Tetrodotoxin derivative compounds and their use as sodium channel blockers

Abstract

The present invention relates to compounds having an inhibitory effect on multiple types of sodium ion channels, or pharmaceutically acceptable derivatives thereof, and pharmaceutical compositions thereof, as well as their use as pansodium ion channel blockers.

Description

[Technical Field]

[0001] The present invention relates to compounds having an inhibitory effect on multiple types of sodium ion channels, or pharmaceutically acceptable derivatives thereof, and pharmaceutical compositions thereof, as well as their use as pansodium ion channel blockers. [Background technology]

[0002] Tetrodotoxin (TTX) is an aminoperhydroquinzaline compound with the following structure. [ka]

[0003] Tetrodotoxin has a local irritant effect on the intestinal tract, and after absorption, it rapidly acts on peripheral and central nerves, inhibiting sodium ion channels on nerve excitatory membranes with high selectivity and affinity, thereby inhibiting nerve conduction and causing nerve paralysis, which can lead to death. Clinically, tetrodotoxin is mainly used for analgesia, local anesthesia, sedation, antispasmodic, antihypertensive, and antiarrhythmic purposes, but its use is severely restricted due to its potent toxicity.

[0004] Voltage-gated sodium channels (VGSCs) are microporous transmembrane glycoproteins widely distributed in the excitable cell membranes of neurons and other cells, and are primarily composed of Na +Voltage-gated sodium channels (VSTs) are the most important ion channels responsible for transmembrane transport, necessary for neurons to generate excitability and exhibit normal electrophysiological function. VSTs consist of one α-subunit and multiple β-subunits. The α-subunit is the main functional unit, and currently, nine subunits (Nav1.1-Nav1.9) have been discovered, each having six α-helix transmembrane segments (S1-S6) surrounded by four highly similar homologous domains, forming the central pore of the ion channel. The amino acid sequence of S4 is highly conserved and is considered the voltage receptor of the VST. The β-subunits consist of four subunits (β1-β4), which assist in the localization and stability of the α-subunit in the membrane and are involved in regulating the voltage sensitivity and inactivation processes of the α-subunit. While there is broad homology among VSTs of different animals, there are also significant differences. Sodium ion channels are classified into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R) types based on their sensitivity to tetrodotoxin (TTX) inhibition. TTX-R sodium ion channels include Nav1.5, Nav1.8, and Nav1.9, while the rest are all TTX-S type sodium ion channels. Nav1.7 is a transmembrane protein encoded by SCN9A, specifically expressed in peripheral sensory nerve terminals and sympathetic ganglion neurons, mainly in large-diameter dorsal root ganglion (DRG) neurons and unmyelinated small-diameter DRGs, i.e., expressed in 85% of pain receptors, indicating that Nav1.7 plays a crucial role in pain conduction. Nav1.7 has a central role in the conduction and maintenance of pain signals and is already a very important target in the research and development of analgesics. The compounds in this invention are obtained by structurally modifying and optimizing tetrodotoxin. The resulting innovative tetrodotoxin derivatives exhibit remarkable 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 pansodium ion channel blockers.

[0005] In the prior art, tetrodotoxin-based derivatives are mainly derived from isolation and extraction from nature. Examples include 4,9-anhydrous TTX (Non-Patent Literature 1), 6-epi-TTX, and 11-deoxy-TTX (Non-Patent Literature 2). Some literature reports the laboratory synthesis of some tetrodotoxin derivatives. Examples include 11-deoxytetrodotoxin (Non-Patent Literature 3) and 8,11-dideoxytetrodotoxin (Non-Patent Literature 4). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Nakamura M, Yasumoto T. Tetrodotoxin derivatives in puffer fish[J].Toxicon, 1985, 23(2):271~276. [Non-Patent Document 2] 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. [Non-Patent Document 3] J.AM.CHEM.SOC.2002, 124, 7847~7852 [Non-Patent Document 4] Chem.Eur.J.2004, 10, 452~462 [Overview of the project]

[0007] A first aspect of the present invention provides a compound or a pharmaceutically acceptable derivative thereof, the compound having the structure of formula (I), [ka] During the ceremony, X does not exist or is -(CH2) m -and [ka] selected from, wherein the -CH2- is optionally replaced by -O- or a carbonyl group or at least one R X and is optionally substituted with Y1 and Y2 are each independently selected from a methylene group, O, S and NH, and the methylene group and NH are each optionally substituted with at least one R X and is optionally substituted with R1 and R3 are each independently hydrogen, a hydroxyl group, an amino group, a cyano group, C 1~8 alkyl group, C 3~8 cycloalkyl group, C 1~8 alkyl-C 3~8 cycloalkyl group, C 3~8 heterocyclyl group, C 1~8 alkyl-C 3~8 heterocyclyl group, C 6~10 aryl group, C 1~8 alkyl-C 6~10 aryl group, C 5~10 heteroaryl group and C 1~8 alkyl-C 5~10 heteroaryl group, and the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each optionally substituted with at least one R X and is optionally substituted with R2 is selected from hydrogen, a hydroxyl group, an amino group, a formyl group, an acetyl group, C 1~8 alkyl group, C 3~8 cycloalkyl group, C 3~8 heterocyclyl group, -(C=O)OR 10 and -O(C=O)R 11 and the formyl group, acetyl group, alkyl group, cycloalkyl group and heterocyclyl group are each optionally substituted with at least one R X and is optionally substituted with [[ID=5,4]] Each R4 is independently selected from hydrogen, deuterium, a hydroxyl group, a halogen, -OR 12 and C 1~8 alkyl group, Alternatively, R3 and R4, together with the atoms bonded to them, form a 5-12 membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R5 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups and -OR 13 Selected from, R6 consists of a hydroxyl group, a mercapto group, an amino group, an azide group, a halogen, a cyano group, and C 1~12 Alkyl alkyl group, C 2~8 Alkenyl group, -OC 1~12 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 5~10 Heteroaryl group, -(C=O)-R 14 , guanidyl group, ureido group, -(OCH2CH2) n -OH, [ka] Selected from, the alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, guanidyl group and ureido group is at least one R X It is arbitrarily replaced with, Alternatively, R5 and R6, together with the atoms bonded to them, form a 3- to 12-membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R7 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~4 alkyl group, -OC 1~4 Alkyl alkyl group, C 3~8 Cycloalkyl groups and C 3~8 Selected from heterocyclyl groups, the alkyl group, cycloalkyl group and heterocyclyl group have at least one R X It is arbitrarily replaced with, R8 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups and -OR15 Selected from, Alternatively, R4 and R8, together with the atoms bonded to them, form a 5-12 membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R9 consists of hydrogen, deuterium, tritium, hydroxyl group, and C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups and -OR 16 Selected from, R 10 and R 11 Each of them is independent of C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~20 Aryl group, C 1~8 Alkyl-C 6~20 Aryl group, C 5~20 Heteroaryl group and C 1~8 Alkyl-C 5~20 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R X It is arbitrarily replaced with, Each R 12 , R 13 , R 14 , R 15 and R 16 Each of them is independent of C 1~8 Alkyl alkyl group, C 2~8 Alkenyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one RX is optionally substituted with, R 6’ is hydrogen, a hydroxyl group, an amino group, a cyano group, C 1~8 alkyl group, C 3~8 cycloalkyl group, C 1~8 alkyl-C 3~8 cycloalkyl group, C 3~8 heterocyclyl group, C 1~8 alkyl-C 3~8 heterocyclyl group, C 6~10 aryl group, C 1~8 alkyl-C 6~10 aryl group, C 5~10 heteroaryl group and C 1~8 alkyl-C 5~10 heteroaryl group, and the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each optionally substituted with at least one R X and, R 6’’ is a hydroxyl group, a mercapto group, an amino group, a halogen, C 1~12 alkyl group, C 2~8 alkenyl group, -O-C 1~12 alkyl group, C 3~8 cycloalkyl group, C 3~8 heterocyclyl group, C 6~10 aryl group and C 5~10 heteroaryl group, and the alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each optionally substituted with at least one R X and, each R X is independently hydrogen, a halogen, a hydroxyl group, a carboxyl group, an amino group, a cyano group, a formyl group, C 1~8 alkyl group, -O-C 1~8 alkyl group, C 2~8 alkenyl group, C 3~20 cycloalkyl group, C 1~8 alkyl-C 3~8 cycloalkyl group, C 3~8 heterocyclyl group, C 1~8 alkyl-C 3~8 heterocyclyl group, C 6~10Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group, C 1~8 Alkyl-C 5~10 heteroaryl group, [ka] Selected from, the amino group, formyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are at least one R Y It is arbitrarily replaced with, Each R Y These are independently hydrogen, halogen, hydroxyl group, amino group, carboxyl group, formyl group, acetyl group, and C 1~8 alkyl group, -OC 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, -OC 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, -OC 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, -OC 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group, -OC 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the formyl group, acetyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one halogen, hydroxyl group, or R Y1 It can be arbitrarily selected, Each R Y1 These are, independently, an amino group, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group and C 5~10Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R Y2 It is arbitrarily replaced with, Each R Y2 These are, independently, an amino group, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group and C 5~10 Selected from heteroaryl groups, If X is a methylene group and R1, R2, and R3 are all hydrogen atoms, then R4, R5, R6, R7, R8, and R9 cannot all be hydroxyl groups at the same time. m is an integer selected from 0 to 6. n is an integer selected from 1 to 12. t is an integer selected from 0 to 4.

[0008] A 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.

[0009] A third aspect of the present invention provides a method for treating a disease or condition related to sodium ion channels, comprising 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, optionally in combination with another therapeutic agent. Accordingly, the present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof in the manufacture of a drug for treating a disease or condition related to sodium ion channels, 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 treating a disease or condition related to sodium ion channels, optionally in combination with another therapeutic agent. In one embodiment, the sodium ion channel is a TTX-S sodium ion channel. In one embodiment, the disease or condition related to sodium ion channels includes pain. In one embodiment, the pain includes neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy-induced pain, traumatic pain, surgical pain, postoperative pain, childbirth pain, labor pains, chronic pain, persistent pain, peripheral pain, central pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, HIV-related pain, acute pain, multiple sclerosis (MS)-related pain, familial rectal pain and fibromyalgia, or depression, cardiovascular disease, neurogenic cystitis, ulcerative colitis, respiratory disease, mental illness, peripheral neuropathy, HIV treatment-induced neuropathy, heat sensitivity, sarcoidosis, irritable bowel syndrome, etc. This includes pain caused by conditions such as Loan'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 disorders, schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, epilepsy, epileptic encephalopathy, focal and generalized tonic seizures, restless legs syndrome, arrhythmias, tachyarrhythmias, atrial fibrillation, or ventricular fibrillation.

