30(d,J=9.6Hz,1H); LCMS(m / z):383.1[M+1] + .

[0764] Example 99: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((2-fluoroethyl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 126)

[0765] Step 1: Synthesis of compound 126-1

[0766] Compound B2 (150 mg, 0.23 mmol), 2-fluoroethylamine hydrochloride (35.04 mg, 0.35 mmol), and KOAc (132.4 mg, 1.35 mmol) were dissolved in anhydrous DMSO (1.5 mL). AcOH (166.3 mg, 2.77 mmol) was added dropwise to the mixture and heated to 60°C for 1 hour. Sodium cyanoborohydride (73.7 mg, 1.17 mmol) was added portionwise to the reaction mixture, and the reaction was continued at 60°C for 1 hour. HPLC monitoring was performed until the reaction was complete. Ice water (15 mL) was added dropwise to the reaction mixture, causing a white solid to precipitate. The suspension was filtered, and the filtrate was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The filtrate was combined with the filter cake to obtain crude compound 126-1 (161 mg), which was used directly in the next step. LCMS (m / z): 687.5 [M+1] + .

[0767] Step 2: Synthesis of compound 126

[0768] Compound 126-1 (161 mg, 0.23 mmol) was dissolved in TFA (2 mL) and purified water (4 mL) and reacted at 60°C for 45 hours. HPLC monitoring was used until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase column chromatography (A: 0.1% AcOH, B: MeOH; 0-0.1%) to afford Compound 126 (35 mg, two-step yield: 30%) as a white solid.

[0769] 1 H NMR (400MHz, MeOD) δ7.45-7.36(m,5H),5.71(d,J=9.1Hz,1H),5.30(s,2H),4.89-4.86(m,1H),4.77-4.73(m,1H),4.28(s, 2H),4.15-3.95(m,2H),3.72(s,2H),3.54-3.50(m,1H),3.50-3.38(m,1H),2.41(d,J=9.3Hz,1H); LCMS(m / z):499.2[M+1] + .

[0770] Example 100: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((2-fluoroethyl)amino)methyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 127)

[0771] Compound 126 (25 mg, 0.05 mmol) was dissolved in MeOH (1.5 mL), and Pd / C (2.5 mg) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 3 hours. HPLC monitoring was used until the reaction of the starting material was complete. 0.5% AcOH / H2O (6 mL) and MeOH (1.5 mL) were then added and stirred for 1 hour. The mixture was filtered, and the filter cake was rinsed with 0.5% AcOH / H2O (10 mL) and MeOH (10 mL). The resulting filtrate was concentrated under reduced pressure and lyophilized to obtain an off-white solid compound 127 (11.69 mg, yield: 64.0%).

[0772] 1H NMR (400MHz, MeOD) δ5.51(d,J=9.4Hz,1H),4.36(d,J=7.6Hz,2H),4.19(s,1H),3.99(s,2H),3.78(d,J=5.5Hz,2H ),3.74-3.67(m,1H),3.65-3.60(m,1H),3.58-3.53(m,1H),2.40(dd,J=9.4,4.8Hz,1H); LCMS(m / z):365.3[M+1] + .

[0773] Example 101: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((3,3-difluoropropyl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 128)

[0774] Step 1: Synthesis of compound 128-1

[0775] Compound B2 (190 mg, 0.30 mmol), 3,3-difluoropropylamine hydrochloride (36.2 mg, 0.45 mmol), acetic acid (196 mg, 3.4 mmol), and potassium acetate (161.7 mg, 1.7 mmol) were dissolved in DMSO (4 mL). Under nitrogen, the mixture was heated to 60°C and stirred for 1 hour. Sodium triacetylborohydride (94.2 mg, 1.5 mmol) was added and stirring continued for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and water (2 mL) was added to the reaction mixture. A white solid precipitated. After stirring for 5 minutes, the mixture was filtered to obtain Compound 128-1 (200 mg, yield: 93.7%) as an off-white solid. LCMS (m / z): 719.3 [M+1] + .

[0776] Step 2: Synthesis of compound 128

[0777] Compound 128-1 (200 mg, 0.28 mmol) was dissolved in a 2:1 TFA:H2O solution (4 mL) and stirred at 60°C under nitrogen for 16 hours. After completion of the reaction, the reaction solution was purified by reverse-phase column chromatography (methanol / 0.1% acetic acid aqueous solution = 5%-8%) to obtain Compound 128 (32.5 mg, yield: 22.2%) as a white solid.

[0778] 1H NMR (400MHz, MeOD) δ7.48-7.23(m,5H),6.28-5.85(m,1H),5.62(d,J=9.4Hz,1H),5.18(s,2H),4.22( s,2H),4.04(s,2H),3.55-3.42(m,2H),3.20-3.06(m,2H),2.35-2.17(m,3H); LCMS(m / z):531.2[M+1] + .

[0779] Example 102: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((3,3-difluoropropyl)amino)methyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 129)

[0780] Compound 128 (7.0 mg, 0.01 mmol) was dissolved in methanol (2 mL) and Pd / C (1 mg) was added. The hydrogen atmosphere was replaced three times and the reaction was stirred at 25°C for 3 hours. After the reaction, 1% aqueous acetic acid was added, stirred for 5 minutes, and filtered. The mixture was rinsed three times with 1% aqueous acetic acid. The filtrate was concentrated to dryness and then lyophilized to obtain Compound 129 (3.5 mg, yield: 67.3%) as an off-white solid.

[0781] 1 H NMR(400MHz,D2O)δ6.06(tt,J=55.5,3.7Hz,1H),5.42(d,J=9.4Hz,1H),4.26(d,J=5.9Hz,2H),4.08( s,1H),3.90(s,1H),3.69-3.55(m,2H),3.39-3.29(m,2H),2.45-2.24(m,3H); LCMS(m / z):397.2[M+1] + .

[0782] Example 103: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((2,2-difluoroethyl)(methyl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 130)

[0783] Step 1: Synthesis of compound 124-1

[0784] Compound B2 (180 mg, 0.28 mmol), 2,2-difluoroethylamine (34.24 mg, 0.42 mmol), and KOAc (158.9 mg, 1.62 mmol) were dissolved in anhydrous DMSO (2 mL). AcOH (199.5 mg, 3.32 mmol) was then added dropwise to the mixture. The reaction mixture was heated at 60°C for 1 hour. NaBH3CN (88.5 mg, 1.41 mmol) was added portionwise to the reaction mixture, and the reaction was continued at 60°C for 1 hour. HPLC monitoring was performed until the reaction of the starting materials was complete. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0-35%) to obtain Compound 124-1 (130 mg, yield: 65.6%) as a white solid. LCMS (m / z): 705.3 [M+1] + .

[0785] Step 2: Synthesis of compound 130-2

[0786] Compound 124-1 (130 mg, 0.18 mmol) and KOAc (104.2 mg, 1.06 mmol) were dissolved in MeOH (2 mL). AcOH (130.8 mg, 2.18 mmol) and 37% aqueous formaldehyde (44.9 mg, 0.55 mmol) were added dropwise to the mixture. The reaction was allowed to react at room temperature for 1 hour. NaBH3CN (58.0 mg, 0.92 mmol) was added portionwise to the reaction mixture, and the reaction was continued at room temperature for 1 hour. HPLC monitoring was used until the reaction was complete. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (EA / PE = 1 / 5) to obtain Compound 130-2 (120 mg, yield: 90.5%) as a white solid. LCMS (m / z): 719.3 [M+1] + .

[0787] Step 3: Synthesis of compound 130

[0788] The synthesis was carried out according to the method of Example 1 to obtain an off-white solid compound 130 (11.14 mg, yield: 11.3%).

[0789] 1H NMR(400MHz,MeOD)δ7.39-7.25(m,5H),6.16-5.83(m,1H),5.54(d,J=4.0Hz,1H),5.06(s,2H),4.70-4.50(m,1H),4.21-4.0 5(m,2H),4.03-3.78(m,2H),3.21-3.12(m,1H),3.01-2.90(m,2H),2.54(s,3H),2.27-2.20(m,1H); LCMS(m / z):531.4[M+1] + .

[0790] Example 104: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 131)

[0791] The synthesis was carried out according to the method of Example 2 to obtain an off-white solid compound 131 (1.04 mg, yield: 16.83%).

[0792] 1 H NMR(400MHz,D2O)δ6.59-6.26(m,1H),5.52(d,J=6.0Hz,1H),4.42-4.30(m,2H),4.24-4.17(m, 1H),4.08-3.98(m,1H),3.95-3.86(m,2H),3.85-3.74(m,2H),3.12(s,3H),2.45-2.37(m,1H). LCMS(m / z):397.3[M+1] + .

[0793] Example 105: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((5-oxopyrrolidin-3-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 132)

[0794] Step 1: Synthesis of compound 132-1

[0795] Compound B2 (150 mg, 0.24 mmol), 4-amino-2-pyrrolidone hydrochloride (64.1 mg, 0.47 mmol), acetic acid (81.1 mg, 1.35 mmol), and potassium acetate (272.1 mg, 2.77 mmol) were dissolved in DMSO (6 mL). Under nitrogen, the mixture was heated to 60°C and stirred for 2 hours. Sodium triacetylborohydride (562.8 mg, 2.66 mmol) was added, and stirring was continued for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and water (30 mL) was added to the reaction mixture. A white solid precipitated. Stirring was continued for 15 minutes, and the mixture was filtered to obtain Compound 132-1 (148 mg, yield: 87%) as an off-white solid. LCMS (m / z): 724.3 [M+1] + .

[0796] Step 2: Synthesis of compound 132

[0797] Compound 132-1 (148 mg, 0.20 mmol) was dissolved in a 1:3 TFA:H₂O solution (12 mL) and stirred at 60°C under nitrogen for 17 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the resulting residue was purified by reverse-phase column chromatography (methanol / 0.1% acetic acid aqueous solution = 0-2%) to afford Compound 132 (21 mg, yield: 19.2%) as a white solid.

[0798] 1 H NMR(400MHz,MeOD)δ7.49-7.18(m,5H),5.61(d,J=8.5Hz,1H),5.19(s,2H),4.60(s,1H),4.20(s,2H),3.95(s,2H ),3.75-3.56(m,2H),3.25-3.09(m,2H),2.63(dd,J=16.9,7.5Hz,1H),2.35-2.20(m,2H); LCMS(m / z):536.2[M+1] + .

[0799] Example 106: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(((5-oxopyrrolidin-3-yl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 133)

[0800] Compound 132 (10.0 mg, 0.02 mmol) was dissolved in methanol (2 mL), and 10% Pd / C (1 mg) was added. The hydrogen atmosphere was replaced three times, and the reaction was stirred at 25°C for 3 hours. After the reaction, 1% aqueous acetic acid was added, stirred for 5 minutes, and filtered. The filter cake was then washed three times with 1% aqueous acetic acid. The filtrate was concentrated to dryness to afford Compound 133 (4.6 mg, yield: 62.2%) as an off-white solid.

[0801] 1 H NMR(400MHz,D2O)δ5.42(d,J=9.4Hz,1H),4.32-4.21(m,3H),4.08(s,1H),3.94-3.81(m,2H),3.68-3.51(m,3 H), 2.92 (dd, J=18.1, 9.0Hz, 1H), 2.60 (dd, J=18.1, 4.8Hz, 1H), 2.29 (d, J=9.5Hz, 1H); LCMS (m / z): 402.2[M+1] + .

[0802] Example 107: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((5,8-dioxa-2-azaspiro[3.4]octan-2-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 134)

[0803] Step 1: Synthesis of compound 134-1

[0804] Compound 63-1 was synthesized using the method described in Example 49. Compound B2 (200 mg, 0.31 mmol) was added. After completion of the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2) and dried to obtain Compound 134-1 (220 mg, yield: 96%) as a white solid. LCMS (m / z): 739.3 [M+1] + .

[0805] Step 2: Synthesis of compound 134

[0806] The reaction mixture was synthesized according to the method of Example 1, and compound 134-1 (210 mg, 0.28 mmol) was added to obtain white solid compound 134 (30.2 mg, yield: 19%).

[0807] 1 H NMR(400MHz,MeOD)δ7.45-7.27(m,5H),5.61(d,J=9.0Hz,1H),5.19(s,2H),4.32-4.16(m,2H),4.12(s,1H) ,4.04(s,1H),4.02(s,4H),3.93(s,4H),3.61-3.37(m,2H),2.32(d,J=9.4Hz,1H); LCMS(m / z):551.2[M+1] + .

[0808] Example 108: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-((5,8-dioxa-2-azaspiro[3.4]octan-2-yl)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 135)

[0809] The synthesis was carried out according to the method of Example 2, and compound 134 (12 mg, 0.02 mmol) was added to obtain white solid compound 135 (8 mg, yield: 88%).

[0810] 1 H NMR(400MHz,D2O)δ5.34(d,J=9.4Hz,1H),4.49(s,4H),4.16(s,1H),4.11(s,1H),3 .95-3.87(m,6H),3.85-3.77(m,2H),2.20(d,J=9.5Hz,1H); LCMS(m / z):417.2[M+1] + .

[0811] Example 109: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((2-(methylamino)-2-oxoethyl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 136)

[0812] Step 1: Synthesis of compound 136-1

[0813] Following the method for compound 63-1 in Example 49, compound B2 (190 mg, 0.30 mmol) was added. After completion of the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated, which was filtered and washed with water (10 mL x 2). The filter cake was collected and dried to obtain compound 136-1 (210 mg, yield: 99%) as a white solid. LCMS (m / z): 712.3 [M+1] + .

[0814] Step 2: Synthesis of compound 136

[0815] The synthesis was carried out according to the method of Example 1, and compound 136-1 (210 mg, 0.30 mmol) was added to obtain white solid compound 136 (32 mg, yield: 21%).

[0816] 1 H NMR(400MHz,MeOD)δ7.44-7.30(m,5H),5.64(d,J=8.9Hz,1H),5.22(s,2H),4.36-3.84(m,4H ),3.45(s,2H),3.25(s,br,2H),2.79(s,3H),2.35(d,J=9.4Hz,1H); LCMS(m / z):524.2[M+1] + .