[0010] Accordingly, the present invention further provides a method for analgesia, comprising administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof to an individual in need, optionally in combination with another therapeutic agent. Accordingly, the present invention further provides the use of the compound of formula (I) or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition thereof in the manufacture of analgesic drugs, optionally in combination with another therapeutic agent. The present invention further provides the 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.

[0011] A fourth aspect of the present invention provides a compound having the structure of formula (II), [ka] In the formula, X and R6 are as defined herein for the compound of formula (I), and Pg1 and Pg2 are independently selected from an acetyl group, a triphenylmethyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a cyclopentyloxycarbonyl group, and a 9-fluorenylmethyloxycarbonyl group (Fmoc). [Brief explanation of the drawing]

[0012] [Figure 1]The following shows the inhibition results of analgesic efficacy tests in an acetate-rising pain model in ICR mice. Figure 1A shows the results of the analgesic efficacy test of compound TTX-S in an acetate-rising pain model in ICR mice. Figure 1B shows the results of the analgesic efficacy test of compound 73 in an acetate-rising pain model in ICR mice. Figure 1C shows the results of the analgesic efficacy test of compound 77 in an acetate-rising pain model in ICR mice. Figure 1D shows the results of the analgesic efficacy test of compound 199 in an acetate-rising pain model in ICR mice. Figure 1E shows the results of the analgesic efficacy test of compound 199-B in an acetate-rising pain model in ICR mice. Figure 1F shows the results of the analgesic efficacy test of compound 210 in an acetate-rising pain model in ICR mice. [Figure 2] Figure 2A shows the results of the analgesic efficacy test of compound TTX in a rat formalin-induced inflammatory pain model. Figure 2B shows the results of the analgesic efficacy test of compound 77 in a rat formalin-induced inflammatory pain model. Figure 2C shows the results of the analgesic efficacy test of compound 199 in a rat formalin-induced inflammatory pain model. Figure 2D shows the results of the analgesic efficacy test of compound 199-B in a rat formalin-induced inflammatory pain model. Figure 2E shows the results of the analgesic efficacy test of compound 189 in a rat formalin-induced inflammatory pain model. Figure 2F shows the results of the analgesic efficacy test of compound 223 in a rat formalin-induced inflammatory pain model. Figure 2G shows the results of the analgesic efficacy test of compound 206 in a rat formalin-induced inflammatory pain model. Figure 2H shows the results of an analgesic efficacy test of compound 209 in a rat formalin-induced inflammatory pain model. [Modes for carrying out the invention]

[0013] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. The technical intent used herein refers to art commonly understood in the art, including variations on or replacements of equivalent art that are obvious to those skilled in the art. The following terms are well understood by those skilled in the art, but their definitions are provided below to better illustrate the invention.

[0014] The terms “include,” “contain,” “have,” “contain,” or “related,” and other variations thereof herein, are inclusive or open and do not exclude other unlisted elements or method steps, but such other unlisted elements or method steps do not necessarily exist (i.e., these terms also include the terms “substantially consist of…” and “consist of…”).

[0015] The term "approximately" refers to a value that is within ±10% of the aforementioned value, preferably within ±5%, and more preferably within ±2%.

[0016] As used herein, the term “alkyl group” is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has 1 to 12 carbon atoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, for example, 1 to 4 carbon atoms. For example, as used herein, the term “C 1~4"Alkyl group" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or tert-butyl group), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (in this case, the group is called a "halogenated alkyl group") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3). Accordingly, "alkoxy group" refers to an alkyl group as described herein that is bonded to the remainder of the molecule via an oxygen atom.

[0017] The term "alkenyl group" refers to an unsaturated aliphatic hydrocarbon group having at least one double bond in a straight or branched chain composed of carbon atoms and hydrogen atoms. In some embodiments, an alkenyl group has 2 to 8 carbon atoms. For example, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl groups, 1-propenyl groups, 2-propenyl groups, 1-butenyl groups, isobutenyl groups, and 1,3-butadienyl groups.

[0018] As used herein, the term “cycloalkyl group” refers to a saturated or unsaturated non-aromatic monocyclic or condensed polycyclic hydrocarbon ring group, and includes, but is not limited to, monocyclic alkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), condensed alkyl groups, crosslinked alkyl groups, or spirocyclic structures. In the present invention, cycloalkyl groups are optionally substituted with one or more (e.g., 1 to 3) identical or different substituents. Carbon atoms on the cycloalkyl group are optionally substituted with oxo groups (i.e., forming C=O). 3~20 A "cycloalkyl group" 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.3~8 A "cycloalkyl group" refers to a cycloalkyl group having 3 to 8 ring-forming carbon atoms, for example, a cycloalkyl group having 3, 4, 5, 6, 7, or 8 ring-forming carbon atoms, or for example, C 3~6 It is a cycloalkyl group, and may be a monocyclic alkyl group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, or cyclooctyl group, C 5~8 Condensed ring alkyl group or C 5~6 It may also be a fused cyclic alkyl group, such as a fused cyclic alkyl group.

[0019] As used herein, the terms “heterocyclyl group” or “heterocyclyl” mean an aliphatic monocyclic, fused polycyclic, bridging, or spirocyclic group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, wherein the heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur atoms, and the carbon atoms and heteroatoms on the heterocyclyl group are optionally substituted with oxo groups (e.g., C=O, S(=O), or S(=O)2), and the carbon atoms and heteroatoms on the heterocyclyl group are further optionally substituted with nitrogen-containing groups (e.g., C=NH).

[0020] As used herein, the term "C 3~8A "heterocyclyl group" refers to a heterocyclyl group containing 3 to 8 ring atoms, for example, a heterocyclyl group containing 3, 4, 5, 6, 7, or 8 ring atoms, including 3-8 membered heterocyclyl groups, 3-7 membered heterocyclyl groups, 4-8 membered heterocyclyl groups, 4-7 membered heterocyclyl groups, 5-6 membered heterocyclyl groups, 3-6 membered heterocyclyl groups, 4-7 membered nitrogen-containing heterocyclyl groups, and 4-7 membered oxygen-containing heterocyclyl groups. This includes cyclyl groups, 4-7 membered sulfur-containing heterocyclyl groups, 5-6 membered nitrogen-containing heterocyclyl groups, 5-6 membered oxygen-containing heterocyclyl groups, 5-6 membered sulfur-containing heterocyclyl groups, etc., where the "nitrogen-containing heterocyclyl group," "oxygen-containing heterocyclyl group," and "sulfur-containing heterocyclyl group" each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur, respectively, but are not limited to these. Examples of 3-8 membered heterocyclyl groups include ethylene oxide group, aziridinyl group, aziridine group, oxacyclobutyl group, tetrahydrofuranyl group, pyrrolidinyl group, pyrrolidone group (for example, [ka] ), imidazolidinyl group, pyrazolidinyl group, tetrahydropyranyl group, piperidinyl group, morpholinyl group, dithianyl group, thiomorpholinyl group, piperazinyl group, trithianyl group, [ka] These include, but are not limited to, the following:

[0021] In the present invention, the heterocyclyl group may form a fused ring structure with a heterocyclyl group or a cycloalkyl group, and the linkage point between the fused ring structure and the other group may be on either the heterocyclyl group or the cycloalkyl group. Therefore, the heterocyclyl group of the present invention can be a fused ring of a heterocyclyl group and a heterocyclyl group, a fused ring of a heterocyclyl group and a cycloalkyl group, a fused ring of a monoheterocyclyl group and a monoheterocyclyl group, a fused ring of a monoheterocyclyl group and a monocycloalkyl group, for example, a fused ring of a 3-7 membered (mono)heterocyclyl group and a 3-7 membered (mono)heterocyclyl group, a fused ring of a 3-7 membered (mono)heterocyclyl group and a cycloalkyl group, or a fused ring of a 3-7 membered (mono)heterocyclyl group and C 4~6 Further comprising (but not limited to) condensed rings of (single) cycloalkyl groups, examples include condensed rings of pyrrolidinyl and cyclopropyl groups, condensed rings of cyclopentyl and azilidinyl groups, condensed rings of pyrrolidinyl and cyclobutyl groups, condensed rings of pyrrolidinyl and pyrrolidinyl groups, condensed rings of pyrrolidinyl and piperidinyl groups, condensed rings of pyrrolidinyl and piperazinyl groups, condensed rings of piperidinyl and morpholinyl groups, [ka] These include, but are not limited to, the following:

[0022] The term "aryl group" refers to a group consisting of 6 to 20 carbon atoms (C) 6~20 (aryl group), for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, or for example, 6 to 14 carbon atoms (C 6~14 (aryl group) or 6 to 10 carbon atoms (C 6~10The aryl group may contain, for example, a phenyl group, a naphthyl group, an indanyl group, a fluorenyl group, etc. The "aryl group" includes six-membered aromatic carbocyclic groups such as a phenyl group, a naphthyl group, an indanyl group, and a bicyclic group having at least one aromatic carbocyclic group such as 1,2,3,4-tetrahydroquinoline, and a tricyclic group having at least one aromatic carbocyclic group such as a flulene group. If the aryl substituent is a bicyclic or tricyclic group and at least one of the rings is a non-aromatic ring, it should be considered to be linked via an aromatic ring. For example, the aryl group contains six-membered aromatic carbocyclic groups, and these aromatic carbocyclic groups are condensed with a five- to seven-membered heterocycle containing one or more heteroatoms selected from N, O, and S, provided that the bonding site is an aromatic carbocyclic group.

[0023] The term "heteroaryl group" refers to a 5-10 membered aromatic monoring, for example, a 5, 6, 7, 8, 9, or 10 membered aromatic monoring, wherein the ring contains 1 to 4 heteroatoms selected from N, O, and S (for example, 1, 2, 3, or 4), and in some examples, 1 to 3 heteroatoms, with the remainder being carbon atoms; and an 8-12 membered bicyclic group, for example, an 8, 9, 10, 11, or 12 membered bicyclic group, wherein the ring contains 1 to 4 heteroatoms selected from N, O, and S ( For example, a group containing 1, 2, 3, or 4 heteroatoms, the remainder being carbon atoms, and at least one of these heteroatoms being in an aromatic ring; and an 11-14 membered tricyclic group, for example, an 11, 12, 13, or 14 membered tricyclic group, wherein the ring contains 1 to 4 heteroatoms selected from N, O, and S (for example, 1, 2, 3, or 4), the remainder being carbon atoms, and at least one of these heteroatoms being in an aromatic ring. 5~20A "heteroaryl group" refers to a heteroaryl group containing 5 to 20 ring atoms, for example, a heteroaryl group containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. Non-exclusive examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinoline, isoquinoline, and tetrazolyl groups (for example, [ka] ), including, but not limited to, triazolyl groups, triazinyl groups, benzofuranyl groups, benzothiophenyl groups, indole groups, isoindole groups, etc.

[0024] As used herein, the terms “halogenated” or “halogen” group are defined to include F, Cl, Br, or I.

[0025] The term "substitution" refers to the selective substitution of one or more hydrogen atoms (e.g., 1, 2, 3, or 4) on a specified atom with a specified group, provided that the substitution does not exceed the normal valence of the atom in its current state and that the substitution forms a stable compound, for example, two hydrogen atoms on a specified carbon atom being substituted with the specified group via a double bond. Substituents and / or variable combinations are permitted only if they form a stable compound.

[0026] If a substituent is described as "optionally substituted with at least one..." or "optionally substituted with one or more...", the substituent may either have (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted with one or more in the substituent list, one or more hydrogens on the carbon (in any amount present) may be substituted individually and / or together with any independently selected substituents. If the nitrogen of a substituent is described as being optionally substituted with one or more in the substituent list, one or more hydrogens on the nitrogen (in any amount present) may each be substituted with any independently selected substituents.

[0027] When a substituent is described as being "independently selected from," each substituent is independently selected from the other substituent. Therefore, each substituent may be identical or different from the other substituent. The groups described herein may be optionally substituted with one or more substituents. Available substituents include, but are not limited to, deuterium, tritium, hydroxyl groups, amino groups, cyano groups, mercapto groups, azide groups, guanidyl groups, ureido groups, halogens, alkyl groups, cycloalkyl groups, heterocyclyl groups, alkoxy groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocyclyl groups as described herein.

[0028] As used herein, the term “at least one” or similar expression “one or more” means one or more under reasonable conditions, for example, two, three, four, five, six, seven, eight, nine, or ten.

[0029] Unless otherwise specified, the linkage points of substituents, as used herein, may originate from any suitable position on the substituent.

[0030] The present invention further includes all pharmaceutically acceptable isotope-labeled compounds that are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but with a different atomic mass or mass number than the atoms that are dominant in nature. Examples of isotopes suitably included in the compounds of the present invention include hydrogen isotopes (e.g., deuterium) 2 H), tritium ( 3 H)) carbon isotopes (for example, 11 C, 13 C and 14 C) Isotopes of chlorine (for example, 36 Cl), fluorine isotopes (e.g., 18 F) Iodine isotopes (for example, 123 I and 125 I) Nitrogen isotopes (for example, 13 N and 15 N), oxygen isotopes (for example, 15 O, 17 O and 18 O), phosphorus isotopes (for example, 32 P), and sulfur isotopes (e.g., 35 Examples include (but are not limited to) S). Compounds of the present invention labeled with several isotopes (e.g., those with radioactive isotopes introduced) can be used in studies (e.g., analysis) of drug and / or substrate tissue distribution. Radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) is particularly useful for this purpose because it can be easily introduced and easily detected. Positron-emitting isotopes (e.g., 11 C, 18 F, 15 O and 13Substitution with N) can be used to investigate substrate receptor occupancy in positron emission tomography (PET) studies. The isotope-labeled compounds of the present invention can be prepared by using a suitable isotope-labeled reagent instead of conventionally used unlabeled reagents, in the same manner as described in the attached route and / or examples and preparations. The pharmaceutically acceptable solvates of the present invention include those in which the crystalline solvent may be isotope-substituted, such as D2O, acetone-d6, or DMSO-d6.

[0031] The term "stereoisomer" refers to an isomer formed by at least one chiral center. Compounds having one or more (e.g., 1, 2, 3, or 4) chiral centers can produce racemic mixtures, single enantiomers, mixtures of non-enantiomers, and single non-enantiomers. Certain individual molecules may exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention may exist in a rapid equilibrium state (generally called tautomers) as mixtures of two or more structurally distinct forms. Representative examples of such tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. For example, nitroso-oximes may exist in equilibrium in solution as the following tautomers: [ka]

[0032] It should be understood that the scope of the present invention encompasses all isomers or mixtures thereof in any such proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0033] The chemical bonds of the compound of this invention are shown by the solid line ( [ka] ), solid wedge shape ( [ka] ), or dashed wedge shape ( [ka] ) can be used to depict the compounds. Using a solid line to depict a bond to a chiral carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are present (e.g., specific enantiomers, racemic mixtures, etc.). Using a solid or dashed wedge to depict a bond to a chiral carbon atom is intended to indicate that the indicated stereoisomers are present. When present in a racemic mixture, solid and dashed wedge shapes are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist in the form of stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), non-enantiomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit one or more isomerization phenomena and consist of mixtures thereof (e.g., racemic mixtures and non-enantiomer pairs).

[0034] It should be understood that some of the compounds of the present invention may exist in a free form for therapeutic purposes, or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, and these can be administered to patients in need, after which the compounds of the present invention or their metabolites or residues can be provided directly or indirectly. Accordingly, when "compounds of the present invention" is used herein, it is intended to include the various derivative forms of the compounds described above.

[0035] The pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. Examples include hexafluorophosphate and meglumine salts.

[0036] The present invention also encompasses compounds of the present invention that contain protecting groups. In any process for producing the compounds of the present invention, protection of the sensitive or reactive groups on the relevant molecules may be necessary and / or desirable, thereby forming chemical protection for the compounds of the present invention. This can be achieved with conventional protecting groups, and the protecting group can be removed in an appropriate subsequent step using methods known in the art.

[0037] A "protecting group" (Pg) refers to a substituent that reacts with other functional groups in a compound to block or protect a specific functional group. For example, an "amino protecting group" refers to a substituent attached to an amino group that blocks or protects an amino functional group on a compound. Suitable amino protecting groups include acetyl, triphenylmethyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), cyclopentyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a class of hydroxyl substituents that can effectively block or protect the function of a hydroxyl group. Suitable protecting groups include acetyl and silyl groups. A "carboxyl protecting group" refers to a class of carboxyl substituents that can effectively block or protect the function of a carboxyl group. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl group, 2-(trimethylsilyl)ethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-(p-toluenesulfonamide)ethyl group, 2-(p-nitrophenylthio)ethyl group, 2-(diphenylphosphine)-ethyl group, and nitroethyl group. For a general description and usage of protecting groups, please refer to TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0038] The term "pharmaceutically acceptable derivative" refers to compounds existing in the form of pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, enantiomers, tautomers, or isotope-labeled compounds or mixtures thereof, or pharmaceutically acceptable excipients. Of these, "pharmaceutically acceptable salts" include, but are not limited to, salts produced from pharmaceutically acceptable non-toxic bases or acids, i.e., inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases may be selected from, for example, aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, and zinc salts. Furthermore, pharmaceutically acceptable inorganic base salts may be selected from ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Solid salts may contain one or more crystalline structures, or they may exist in hydrate form. The pharmaceutically acceptable organic non-toxic base salts may be selected from, for example, primary amine salts, secondary amine salts, and tertiary amine salts, and the substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0039] The term "effective dose" refers to the amount of the compound of interest or a pharmaceutically acceptable derivative thereof that can induce a biological or medical response in a tissue, system, animal, or human that can be observed by a researcher, veterinarian, clinician, or other practitioner.

[0040] "Composition" includes products containing a specific amount of a specific component, and any product formed by directly or indirectly combining these specific amounts of specific components. Pharmaceutical compositions include products containing an active ingredient and an inactive component as a carrier, as well as products produced by the direct or indirect combination, compounding, or aggregation of any two or more components, or products resulting from the decomposition of one or more components, or products resulting from one or more components undergoing other types of reactions or interactions.

[0041] The term "pharmaceutically acceptable" refers to a substance that is compatible with other components in a preparation and does not have unacceptable toxicity to the user.

[0042] The term "individual" refers to an individual suffering from a disease, illness, etc., and includes both mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian species, such as humans, non-human primates such as chimpanzees, other apes and monkeys, farm animals such as cattle, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats, and laboratory animals such as rodents such as rats, mice and guinea pigs. Non-mammalian animals include, but are not limited to, birds and fish. In one embodiment, the mammal is a human.

[0043] The term “treatment” includes alleviating, reducing or improving a disease or symptom, preventing other symptoms, improving or preventing potential metabolic factors of symptoms, and inhibiting a disease or symptom, for example, halting the progression of a disease or symptom, reducing a disease or symptom, promoting remission of a disease or symptom, or ceasing the signs of a disease or symptom, and further encompasses prevention. “Treatment” also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit means the fundamental elimination or improvement of the disease being treated. A therapeutic benefit is achieved by the fundamental elimination or improvement of one or more physiological symptoms associated with a potential disease, and an improvement in the patient's condition is observed despite the patient potentially having a potential disease. A preventive benefit means that a patient takes the composition to prevent the risk of a disease, even though a disease has not yet been diagnosed, or that a patient takes the composition if they develop physiological symptoms of one or more diseases.

[0044] In the present invention, "pharmaceutically acceptable carrier" means a diluent, excipient, medium, or vessel that is administered with a therapeutic agent and is suitable for contact with human and / or other animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio, within the bounds of reasonable medical judgment.

[0045] As used herein, the term “therapeutic range” refers to the range of doses or concentrations of a drug in which the drug can effectively treat a disease without causing unacceptable toxic effects.