[0817] Example 110: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(((2-(methylamino)-2-oxoethyl)amino)methyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 137)

[0818] The synthesis was carried out according to the method of Example 2, and compound 136 (30 mg, 0.06 mmol) was added to obtain white solid compound 137 (19 mg, yield: 85%).

[0819] 1 H NMR (400MHz, D2O) δ5.57(d,J=9.4Hz,1H),4.42(d,J=13.6Hz,2H),4.26(s,1H),4.06(s,3H),3.82-3.70(m,2H),2.87(s,3H),2.45(d,J=9.4Hz,1H). LCMS(m / z):390.4[M+1] + .

[0820] Example 111: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((6-oxopiperidin-3-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 138)

[0821] Step 1: Synthesis of compound 138-1

[0822] Compound 63-1 was synthesized using the method described in Example 49, with Compound B2 (180 mg, 0.28 mmol) added. After completion of the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated and was filtered. The filter cake was washed with water (10 mL x 2) and dried to afford Compound 138-1 (190 mg, yield: 92%) as a white solid. LCMS (m / z): 738.3 [M+1] + .

[0823] Step 2: Synthesis of compound 138

[0824] The synthesis was carried out according to the method of Example 1, and compound 138-1 (190 mg, 0.26 mmol) was added to obtain white solid compound 138 (33 mg, yield: 23%).

[0825] 1 H NMR (400MHz, MeOD) δ7.41-7.29(m,5H),5.57(d,J=9.5Hz,1H),5.17-5.08(m,2H),4.22(d,J=5.9Hz,1H),4.16-4.01(m, 3H),4.00-3.80(m,2H),3.79-3.63(m,1H),3.39-3.32(m,1H),3.23-3.11(m,1H),2.66-2.21(m,4H),2.06-1.98(m,1H). LCMS(m / z):550.2[M+1] + .

[0826] Example 112: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(((6-oxopiperidin-3-yl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 139)

[0827] The synthesis was carried out according to the method of Example 2, and compound 138 (30 mg) was added as a raw material to obtain compound 139 (22 mg, yield: 97%) as a white solid.

[0828] 1 H NMR(400MHz,D2O)δ5.34(d,J=9.4Hz,1H),4.18-4.00(m,4H),3.92-3.78(m,2H),3.49(dd,J=14.3,7.3Hz,1H),3.26(d,J=13.3Hz ,1H),3.15-3.07(m,1H),2.49-2.37(m,2H),2.33-2.24(m,1H),2.19(t,J=8.9Hz,1H),1.92-1.89(m,1H); LCMS(m / z):416.4[M+1] + .

[0829] Example 113: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3,3-difluoroazetidin-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine- Synthesis of benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3,3-difluoroazetidin-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 141)

[0830] Step 1: Synthesis of compound 140-1

[0831] Compound B2 (250 mg, 0.39 mmol) was dissolved in DMSO (5 mL). 3,3-Difluoroazetidine hydrochloride (75.9 mg, 0.59 mmol), glacial acetic acid (276.35 mg, 4.6 mmol), and potassium acetate (220 mg, 2.24 mmol) were added. The mixture was heated to 60°C and stirred under nitrogen for 1 hour. Sodium cyanoborohydride (138 mg, 2.2 mmol) was added portionwise to the reaction mixture and allowed to react for 30 minutes. HPLC monitoring was performed until the reaction was complete. The reaction mixture was cooled to room temperature, then ice water (50 mL) was added and extracted with ethyl acetate (25 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 to yield approximately 230 mg of residue. The residue was purified by flash column chromatography (MeOH / DCM=0-5%) to obtain compound 140-1 (100 mg, yield: 35.8%). LCMS (m / z): 717.3 [M+1] + .

[0832] Step 2: Synthesis of Compound 140 and Compound 141

[0833] Compound 140-1 (100 mg, 0.14 mmol) was dissolved in water (7.5 mL) and TFA (7.5 mL). The mixture was heated to 60°C under nitrogen protection for 20 hours. The reaction solution was concentrated to dryness and the residue was purified by flash column chromatography (MeOH / DCM = 0-4%) to give compound 140 (20 mg, yield: 27.2%) and compound 141 (20 mg, yield: 27.3%).

[0834] Compound 140:

[0835] 1 H NMR (400MHz, MeOD) δ7.48-7.29(m,5H),5.61(d,J=9.1Hz,1H),5.16(s,2H),4.65-4.42(m,1H),4.16( d,J=19.5Hz,2H),3.94(s,2H),3.77(t,J=12.3Hz,4H),3.17(d,J=12.0Hz,1H),2.28(d,J=9.3Hz,1H). LCMS(m / z):529.2[M+1] + .

[0836] Compound 141:

[0837] 1H NMR (400MHz, MeOD) δ7.49-7.34(m,5H),5.49(s,1H),5.28(s,2H),4.56(d,J=2.1Hz,1H),4.55(s,1H),4.27-4.21(m,1 H), 4.10-4.03 (m, 1H), 3.77 (t, J = 12.2Hz, 4H), 3.23 (d, J = 13.3Hz, 1H), 3.08 (d, J = 13.4Hz, 1H), 2.88 (d, J = 3.0Hz, 1H). LCMS(m / z):511.2 [M+1] + .

[0838] Example 114: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-((3,3-difluoroazetidin-1-yl)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 142)

[0839] Compound 141 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (15 mg, 0.01 mmol) was added. The hydrogen was replaced three times, and hydrogen was introduced into the reaction solution for approximately 3 hours. HPLC was used to monitor the reaction until the raw material reaction was complete. The reaction solution was filtered, and the filter cake was rinsed with 0.05 M acetic acid aqueous solution. The filtrate was concentrated to obtain the crude compound, which was then slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was aspirated. The residue was concentrated and dried to obtain compound 142 (13 mg, yield: 87.2%).

[0840] 1 H NMR(400MHz,D2O)δ5.47-5.37(m,1H),5.09-5.01(m,1H),4.66-4.54(m,1H),4.28-4.16(m,2H),4.01( s,1H),3.97-3.76(m,4H),2.27(d,J=9.5Hz,1H),1.97(dt,J=4.4,2.2Hz,1H); LCMS(m / z):395.1[M+1] + .

[0841] Example 115: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((3,3-difluorocyclobutyl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 143)

[0842] Step 1: Synthesis of compound 143-1

[0843] Compound B2 (250 mg, 0.39 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 3,3-difluorocyclobutane-1-amine hydrochloride (75.9 mg, 0.529 mmol), acetic acid (276.35 mg, 4.6 mmol), and potassium acetate (220 mg, 2.24 mmol) were added. Under nitrogen, the mixture was heated to 60°C and stirred for 1 hour. Sodium cyanoborohydride (138 mg, 2.2 mmol) was then added portionwise to the reaction mixture, and the mixture was allowed to react at 60°C for 30 minutes. HPLC monitoring was used until the reaction of the starting material was complete. The reaction mixture was cooled to room temperature, then ice water (50 mL) was added and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated to dryness to obtain a residue (220 mg). The residue was purified by flash column chromatography (MeOH / DCM = 0-5%) to give compound 143-1 (150 mg, yield: 52.6%). LCMS (m / z): 731.3 [M+1] + .

[0844] Step 2: Synthesis of compound 143

[0845] Compound 143 (150 mg, 0.2 mmol) was dissolved in water (7.5 mL) and TFA (7.5 mL) and heated to 60°C under nitrogen for 20 hours. HPLC was used to monitor the reaction until the starting material was completely reacted. The reaction solution was concentrated to dryness, and the residue was purified by flash column chromatography (MeOH / DCM = 0-4%) to obtain compound 143 (20 mg, yield: 18%).

[0846] 1H NMR (400MHz, MeOD) δ7.43-7.27(m,5H),5.59(d,J=9.1Hz,1H),5.15(s,2H),4.30-3.81(m,4H),3.36-3.32(m,1 H),3.12(d,J=6.8Hz,2H),2.88-2.74(m,2H),2.51-2.34(m,2H),2.28(d,J=9.5Hz,1H); LCMS(m / z):543.2[M+1] + .

[0847] Example 116: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(((3,3-difluorocyclobutyl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 144)

[0848] Compound 143 (15 mg, 0.03 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (7.5 mg) was added to displace the hydrogen gas. The reaction mixture was allowed to react for approximately 3 hours. HPLC monitoring was performed until the reaction of the raw materials was complete. The reaction mixture was filtered, and the filter cake was rinsed with 0.05 M AcOH aqueous solution. The filtrate was concentrated to obtain the crude compound, which was slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was removed by aspiration. The residue was concentrated and dried to obtain compound 144 (8 mg, yield: 70.8%).

[0849] 1 H NMR(400MHz,D2O)δ5.35(d,J=9.4Hz,1H),4.18(s,2H),4.00(s,1H),3.87-3.69(m,2 H), 3.57-3.39 (m, 2H), 3.06-2.94 (m, 2H), 2.91-2.78 (m, 2H), 2.22 (d, J = 9.4Hz, 1H). LCMS(m / z):409.2[M+1] + .

[0850] Example 117: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(piperazin-1-ylmethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 145)

[0851] Step 1: Synthesis of compound 145-1

[0852] Compound B2 (160 mg, 0.25 mmol), 1-(piperazin-1-yl)ethanone (36.2 mg, 0.45 mmol), acetic acid (196 mg, 3.4 mmol), and potassium acetate (161.7 mg, 1.7 mmol) were dissolved in DMSO (4 mL). Under nitrogen, the mixture was heated to 60°C and stirred for 1 hour. Sodium triacetylborohydride (94.2 mg, 1.5 mmol) was added, and the reaction was stirred for another 1 hour. After the reaction was completed, the mixture was cooled to room temperature and water (2 mL) was added. A white solid precipitated. After stirring for 5 minutes, the mixture was filtered to obtain Compound 145-1 (150 mg, yield: 80.2%) as an off-white solid. LCMS (m / z): 752.3 [M+1] + .

[0853] Step 2: Synthesis of compound 145

[0854] Compound 145-1 (150 mg, 0.20 mmol) was dissolved in a 2:1 TFA:H2O solution (4 mL) and stirred at 60°C under nitrogen for 16 hours. After completion of the reaction, the reaction solution was purified by reverse-phase column chromatography (methanol / 0.1% acetic acid aqueous solution = 5%-8%) to obtain Compound 145 (18.6 mg, yield: 17.9%) as a white solid.

[0855] 1 H NMR(400MHz,MeOD)δ7.42-7.22(m,5H),5.54(s,1H),5.06(s,2H),4.56(s,2H),4.14(s, 2H),3.91(s,1H),3.23-3.12(m,4H),3.04(s,2H),2.88(s,4H); LCMS(m / z):522.2[M+1] + .

[0856] Example 118: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((1,3-dihydroxypropan-2-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 146)

[0857] Step 1: Synthesis of compound 146-1

[0858] Compound B2 (150 mg, 0.23 mmol), 3-oxetanamine (25.73 mg, 0.35 mmol), and KOAc (132.4 mg, 1.35 mmol) were dissolved in anhydrous DMSO (2.5 mL). AcOH (166.3 mg, 2.77 mmol) was then added dropwise to the mixture. The reaction mixture was heated to 60°C for 1 hour. NaBH3CN (73.7 mg, 1.17 mmol) was added portionwise to the reaction mixture, and the reaction was continued at 60°C for 1 hour. HPLC monitoring was used until the reaction was complete. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (12 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0-5%) to obtain Compound 146-1 (149 mg, yield: 91.2%) as a white foamy solid. LCMS (m / z): 697.3 [M+1] + .

[0859] Step 2: Synthesis of compound 146

[0860] Compound 146-1 (149 mg, 0.21 mmol) was dissolved in TFA (2 mL) and purified water (8 mL) and heated to 60°C with stirring for 15 hours. LCMS was used to monitor the reaction until completion. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-HPLC (A: 0.1% AcOH, B: MeOH; 0-0.5%) to afford Compound 146 (22.85 mg, 20.3% yield) as a white solid.

[0861] 1 H NMR (400MHz, MeOD) δ7.43-7.35(m,5H),5.64(d,J=9.3Hz,1H),5.21(s,2H),4.26(d,J=9.0Hz,2H),4.15-3.96(m,2H),3.84(dd,J =11.6,4.6Hz,2H),3.75(dd,J=11.8,6.3Hz,2H),3.63(s,2H),3.27-3.22(m,1H),2.34(d,J=9.4Hz,1H); LCMS(m / z):527.2[M+1] + .

[0862] Example 119: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(((1,3-dihydroxypropan-2-yl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 147)

[0863] Compound 146 (17 mg, 29.01 μmol) was dissolved in MeOH (8 mL) and 10% Pd / C (5 mg) was added. The mixture was allowed to react at room temperature under hydrogen for 2 hours. HPLC was used to monitor the reaction until completion. H₂O (8 mL) was added to the reaction mixture and stirred for 10 minutes. The mixture was filtered, and the filter cake was rinsed with MeOH / H₂O = 1:1 (20 mL). The filtrate was concentrated under reduced pressure and lyophilized to afford Compound 147 (7.39 mg, 58.3% yield) as a white solid.

[0864] 1 H NMR(400MHz,D2O)δ5.39(dd,J=9.5,3.1Hz,1H),4.24(d,J=1.8Hz,1H),4.18(s,1H),4.13(s,1H),3.99(s ,1H),3.76-3.67(m,2H),3.66-3.57(m,2H),3.43-3.28(m,2H),3.09-2.98(m,1H),2.27(d,J=9.5Hz,1H). LCMS(m / z):393.2[M+1] + .

[0865] Example 120: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(aminomethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 148)

[0866] Compound B3 (120 mg, 0.19 mmol) was dissolved in TFA (2 mL) and H2O (2 mL) and heated to 60°C for 48 hours. HPLC monitoring was used until the reaction was complete. The reaction solution was concentrated to dryness, and the residue was purified by reverse phase column chromatography (MeOH / 0.1% HOAc aqueous solution = 0-1.5%) to obtain compound 148 (25 mg, yield: 28.3%).

[0867] 1H NMR (400MHz, MeOD) δ7.53-7.30 (m, 5H), 5.73 (d, J = 9.3Hz, 1H), 5.32 (s, 2H), 4.28 ( d,J=10.8Hz,2H),4.04(d,J=6.7Hz,2H),3.62-3.52(m,2H),2.43(d,J=9.3Hz,1H); LCMS(m / z):453.2[M+1] + .