[0046] Compound of the present invention In some embodiments, the present invention provides a compound or a pharmaceutically acceptable derivative thereof, wherein the compound has the structure of formula (I), [ka] During the ceremony, X does not exist or is -(CH2) m -and [ka] Selected from, the -CH2- is optionally replaced with an -O- or carbonyl group or at least one R X It is arbitrarily replaced with, Y1 and Y2 are each independently selected from a methylene group, O, S, and NH, and the methylene group and NH are at least one R X It is arbitrarily replaced with, R1 and R3 are independently hydrogen, a hydroxyl group, an amino group, a cyano group, and C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R X It is arbitrarily replaced with, R2 consists of hydrogen, hydroxyl group, amino group, formyl group, acetyl group, and C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, -(C=O)OR 10 and -O(C=O)R 11 Selected from, the formyl group, acetyl group, alkyl group, cycloalkyl group and heterocyclyl group are at least one R X It is arbitrarily replaced with, Each R4 independently consists of hydrogen, deuterium, a hydroxyl group, a halogen, and -OR. 12 and C 1~8 Selected from alkyl groups, Alternatively, R3 and R4, together with the atoms bonded to them, form a 5-12 membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R5 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups and -OR 13 Selected from, R6 consists of a hydroxyl group, a mercapto group, an amino group, an azide group, a halogen, a cyano group, and C 1~12 Alkyl alkyl group, C 2~8 Alkenyl group, -OC 1~12 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 5~10 Heteroaryl group, -(C=O)-R 14 , guanidyl group, ureido group, -(OCH2CH2) n -OH, [ka] Selected from, the alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, guanidyl group and ureido group is at least one R X It is arbitrarily replaced with, Alternatively, R5 and R6, together with the atoms bonded to them, form a 3- to 12-membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R7 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~4 alkyl group, -OC 1~4 Alkyl alkyl group, C 3~8 Cycloalkyl groups and C 3~8 Selected from heterocyclyl groups, the alkyl group, cycloalkyl group and heterocyclyl group have at least one R X It is arbitrarily replaced with, R8 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups and -OR15 Selected from, Alternatively, R4 and R8, together with the atoms bonded to them, form a 5-12 membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R9 consists of hydrogen, deuterium, tritium, hydroxyl group, and C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups and -OR 16 Selected from, R 10 and R 11 Each of them is independent of C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~20 Aryl group, C 1~8 Alkyl-C 6~20 Aryl group, C 5~20 Heteroaryl group and C 1~8 Alkyl-C 5~20 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R X It is arbitrarily replaced with, Each R 12 , R 13 , R 14 , R 15 and R 16 Each of them is independent of C 1~8 Alkyl alkyl group, C 2~8 Alkenyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one RX It is arbitrarily replaced with, R 6’ C is hydrogen, hydroxyl group, amino group, cyano group, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R X It is arbitrarily replaced with, R 6’’ These are hydroxyl groups, mercapto groups, amino groups, halogens, and C 1~12 Alkyl alkyl group, C 2~8 Alkenyl group, -OC 1~12 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group and C 5~10 Selected from heteroaryl groups, the alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R X It is arbitrarily replaced with, Each R X These are independently hydrogen, halogen, hydroxyl group, carboxyl group, amino group, cyano group, formyl group, and C 1~8 alkyl group, -OC 1~8 Alkyl alkyl group, C 2~8 Alkenyl group, C 3~20 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group, C 1~8 Alkyl-C 5~10 heteroaryl group, [ka] Selected from, the amino group, formyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are at least one R Y It is arbitrarily replaced with, Each R Y These are independently hydrogen, halogen, hydroxyl group, amino group, carboxyl group, formyl group, acetyl group, and C 1~8 alkyl group, -OC 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, -OC 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, -OC 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, -OC 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group, -OC 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the formyl group, acetyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one halogen, hydroxyl group, or R Y1 It can be arbitrarily selected, Each R Y1 These are, independently, an amino group, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group and C 5~10Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R Y2 It is arbitrarily replaced with, Each R Y2 These are, independently, an amino group, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group and C 5~10 Selected from heteroaryl groups, If X is a methylene group and R1, R2, and R3 are all hydrogen atoms, then R4, R5, R6, R7, R8, and R9 cannot all be hydroxyl groups at the same time. m is an integer selected from 0 to 6. n is an integer selected from 1 to 12. t is an integer selected from 0 to 4.

[0047] In some embodiments, X is absent or a methylene group, a carbonyl group and [ka] Selected from. In one specific embodiment, X is absent. As those skilled in the art will understand, the absence of X means that R6 is directly bonded to the rest of the molecule. In one specific embodiment, X is a methylene group. In one specific embodiment, X is a carbonyl group. In one embodiment, X is a methylene group, and further R X It is replaced by. In one embodiment, X is a methylene group, and further R X Replaced by the R X is a halogen. In one specific embodiment, X is a methylene group, and further R X Replaced by the R X It is fluorine.

[0048] In some embodiments, Y1 is a methylene group. In some embodiments, Y1 is oxygen (O). In some embodiments, Y1 is sulfur (S). In some embodiments, Y1 is NH (NH).

[0049] In some embodiments, Y2 is a methylene group. In some embodiments, Y2 is oxygen (O). In some embodiments, Y2 is sulfur (S). In some embodiments, Y2 is NH (NH).

[0050] In one specific embodiment, R1 is hydrogen. In one specific embodiment, R1 is a hydroxyl group. In one specific embodiment, R1 is an amino group. In one specific embodiment, R1 is a cyano group.

[0051] In some embodiments, R2 is hydrogen, a hydroxyl group, an amino group, a formyl group, an acetyl group, and -(C=O)OR 10 Selected from: In some embodiments, R2 is hydrogen, an acetyl group, and -(C=O)OR 10 Selected from: In one specific embodiment, R2 is hydrogen. In one specific embodiment, R2 is a hydroxyl group. In one specific embodiment, R2 is an amino group. In one specific embodiment, R2 is a formyl group. In one specific embodiment, R2 is an acetyl group. In one specific embodiment, R2 is -(C=O)OR 10 And R 10 R2 is a benzyl group. In one specific embodiment, R2 is -(C=O)OR 10 And R 10 This is a cyclopentyl group.

[0052] In some embodiments, R3 is hydrogen, a hydroxyl group, an amino group, a cyano group, or C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups and C 1~8 Alkyl-C 6~10Selected from aryl groups, the alkyl group, cycloalkyl group and aryl group have at least one R X It is optionally substituted with. In some embodiments, R3 is hydrogen, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups and C 1~8 Alkyl-C 6~10 Selected from aryl groups, the alkyl group, cycloalkyl group and aryl group have at least one R X It is optionally substituted with. In some embodiments, R3 is hydrogen, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups and C 1~8 Alkyl-C 6~10 Selected from aryl groups, the alkyl group, cycloalkyl group and aryl group have at least one R X It is arbitrarily replaced with R X R3 is selected from hydroxyl groups and carboxyl groups. In one specific embodiment, R3 is hydrogen. In one specific embodiment, R3 is a methyl group. In one specific embodiment, R3 is an ethyl group. In one specific embodiment, R3 is an isopropyl group. In one specific embodiment, R3 is [ka] In one specific embodiment, R3 is [ka] In one specific embodiment, R3 is [ka] In one specific embodiment, R3 is [ka] In one specific embodiment, R3 is [ka] In one specific embodiment, R3 is [ka] In one specific embodiment, R3 is [ka] In one specific embodiment, R3 is a hydroxyl group. In one specific embodiment, R3 is an amino group. In one specific embodiment, R3 is a cyano group.

[0053] In some embodiments, R4 is selected from hydrogen, deuterium, and a hydroxyl group. In one specific embodiment, R4 is hydrogen. In one specific embodiment, R4 is deuterium. In one specific embodiment, R4 is a hydroxyl group.

[0054] In some embodiments, R3 and R4, together with the atoms bonded to them, form a six-membered heteroring. In some embodiments, the heteroring formed by R3 and R4 and the atoms bonded to them is [ka] Selected from. In one specific embodiment, the heterorings formed with R3 and R4 and the atoms bonded to them are [ka] In one specific embodiment, the heterorings formed with R3 and R4 and the atoms bonded to them are [ka] That is the case.

[0055] In one specific embodiment, R5 is a hydroxyl group. In one specific embodiment, R5 is hydrogen. In one specific embodiment, R5 is deuterium.

[0056] In one embodiment, R5 is a halogen. In one specific embodiment, R5 is fluorine.

[0057] In one embodiment, R5 is -OR 13 In one specific embodiment, R5 is a methoxy group. In one specific embodiment, R5 is [ka] That is the case.

[0058] In some embodiments, R6 is a hydroxyl group, a mercapto group, an amino group, an azide group, a halogen, a cyano group, or C 2~8 Alkenyl group, -OC 1~12 Alkyl alkyl group, C 3~8 Heterocyclyl group, C 5~10 Heteroaryl group, guanidyl group, ureido group and [ka] Selected from, the amino group, alkyl group, heterocyclyl group, heteroaryl group, guanidyl group and ureido group are at least one R X It is optionally substituted with a hydroxyl group, a mercapto group, an amino group, an azide group, a halogen, a cyano group, or C 2~8 Alkenyl group, -OC 1~12 Alkyl alkyl group, C 3~8 Heterocyclyl group, C 5~10 Heteroaryl group, guanidyl group, ureido group and [ka] Selected from, the amino group, alkyl group, heterocyclyl group, heteroaryl group, guanidyl group and ureido group are at least one R XIt is arbitrarily replaced with R X C is a hydrogen, halogen, hydroxyl group, carboxyl group, amino group, C 1~8 Alkyl alkyl group, C 1~8 Alkyl-C 6~10 Aryl group, C 3~20 Cycloalkyl groups, C 3~8 Heterocyclyl group and C 5~10 Selected from heteroaryl groups. In some embodiments, R X These are halogens, hydroxyl groups, amino groups, formyl groups, and C 1~8 Alkyl alkyl group, C 3~20 Cycloalkyl groups, C 1~8 Alkyl-C 6~10 Aryl group, C 3~8 Heterocyclyl group and [ka] Selected from, the amino group, formyl group, alkyl group, cycloalkyl group and heterocyclyl group are at least one R Y It is optionally replaced by R. In some other embodiments, Y These include halogens, hydroxyl groups, carboxyl groups, formyl groups, acetyl groups, and C 1~8 Selected from alkyl groups, the formyl group is a hydroxyl group or R Y1 It is optionally replaced by R. In several other embodiments, Y1 is selected from amino groups, and the amino group is R Y2 It is optionally replaced by R. In some embodiments, Y2 C 1~8 Selected from alkyl groups.