[0868] Example 121: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((3-fluorocyclobutyl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 149)

[0869] Step 1: Synthesis of compound 149-1

[0870] Compound B2 (200 mg, 0.31 mmol) was dissolved in dimethyl sulfoxide (4 mL), and 3-fluorocyclobutane-1-amine hydrochloride (43.86 mg, 0.35 mmol), acetic acid (221 mg, 3.69 mmol), and potassium acetate (176.3 mg, 1.8 mmol) were added. Under nitrogen protection, the mixture was heated to 60°C for 1 hour. Sodium cyanoborohydride (110.8 mg, 1.77 mmol) was added to the reaction solution in batches and reacted at 60°C for 30 minutes. HPLC was used to monitor the reaction until the raw materials were completely reacted. The reaction solution was cooled to room temperature, and then ice water (20 mL) was added and stirred. A large amount of solid precipitated. The filter cake was collected by filtration and concentrated to dryness to obtain the crude product of compound 149-1 (180 mg, yield: 80%), which was used directly in the next reaction. LCMS (m / z): 713.3 [M+1] + .

[0871] Step 2: Synthesis of compound 149

[0872] Compound 149-1 (180 mg, 0.25 mmol) was dissolved in water (10 mL) and TFA (5 mL) and heated to 60°C under nitrogen for 20 hours. HPLC monitoring was used until the reaction was complete. The reaction solution was concentrated to dryness, and the residue was purified by flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 149 (30 mg, yield: 22.6%).

[0873] 1 H NMR (400MHz, MeOD) δ7.49-7.26(m,5H),5.66(d,J=9.3Hz,1H),5.22(s,2H),4.25(s,2H),4.17-3.85(m,3H),3. 52-3.37(m,2H),3.00-2.82(m,2H),2.73-2.50(m,2H),2.46-2.29(d,J=9.4Hz,2H); LCMS(m / z):525.2[M+1]+.

[0874] Example 122: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(((3-fluorocyclobutyl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 150)

[0875] Compound 149 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), 10% Pd / C (20 mg) was added, hydrogen was replaced, and hydrogen was introduced into the reaction solution for 3 hours. HPLC was used to monitor until the reaction of the raw materials was complete. The reaction solution was filtered and the filter cake was rinsed with 0.05 M AcOH aqueous solution. The filtrate was concentrated to obtain a crude compound, which was slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was sucked off. The residue was concentrated and dried to obtain the acetate salt of compound 150 (15 mg, yield: 100%).

[0876] 1 H NMR(400MHz,D2O)δ5.42(d,J=9.4Hz,1H),4.25(s,2H),4.17-4.00(m,2H),3.90(s,1H),3.61-3.38(m,3H) ,2.92-2.82(m,1H),2.71-2.57(m,2H),2.52-2.36(m,1H),2.29(d,J=9.4Hz,1H); LCMS(m / z):391.2[M+1] + .

[0877] Example 123: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2(1H)-ylidene)carbamic acid benzyl octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-carboxylic acid methyl ester (Compound 151)

[0878] Compound 67 (44 mg, 0.09 mmol), 18-crown-6 (25 mg, 0.09 mmol), methanol (150 mg, 4.7 mmol), HATU (53 mg, 0.14 mmol), and triethylamine (29 mg, 0.28 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 17 hours. After completion of the reaction, the mixture was concentrated to a crude product, which was then purified via a reverse-phase column (methanol / 0.1% aqueous acetic acid = 0-4%) to afford compound 151 (4.2 mg, yield: 9.3%).

[0879] 1 H NMR(400MHz,MeOD)δ7.44-7.19(m,5H),5.32(s,1H),5.07(s,2H),4.65(dd,J=3.0,1.7Hz,1H),4.5 3(t,J=1.9Hz,1H),4.47-4.40(m,2H),3.81(s,3H),2.68(d,J=2.8Hz,1H); LCMS(m / z):482.1[M+1] + .

[0880] Example 124: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(3-fluoroazetidine-1-formyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 152)

[0881] Compound 67 (32 mg, 0.07 mmol), 3-fluoroazetidine hydrochloride (7.6 mg, 0.07 mmol), and EDCI (20 mg, 0.11 mmol) were dissolved in pyridine (2 mL) and stirred at 25°C under nitrogen for 1 hour. After completion of the reaction, the reaction solution was purified by reverse-phase column chromatography (methanol / 5% aqueous acetic acid = 0%-10%) to obtain Compound 152 (11.3 mg, yield: 31.4%) as an off-white solid.

[0882] 1 H NMR(400MHz,MeOD)δ7.45-7.17(m,5H),5.57(d,J=9.4Hz,1H),5.48-5.26(m,1H),5.07(s,2H),4 .57(s,4H),4.47-4.30(m,2H),4.27-3.83(m,2H),2.18(d,J=7.3Hz,1H); LCMS(m / z):525.2[M+1] + .

[0883] Example 125: Synthesis of benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(3-fluoroazetidine-1-formyl)octahydro-4,8,11a-(methanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 153)

[0884] Compound 68 (25 mg, 0.06 mmol), 3-fluoroazetidine hydrochloride (7.6 mg, 0.07 mmol), and EDCI (20 mg, 0.11 mmol) were dissolved in pyridine (2 mL) and stirred at 25°C under nitrogen for 1 hour. After completion of the reaction, the reaction solution was purified by reverse-phase column chromatography (methanol / 5% aqueous acetic acid = 0%-10%) to obtain Compound 153 (10.5 mg, yield: 37.3%) as an off-white solid.

[0885] 1 H NMR(400MHz,MeOD)δ7.44-7.22(m,5H),5.46-5.39(m,0.5H),5.32(s,1H),5.31-5.26(m,0.5H),5.07(s,2H),4.58(s,4H),4.4 5(d,J=3.1Hz,1H),4.43(d,J=2.0Hz,1H),4.39-4.27(m,1H),4.22-3.97(m,1H),2.70(d,J=2.9Hz,1H); LCMS(m / z):507.1[M+1] + .

[0886] Example 126: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(3-fluoroazetidine-1-formyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 154)

[0887] Compound 152 (7.0 mg, 0.01 mmol) was dissolved in methanol (2 mL), and Pd / C (1 mg) was added. The hydrogen atmosphere was replaced three times, and the mixture was stirred at 25°C for 3 hours. After the reaction, 1% aqueous acetic acid was added, stirred for 5 minutes, filtered, and rinsed three times with 1% aqueous acetic acid. The filtrate was concentrated to dryness and lyophilized to obtain Compound 154 (3.4 mg, yield: 65.3%) as an off-white solid.

[0888] 1 H NMR(400MHz,D2O)δ5.48-5.24(m,2H),4.65-4.45(m,3H),4.42-4.25(m,2H),4.22-4 .07(m,2H),4.03-3.86(m,1H),2.25(dd,J=24.1,9.8Hz,1H); LCMS(m / z):391.1[M+1] + .

[0889] Example 127: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-fluorocyclobutyl)carbamoyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 155)

[0890] Step 1: Synthesis of compound 155-1

[0891] Compound B1 (150 mg, 0.23 mmol) was dissolved in DCM (10 mL), followed by the addition of 3-fluorocyclobutane-1-amine hydrochloride (43 mg, 0.34 mmol) and HATU (130 mg, 0.34 mmol). TEA (69.4 mg, 0.69 mmol) was then added dropwise. The mixture was reacted overnight at room temperature under nitrogen. The reaction solution was poured into water (50 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column chromatography (EA / PE = 0-40%) to obtain compound 155-1 (100 mg, yield: 60%). LCMS (m / z): 727.3 [M+1] + .

[0892] Step 2: Synthesis of compound 155

[0893] Compound 155-1 (120 mg, 0.17 mmol) was dissolved in water (10 mL) and TFA (5 mL) and heated to 60°C under nitrogen for 20 hours. The reaction solution was concentrated to dryness, and the residue was purified by reverse-phase column chromatography (MeOH / H2O = 0-15%) to obtain compound 155 (20 mg, yield: 22.5%).

[0894] 1H NMR (400MHz, MeOD) δ7.57-7.12(m,5H),5.58(d,J=9.3Hz,1H),5.09(s,2H),4.8-4.68(m,1H),4.64-4.47(m,1H),4.38(s,1 H),4.30-4.14(m,2H),4.11-3.86(m,1H),2.87-2.75(m,1H),2.65-2.40(m,2H),2.38-2.19(m,2H); LCMS(m / z):539.2[M+1] + .

[0895] Example 128: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-((3-fluorocyclobutyl)carbamoyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 156)

[0896] Compound 155 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), 10% Pd / C (20 mg) was added, hydrogen was replaced, and hydrogen was introduced into the reaction solution for 3 hours. HPLC was used to monitor until the reaction of the raw materials was complete. The reaction solution was filtered and the filter cake was rinsed with 0.05 M AcOH aqueous solution. The filtrate was concentrated to obtain a crude compound, which was slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was sucked off. The residue was concentrated and dried to obtain the acetate salt of compound 156 (15 mg, yield: 100%).

[0897] 1 H NMR(400MHz,D2O)δ5.42(d,J=9.5Hz,1H),4.52(s,1H),4.41(s,1H),4.33(s,1H),4.21(s,1H),3.90(s,1H),3.87-3.73( m,1H),2.85-2.71(m,1H),2.65-2.49(m,1H),2.4-2.33(m,1H),2.31-2.12(m,2H),1.99(s,3H); LCMS(m / z):405.1[M+1] + .

[0898] Example 129: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-hydroxycyclobutyl)carbamoyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 157)

[0899] Step 1: Synthesis of compound 157-1

[0900] Compound B1 (200 mg, 0.30 mmol) and 3-hydroxycyclobutylamine hydrochloride (68 mg, 0.56 mmol) were dissolved in anhydrous DCM (10 mL). Triethylamine (92.1 mg, 0.91 mmol), DMAP (3.7 mg, 0.03 mmol) and HATU (173.3 mg, 0.46 mmol) were added to the mixture and reacted at room temperature for 3 h.

[0901] The reaction was monitored by LC-MS until completion. The mixture was diluted with dichloromethane (40 mL), washed with saturated sodium chloride (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by flash column chromatography (methanol / dichloromethane = 0-8%) to obtain compound 157-1 (120 mg, yield: 54.3%) as a white solid. LCMS (m / z): 725.3 [M+1] + .

[0902] Step 2: Synthesis of compound 157

[0903] Compound 157-1 (120 mg, 0.17 mmol) was dissolved in TFA (5 mL) and purified water (10 mL) and heated to 60°C for 18 hours. MS monitoring was performed until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (A: 0.1% AcOH, B: MeOH; 0-8%) to afford Compound 157 (13 mg, yield: 25.9%) as a white solid.

[0904] 1 H NMR(400MHz,MeOD)δ7.45-7.37(m,5H),5.71(d,J=9.4Hz,1H),5.30(s,2H),4.48-4.38 (m,3H),4.24(d,J=8.4Hz,2H),4.02(s,1H),2.48-2.24(m,5H); LCMS(m / z):537.2[M+1] + .

[0905] Example 130: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-((3-hydroxycyclobutyl)carbamoyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 158)

[0906] Compound 157 (17 mg, 0.03 mmol) and 10% palladium on carbon (2 mg) were added to methanol (10 mL). The hydrogen atmosphere was replaced three times and the mixture was allowed to react at room temperature for 2 hours. HPLC monitoring was performed until the reaction was complete. The reaction solution was concentrated under reduced pressure and lyophilized to afford Compound 158 (10 mg, yield: 78.4%) as a white solid.

[0907] 1 H NMR(400MHz,D2O)δ5.45(d,J=9.4Hz,1H),4.55(s,1H),4.48-4.40(m,1H),4.39-4 .28(m,2H),4.24(s,1H),3.93(s,1H),2.46-2.11(m,5H); LCMS(m / z):403.4[M+1] + .

[0908] Example 131: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((2,2-difluoroethyl)carbamoyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 159)

[0909] Step 1: Synthesis of compound 159-1

[0910] Compound B1 (150 mg, 0.23 mmol), 2,2-difluoroethylamine (28 mg, 0.345 mmol), HATU (132 mg, 0.345 mmol), and triethylamine (70 mg, 0.69 mmol) were dissolved in dichloromethane (3 mL) and stirred at 25°C for 17 hours. After completion of the reaction, water was added, followed by extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed once with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness and then purified by normal phase column chromatography (ethyl acetate / petroleum ether = 0-32%) to obtain compound 159-1 (161 mg, yield: 98%). LCMS (m / z): 719.2 [M+1]+ .

[0911] Step 2: Synthesis of compound 159

[0912] Compound 159-1 (161 mg, 0.22 mmol) was added to a 1:1 solution of water and trifluoroacetic acid (16 mL) and stirred at 65°C for 17 hours. After completion of the reaction, the crude product was concentrated and purified via a reverse-phase column (methanol / 0.1% aqueous acetic acid = 0-7%) to afford compound 159 (14 mg, yield: 11.8%).

[0913] 1 H NMR (400MHz, MeOD) δ7.46-7.25(m,5H),5.99(tt,J=56.2,4.1Hz,1H),5.62(d,J=9.4Hz,1H),5.14(s,2H),4.43(s, 1H),4.24(s,2H),4.11-3.97(m,1H),3.71(td,J=14.7,4.1Hz,2H),2.33(d,J=9.5Hz,1H); LCMS(m / z):531.2[M+1] + .

[0914] Example 132: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-((2,2-difluoroethyl)carbamoyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 160)

[0915] Compound 159 (6 mg, 0.01 mmol) and 10% Pd / C (3 mg) were added to methanol (5 mL). The hydrogen atmosphere was replaced, and the mixture was stirred at 25°C for 4 hours under a hydrogen atmosphere. After completion of the reaction, 1% aqueous acetic acid was added and stirred for 0.5 hours. The mixture was then filtered, and the filtrate was collected and concentrated under reduced pressure to provide compound 160 (2.1 mg, yield: 46.9%).

[0916] 1 H NMR(400MHz,D2O)δ6.15-5.80(m,1H),5.45(d,J=9.4Hz,1H),4.56(s,1H),4.36(s, 1H), 4.25 (s, 1H), 4.05-3.85 (m, 1H), 3.77-3.62 (m, 2H), 2.31 (d, J = 9.4Hz, 1H); LCMS (m / z):397.1[M+1] +.

[0917] Example 133: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(cyclopropanecarboxamidomethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 161)

[0918] Step 1: Synthesis of compound 161-1

[0919] In a 25 mL single-necked flask, compound B3 (140 mg, 0.22 mmol) and cyclopropionic acid (22.6 mg, 0.26 mmol) were dissolved in anhydrous dichloromethane (5 mL). The reaction mixture was cooled to 0°C, and HATU (100 mg, 0.26 mmol) and triethylamine (55.5 mg, 0.55 mmol) were added. Under nitrogen, the mixture was stirred for 30 minutes and monitored by HPLC until most of the starting materials had reacted completely. Water (10 mL) was added to the reaction mixture, 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 to dryness to obtain the crude product. The crude product was purified by normal phase column chromatography (dichloromethane / methanol = 20:1) to obtain compound 161-1 (150 mg, yield: 97.3%) as a white solid. LCMS (m / z): 709.3 [M+1] + .

[0920] Step 2: Synthesis of compound 161

[0921] In a 25 mL reaction vial, compound 161-1 (140 mg, 0.20 mmol) was dissolved in 5 mL of trifluoroacetic acid:water (2:1), heated to 60°C, and allowed to react overnight. HPLC monitoring was used until the reaction was complete. The reaction solution was concentrated to dryness to obtain the crude product. The crude product was purified by prep-HPLC to afford compound 161 (24.5 mg, yield: 23.5%).

[0922] 1 H NMR(400MHz,MeOD)δ7.49-7.31(m,5H),5.62(d,J=9.4Hz,1H),5.13(s,2H),4.35-3.84(m, 6H),2.28(d,J=9.7Hz,1H),1.79-1.72(m,1H),0.99-0.83(m,4H); LCMS(m / z):521.2[M+1] + .

[0923] Example 134: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(cyclopropanecarboxamidomethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 162)

[0924] Take a 25mL single-necked bottle, dissolve compound 161 (10.0mg, 0.02mmol) in methanol (2mL), add 10% palladium carbon (2mg), replace hydrogen three times, and use a hydrogen balloon to pressurize the hydrogenation reaction for 3 hours. Use HPLC detection until the raw material reaction is complete. Filter the reaction solution, collect the filter cake, add deionized water (10mL) and 2.5% acetic acid aqueous solution (5mL) thereto, stir at room temperature for 1 hour, and filter. Repeat this operation once. Combine all the filtrates, concentrate and dry, and rinse twice with methanol to obtain a crude product. Add two drops of methanol to the crude product to dissolve all the products, then add methyl tert-butyl ether (2mL), stir for 5 minutes, let stand, and suck out the supernatant. Then add methyl tert-butyl ether (2mL) again, stir for 5 minutes, let stand, and suck out the supernatant. The residue is concentrated and dried to obtain white solid compound 162 (5.2mg, yield: 69.4%).

[0925] 1 H NMR (400MHz, D2O) δ5.47(d,J=9.4Hz,1H),4.43(s,1H),4.25(d,J=9.0Hz,1H),4.17(s,1H),4.00(s,1H),3.95(d,J =7.6Hz,1H),3.84(s,1H),2.31(d,J=9.4Hz,1H),1.71-1.63(m,1H),0.85(d,J=6.2Hz,4H); LCMS(m / z):387.1[M+1] + .

[0926] Example 135: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(acetamidomethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 163)

[0927] Step 1: Synthesis of compound 163-1

[0928] In a 25 mL single-necked flask, compound B3 (150 mg, 0.23 mmol) and acetic acid (16.8 mg, 0.28 mmol) were dissolved in anhydrous dichloromethane (5 mL). The temperature was lowered to 0°C, and HATU (106 mg, 0.28 mmol) and triethylamine (59 mg, 0.59 mmol) were added to the reaction mixture. The reaction was stirred under nitrogen for 30 minutes. HPLC monitoring was performed until most of the starting materials had reacted. Water (10 mL) was added to the reaction mixture, 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 to dryness to obtain the crude product. The crude product was purified by normal phase column chromatography (dichloromethane / methanol = 20:1) to obtain compound 163-1 (135 mg, yield: 85.1%) as a white solid. LCMS (m / z): 683.3 [M+1] + .

[0929] Step 2: Synthesis of compound 163

[0930] In a 25 mL reaction vial, compound 163-1 (135 mg, 0.20 mmol) was dissolved in 5 mL of trifluoroacetic acid:water (2:1), heated to 60°C, and allowed to react overnight. The reaction was monitored by HPLC until the reaction was complete. The reaction solution was concentrated to dryness to obtain the crude product. The crude product was purified by prep-HPLC to afford compound 163 (24.5 mg, yield: 23.5%).

[0931] 1 H NMR (400MHz, MeOD) δ7.41-7.26 (m, 5H), 5.56 (d, J = 9.3Hz, 1H), 5.08 (s, 2H), 4.30-3.75(m,6H),2.22(d,J=9.3Hz,1H),1.96(s,3H); LCMS(m / z):495.2[M+1] + .

[0932] Example 136: Synthesis of (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11S)-6-(acetamidomethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 164)

[0933] Take a 25mL single-necked bottle, dissolve compound 163 (7.1mg, 0.01mmol) in methanol (2mL), add 10% palladium carbon (1mg), replace hydrogen three times, and use a hydrogen balloon to pressurize the hydrogenation reaction for 3 hours. Use HPLC monitoring until the raw material reaction is complete. Filter the reaction solution, collect the filter cake, add deionized water (10mL) and 2.5% acetic acid aqueous solution (5mL) thereto, stir at room temperature for 1 hour, and filter. Repeat the above operation once. Combine all the filtrates, concentrate and dry, and rinse twice with methanol to obtain a crude product. Add two drops of methanol to the crude product to dissolve all the products, then add methyl tert-butyl ether (2mL), stir for 5 minutes, let stand, and suck out the supernatant. Then add methyl tert-butyl ether (2mL) again, stir for 5 minutes, let stand, and suck out the supernatant. The residue is concentrated and dried to obtain white solid compound 164 (4.1mg, yield: 82.7%).

[0934] 1 H NMR(400MHz,D2O)δ5.52(dd,J=8.8,3.6Hz,1H),4.47(s,1H),4.22(s,1H),4.06-3.96( m,2H),3.92-3.83(m,2H),2.36(d,J=9.5Hz,1H),2.08(s,3H); LCMS(m / z):361.1[M+1] + .

[0935] Example 137: Synthesis of N-((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,Z)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)acetamide (Compound 165) and N-((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,Z)-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)acetamide (Compound 166)

[0936] Step 1: Synthesis of compound 165-2

[0937] Compound 165-1 (1 g, 5.26 mmol) was dissolved in DCM (3 mL), and diisopropylethylamine (0.7 g, 5.43 mmol) was added. Under nitrogen, the temperature was lowered to 0°C, and acetic anhydride (0.54 g, 5.32 mmol) was added dropwise. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was poured into water (100 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (EA / PE = 0-30%) to obtain compound 165-2 (1.1 g, yield: 90.2%) as a colorless oil.

[0938] HRMS(ESI + ):C9H 16 N2O3S([M+H] + ):Calculated value: 233.09, measured value: 232.30

[0939] Step 2: Synthesis of compound 165-3

[0940] Compound S8 (200 mg, 0.54 mmol) was dissolved in acetonitrile (10 mL), and compound 165-2 (150 mg, 0.65 mmol) and triethylamine (272 mg, 2.7 mmol) were added. Under nitrogen, the temperature was lowered to 0°C, and silver trifluoromethanesulfonate (277.5 mg, 1.08 mmol) was added. After the addition was complete, the temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by flash column chromatography (EA / PE = 0-30%) to obtain compound 165-3 (225 mg, yield: 75.2%) as a white foamy solid.

[0941] HRMS(ESI+):C 25 H 37 N3O 11 ([M+H] + ):Calculated value: 556.24, measured value: 556.58.

[0942] Step 3: Synthesis of Compound 165 and Compound 166

[0943] Compound 165-3 (220 mg, 0.40 mmol) was dissolved in water (10 mL) and TFA (10 mL). The mixture was heated to 60°C under nitrogen and allowed to react for 18 hours. HPLC monitoring was used until the reaction was complete. The reaction solution was concentrated to dryness, and the residue was purified by Prep-HPLC to afford compound 165 formate (22 mg, yield: 15%) and compound 166 formate (12 mg, yield: 8.2%), with a total yield of 23.2%.

[0944] Compound 165:

[0945] 1 H NMR(400MHz,MeOD)δ8.49(s,1H),5.66(d,J=8.7Hz,1H),4.28-4.12(m,2H),4 .06-3.92(m,4H),2.34(d,J=9.6Hz,1H),2.16(s,3H); LCMS(m / z):362.1[M+1] + .

[0946] Compound 166:

[0947] 1 H NMR(400MHz,MeOD)δ8.42(s,1H),5.39(s,1H),4.52(d,J=1.9Hz,1H),4.50(s,1H),4.21(s,1H),4.04(s,1H) ,3.97(d,J=11.4Hz,1H),3.91(d,J=11.4Hz,1H),2.79(d,J=2.8Hz,1H),2.12(s,3H); LCMS(m / z):344.1[M+1] + .

[0948] Example 138: Synthesis of Cyclopentyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,Z)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 167)

[0949] Step 1: Synthesis of compound 167-2

[0950] Compound 165-1 (0.25 g, 1.68 mmol) and DIPEA (0.24 g, 1.85 mmol) were dissolved in anhydrous dichloromethane (2.5 mL). Under nitrogen, the temperature was lowered to 0°C, and cyclopentyl chloroformate (0.26 g, 1.35 mmol) was added. The reaction mixture was allowed to react at 0°C for 30 minutes, then stirred at room temperature for 2.5 hours. Dichloromethane (50 mL) was added to dilute the reaction mixture, which was then washed with saturated sodium chloride (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain Compound 167-2 (0.30 g, yield: 56.7%) as a white solid. LCMS (m / z): 303.1 [M+1] + .

[0951] Step 2: Synthesis of compound 167-3

[0952] Compound S8 (0.20 g, 0.54 mmol), compound 167-2 (0.18 g, 0.59 mmol), triethylamine (0.24 g, 1.85 mmol), and silver trifluoroacetate (0.28 g, 1.08 mmol) were dissolved in anhydrous acetonitrile (2.0 mL) and stirred at room temperature under nitrogen for 16 hours. The reaction solution was quenched with saturated sodium chloride (1 mL), diluted with ethyl acetate (30 mL), and washed with saturated sodium chloride (2 × 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0%-20%) to obtain compound 167-3 as a white solid (0.35 g, yield: >100%). LCMS (m / z): 626.3 [M+1] + .

[0953] Step 3: Synthesis of compound 167

[0954] Compound 167-3 (0.15 g, 0.25 mmol) was dissolved in a mixture of trifluoroacetic acid (0.5 mL) and purified water (0.5 mL). The mixture was heated to 60°C and stirred under nitrogen for 18 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by reverse phase preparative chromatography to afford Compound 167 (31 mg, 30% yield) as a white solid.

[0955] 1H NMR(400MHz,MeOD)δ5.66(d,J=9.4Hz,1H),5.23-5.17(m,1H),4.22(d,J=20.6Hz,2H),4.01(d,J=22.7Hz,4 H),2.36(d,J=9.4Hz,1H),1.96-1.89(m,2H),1.83-1.76(m,4H),1.71-1.63(m,2H); LCMS(m / z):432.2[M+1] + .

[0956] Example 139: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-cyanooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 168) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-cyanooctahydro-4,8,11a-(methanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 169)

[0957] Step 1: Synthesis of compound 168-2

[0958] Compound B2-1 (210 mg, 0.32 mmol) was dissolved in acetonitrile (4 mL) and tetrahydrofuran (2 mL), and N,N'-carbonyldiimidazole (CDI, 182.2 mg, 1.12 mmol) was added. The reaction was stirred at room temperature overnight under nitrogen. The reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain crude compound 168-2 (220 mg, yield: 108%), which was used directly in the next step. LCMS (m / z): 637.2 [M+1] + .

[0959] Step 2: Synthesis of Compound 168 and Compound 169

[0960] Compound 168-2 (220 mg, 0.35 mmol) was dissolved in 10 mL of TFA (10 mL) and stirred at 60°C under nitrogen overnight. HPLC monitoring was performed until the reaction was complete. The reaction solution was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 168 (79 mg, yield: 51%) and compound 169 (25 mg, yield: 16.12%).

[0961] Compound 168:

[0962] 1 H NMR(400MHz,MeOD)δ7.41-7.25(m,5H),5.58(d,J=9.3Hz,1H),5.10(s,2H),4.64-4.34 (m,1H),4.21(s,1H),4.11-3.82(m,2H),2.16(d,J=8.0Hz,1H); LCMS(m / z):449.1[M+1] + .

[0963] Compound 169:

[0964] 1 H NMR(400MHz,MeOD)δ7.49-7.11(m,5H),5.36(s,1H),5.09(s,2H),4.52-4.46(m,2H) ,4.41(d,J=2.1Hz,1H),4.34(s,1H),2.71(d,J=2.9Hz,1H); LCMS(m / z):431.1[M+1] + .

[0965] Example 140: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((5-methyl-1,2,4-oxadiazepin-3-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 170), ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((5-methyl-1,2,4-oxadiazepin-3-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate Synthesis of benzyl 6,9,10,11-pentahydroxy-6-(ureidomethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 171) and (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(ureidomethyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-4,6,9,10,11(10H)-pentanol (Compound 172)

[0966] Step 1: Synthesis of compound B3-1

[0967] Compound B3 (100 mg, 0.16 mmol) and NaHCO3 (26 mg, 0.31 mmol) were dissolved in methanol (6 mL), cooled to 0°C in an ice bath, and BrCN (18 mg, 0.17 mmol) was added to allow the reaction to proceed. After completion of the reaction, water was added to the reaction solution, which was extracted with dichloromethane. The organic phase was concentrated and purified by column chromatography to afford Compound B3-1 (70 mg, yield: 67.4%) as a white solid.