[0059] In some embodiments, R6 is [ka] And in the formula, R 6’ R6 is selected from hydrogen and methyl groups. In some embodiments, R6 is [ka] And in the formula, R 6’’ C 1~12 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 6~10 Aryl group and C 5~10 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, aryl group and heteroaryl group have at least one R X It is optionally replaced by R. In some other embodiments, X is halogen, C 1~8 alkyl group, -OC 1~8 Alkyl alkyl group, C 3~20 Cycloalkyl groups and C 6~10 Selected from aryl groups, the alkyl group, cycloalkyl group and aryl group have at least one R Y It is optionally replaced by R. In some embodiments, Y is a halogen, and the halogen is fluorine.

[0060] In some embodiments, R6 is a hydroxyl group, halogen, cyano group, amino group, azide group, methoxy group, methylamino group, tert-butyl group, propenyl group, guanidyl group, ureido group, [ka] [ka] Selected from.

[0061] In some preferred embodiments, R6 is a hydroxyl group, an amino group, a methoxy group, a methylamino group, a guanidyl group, a ureido group, [ka] Selected from.

[0062] In some more preferred embodiments, R6 is a hydroxyl group, an amino group, a methylamino group, a guanidyl group, a ureido group, [ka] Selected from.

[0063] In one specific embodiment, R6 is a hydroxyl group. In some embodiments, R6 is selected from halogens. In some embodiments, R6 is fluorine. In some embodiments, R6 is a cyano group. In some embodiments, R6 is an azide group. In one specific embodiment, R6 is an amino group. In one specific embodiment, R6 is a methoxy group. In one specific embodiment, R6 is a methylamino group. In one specific embodiment, R6 is a tert-butyl group. In one specific embodiment, R6 is a propenyl group. In one specific embodiment, R6 is a guanidyl group. In one specific embodiment, R6 is a ureido group. In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] In one specific embodiment, R6 is [ka] That is the case.

[0064] In some embodiments, R5 and R6, together with the atoms bonded to them, form a 3- to 12-membered heterocycle. In one specific embodiment, the heterocycle formed with R5 and R6 and the atoms bonded to them is ethylene oxide, [ka] Selected from. In one specific embodiment, the heterocycle formed with R5 and R6 and the atoms bonded to them is ethylene oxide. In one specific embodiment, the heterocycle formed with R5 and R6 and the atoms bonded to them is, [ka] In one specific embodiment, the heterorings formed with R5 and R6 and the atoms bonded to them are [ka] In one specific embodiment, the heterorings formed with R5 and R6 and the atoms bonded to them are [ka] In one specific embodiment, the heterorings formed with R5 and R6 and the atoms bonded to them are [ka] In one specific embodiment, the heterorings formed with R5 and R6 and the atoms bonded to them are [ka] That is the case.

[0065] In some embodiments, R7 is hydrogen, a hydroxyl group, C 1~8 Alkyl and -OC 1~8 A alkyl group is arbitrarily selected, and the alkyl group has at least one R X It is substituted with. In one specific embodiment, R7 is hydrogen. In one specific embodiment, R7 is a hydroxyl group. In one specific embodiment, R7 is a methoxy group. In one specific embodiment, R7 is a trifluoromethoxy group. R7 is a difluoromethoxy group. In one specific embodiment, R7 is a methyl group. In one specific embodiment, R7 is a trifluoromethyl group. In one specific embodiment, R7 is a difluoromethyl group.

[0066] In one specific embodiment, R8 is a hydroxyl group.

[0067] In some embodiments, R4 and R8 form a heterocycle together with the atoms bonded to them. [ka] It has the following structure, In the formula, 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 to 3, for example, t' is 0, 1, 2, or 3.

[0068] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable derivative thereof according to the present invention, R4 and R8 together with the atoms bonded thereto form a heterocycle. [ka] It has the following structure, In the formula, X, R1, R2, R3, R5, R6, R7, and R9 are as defined herein for formula (I).

[0069] In some embodiments, R9 is hydrogen, deuterium, a hydroxyl group, and -OR 16 Selected from: In one specific embodiment, R9 is hydrogen. In one specific embodiment, R9 is deuterium. In one specific embodiment, R9 is a hydroxyl group. In one specific embodiment, R9 is a methoxy group. In one specific embodiment, R9 is, [ka] That is the case.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] The present invention includes any combination of the embodiments described above.

[0074] In some embodiments, the compounds of the present invention are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] This includes, but is not limited to, the following:

[0075] In some preferred embodiments, the compound of the present invention is [ka] [ka] [ka] It includes the following structure.

[0076] In some more preferred embodiments, the compounds of the present invention are [ka] [ka] It includes the following structure.

[0077] Pharmaceutical composition, formulation, and therapeutic method of the present invention 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.

[0078] In some embodiments, the pharmaceutical composition may be administered orally, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly, or percutaneously.

[0079] The pharmaceutical compositions of the present invention can act systemically and / or topically. For this purpose, they can be administered via an appropriate route.

[0080] The pharmaceutical composition of the present invention can be administered in an appropriate dosage form for these routes of administration.

[0081] The administration regimen can be adjusted to obtain the optimal desired response. For example, it may be administered as a single bolus dose, as multiple divided doses over time, or proportionally reduced or increased depending on the urgency of the treatment situation. The dose value may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific administration regimen should be adjusted over time based on the individual's needs and the professional judgment of the person administering the pharmaceutical composition or supervised composition.

[0082] The amount of the compound of the present invention administered depends on the individual being treated, the severity of the disease or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.

[0083] In some embodiments, the pharmaceutical composition of the present invention may further comprise one or more other therapeutic agents (e.g., other drugs related to sodium ion channels). In some embodiments, the therapeutic method of the present invention may further comprise administering one or more additional therapeutic agents (e.g., other drugs related to sodium ion channels).

[0084] Method for synthesizing the compound of formula (I) The present invention provides a compound having the structure of formula (II), [ka] In the formula, X and R6 are as defined herein for formula (I), and Pg1 and Pg2 are independently selected from an acetyl group, a triphenylmethyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a cyclopentyloxycarbonyl group, and a 9-fluorenylmethyloxycarbonyl group (Fmoc).

[0085] 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 some 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 group (Cbz). In some embodiments, Pg2 in the compound of formula (II) is a benzyloxycarbonyl group (Cbz).

[0086] In some embodiments, the compound of formula (II) is [ka] That is the case.

[0087] In some embodiments, the compound of formula (II) is [ka] That is the case.

[0088] In some embodiments, the compound of formula (II) is [ka] That is the case.

[0089] In some embodiments, the compound of formula (II) is used as an intermediate for producing the compound of formula (I) or a pharmaceutically acceptable derivative thereof. Therefore, the present invention further relates to a method for producing the compound of formula (I) or a pharmaceutically acceptable derivative thereof, comprising using the compound of formula (II), or to the use of the compound of formula (II) in the production of the compound of formula (I) or a pharmaceutically acceptable derivative thereof.

[0090] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable derivatives can be synthesized by the following route: [ka] In the formula, R represents any suitable group at the corresponding position as used herein.

[0091] In some specific embodiments, the synthesis of a compound of formula (I) or a pharmaceutically acceptable derivative thereof includes the following intermediate synthesis steps. [ka]

[0092] In some other specific embodiments, the synthesis of the compound of formula (I) or a pharmaceutically acceptable derivative thereof includes the following intermediate synthesis steps. [ka]

[0093] In one specific embodiment, the synthesis of a compound of formula (I) or a pharmaceutically acceptable derivative thereof includes the following intermediate synthesis step: [ka]

[0094] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable derivatives can be synthesized by the following route: [ka] In the formula, R represents any suitable group at the corresponding position as used herein.

[0095] In some other embodiments, the compound of formula (I) or its pharmaceutically acceptable derivatives can be synthesized by the following route: [ka] In the formula, R represents any suitable group at the corresponding position as used herein.

[0096] Furthermore, in some embodiments, the compound of formula (I) or its pharmaceutically acceptable derivatives can be synthesized by the following route: [ka] In the formula, R represents any suitable group at the corresponding position as used herein.

[0097] Exemplary Embodiments Embodiment 1: In one embodiment, the present invention provides a compound or a pharmaceutically acceptable derivative thereof, the compound having the structure of formula (I), [ka] During the ceremony, X does not exist or is -(CH2) m -The -CH2- is optionally replaced with -O- or a carbonyl group or at least one R X It is arbitrarily replaced with, Y1 and Y2 are each independently selected from a methylene group, O, S, and NH, and the methylene group and NH are at least one R X It is arbitrarily replaced with, R1 and R3 are independently hydrogen, a hydroxyl group, an amino group, a cyano group, and C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R X It is arbitrarily replaced with, R2 consists of hydrogen, a hydroxyl group, an amino group, and C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, -(C=O)OR 10 and -O(C=O)R 11 Selected from, the alkyl group, cycloalkyl group and heterocyclyl group are at least one R X It is arbitrarily replaced with, Each R4 independently consists of hydrogen, deuterium, a hydroxyl group, a halogen, and -OR. 12 and C 1~8 Selected from alkyl groups, Alternatively, R3 and R4, together with the atoms bonded to them, form a 5-12 membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R5 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups and -OR 13 Selected from, R6 consists of a hydroxyl group, a mercapto group, an amino group, an azide group, a halogen, a cyano group, and C 1~12 Alkyl alkyl group, C 2~8 Alkenyl group, -OC 1~12 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 5~10 Heteroaryl group, -(C=O)-R 14 , guanidyl group, ureido group and -(OCH2CH2) n Selected from -OH, the alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, guanidyl group and ureido group are at least one R X It is arbitrarily replaced with, Alternatively, R5 and R6, together with the atoms bonded to them, form a 3- to 12-membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R7 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~4 alkyl group, -OC 1~4 Alkyl alkyl group, C 3~8 Cycloalkyl groups and C 3~8 Selected from heterocyclyl groups, the alkyl group, cycloalkyl group and heterocyclyl group have at least one R X It is arbitrarily replaced with, R8 is a hydroxyl group, Alternatively, R4 and R8, together with the atoms bonded to them, form a 5-12 membered heteroring, and the heteroring has at least one R X It is arbitrarily replaced with, R9 consists of hydrogen, deuterium, tritium, hydroxyl group, and C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups and -OR 15 Selected from, R 10 and R 11 Each of them is independent of C 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R X It is arbitrarily replaced with, R 12 , R 13 , R 14 and R 15 Each of them is independent of C 1~8 Alkyl alkyl group, C 2~8 Alkenyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R X It is arbitrarily replaced with, Each R X These are independently hydrogen, halogen, hydroxyl group, carboxyl group, amino group, cyano group, formyl group, and C 1~8 Alkyl alkyl group, C 2~8 Alkenyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the amino group, formyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R Y It is arbitrarily replaced with, Each R Y These are independently hydrogen, halogen, hydroxyl group, and C 1~8 alkyl group, -OC 1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, -OC 3~8 Cycloalkyl groups, C 3~8 Heterocyclyl group, -OC 3~8 Heterocyclyl group, C 1~8 Alkyl-C 3~8 Heterocyclyl group, C 6~10Aryl group, -OC 6~10 Aryl group, C 1~8 Alkyl-C 6~10 Aryl group, C 5~10 Heteroaryl group, -OC 5~10 Heteroaryl group and C 1~8 Alkyl-C 5~10 Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally substituted with at least one halogen or hydroxyl group. If X is a methylene group and R1, R2, and R3 are all hydrogen atoms, then R4, R5, R6, R7, R8, and R9 cannot all be hydroxyl groups at the same time. m is an integer selected from 0 to 6. n is an integer selected from 1 to 12. t is an integer selected from 0 to 4.