[0968] Step 2: Synthesis of Compound 170-1 and Compound 171-1

[0969] Compound B3-1 (240 mg, 0.36 mmol) and potassium carbonate (149 mg, 1.08 mmol) were added to ethanol (12 mL), followed by hydroxylamine hydrochloride (30.1 mg, 0.43 mmol), and the reaction was stirred at room temperature. After completion of the reaction, water (40 mL) was added to the system, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography to obtain Compound 170-1 (105 mg, yield: 41.7%) as a white solid and Compound 171-1 (50 mg, yield: 20.3%) as a colorless oil.

[0970] Step 3: Synthesis of compound 170-2

[0971] Compound 170-1 (95 mg, 0.14 mmol) was dissolved in DCM (5 mL) and the temperature was maintained at 0°C in an ice bath. Acetyl chloride (13.5 mg, 0.171 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. 1,2-Dichloroethane (15 mL) was then added, and the mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain compound 170-2 (70 mg, yield: 71.2%).

[0972] Step 4: Synthesis of compound 170

[0973] Compound 170-2 (70 mg, 0.10 mmol) was dissolved in a mixture of water (3.2 mL) and TFA (0.8 mL) and stirred at 60°C for 16 hours. The reaction solution was then concentrated to dryness to obtain a crude product. The crude product was purified by wet-load reverse-phase column chromatography and lyophilized to obtain compound 170 as a white solid (16 mg, yield: 30.9%). LCMS (m / z): 535.2 [M+1] + .

[0974] Step 5: Synthesis of compound 171

[0975] Compound 171-1 (49 mg, 0.07 mmol) was dissolved in a mixture of water (4 mL) and TFA (1 mL) and stirred at 60°C for 16 hours. The reaction mixture was then concentrated to dryness to obtain a crude product, which was purified by wet-load reverse-phase column chromatography and lyophilized to afford Compound 171 (14 mg, 39.4% yield) as a white solid.

[0976] 1 H NMR (400MHz, MeOD) δ7.39(dt,J=19.2,6.5Hz,5H),5.66(d,J=9.4Hz,1H),5.24(d,J=12.5Hz,2H),4.19(d,J=15. 5Hz,1H),4.12(d,J=11.9Hz,1H),3.98-3.85(m,2H),3.74(s,2H),2.35(d,J=9.4Hz,1H); LCMS(m / z):496.2[M+1] + .

[0977] Step 6: Synthesis of compound 172

[0978] Compound 171 (11 mg, 0.02 mmol) was dissolved in methanol (3 mL), and 10% palladium on carbon (4 mg) was added to replace the hydrogen atmosphere. The mixture was stirred under a hydrogen balloon for 3 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to afford Compound 172 (7 mg, yield: 87.3%) as a white solid.

[0979] 1 H NMR(400MHz,D2O)δ5.40(d,J=9.5Hz,1H),4.27-4.05(m,2H),3.90(d,J=26.2Hz,2H),3.65(s,2H),2.24(d,J=9.4Hz,1H); LCMS(m / z):362.1[M+1] + .

[0980] Example 141: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((E)-2-hydroxyguanidino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 173)

[0981] Step 1: Synthesis of compound 173-1

[0982] Compound 170-1 (95 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL) and the temperature was maintained at 0°C in an ice bath. Trifluoroacetic anhydride (36 mg, 0.17 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. 1,2-Dichloroethane (15 mL) was then added and the mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the system was concentrated to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 0-35%) and concentrated to obtain crude compound 173-1 (50 mg, yield: 47.3%). LCMS (m / z): 777.2 [M+1] + .

[0983] Step 2: Synthesis of compound 173

[0984] Compound 173-1 (50 mg, 0.06 mmol) was dissolved in a mixture of water (2.4 mL) and TFA (0.6 mL) and stirred at 60°C for 16 hours. The reaction mixture was then dried to obtain a crude product, which was purified by wet-load reverse-phase column chromatography and lyophilized to afford Compound 173 (7 mg, yield: 21.3%) as a white solid.

[0985] 1H NMR(400MHz,MeOD)δ7.38-7.25(m,5H),5.52(dd,J=17.6,8.1Hz,1H),5.06(s,2H),4.17(s,1H),4.10 (d,J=9.8Hz,2H),3.96(s,1H),3.76(d,J=14.8Hz,2H),2.22(d,J=9.4Hz,1H); LCMS(m / z):511.2[M+1] + .

[0986] Example 142: ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-9-((3-hydroxyazetidin-1-yl)methyl)-2-iminooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]diazepin-9-yl)methanone (Compound 175)

[0987] The product was synthesized according to the method of Example 2 to obtain the acetate salt of white solid Compound 175 (4.8 mg, yield: 66%).

[0988] 1 H NMR(400MHz,D2O)δ5.49(s,1H),4.60-4.52(m,4H),4.33-4.28(m,1H),4.20-4.08 (s,4H),3.88(d,J=14.1Hz,1H),3.76(d,J=14.1Hz,1H),2.95(d,J=2.8Hz,1H),1.91(s,3H); LCMS(m / z):357.1[M+1] + .

[0989] Example 143: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(benzylcarbamoyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 176) and benzyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(benzylcarbamoyl)octahydro-4,8,11a-(methantriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiazepine-2(1H)-ylidene)carbamate (Compound 177)

[0990] Step 1: Synthesis of compound 176-1

[0991] Compound B1 (50 mg, 0.08 mmol) and benzylamine (9.5 mg, 0.09 mmol) were dissolved in dichloromethane (4 mL), followed by the addition of HATU (36 mg, 0.09 mmol) and triethylamine (24 mg, 0.24 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, 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 to dryness to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain compound 176-1 as a white solid (60 mg, yield >100%). LCMS (m / z): 745.3 [M+1] + .

[0992] Step 2: Synthesis of Compound 176 and Compound 177

[0993] Compound 176-1 (60 mg, 0.08 mmol) was dissolved in a mixture of water (1 mL) and trifluoroacetic acid (2 mL). The reaction system was heated to 60°C and stirred for 16 hours. The reaction solution was concentrated to dryness to obtain a crude product. The crude product was purified by HPLC to obtain compound 176 (12 mg, yield: 28.3%) and compound 177 (6 mg, yield: 14.1%) as a white solid. The total yield was 42.4%.

[0994] Compound 176: 1 H NMR(400MHz,MeOD)δ7.39-7.21(m,10H),5.56(d,J=9.4Hz,1H),5.05(s,2H),4.54(d,J=3.1Hz,2H) ,4.37(s,1H),4.21(s,2H),4.08(d,J=14.2Hz,1H),2.29(d,J=9.4Hz,1H); LCMS(m / z):557.2[M+1] + .

[0995] Compound 177: 1 H NMR(400MHz,MeOD)δ7.43-7.20(m,10H),5.30(s,1H),5.07(s,2H),4.54(s,2H),4.50(d,J=2.0 Hz,1H),4.47(s,1H),4.34(s,1H),4.21(s,1H),2.77(d,J=2.8Hz,1H); LCMS(m / z):539.2[M+1] + .

[0996] Example 144: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((4,5-dihydro-1H-imidazol-2-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 178)

[0997] Step 1: Synthesis of compound 178-1

[0998] Compound B3 (80 mg, 0.12 mmol) and 2-(methylthio)-4,5-dihydro-1H-imidazole (36.5 mg, 0.15 mmol) were dissolved in pyridine (2 mL) and stirred at 50°C under nitrogen for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain a residue. The residue was purified by reverse phase column chromatography (methanol / 5% aqueous acetic acid = 5%-20%) to obtain compound 178-1 (60 mg, yield: 67.8%) as an off-white solid. LCMS (m / z): 709.3 [M+1] + .

[0999] Step 2: Synthesis of compound 178

[1000] Compound 178-1 (60 mg, 0.08 mmol) was dissolved in a 2:1 mixture of TFA and H₂O (4 mL). The mixture was heated to 60°C and stirred under nitrogen for 16 hours. After completion, the reaction solution was concentrated to dryness to obtain a residue. The residue was purified by reverse-phase column chromatography (methanol:0.1% acetic acid in water = 5%-8%) to afford Compound 178 (7.5 mg, 17% yield) as a white solid.

[1001] 1 H NMR(400MHz,MeOD)δ7.47-7.22(m,5H),5.55(d,J=8.7Hz,1H),5.07(s,2H),4.17(s,1H),4.09 (s,1H),4.04-3.82(m,2H),3.81-3.65(m,6H),2.23(d,J=9.6Hz,1H); LCMS(m / z):521.2[M+1] + .

[1002] Example 145: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-6-(((4,5-dihydro-1H-imidazol-2-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 179)

[1003] Compound 178 (7.5 mg, 0.01 mmol) was dissolved in methanol (2 mL) and 10% Pd / C (1 mg) was added. The hydrogen atmosphere was replaced three times and the reaction was stirred at 25°C for 8 hours. After completion of the reaction, 1% aqueous acetic acid was added and stirred for 5 minutes. The mixture was filtered and then rinsed 2-3 times with 1% aqueous acetic acid. The solution was lyophilized to obtain Compound 179 (3.2 mg, 57.3% yield) as an off-white solid.

[1004] 1 H NMR(400MHz,D2O)δ5.41(d,J=9.3Hz,1H),4.27-4.19(m,1H),4.15(s,1H),3.97 (s,1H),3.91(d,J=8.5Hz,1H),3.68-3.61(m,6H),2.27(d,J=9.4Hz,1H); LCMS(m / z):387.2[M+1] + .

[1005] Example 146: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(guanidinomethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 180)

[1006] Step 1: Synthesis of compound 180-1

[1007] Compound B3 (238 mg, 0.37 mmol) was dissolved in acetonitrile (15 mL), and N,N'-di-BOC-S-methylisothiourea (130 mg, 0.447 mmol) was added. Under nitrogen protection, the mixture was heated to 50°C and stirred for 16 hours. HPLC was used to monitor the reaction until the raw material reaction was complete. The reaction solution was concentrated to dryness to obtain a residue (400 mg). The residue was purified by flash column chromatography (EA / PE = 0-30%) to obtain compound 180-1 (180 mg, yield: 54.8%). LCMS (m / z): 883.4 [M+1] + .

[1008] Step 2: Synthesis of compound 180

[1009] Compound 180-1 (180 mg, 0.2 mmol) was dissolved in a mixture of water (10 mL) and TFA (5 mL). The mixture was heated to 60°C under nitrogen and stirred for 20 hours. HPLC was used to monitor the reaction until the starting material was completely reacted. The reaction solution was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (MeOH / DCM = 0-4%) to obtain compound 180 (37.5 mg, yield: 37.2%).

[1010] 1 H NMR(400MHz,MeOD)δ7.47-7.25(m,5H),5.64(d,J=8.8Hz,1H),5.19(s,2H),4.24(s,1H),4.14 (s,1H),4.00(s,1H),3.92(s,1H),3.81(s,2H),2.32(d,J=9.5Hz,1H); LCMS(m / z):495.2[M+1] + .

[1011] Example 147: (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)guanidine (Compound 181)

[1012] Compound 180 (30 mg, 0.06 mmol) was dissolved in methanol (10 mL), 10% Pd / C (15 mg) was added, hydrogen was replaced, and hydrogen was introduced into the reaction solution for 3 hours. HPLC was used to monitor until the reaction of the raw materials was complete. The reaction solution was filtered and the filter cake was rinsed with 0.05 M HOAc aqueous solution. The filtrate was concentrated to dryness to obtain the crude compound. The crude product was slurried with methyl tert-butyl ether (10 mL), allowed to stand, the supernatant was aspirated, and the residue was concentrated to dryness to obtain compound 181 (20 mg, yield: 91.5%).

[1013] 1H NMR(400MHz,D2O)δ5.42(d,J=9.3Hz,1H),4.23(s,1H),4.17(s,1H),3.98(s,1H),3 .90(s,1H),3.79(d,J=15.1Hz,1H),3.70(d,J=15.1Hz,1H),2.28(d,J=9.2Hz,1H). LCMS(m / z):361.1[M+1] + .

[1014] Example 148: Benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(methylsulfonamidomethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 182)

[1015] Step 1: Synthesis of compound 182-1

[1016] Compound B3 (140 mg, 0.22 mmol), methanesulfonic anhydride (46 mg, 0.26 mmol), and triethylamine (67 mg, 0.66 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated to dryness to obtain crude compound 182-1 (157 mg, yield: 100%). LCMS (m / z): 719.2 [M+1] + .

[1017] Step 2: Synthesis of compound 182

[1018] Compound 182-1 (157 mg, 0.22 mmol) was dissolved in a 1:1 mixture of water and trifluoroacetic acid (6 mL) and heated to 65°C with stirring for 17 hours. After completion, the reaction was concentrated to dryness to obtain a crude product. The crude product was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid = 0-7%) to obtain compound 182 (14 mg, yield: 12%).

[1019] 1 H NMR(400MHz,MeOD)δ7.41-7.27(m,5H),5.59(d,J=8.8Hz,1H),5.09(s,2H),4.56(s,1H),4.19(s, 1H),3.96(s,1H),3.80-3.52(m,3H),3.05(s,3H),2.26(d,J=9.1Hz,1H); LCMS(m / z):531.1[M+1] +.

[1020] Example 149: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)methanesulfonamide (Compound 183)

[1021] Compound 182 (6 mg, 0.01 mmol) was dissolved in methanol (2 mL), and 10% Pd / C (3 mg) was added to displace the hydrogen atmosphere. The mixture was stirred at 28°C for 4 hours. After completion of the reaction, 0.5% aqueous acetic acid was added and stirred for 0.5 hours. The mixture was filtered, and the filtrate was concentrated to dryness and lyophilized to obtain compound 183 (3 mg, yield: 67%). LCMS (m / z): 397.1 [M+1] + .

[1022] Example 150: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((N-methylmethylsulfonamido)methyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 184)

[1023] Step 1: Synthesis of compound 89-1

[1024] Compound B2 (120 mg, 0.19 mmol), methylamine hydrochloride (19 mg, 0.28 mmol), potassium acetate (106 mg, 1.08 mmol), and acetic acid (133 mg, 2.22 mmol) were dissolved in dimethyl sulfoxide (6 mL) and heated to 60°C under nitrogen for 30 minutes. Sodium triacetylborohydride (450 mg, 2.12 mmol) was then added portionwise and allowed to react for 3 hours. HPLC was used to monitor the reaction until the starting materials were completely reacted. After completion of the reaction, the reaction solution was cooled to room temperature and then added to water (30 mL). A white solid precipitated, which was filtered and washed with water (10 mL x 2). The filter cake was collected and dried to obtain Compound 89-1 (140 mg, yield: >100%) as a white solid. LCMS (m / z): 655.3 [M+1] + .

[1025] Step 2: Synthesis of compound 184-2

[1026] Compound 89-1 (170 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (105 mg, 1.04 mmol) was added. Methanesulfonic anhydride (68 mg, 0.39 mmol) was added under ice-bath temperature control, and the reaction was stirred at room temperature for 1 hour. Water was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 0-54%) to obtain compound 184-2 (150 mg, yield: 79%). LCMS (m / z): 733.2 [M+1] + .

[1027] Step 3: Synthesis of compound 184

[1028] Compound 184-2 (150 mg, 0.20 mmol) was dissolved in a mixture of water (8 mL) and TFA (2 mL) and heated to 60°C with stirring for 16 hours. The reaction system was concentrated to dryness to obtain a crude product. The crude product was purified by wet-loading reverse-phase column chromatography and lyophilized to obtain Compound 184 (25 mg, 22% yield) as a white solid.

[1029] 1 H NMR(400MHz,MeOD)δ7.49-7.36(m,5H),5.65(d,J=9.4Hz,1H),5.16(s,2H),4.45- 3.82(m,6H),3.35(s,3H),2.37-2.29(m,1H),2.03(s,3H); LCMS(m / z):545.2[M+1] + .

[1030] Example 151: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)methanesulfonamide (Compound 185)

[1031] Compound 184 (20 mg, 0.04 mmol) was dissolved in methanol (3 mL), and 10% palladium on carbon (3 mg) was added. The hydrogen atmosphere was replaced three times, and the mixture was stirred for 3 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to dryness to afford Compound 185 (15 mg, yield: 99%) as a white solid.

[1032] 1H NMR (400MHz, D2O) δ5.40 (dd, J=9.3, 6.0Hz, 1H), 4.16 (d, J=5.2Hz, 2H), 4.08 (s, 1H), 3.90 (dd, J= 14.3,5.5Hz,3H),3.12(s,3H),2.75-2.68(m,1H),2.09(d,J=4.9Hz,3H); LCMS(m / z):411.1[M+1] + .

[1033] Example 152: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(guanidinomethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 186)

[1034] Step 1: Synthesis of compound 186-1

[1035] Compound B3 (150 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (70 mg, 0.69 mmol) and trifluoromethanesulfonic anhydride (99 mg, 0.35 mmol) were added. The mixture was stirred at 17°C for 1.5 hours. After the reaction was completed, water was added to the reaction solution, and then extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, separated, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (methanol / dichloromethane = 0-2%) to obtain compound 186-1 (145 mg, yield: 80.2%). LCMS (m / z): 773.2 [M+1] + .

[1036] Step 2: Synthesis of compound 186

[1037] Compound 186-1 (145 mg, 0.19 mmol) was dissolved in a 1:2 mixture of water and trifluoroacetic acid (10 mL) and heated to 60°C with stirring for 20 hours. After completion, the reaction solution was concentrated to dryness to obtain a residue. The residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid = 0-7%) to obtain compound 186 (17.1 mg, yield: 15.6%).

[1038] 1H NMR(400MHz,MeOD)δ7.40-7.29(m,5H),5.59(d,J=10.0Hz,1H),5.09(s,2H),4.18(s,2 H),3.94(s,2H),3.84(d,J=14.1Hz,2H),2.26(d,J=9.2Hz,1H); LCMS(m / z):585.1[M+1] + .

[1039] Example 153: Synthesis of 1,1,1-trifluoro-N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)methanesulfonamide (Compound 187)

[1040] Compound 186 (8 mg, 0.014 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (4 mg) was added. The hydrogen atmosphere was replaced, and the mixture was stirred at 25°C for 4 hours under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to dryness and then lyophilized to afford compound 187 (4.0 mg, yield: 64.9%).

[1041] 1 H NMR(400MHz,D2O)δ5.42(d,J=9.5Hz,1H),4.24(s,1H),4.18(s,1H),4.02(s,1H) ,3.89(s,1H),3.78-3.65(m,2H),2.29(d,J=9.4Hz,1H); LCMS(m / z):451.1[M+1] + .

[1042] Example 154: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(propylsulfonamidomethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 188)

[1043] Step 1: Synthesis of compound 188-1

[1044] Compound B3 (130 mg, 0.20 mmol), propane-1-sulfonyl chloride (42.61 mg, 0.30 mmol) and pyridine (38.9 mg, 0.50 mmol) were dissolved in DCM (5 mL). The reaction was stirred at 25°C for 3 hours under nitrogen protection. After the reaction was completed, water (5 mL) was added to the reaction solution, extracted with DCM (5 mL x 3), and the organic phases were combined and concentrated to obtain a residue. The residue was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to obtain an off-white solid compound 188-1 (140 mg, yield: 92.6%). LCMS (m / z): 747.3 [M+1] + .

[1045] Step 2: Synthesis of compound 188

[1046] Compound 188-1 (140 mg, 0.18 mmol) was dissolved in a 2:1 mixture of trifluoroacetic acid and water (4 mL). The mixture was heated to 60°C and stirred under nitrogen for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain a residue. The residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5-8%) to obtain Compound 188 (24.3 mg, yield: 23.1%) as a white solid.

[1047] 1 H NMR (400MHz, MeOD) δ7.44-7.15(m,5H),5.57(d,J=9.3Hz,1H),5.09(s,2H),4.58(d,J=6.7Hz,1H),4.16(s,2H),3.93(s,1H),3 .75-3.59(m,2H),3.17-3.07(m,2H),2.24(d,J=9.5Hz,1H),1.88-1.76(m,2H),1.07(t,J=7.5Hz,3H); LCMS(m / z):559.2[M+1] + .

[1048] Example 155: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)propane-1-sulfonamide (Compound 189)

[1049] Compound 188 (10 mg, 0.02 mmol) was dissolved in methanol (2 mL), and 10% Pd / C (1 mg) was added. The hydrogen atmosphere was replaced three times, and the reaction was stirred at 25°C for 8 hours. After the reaction was completed, 1% aqueous acetic acid was added, stirred for 5 minutes, and the Pd / C was removed by filtration. The filter cake was then washed three times with 1% aqueous acetic acid. The filtrate was concentrated to dryness and then lyophilized to obtain Compound 189 (4.6 mg, yield: 60.6%) as an off-white solid. LCMS (m / z): 425.1 [M+1] + .

[1050] Example 156: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(cyclohexanesulfonamidomethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 190)

[1051] Step 1: Synthesis of compound 190-1

[1052] Compound B3 (140 mg, 0.22 mmol) was dissolved in DCM (8 mL), and pyridine (69.2 mg, 0.33 mmol) and 4-dimethylaminopyridine (DMAP) (13.6 mg, 0.11 mmol) were added. Cyclohexanesulfonyl chloride (60 mg, 0.33 mmol) was added under ice-bath temperature control, and the reaction was stirred at room temperature for 4 hours. HPLC was used to monitor the reaction until the raw material reaction was complete. Water was added to the reaction solution, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (EA / PE = 0-35%) to obtain compound 190-1 (126 mg, yield: 73%). LCMS (m / z): 787.3 [M+1] + .

[1053] Step 2: Synthesis of compound 190

[1054] Compound 190-1 (125 mg, 0.16 mmol) was dissolved in water (4 mL), dioxane (1.5 mL), and TFA (1 mL), heated to 60°C, and reacted for 16 hours. The reaction solution was concentrated to dryness, purified by wet-loading reverse-phase column chromatography, and lyophilized to afford Compound 190 (13 mg, 14% yield) as a white solid.

[1055] 1HNMR(400MHz,MeOD)δ7.43-7.26(m,5H),5.58(d,J=9.4Hz,1H),5.09(s,2H),4.18(s,2H),3.95(s,2H),3.78-3.60(m,2H),3.17-3.06 (m,1H),2.30-2.14(m,3H),1.95-1.87(m,2H),1.74(d,J=12.3Hz,1H),1.59-1.47(m,2H),1.42-1.27(m,3H).LCMS(m / z):599.2[M+1] + .

[1056] Example 157: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)guanidine (Compound 191)

[1057] Compound 190 (11 mg, 0.02 mmol) was dissolved in methanol (3 mL), and 10% palladium on carbon (3 mg) was added. The hydrogen atmosphere was replaced three times and the mixture was stirred for 3 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to afford Compound 191 (8 mg, yield: 94%) as a white solid.

[1058] 1 HNMR(400MHz,MeOD)δ5.51(d,J=9.3Hz,1H),4.15(d,J=10.3Hz,2H),3.96(s,2H),3.74-3.51(m,2H),3.13-3.00(m,1H),2.23(d,J=9. 4Hz,1H),2.15(d,J=10.9Hz,2H),1.86(s,2H),1.71(d,J=13.2Hz,1H),1.55-1.42(m,2H),1.40-1.16(m,3H); LCMS(m / z):465.2[M+1] + .

[1059] Example 158: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(cyclopropanesulfonamidomethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 192)

[1060] Step 1: Synthesis of compound 192-1

[1061] Compound B3 (160 mg, 0.25 mmol) was dissolved in DCM (5 mL), and triethylamine (TEA) (76 mg, 0.75 mmol) was added. Cyclopropylsulfonyl chloride (53 mg, 0.375 mmol) was added under ice-bath temperature control, and the reaction was stirred at room temperature for 16 hours. HPLC was used to monitor the reaction until the raw materials were completely reacted. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (EA). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product of compound 192-1 (210 mg, yield: 100%). LCMS (m / z): 745.2 [M+1] + .

[1062] Step 2: Synthesis of compound 192

[1063] Compound 192-1 (210 mg, 0.25 mmol) was dissolved in a mixture of water (6 mL) and TFA (1.5 mL) and stirred at 60°C for 16 hours. The reaction system was concentrated to dryness to obtain a residue. The residue was purified by wet-loading reverse-phase column chromatography and then lyophilized to obtain Compound 192 (32 mg, 23% yield) as a white solid.

[1064] 1 HNMR(400MHz,MeOD)δ7.40-7.25(m,5H),5.55(d,J=9.1Hz,1H),5.05(s,2H),4.18(s,2H),4.01(s,2H),3.78-3.5 8(m,2H),2.72-2.61(m,1H),2.23(d,J=9.4Hz,1H),1.13-1.06(m,2H),1.05-0.99(m,2H); LCMS(m / z):557.4[M+1] + .

[1065] Example 159: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)cyclopropanesulfonamide (Compound 193)

[1066] Compound 192 (20 mg, 0.04 mmol) was dissolved in methanol (3 mL), and 10% palladium on carbon (3 mg) was added. The hydrogen atmosphere was replaced three times, and the mixture was stirred for 3 hours. The reaction was monitored by HPLC. Filtering and concentrating the filtrate gave Compound 193 (14 mg, yield: 92%) as a white solid.

[1067] 1 H NMR(400MHz,D2O)δ5.42(d,J=9.4Hz,1H),4.24-4.17(m,2H),4.02(s,1H),3.89(d,J=7.3Hz,1H),3.7 5-3.57(m,2H),2.70-2.59(m,1H),2.27(d,J=9.4Hz,1H),1.09-1.02(m,4H); LCMS(m / z):423.1[M+1] + .

[1068] Example 160: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((isopropyl)sulfonylamino)methyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 194)

[1069] Step 1: Synthesis of compound 194-1

[1070] Compound B3 (180 mg, 0.28 mmol), 2-propanesulfonyl chloride (53.25 mg, 0.37 mmol), DMAP (3.7 mg, 0.031 mmol), and triethylamine (78.9 mg, 0.78 mmol) were dissolved in DCM (5 mL) and stirred at 5°C under nitrogen for 16 hours. After completion of the reaction, water (5 mL) was added to the reaction solution, and the mixture was extracted with DCM (5 mL x 3). The organic phases were combined and concentrated to obtain a residue. The residue was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 5%-30%) to obtain compound 194-1 (100 mg, yield: 47.6%) as an off-white solid. LCMS (m / z): 747.3 [M+1] + .

[1071] Step 2: Synthesis of compound 194

[1072] Compound 194-1 (100 mg, 0.13 mmol) was dissolved in a 2:1 mixture of TFA:H₂O (4 mL) and stirred at 60°C under nitrogen for 16 hours. After completion, the reaction solution was concentrated to dryness to obtain a residue. The residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid = 5-8%) to afford Compound 194 (10 mg, yield: 13.3%) as a white solid.

[1073] 1 H NMR (400MHz, MeOD) δ7.41-7.23(m,5H),5.56(d,J=9.4Hz,1H),5.06(s,2H),4.58(s,1H),4.16(d,J=5.9Hz,2H),3.92(d,J =8.4Hz,2H),3.70(d,J=10.9Hz,1H),3.39-3.33(m,1H),2.26-2.20(m,1H),1.35(t,J=8.5Hz,6H); LCMS(m / z):559.2[M+1] + .

[1074] Example 161: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)isopropanesulfonamide (Compound 195)

[1075] Compound 194 (10 mg, 0.02 mmol) was dissolved in methanol (2 mL) and 10% Pd / C (1 mg) was added. The hydrogen atmosphere was replaced three times and the reaction was stirred at 25°C for 8 hours. After completion of the reaction, 1% aqueous acetic acid was added, stirred for 5 minutes, filtered, and rinsed three times with 1% aqueous acetic acid. The filtrate was concentrated to dryness and lyophilized to afford Compound 195 (4.6 mg, yield: 60.6%) as an off-white solid.

[1076] 1 H NMR(400MHz,D2O)δ5.40(d,J=9.4Hz,1H),4.24-4.13(m,2H),3.98(d,J=15.8Hz,1H),3.88(d,J=7.2Hz,1H), 3.69-3.54(m,2H),3.41-3.32(m,1H),2.26(d,J=9.4Hz,1H),1.27(d,J=6.8Hz,6H); LCMS(m / z):425.1[M+1] + .