[0098] Embodiment 2: In one embodiment, in the compound described in Embodiment 1 or a pharmaceutically acceptable derivative thereof, X is selected from a methylene group and a carbonyl group.

[0099] Embodiment 3: In one embodiment, in the compound described in Embodiment 1 or Embodiment 2 or a pharmaceutically acceptable derivative thereof, R1 is hydrogen.

[0100] Embodiment 4: In one embodiment, in a compound or pharmaceutically acceptable derivative thereof described in any one of Embodiments 1 to 3, R2 is hydrogen and -(C=O)OR 10 Selected from.

[0101] Embodiment 5: In one embodiment, in the compound described in Embodiment 4 or a pharmaceutically acceptable derivative thereof, the R 10 This is a benzyl group.

[0102] Embodiment 6: In one embodiment, in a compound or a pharmaceutically acceptable derivative thereof described in any one of Embodiments 1 to 5, R3 is hydrogen, C1~8 Alkyl alkyl group, C 3~8 Cycloalkyl groups, C 1~8 Alkyl-C 3~8 Cycloalkyl groups and C 1~8 Alkyl-C 6~10 Selected from aryl groups, the alkyl group, cycloalkyl group and aryl group have at least one R X It can be arbitrarily replaced with.

[0103] Embodiment 7: In one embodiment, in the compound described in Embodiment 6 or a pharmaceutically acceptable derivative thereof, the R X The group is selected from a hydroxyl group and a carboxyl group.

[0104] Embodiment 8: In one embodiment, in the compound described in Embodiment 6 or a pharmaceutically acceptable derivative thereof, R3 is hydrogen, a methyl group, an ethyl group, an isopropyl group, [ka] Selected from.

[0105] Embodiment 9: In one embodiment, in a compound or a pharmaceutically acceptable derivative thereof described in any one of Embodiments 1 to 8, R4 is selected from hydrogen, deuterium, and a hydroxyl group.

[0106] Embodiment 10: In one embodiment, in the compound described in any one of Embodiments 1 to 9 or a pharmaceutically acceptable derivative thereof, R3 and R4 together with the atoms bonded to them form a six-membered heterocycle.

[0107] Embodiment 11: In one embodiment, in the compound described in Embodiment 10 or a pharmaceutically acceptable derivative thereof, the heterocycle formed with R3 and R4 and the atoms bonded thereto is [ka] Selected from.

[0108] Embodiment 12: In one embodiment, in the compound described in any one of Embodiments 1 to 11 or a pharmaceutically acceptable derivative thereof, R5 is a hydroxyl group.

[0109] Embodiment 13: In one embodiment, in a compound or pharmaceutically acceptable derivative thereof described in any one of Embodiments 1 to 12, the R6 is a hydroxyl group, an amino group, -OC 1~12 Alkyl and C 3~8 Selected from heterocyclyl groups, the amino group, alkyl group and heterocyclyl group are at least one R X It can be arbitrarily replaced by.

[0110] Embodiment 14: In one embodiment, in the compound described in Embodiment 13 or a pharmaceutically acceptable derivative thereof, the R X is a hydroxyl group, -C 1~8 Alkyl alkyl group, C 1~8 Alkyl-C 6~10 Selected from aryl groups.

[0111] Embodiment 15: In one embodiment, in the compound described in Embodiment 13 or a pharmaceutically acceptable derivative thereof, R6 is a hydroxyl group, an amino group, a methoxy group, a methylamino group, [ka] Selected from.

[0112] Embodiment 16: In one embodiment, in the compound described in any one of Embodiments 1 to 15 or a pharmaceutically acceptable derivative thereof, R7 is a hydroxyl group.

[0113] Embodiment 17: In one embodiment, in the compound or a pharmaceutically acceptable derivative thereof described in any one of Embodiments 1 to 16, R8 is a hydroxyl group.

[0114] Embodiment 18: In one embodiment, in a compound or a pharmaceutically acceptable derivative thereof described in any one of Embodiments 1 to 17, R4 and R8 together with the atoms bonded to them form a heterocycle. [ka] It has the following structure, In the formula, X, Y1, Y2, R1, R2, R3, R5, R6, R7, and R9 are as defined in any one of Embodiments 1 to 17, and t' is an integer selected from 0 to 3.

[0115] Embodiment 19: In one embodiment, in a compound or a pharmaceutically acceptable derivative thereof described in any one of Embodiments 1 to 18, R4 and R8 form a heterocycle together with the atoms bonded to them, [ka] It has the following structure, In the formula, X, R1, R2, R3, R5, R6, R7, and R9 are as defined in any one of Embodiments 1 to 18.

[0116] Embodiment 20: In one embodiment, the compound or a pharmaceutically acceptable derivative thereof is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It has the following structure.

[0117] Embodiment 21: In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof described in any one of Embodiments 1 to 20 and one or more pharmaceutically acceptable carriers.

[0118] Embodiment 22: In one embodiment, the present invention provides the use of a compound described in any one of Embodiments 1 to 20 or a pharmaceutically acceptable derivative thereof, or a pharmaceutical composition described in Embodiment 21, in the manufacture of a drug for the treatment or analgesia of a disease or condition related to sodium ion channels.

[0119] Embodiment 23: In one embodiment, the present invention provides a compound having the structure of formula (II), [ka] During the ceremony, X, R6 are as defined in any one of Embodiments 1 to 20, Pg1 and Pg2 are independently selected from an acetyl group, a triphenylmethyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), and a 9-fluorenylmethyloxycarbonyl group (Fmoc).

[0120] Embodiment 24: In one embodiment, the compound described in Embodiment 23 is [ka] It has the following structure.

[0121] Beneficial effects The compound of formula (I) according to the present invention, or its pharmaceutically acceptable derivative, has an excellent blocking effect on sodium ion channels. Furthermore, compared to tetrodotoxin, the compound of formula (I) according to the present invention, or its pharmaceutically acceptable derivative, can be synthesized in large quantities by chemical synthesis, is readily available, has higher analgesic strength and a better therapeutic range, and has greater potential for broader applications. The compound of the present invention, or its pharmaceutically acceptable derivative, further has superior toxicity (e.g., lower toxicity) and selectivity for sodium ion channel subtypes, can avoid action on the sodium ion channel hNav1.5 which can cause cardiac disease, and thereby has better drug safety when having the same or equivalent therapeutic effect.

[0122] Examples Synthetic preparation example Unless otherwise specified, the reagents and solvents used in the synthesis are all supplied by Chinese domestic manufacturers and can be used without further purification.

[0123] Synthesis of intermediates: Synthesis of intermediate Example 1: Synthesis of (Z)-((methylamino)(methylthio)methylene)benzylcarbamate A1 [ka]

[0124] 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. The mixture was cooled to 0°C under a nitrogen atmosphere, and benzyl chloroformate (8.60 g, 50.41 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined and concentrated to obtain the 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] + .

[0125] Synthesis of Intermediate Example 2: Synthesis of (E)-((ethylamino)(methylthio)methylene)benzylcarbamate A2 [ka]

[0126] Step 1: Synthesis of 1-(tert-butyl)-3-ethylthiourea (A2-2) [ka]

[0127] At 0°C, tert-butyl isothiocyanate (2.00 g, 17.36 mmol) was added to a 40 mL DCM solution of ethylamine (0.78 g, 17.30 mmol). After the addition was complete, the mixture was stirred at room temperature for 3 hours, and then concentrated to obtain compound A2-2 (2.50 g, yield: 90%), a white solid, which was used directly in the next reaction. LCMS (m / z): 161.1 [M+1] + .

[0128] Step 2: Synthesis of 1-ethylthiourea (A2-3) [ka]

[0129] Concentrated hydrochloric acid (15 mL) and compound A2-2 (2.50 g, 15.60 mmol) were added to a reaction flask, and the mixture was 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, yield: 100%), a pale yellow oily substance. LCMS (m / z): 105.0 [M+1] + .

[0130] Step 3: Synthesis of methylethylcarbamimidothioate (A2-4) [ka]

[0131] Compound A2-3 (2.50 g, 15.60 mmol, crude product) and methanol (10 mL) were added to a reaction flask. Iodomethane (2 mL, 32.13 mmol) was added dropwise at room temperature, and the reaction was stirred for 16 hours. The reaction mixture was concentrated to obtain the crude product of compound A2-4 (2.50 g, yield: 100%), a pale yellow oily substance. LCMS (m / z): 119.1 [M+1] + .

[0132] Step 4: Synthesis of Compound A2 [ka]

[0133] Crude compound A2-4 (2.50 g, 15.60 mmol), dichloromethane (40 mL), and triethylamine (8.48 g, 83.80 mmol) were added to a reaction flask. The mixture was cooled to 0°C under a nitrogen atmosphere, and benzyl chloroformate (5.30 g, 31.07 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (100 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phase was concentrated to obtain the residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 10%~100%) to obtain compound A2 (2.40 g, 3-step reaction yield: 61%) as a yellow solid. LCMS (m / z): 253.1 [M+1] + .