[1077] Example 162: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-(methylsulfonyl)guanidino)methyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 196)

[1078] Step 1: Synthesis of compound 196-2

[1079] Compound 165-1 (500 mg, 2.63 mmol) was dissolved in dichloromethane (10 mL), and diisopropylethylamine (339 mg, 2.63 mmol) was added. Under nitrogen protection, the temperature was lowered to 0°C, and methylsulfonyl chloride (300 mg, 2.63 mmol) was added dropwise. The reaction was allowed to react at room temperature overnight. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column chromatography (EA / PE = 0-20%) to obtain compound 196-2 (669 mg, yield: 94.9%). LCMS (m / z): 269.1 [M+1] + .

[1080] Step 2: Synthesis of compound 196-3

[1081] Compound B3 (200 mg, 0.31 mmol) was dissolved in acetonitrile (15 mL), and compound 196-2 (125.6 mg, 0.468 mmol) was added. The mixture was heated to 60°C under nitrogen and allowed to react overnight. HPLC was used to monitor the reaction until the starting material was completely reacted. The reaction solution was concentrated to obtain a residue (310 mg). The residue was purified by flash column chromatography (EA / PE = 0-30%) to obtain compound 196-3 (160 mg, yield: 59.5%). LCMS (m / z): 861.3 [M+1] + .

[1082] Step 3: Synthesis of compound 196

[1083] Compound 196-3 (170 mg, 0.20 mmol) was dissolved in a mixture of water (10 mL) and TFA (5 mL) and heated to 60°C under nitrogen for 20 hours. HPLC was used to monitor the reaction until the starting material was completely reacted. The reaction solution was concentrated to dryness to obtain a residue. The residue was purified by reverse-phase column chromatography (MeOH / H2O = 0-10%) to obtain the acetate salt of compound 196 (30 mg, yield: 26.5%).

[1084] 1H NMR (400MHz, MeOD) δ7.48-7.22 (m, 5H), 5.58 (d, J = 9.4Hz, 1H), 5.12 (s, 2H), 4.35-3. 71(m,6H),2.92(s,3H),2.26(d,J=8.9Hz,1H),1.97(s,3H); LCMS(m / z):573.2[M+1] + .

[1085] Example 163: Synthesis of (N-(((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)guanidino)methanesulfonamide (Compound 197)

[1086] Compound 196 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), 10% Pd / C (20 mg) was added, hydrogen was replaced, and hydrogen was passed into the reaction solution for 3 hours. HPLC was used to monitor until the raw material reaction was complete. The reaction solution was filtered and the filter cake was rinsed with 0.05 M AcOH aqueous solution. The filtrate was concentrated to obtain a crude product, which was slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was sucked off to obtain a residue. The residue was concentrated and dried to obtain the acetate salt of compound 197 (13 mg, yield: 85%).

[1087] 1 H NMR (400MHz, MeOD) δ5.51(d,J=9.4Hz,1H),4.29(d,J=5.9Hz,1H),4.23(s,1H),4.04(s,1H),3.99(d,J= 7.7Hz,1H),3.95-3.81(m,2H),3.06(s,3H),2.35(d,J=9.3Hz,1H),2.09(s,3H); LCMS(m / z):439.1[M+1] + .

[1088] Example 164: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(phenylsulfonylaminomethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 198)

[1089] Step 1: Synthesis of Compound 198-1

[1090] Compound B3 (500 mg, 0.78 mmol) was dissolved in DCM (10 mL), and triethylamine (58.78 mg, 0.583 mmol) was added. Benzenesulfonic anhydride (279.7 mg, 0.94 mmol) was added under nitrogen protection and allowed to react at room temperature for 1 hour. The reaction solution was poured into water (50 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (EA / PE = 0-30%) to obtain compound 198-1 (510 mg, yield: 83.7%) as a white solid. LCMS (m / z): 781.2 [M+1] + .

[1091] Step 2: Synthesis of Compound 198

[1092] Compound 198-1 (500 mg, 0.64 mmol) was dissolved in a mixture of water (20 mL) and TFA (20 mL). The mixture was heated to 60°C under nitrogen and allowed to react overnight. HPLC was used to monitor the reaction until the starting material was completely reacted. The reaction solution was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (MeOH / DCM = 0-10%) to obtain Compound 198 (200 mg, yield: 52.7%) as a white solid.

[1093] 1 H NMR (400MHz, DMSO) δ7.89-7.82(m,2H),7.69-7.59(m,3H),7.37-7.28(m,5H),5.68-5.45(m,1H),5.36-5.20(m,2H) ,4.98(s,2H),4.23-4.12(m,1H),3.99-3.93(m,1H),3.82-3.60(m,2H),2.02-1.93(m,1H); LCMS(m / z):593.2[M+1] + .

[1094] Example 165: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (Compound 199)

[1095] Compound 198 (200 mg, 0.338 mmol) was dissolved in methanol (50 mL), 10% Pd / C (50 mg) was added, hydrogen was replaced, and hydrogen was introduced into the reaction solution for 3 hours. HPLC was used to monitor until the reaction of the raw materials was complete. The reaction solution was filtered and the filter cake was rinsed with 0.05 M AcOH aqueous solution. The filtrate was concentrated to obtain a crude product. The crude product was slurried with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was sucked off to obtain a residue. The residue was concentrated and dried to obtain compound 199 acetate (220 mg, yield:> 100%) as a white solid.

[1096] 1 H NMR(400MHz,D2O)δ7.85(d,J=7.4Hz,2H),7.66(t,J=7.4Hz,1H),7.58(t,J=7.6Hz,2H),5.39(d,J=9.5Hz,1H),4.20(s, 1H),4.12(s,1H),3.95(s,1H),3.87(d,J=8.0Hz,1H),3.49-3.37(m,2H),2.25(d,J=9.4Hz,1H); LCMS(m / z):459.1[M+1] + .

[1097] Example 166: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4(a),6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (Compound 199-A) and (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4(e),6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (Compound 199-B)

[1098] Compound 199 was further isolated and purified to obtain Compound 199-A and Compound 199-B.

[1099] The acetate salt of compound 199 (100.94 mg, HPLC showed that compound 199-A accounted for 12.83% and compound 199-B accounted for 70.15%) was separated by high performance liquid chromatography (mobile phase A: 0.5% acetic acid aqueous solution; mobile phase B: ACN; wavelength: 214 nm; chromatographic column: Waters Atlantis T3, 19x150 mm, 5 um, flow rate: 15 mL / min) to give compound 199-B (34.61 mg, recovery: 48.9%, HPLC purity: 98.70%, retention time: 24.92 min) and compound 199-A (2.26 mg, recovery: 17.5%, HPLC purity: 96.05%, retention time: 25.19 min).

[1100] Compound 199-A: LCMS (m / z): 459.1 [M+1] + .

[1101] Compound 199-B: 1 H NMR (400MHz, MeOD) δ7.99-7.85(m,2H),7.74-7.54(m,3H),5.52(d,J=9.3Hz,1H),4.16(d,J=20. 9Hz,2H),3.99(s,2H),3.44(s,2H),2.24(d,J=9.4Hz,1H),1.90(s,3H); LCMS(m / z):459.1[M+1] + .

[1102] Example 167: Cyclopentyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4(a),6,9,10,11-pentahydroxy-6-(phenylsulfonylaminomethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 200-A), ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4(e),6,9,10,11-pentahydroxy-6-(phenylsulfonylaminomethyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate Cyclopentyl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,Z)-9-(phenylsulfonylaminomethyl)-6,9,11-trihydroxyoctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxy[4,3-f][1,3,5]oxadiaza-2(1H)-ylidene)carbamate (Compound 201)

[1103] Step 1: Synthesis of compound 200-1

[1104] 2-Methyl-2-mercaptosulfuric acid urea (2 g, 7.18 mmol) was dissolved in H₂O (20 mL), cooled to 0°C, and benzyl chloroformate (CbzCl) (2.45 g, 14.37 mmol) and a NaOH (1.15 g, 28.74 mmol) / H₂O (8 mL) solution were added dropwise. A white solid precipitated during the addition. The reaction was continued for 2 hours after completion. TLC (PE / EA = 5:1) revealed the formation of two product spots. Dichloromethane (50 mL) was added to the reaction solution, stirred, and the layers were separated. The aqueous phase was extracted with dichloromethane (30 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (EA / PE = 0-35%) to afford Compound 200-1 as a white solid (1.6 g, yield: 49.7%). LCMS (m / z): 225.1 [M+1] + .

[1105] 1 H NMR (400MHz, CDCl3) δ7.41 (d, J = 7.0Hz, 2H), 7.38-7.28 (m, 3H), 5.16 (s, 2H), 2.47 (s, 3H); LCMS (m / z): 225.1 [M+1] + .

[1106] Step 2: Synthesis of compound 200-2

[1107] Compound 200-1 (600 mg, 2.68 mmol) was dissolved in anhydrous dichloromethane (10 mL). Triethylamine (1.35 g, 13.38 mmol) was added dropwise in an ice bath, followed by the dropwise addition of cyclopentyl chloroformate (795 mg, 5.35 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (EA / PE = 0-15%) to obtain compound 200-2 (374 mg, yield: 41.6%) as an oil.

[1108] 1 H NMR (400MHz, CDCl3) δ11.81 (d, J=99.8Hz, 1H), 7.46-7.30 (m, 5H), 5.25-5.05 (m, 3H), 2.41 (s,3H),1.97-1.84(m,2H),1.82-1.67(m,4H),1.65-1.56(m,2H); LCMS(m / z):337.1[M+1]+ .

[1109] Step 3: Synthesis of compound 200-3

[1110] Compound S8 can be synthesized by referring to the method of patent application CN 113956266 A, the entire content of which is incorporated herein by reference.

[1111] Compound S8 (371 mg, 1 mmol) was dissolved in acetonitrile (10 mL), and compound 200-2 (336 mg, 1 mmol) and triethylamine (505 mg, 5 mmol) were added. Under nitrogen, the temperature was lowered to 0°C, and silver trifluoromethanesulfonate (514 mg, 2 mmol) was then added. After the addition was complete, the reaction solution was slowly returned to room temperature and allowed to react overnight. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain a gummy residue. The residue was purified by flash column chromatography (EA / PE = 0-30%) to obtain compound 200-3 (330 mg, yield: 50%) as a white foamy solid. LCMS (m / z): 660.3 [M+1] + .

[1112] Step 4: Synthesis of compound 200-4

[1113] Compound 200-3 (330 mg, 0.5 mmol) was dissolved in a mixture of water (15 mL) and TFA (15 mL) and allowed to react overnight at approximately 10°C under nitrogen. The reaction solution was poured into water (100 mL) and extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by flash column chromatography (MeOH / DCM = 0-10%) to obtain compound 200-4 (280 mg, yield: 80%) as a white foamy solid. LCMS (m / z): 620.2 [M+1] + .

[1114] Step 5: Synthesis of Compound 200-5

[1115] Under nitrogen at -78°C, oxalyl chloride (86.3 mg, 0.68 mmol) was dissolved in DCM (8 mL). Dimethyl sulfoxide (106.2 mg, 1.36 mmol) was then slowly added dropwise. The reaction was maintained at -78°C for 30 minutes. Compound 200-4 (280 mg, 0.45 mmol) in DCM (2 mL) was then added dropwise. After the addition was complete, TEA (228.7 mg, 2.26 mmol) was added dropwise. The reaction mixture was then slowly returned to room temperature and allowed to react for 1 hour. HPLC was used to monitor the reaction until the starting material reacted completely. The reaction mixture was poured into water (50 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain a residue. The residue was purified by flash column chromatography (EA / PE = 0-35%) to afford Compound 200-5 (160 mg, 80% yield) as a white foamy solid. LCMS (m / z): 618.2 [M+1] + .

[1116] Step 6: Synthesis of compound 200-6

[1117] Compound 200-5 (160 mg, 0.26 mmol) was dissolved in methanol (10 mL), and sodium acetate (31.9 mg, 0.39 mmol) and hydroxylamine hydrochloride (39.6 mg, 0.57 mmol) were added. The mixture was allowed to react overnight at 35°C under nitrogen. The reaction solution was concentrated to dryness, and water (30 mL) was added to the residue. The mixture was stirred for approximately 30 minutes, resulting in the precipitation of a large amount of white solid. The filter cake was collected by filtration and air-dried to obtain crude compound 200-6 (160 mg, yield: 97.6%), which was used directly in the next step. LCMS (m / z): 633.2 [M+1] + .

[1118] Step 7: Synthesis of compound 200-7

[1119] Compound 200-6 (150 mg, 0.24 mmol) was dissolved in a mixture of methanol (5.9 mL) and DCM (1.5 mL), and nickel chloride hexahydrate (140 mg, 0.59 mmol) was added. NaBH4 (53.8 mg, 1.42 mmol) was added portionwise under nitrogen protection and below -40°C. After the addition was complete, the temperature was maintained at -40°C for 30 minutes. HPLC monitoring was used until the reaction was complete. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution and stirred until the solution turned light green. DCM (30 mL) was added and filtered through celite. The filter cake was washed with DCM (10 mL x 2). The filtrate was separated and the aqueous phase was extracted with dichloromethane / methanol (10:1, 30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 200-7 (125 mg, yield: 85.3%) as a white foamy solid. LCMS (m / z): 619.3 [M+1] + .

[1120] Step 8: Synthesis of Compound 200-8

[1121] Compound 200-7 (120 mg, 0.194 mmol) was dissolved in DCM (5 mL), and triethylamine (58.78 mg, 0.583 mmol) and benzenesulfonic anhydride (69.5 mg, 0.233 mmol) were added. The mixture was reacted at room temperature under nitrogen for 1 hour. The reaction solution was poured into water (50 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (EA / PE = 0-30%) to obtain compound 200-8 (108 mg, yield: 73.5%) as a white foamy solid. LCMS (m / z): 759.3 [M+1] + .

[1122] Step 9: Synthesis of compound 200-9

[1123] Compound 200-8 (100 mg, 0.132 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (50 mg) was added to displace the hydrogen atmosphere. Hydrogen was then introduced into the reaction mixture and allowed to react at room temperature for 3 hours. HPLC was used to monitor the reaction until the reaction was complete. The reaction mixture was filtered, the filter cake rinsed with methanol, and the filtrate concentrated to dryness to obtain crude compound 200-9 (83 mg, yield: 100%), which was used directly in the next step. LCMS (m / z): 625.2 [M+1]+ .

[1124] Step 10: Synthesis of Compound 200-A, Compound 200-B and Compound 201

[1125] Compound 200-9 (82 mg, 0.131 mmol) was dissolved in a mixed solution of water (3 mL) and TFA (3 mL) and heated to 60°C under nitrogen protection to react overnight. HPLC monitoring was used until the reaction of the raw materials was complete. The reaction solution was concentrated to dryness to obtain a residue. The residue was purified by flash column chromatography (MeOH / DCM = 0-10%) to obtain white foamy solid compound 200-A (2.7 mg, yield: 3.6%), compound 200-B (25 mg, yield: 33.3%) and compound 201 (12 mg, yield: 16.5%), with a total yield of 53.4%.

[1126] Compound 200-A:

[1127] LCMS (m / z): 571.2 [M+1] + .

[1128] Compound 200-B:

[1129] 1 H NMR(400MHz,MeOD)δ7.91(d,J=7.1Hz,2H),7.68-7.54(m,3H),5.55(d,J=9.3Hz,1H),5.09-5.00(m,1H),4.12(s,2H),3.90 (s,2H),3.45(s,2H),2.29-2.21(m,1H),1.94-1.80(m,2H),1.79-1.67(m,4H),1.65-1.56(m,2H); LCMS(m / z):571.2[M+1] + .

[1130] Compound 201:

[1131] 1H NMR (400MHz, MeOD) δ7.95-7.86(m,2H),7.67-7.54(m,3H),5.26(s,1H),5.04-4.97(m,1H),4.45(d,J=1.9Hz,1H),4.40(s,1H),4.13(d,J=2. 7Hz,1H),4.00(s,1H),3.38(s,2H),2.68(d,J=2.8Hz,1H),1.91-1.79(m,2H),1.78-1.65(m,4H),1.64-1.55(m,2H); LCMS(m / z):553.2[M+1] + .

[1132] Example 168: Synthesis of benzyl ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((4-methoxyphenyl)sulfonamido)methyl)octahydro-5,9-epoxy-7,10a-methoxy[4,5-d]pyrimidin-2(1H)-ylidene)carbamate (Compound 202)

[1133] Step 1: Synthesis of Compound 202-1

[1134] Compound B3 (110 mg, 0.17 mmol), 4-methoxybenzenesulfonyl chloride (43.3 mg, 0.21 mmol), and pyridine (27.5 mg, 0.34 mmol) were dissolved in DCM (5 mL) and stirred at 25°C for 3 hours under nitrogen. After completion of the reaction, water (5 mL) was added to the reaction solution, and the mixture was extracted with DCM (5 mL x 3). The organic phases were combined and concentrated to dryness to obtain a residue. The residue was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 5%-40%) to obtain compound 202-1 (120 mg, yield: 86.3%) as an off-white solid. LCMS (m / z): 811.2 [M+1] + .

[1135] Step 2: Synthesis of compound 202

[1136] Compound 202-1 (120 mg, 0.15 mmol) was dissolved in a mixture of TFA:H₂O = 2:1 (4 mL) and heated to 60°C with stirring under nitrogen for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain a residue. The residue was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 5%-40%) to obtain Compound 202 (24.3 mg, yield: 26.4%) as a white solid.

[1137] 1 H NMR (400MHz, MeOD) δ7.86(d,J=8.9Hz,2H),7.43-7.26(m,5H),7.11(d,J=8.9Hz,2H),5.57(d,J=9.3Hz,1H),5.10(d,J =4.6Hz,2H),4.15(s,2H),3.98-3.92(s,2H),3.91(s,3H),3.48(s,2H),2.25(d,J=9.4Hz,1H); LCMS(m / z):623.2[M+1] + .

[1138] Example 169: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-2-iminooctahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidin-6-yl)methyl)benzenesulfonamide (Compound 203)

[1139] Compound 202 (10 mg, 0.016 mmol) was dissolved in methanol (2 mL), and 10% Pd / C (1 mg) was added. The hydrogen atmosphere was replaced three times, and the reaction was stirred at 25°C for 8 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to dryness and lyophilized to afford Compound 203 (3.5 mg, 44.6% yield) as an off-white solid. [114...

Claims

1. A compound or a pharmaceutically acceptable derivative thereof, wherein the compound has the structure of formula (I): in, X is absent or selected from -(CH2) m -and wherein the -CH2- is optionally replaced by -O- or a carbonyl group or optionally by at least one R X replace; Y1 and Y2 are each independently selected from methylene, O, S and NH, wherein the methylene and NH are optionally replaced by at least one R X replace; R1 and R3 are each independently selected from hydrogen, hydroxy, amino, cyano, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3- 8 cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace; R2 is selected from hydrogen, hydroxy, amino, formyl, acetyl, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, -(C=O)OR 10 and -O(C=O)R 11 wherein the formyl, acetyl, alkyl, cycloalkyl and heterocyclic groups are optionally replaced by at least one R X replace; Each R4 is independently selected from hydrogen, deuterium, hydroxyl, halogen, -OR 12 and C 1-8 alkyl; or R3 and R4 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally replaced by at least one R X replace; R5 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 13 ; R6 is selected from hydroxyl, thiol, amino, azido, halogen, cyano, C 1-12 Alkyl, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl, C 5-10 Heteroaryl, -(C=O)-R 14 , guanidine, urea, -(OCH2CH2) n -OH, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, guanidinyl and ureido groups are optionally substituted by at least one R X replace; or R5 and R6 together with the atoms to which they are attached form a 3-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally replaced by at least one R X replace; R7 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-8 Cycloalkyl and C 3-8 Heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted by at least one R X replace; R8 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 15 ; or R4 and R8 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally At least one R X replace; R9 is selected from hydrogen, deuterium, tritium, hydroxyl, C 1-8 Alkyl, C 3-8 Cycloalkyl and -OR 16 ; R 10 and R 11 Each independently selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-20 Aryl, C 1-8 Alkyl-C 6-20 Aryl, C 5-20 Heteroaryl and C 1-8 Alkyl-C 5-20 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace; Each R 12 , R 13 , R 14 , R 15 and R 16 Each independently selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 3-8 Cycloalkyl, C 1- 8-Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace; R 6’ Selected from hydrogen, hydroxyl, amino, cyano, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace; R 6” Selected from hydroxyl, thiol, amino, halogen, C 1-12 Alkyl, C 2-8 Alkenyl, -OC 1-12 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by at least one R X replace; Each R X independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, formyl, C 1-8 Alkyl, -OC 1- 8 alkyl, C 2-8 Alkenyl, C 3-20 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl, C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the amino, formyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R Y replace; Each R Y independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, formyl, acetyl, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, C 3-8 Heterocyclic group, -OC 3-8 Heterocyclic group, C 1-8 Alkyl-C 3-8 Heterocyclic group, C 6-10 Aryl, -OC 6-10 Aryl, C 1-8 Alkyl-C 6-10 Aryl, C 5-10 Heteroaryl, -OC 5-10 Heteroaryl and C 1-8 Alkyl-C 5-10 Heteroaryl, wherein the formyl, acetyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by at least one halogen, hydroxyl or R Y1 replace; Each R Y1 Independently selected from amino, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by at least one R Y2 replace; Each R Y2 Independently selected from amino, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl and C 5-10 heteroaryl; When X is methylene and R1, R2 and R3 are simultaneously hydrogen, R4, R5, R6, R7, R8 and R9 are not simultaneously hydroxyl groups; m is an integer selected from 0-6; n is an integer selected from 1-12; t is an integer selected from 0-4.

2. The compound of claim 1 or a pharmaceutically acceptable derivative thereof, wherein X is selected from the group consisting of methylene, carbonyl and 3. The compound or pharmaceutically acceptable derivative thereof according to claim 1 or 2, wherein R1 is hydrogen.

4. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 3, wherein said R2 is selected from hydrogen, acetyl and -(C=O)OR 10 .

5. The compound according to claim 4 or a pharmaceutically acceptable derivative thereof, wherein R 10 Selected from benzyl and cyclopentyl.

6. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 5, wherein R3 is selected from hydrogen, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkyl-C 3-8 Cycloalkyl and C 1-8 Alkyl-C 6-10 Aryl, wherein the alkyl, cycloalkyl and aryl groups are optionally substituted by at least one R X replace.

7. The compound of claim 6 or a pharmaceutically acceptable derivative thereof, wherein said R X Selected from hydroxyl and carboxyl.

8. The compound of claim 6 or a pharmaceutically acceptable derivative thereof, wherein R3 is selected from hydrogen, methyl, ethyl, isopropyl, Preferably hydrogen and 9. The compound of any one of claims 1-8 or a pharmaceutically acceptable derivative thereof, wherein said R4 is selected from hydrogen, deuterium and hydroxyl.

10. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 9, wherein R3 and R4 together with the atoms to which they are attached form a six-membered heterocyclic ring.

11. The compound of claim 10 or a pharmaceutically acceptable derivative thereof, wherein the heterocyclic ring formed by R3 and R4 together with the atoms to which they are attached is selected from 12. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 11, wherein R5 is hydroxyl.

13. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 12, wherein R6 is selected from hydroxyl, amino, cyano, -OC 1-12 Alkyl, guanidine, urea, C 3-8 Heterocyclic and wherein the amino, alkyl, guanidinyl and heterocyclic groups are optionally substituted by at least one R X replace.

14. The compound of claim 13 or a pharmaceutically acceptable derivative thereof, wherein said R X Selected from halogen, hydroxy, amino, formyl, C 1-8 Alkyl, C 3-20 Cycloalkyl, C 1-8 Alkyl-C 6-10 Aryl, C 3-8 Heterocyclic and wherein the amino, formyl, alkyl, cycloalkyl and heterocyclic groups are optionally substituted by at least one R Y replace.

15. The compound of claim 14 or a pharmaceutically acceptable derivative thereof, wherein said R Y is selected from halogen, hydroxy, carboxyl, formyl, acetyl and C 1-8 alkyl, wherein the formyl group is optionally replaced by a hydroxyl group or R Y1 Substitution; said R Y1 is selected from amino groups, the amino groups are optionally replaced by R Y2 Substitution; said R Y2 Selected from C 1-8 alkyl.

16. The compound of claim 13 or a pharmaceutically acceptable derivative thereof, wherein said R 6’ is selected from hydrogen and methyl.

17. The compound of claim 13 or a pharmaceutically acceptable derivative thereof, wherein said R 6” Selected from C 1-12 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted by at least one R X replace.

18. The compound of claim 17 or a pharmaceutically acceptable derivative thereof, wherein said R X Selected from halogen, C 1-8 Alkyl, -OC 1-8 Alkyl, C 3-20 Cycloalkyl and C 6-10 Aryl, wherein the alkyl, cycloalkyl and aryl groups are optionally substituted by at least one R Y replace.

19. The compound of claim 18 or a pharmaceutically acceptable derivative thereof, wherein said R Y is a halogen, wherein the halogen is fluorine.

20. The compound of claim 17 or a pharmaceutically acceptable derivative thereof, wherein said R 6” is selected from methyl, trifluoromethyl, propyl, isopropyl, 21. The compound or pharmaceutically acceptable derivative thereof of any one of claims 13 to 20, wherein R6 is selected from hydroxyl, halogen, cyano, amino, azido, methoxy, methylamino, tert-butyl, propenyl, guanidine, urea, Preferably, hydroxyl, amino, methoxy, methylamino, guanidine, urea, More preferably, hydroxyl, amino, methylamino, guanidine, urea, 22. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 21, wherein R7 is hydroxyl.

23. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 22, wherein R8 is hydroxyl.

24. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 23, wherein R4 and R8 together with the atoms to which they are attached form a heterocyclic ring having the following structure: in, X, Y1, Y2, R1, R2, R3, R5, R6, R7 and R9 are as defined in any one of claims 1 to 23, and t' is an integer selected from 0-3.

25. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 24, wherein R4 and R8 together with the atoms to which they are attached form a heterocyclic ring having the following structure: in, X, R1, R2, R3, R5, R6, R7 and R9 are as defined in any one of claims 1-24.

26. The compound or pharmaceutically acceptable derivative thereof according to any one of claims 1 to 25, wherein R9 is hydroxyl.

27. A compound or a pharmaceutically acceptable derivative thereof having the following structure: Best More preferred 28. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable carriers.

29. Use of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 28 in the preparation of a medicament for treating a disease or condition associated with a sodium ion channel or for analgesia.

30. The use according to claim 29, wherein The sodium channel-related disease or condition includes pain, including 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, dental pain, HIV-related pain, acute pain, pain associated with multiple sclerosis (MS), familial rectal pain, fibromyalgia, or pain caused by the following conditions Pain: depression, cardiovascular disease, neurogenic cystitis, 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, myasthenic syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety anxiety, schizophrenia, sodium channel toxin-related disorders, familial erythromelalgia, primary erythromelalgia, epilepsy, epileptic encephalopathy, partial and generalized tonic seizures, restless legs syndrome, cardiac arrhythmias, tachyarrhythmias, atrial fibrillation, or ventricular fibrillation; The pain targeted by the analgesic includes: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, dental pain, HIV-related pain, acute pain, pain associated with multiple sclerosis (MS), familial rectal pain, fibromyalgia, or pain caused by the following conditions: depression, cardiovascular disease, neurogenic cystitis, ulcerative colitis, respiratory disease, psychiatric disease, peripheral nerve damage, HIV treatment-induced neuropathic pain, lesions, heat sensitivity, 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, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related disease, familial erythromelalgia, primary erythromelalgia, epilepsy, epileptic encephalopathy, partial and generalized tonic seizures, restless legs syndrome, arrhythmia, tachyarrhythmia, atrial fibrillation, or ventricular fibrillation.

31. A compound having the structure of formula (II): in, X, R6 as defined in any one of claims 1 to 27, Pg1 and Pg2 are independently selected from acetyl, trityl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), cyclopentyloxycarbonyl and methyloxycarbonyl (Fmoc).

32. The compound of claim 31 having the following structure:

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