[0134] Synthesis of intermediates Example 3: Synthesis of (E)-((cyclopropylamino)(methylthio)methylene)benzylcarbamate (A3) [ka]

[0135] The synthesis of compound A3 began with cyclopropylamine as the starting material. The first two steps of the synthesis of compound A3-3 were performed by referring to the synthesis method of compound A2. The third step of the synthesis of compound A3 was performed using a one-pot method.

[0136] Step 3: Synthesis of Compound A3 [ka]

[0137] Compound A3-3 (2.50 g, 21.52 mmol) and tetrahydrofuran (30 mL) were added to a reaction flask. While stirring, iodomethane (3.67 g, 25.86 mmol) and sodium bicarbonate (9.05 g, 107.73 mmol) were added, and the mixture was reacted overnight at room temperature under a nitrogen atmosphere. The reaction mixture was then cooled to 0°C, benzyl chloroformate (4.40 g, 25.79 mmol) was added, and the mixture was reacted 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, yield: 62%) as a white solid. LCMS (m / z): 265.1 [M+1] + .

[0138] Synthesis of intermediates Example 4: Synthesis of (E)-((isopropylamino)(methylthio)methylene)benzylcarbamate (A4) [ka]

[0139] The synthesis of compound A4 uses isopropylamine as a starting material, and the synthesis method is the same as that for compound A3. LCMS (m / z): 267.1 [M+1] + .

[0140] Synthesis of intermediate Example 5: Synthesis of (E)-(((cyclobutylmethyl)amino)(methylthio)methylene)benzylcarbamate (A5) [ka]

[0141] The synthesis of compound A5 uses cyclobutylmethylamine as a starting material, and the synthesis method is the same as that for compound A3. LCMS (m / z): 293.1 [M+1] + .

[0142] Synthesis of intermediates Example 6: Synthesis of (E)-((cyclobutylamino)(methylthio)methylene)benzylcarbamate (A6) [ka]

[0143] Step 1: Synthesis of Compound A6-2 [ka]

[0144] Sodium thiocyanate (1.25 g, 15.42 mmol) and acetonitrile (10 mL) were added to a reaction flask, the temperature was lowered 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, after which cyclobutylamine (1.00 g, 14.06 mol) was added. After the addition was complete, the mixture was stirred at 50°C for 10 hours. The reaction mixture was concentrated to obtain the residue. The residue was subjected to flash column chromatography to obtain compound A6-2 (360 mg, yield: 10%) as a grayish-white solid.

[0145] 1 H NMR (400MHz, DMSO) δ 11.09 (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] + .

[0146] Step 2: Synthesis of 1-cyclobutylthiourea (A6-3) [ka]

[0147] 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 while stirring, and the reaction was carried out at room temperature for 1 hour. 1 M dilute hydrochloric acid was added to the reaction mixture to adjust the pH to approximately 6. The reaction mixture was then concentrated to obtain the crude product of compound A6-3 (250 mg, yield >100%). LCMS (m / z): 131.1 [M+1] + .

[0148] Step 3: Synthesis of methylcyclobutylcarbamimidothioate (A6-4) [ka]

[0149] Compound A6-3 (1.50 g, 8.75 mmol, crude product) and methanol (20 mL) were added to a reaction flask. Iodomethane (1.86 g, 13.10 mmol) was added dropwise at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was concentrated to obtain the crude product of compound A6-4 (2.00 g, yield >100%) as a yellow oily liquid. LCMS (m / z): 145.1 [M+1] + .

[0150] Step 4: Synthesis of Compound A6 [ka]

[0151] Crude compound A6-4 (2.00 g, 8.75 mmol) and dichloromethane (40 mL) were added to a reaction flask, then triethylamine (5.60 g, 55.34 mmol) was added. The mixture was cooled to 0°C under a nitrogen atmosphere, and benzyl chloroformate (3.50 g, 20.52 mmol) was added dropwise. After the addition was complete, 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 the 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.

[0152] 1 H NMR (400MHz, DMSO) δ 10.19-9.03 (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] + .

[0153] Synthesis of intermediate Example 7: Synthesis of (E)-(((cyclopropylmethyl)amino)(methylthio)methylene)benzylcarbamate (A7) [ka]

[0154] Compound A7 is synthesized using cyclopropylmethylamine as the starting material, and the synthesis method is the same as that for compound A6. LCMS (m / z): 279.1 [M+1] + .

[0155] Synthesis of intermediates Example 8: Synthesis of (E)-((benzylamino)(methylthio)methylene)tert-butylcarbamate (A8) [ka]

[0156] Compound A8 was synthesized using benzylamine as a starting material, and the first three steps of the synthesis of compound A8-4 were carried out by referring to the synthesis method of compound A2.

[0157] Step 4: Synthesis of (E)-((benzylamino)(methylthio)methylene)tert-butylcarbamate (A8) [ka]

[0158] Crude compound A8-4 (2.10 g, 11.60 mmol) and dichloromethane (40 mL) were added to a reaction flask. While stirring, 4-dimethylaminopyridine (130 mg, 1.06 mmol) and triethylamine (3.50 g, 34.59 mmol) were added. The temperature was lowered to 0°C, and di-tert-butyl dicarbonate (3.00 g, 13.75 mmol) was slowly added dropwise. After the additions were complete, the mixture was reacted 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] + .

[0159] Synthesis of intermediates Example 9: Synthesis of (E)-(10,10-dimethyl-9,9-diphenyl-8-oxo-2-thia-4-aza-9-dodecane-3-ylidene)benzylcarbamate (A9) [ka]

[0160] Compound A9 was synthesized using 3-aminopropanol as a starting material, and the first three steps of the synthesis of compound A9-4 were carried out by referring to the synthesis method of compound A2.

[0161] Step 4: (3-((tert-butyldiphenylsilyl)oxy)propyl)methylcarbamidine thioate (A9-5) [ka]

[0162] Compound A9-4 (1.6 g, 10.79 mmol) and tetrahydrofuran (20 mL) were added to a reaction flask. Under a nitrogen atmosphere, triethylamine (3.27 g, 32.32 mmol) and tert-butyldiphenylchlorosilane (5.92 g, 21.54 mmol) were added, and the reaction was stirred at room temperature for 16 hours. Then, water (80 mL) was added to quench the reaction, and the mixture was 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] + .

[0163] Step 5: Synthesis of (E)-(10,10-dimethyl-9,9-diphenyl-8-oxo-2-thia-4-aza-9-dodecane-3-ylidene)benzylcarbamate (A9) [ka]

[0164] Compound A9-5 (1.20 g, 3.10 mmol) and dichloromethane (20 mL) were added to a reaction flask, followed by the addition of triethylamine (0.94 g, 9.29 mmol). After cooling to 0°C, benzyl chloroformate (0.64 g, 3.76 mmol) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was quenched with water (20 mL), 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 subjected to 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] + .

[0165] Synthesis of intermediates Example 10: (E)-3-(benzyloxy)carbonyl)imino)(methylthio)methyl)amino)methylpropionic acid (A10) [ka]

[0166] Compound A10 was synthesized using tert-butyl 3-aminopropionate as the starting material, following the synthesis method for compound A2. LCMS (m / z): 311.1 [M+1] + .

[0167] Synthesis of Intermediate 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]dioxane[4,5-e]isobenzofuran-4-carboxylic acid (B1) [ka]

[0168] The starting materials S8 and TTX-42 can be prepared by reference to the method of patent application CN113956266A, all of which are incorporated herein by reference.

[0169] Step 3: Synthesis of (6S,8S)-8a-((E)-2,3-bis((benzyloxy)carbonyl)guanidine)-4-hydroxy-6-methoxy-2,2-dimethyl-9-oxooctahydro-5,8-(epoxymethoxy)[1,3]dioxane[4,5-e]isobenzofuran-4-carboxylic acid (B1) [ka]

[0170] In a reaction flask, TTX-42 (160 mg, 0.25 mmol), acetonitrile (2 mL), 2,2,6,6-tetramethylpiperidine oxide (7 mg, 0.04 mmol), and 7% potassium dihydrogen phosphate aqueous solution (2 mL) were added and heated to 40°C. 7.5% sodium hypochlorite solution (0.1 mL) and sodium chlorite (45.22 mg, 0.50 mmol) were added over approximately 10 minutes. The reaction was then stirred and allowed to continue overnight at 40°C. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate aqueous solution (1 mL) and sodium sulfite aqueous solution (1 mL) were added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (methanol / dichloromethane = 10%) to obtain compound B1 (100 mg, yield: 61%).

[0171] 1 H NMR (400 MHz, CDCl3) δ 11.49 (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 = 1.5 Hz, 1H), 4.56 (dd, J = 8.1, 1.1 Hz, 1H), 3.98 (t, J = 1.5 Hz, 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]+ .

[0172] Synthesis of Intermediate 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]dioxane[4,5-e]isobenzofuran-4-carbaldehyde (B2) [ka]

[0173] Anhydrous dichloromethane (2 mL) was added to a 10 mL reaction flask, substituted with nitrogen three times, oxalyl chloride (30 mg, 0.23 mmol) was added, the temperature was lowered to -78°C, and dimethyl sulfoxide (37 mg, 0.47 mmol) was added dropwise. After the addition was complete, the reaction was stirred for 30 minutes, and TTX-42 (100 mg, 0.16 mmol) / dichloromethane (0.5 mL) solution was added dropwise. After the addition was complete, the reaction was stirred at -78°C for 25 minutes, and triethylamine (79 mg, 0.78 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. The complete reaction of the starting materials was monitored by HPLC. Water (10 mL) was added to the reaction mixture, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (10 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 = 0-60%) to obtain compound B2 (52 mg, yield: 51%) as a white solid.

[0174] 1H NMR (400 MHz, CDCl3) δ 11.85-11.36 (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), 4.86-4.74 (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] + .

[0175] Synthesis of Intermediate 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]dioxane[4,5-e]isobenzofuran-4-methylamine (B3) [ka]

[0176] Step 1: Synthesis of (6S,8S)-8a-((E)-2,3-bis((benzyloxy)carbonyl)guanidine)-4-hydroxy-6-methoxy-2,2-dimethyl-9-oxooctahydro-5,8-(epoxymethoxy)[1,3]dioxane[4,5-e]isobenzofuran-4-carbaldehyde oxime (B2-1) [ka]

[0177] 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. After the addition was complete, the reaction mixture was raised to room temperature and reacted for 48 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried to obtain the residue. Ethyl acetate (30 mL) was added to the residue, and the mixture was filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated and dried to obtain 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.

[0178] 1 H NMR (400 MHz, CDCl3) δ 11.58 (s, 1H), 8.92 (s, 1H), 7.90 (s, 1H), 7.51 (d, J = 8.3 Hz, 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] + .

[0179] Step 2: Synthesis of Compound B3 [ka]

[0180] 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, and the reaction mixture was cooled to -45°C under a nitrogen atmosphere. Then, sodium borohydride (100 mg) was added, and the mixture was stirred until the reaction started (the reaction mixture darkened in color and a large amount of bubbles were generated). The remaining sodium borohydride (187 mg) was then added in portions. After the addition was complete, the reaction was allowed to continue for 30 minutes. The reaction was monitored by HPLC until the starting materials were completely reacted. Acetic acid (2 mL) was added to the reaction mixture, the cooling bath was removed, and the mixture was stirred until the solution turned pale green. Then, dichloromethane (20 mL) was added, and saturated sodium bicarbonate solution was slowly added until the pH reached 8. The mixture was filtered, and the filter cake was slurryed with dichloromethane / methanol (1 / 10, 30 mL x 2) and filtered again. The filtrates were combined and separated, and the aqueous phase was extracted with dichloromethane / methanol (1 / 10, 20 mL x 2). Then, all organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by flash column chromatography (MeOH / DCM = 0-10%) to obtain compound B3 as a white solid (558 mg, yield: 67.4%).

[0181] 1 H NMR (400 MHz, CDCl3) δ 11.53 (s, 1H), 8.92 (s, 1H), 7.43-7.30 (m, 10H), 5.24-5.19 (m, 2H), 5.16 (d, J = 8.9 Hz, 2H), 5.12-5.08 (dd, J = 6.1, 4.1 Hz, 2H), 4.61 (d, J = 1.5 Hz, 1H), 4.42 (s, 1H), 4.33 (d, J = 8.3 Hz, 1H), 3.91 (s, 1H), 3.27 (s, 3H), 3.24 (s, 1H), 2.91 (d, J = 13.5 Hz, 1H), 1.38 (s, 3H), 1.24 (d, J = 8.2 Hz, 6H). LCMS(m / z):641.2[M+1] + .

[0182] Synthesis of the target compound: The target compound was synthesized according to the following synthetic routes 1, 2, 3, or 4.

[0183] Synthesis route 1: [ka] Synthesis route 2: [ka] Synthesis route 3: [ka] Synthesis route 4: [ka] In the formula, R represents any suitable group at the corresponding position as used herein.

[0184] Example 1: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 1) and ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (Compound 2) [ka]

[0185] TTX-39 (850 mg, 1.25 mmol), water (12 mL), and trifluoroacetic acid (12 mL) were added to a reaction flask and heated to 60°C under a nitrogen atmosphere, and the mixture was allowed to react overnight. The complete reaction of the starting materials was monitored by HPLC, and the reaction mixture was concentrated to obtain the residue. The residue was purified by flash column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 1 (368 mg, yield: 65%) and compound 2 (150 mg, yield: 28%) as white solids. Total yield: 93%.

[0186] Compound 1: 1 H NMR (400 MHz, MeOD) δ 7.45-7.33 (m, 5H), 5.69 (t, J = 8.7 Hz, 1H), 5.29 (s, 2H), 4.24 (d, J = 7.9 Hz, 1H), 4.18 (s, 1H), 4.06-3.95 (m, 4H), 2.40 (d, J = 9.4 Hz, 1H). LCMS(m / z):454.1[M+1] + .

[0187] Compound 2: 1 H NMR (400 MHz, MeOD) δ 7.42-7.31 (m, 5H), 5.40 (s, 1H), 5.18 (s, 2H), 4.54 (d, J = 2.0 Hz, 1H), 4.49 (s, 1H), 4.21 (dd, J = 2.8, 1.4 Hz, 1H), 4.05 (s, 1H), 3.97 (d, J = 11.5 Hz, 1H), 3.91 (d, J = 11.5 Hz, 1H), 2.81 (d, J = 2.8 Hz, 1H). LCMS(m / z):436.1[M+1] + .

[0188] Example 2: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (Compound 3) [ka]

[0189] Compound 2 (30 mg, 0.07 mmol), methanol (6 mL), and 10% palladium-carbon (5 mg) were added to a reaction flask, and the mixture was substituted three times with hydrogen. The mixture was then hydrogenated under hydrogen balloon pressure at 25°C and stirred for 3 hours. The complete reaction was monitored by HPLC, the reaction mixture was filtered, the filter cake was washed with methanol (200 mL), and the filtrate was concentrated to obtain compound 3 (8 mg, yield: 38%) as a white solid.

[0190] 1 H NMR (400 MHz, D2O) δ 5.36 (s, 1H), 4.46 (d, J = 2.1 Hz, 1H), 4.42 (s, 1H), 4.19 (s, 1H), 4.01 (s, 1H), 3.81 (d, J = 7.2 Hz, 1H), 3.76 (d, J = 12.2 Hz, 1H), 2.78 (d, J = 2.9 Hz, 1H). LCMS(m / z):302.1[M+1] + .

[0191] Example 3: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(hydroxymethyl)-2-iminooctahydro-5,9-epoxy-7,10aRmethyleneoxy[4,5-d]pyrimidine-4-d-6,9,10,11(10H)-tetraol (compound 4) [ka]

[0192] Step 1: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,Z)-6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxyno[4,5-d]pyrimidine-2(1H)-ylidene-4-d)benzylcarbamate (compound 4-1) [ka]

[0193] 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. While stirring, sodium deuterated cyanoborohydride (73 mg, 1.1 mmol) was added, and the mixture was reacted at 50°C for 8 hours, monitoring by HPLC to ensure that the starting materials were not completely reacted. Sodium deuterated cyanoborohydride (73 mg, 1.1 mmol) was added, and the mixture was continued to react for approximately 48 hours, leaving about 20% of the starting materials. The reaction mixture was concentrated to obtain the residue, which was slurryed with diethyl ether (15 mL). Part of the acetic acid was filtered off, and the filter cake was collected. The mixture was purified by high-performance liquid chromatography (Welch Xtimate C18 × 30 mm × 150 mm, 10 μm, flow rate: 30 mL / min (0.1% NH4OAc, ACN)) to obtain Compound 4-1 (39 mg, yield: 40%).

[0194] 1 H NMR (400 MHz, MeOD) δ 7.45-7.30 (m, 5H), 5.18 (s, 2H), 4.44-3.73 (m, 7H), 2.50 (d, J = 12.4 Hz, 1H). HRMS(ESI+):C 19 H 22 DN3O9([M+H] + Calculated value: 439.15, Measured value: 439.21.

[0195] Step 2: Synthesis of Compound 4 [ka]

[0196] Compound 4 (26 mg, yield: 88%) was synthesized by referring to the method of Example 2.

[0197] 1 H NMR (400 MHz, D2O) δ 4.11 (d, J = 1.3 Hz, 1H), 3.96 (s, 1H), 3.93 (s, 1H), 3.90 -3.87 (m, 2H), 3.74 (d, J = 14.9 Hz, 1H), 3.67 (d, J = 8.7 Hz, 1H), 2.49-2.36 (m, 1H).

[0198] 13 C 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.

[0199] Example 4: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 5) [ka]

[0200] Compound 1 (500 mg, 1.10 mmol), acetonitrile (10 mL), and glacial acetic acid (10 mL) were added to a reaction flask. Sodium borohydride cyanohydride (0.69 g, 11.00 mmol) was added in installments while stirring, and the mixture was reacted at 50°C for 16 hours. Most of the solvent was concentrated, and the residue was separated to obtain compound 5 (135 mg, yield: 28%), a colorless oily substance.

[0201] 1 H NMR (400MHz, MeOD) δ 7.44-7.25 (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] + .

[0202] 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)-tetraol (compound 6) [ka]

[0203] Compound 6 (30 mg, yield: 100%) was synthesized by referring to the method of Example 2.

[0204] 1 H NMR (400MHz, D2O) δ 4.17 (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] + .

[0205] Example 6: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 7) and ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(hydroxymethyl)-3-methyloctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (Compound 8) [ka]

[0206] Step 1: Synthesis of compound S8-A1 [ka]

[0207] 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. The mixture was cooled to 0°C under a nitrogen atmosphere, and silver trifluoromethanesulfonate (1.1 g, 4.31 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated to obtain the residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 10%~25%) to obtain the grayish-white solid compound S8-A1 (0.50 g, yield: 41%). LCMS (m / z): 562.2 [M+1] + .

[0208] Step 2: Synthesis of Compound 7 and Compound 8 [ka]

[0209] Compound 7 (170 mg, yield: 36%) and compound 8 (130 mg, yield: 29%) were synthesized according to the method of Example 1. Total yield: 65%.

[0210] Compound 7: 1 H NMR (400 MHz, MeOD) δ 7.54-7.20 (m, 5H), 5.35-5.11 (m, 3H), 4.19 (t, J = 7.2 Hz, 1H), 4.14 (d, J = 5.5 Hz, 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] + .

[0211] Compound 8: 1 H NMR (400 MHz, MeOD) δ 7.48-7.17 (m, 5H), 5.30 (s, 1H), 5.10 (s, 2H), 4.47 (d, J = 1.9 Hz, 1H), 4.38 (s, 1H), 4.16 (d, J = 1.3 Hz, 1H), 4.00 (s, 1H), 3.96 (d, J = 11.4 Hz, 1H), 3.90 (d, J = 11.4 Hz, 1H), 3.05 (s, 3H), 2.73 (d, J = 3.0 Hz, 1H). LCMS(m / z):450.1[M+1] + .

[0212] 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) [ka]

[0213] Compound 9 (9.0 mg, yield: 90%) was synthesized by referring to the method of Example 2. 1 H NMR (400 MHz, MeOD) δ 5.55-5.05 (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] + .

[0214] Example 8: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 10) [ka]

[0215] Compound 10 (19.5 mg, yield: 12%) was synthesized by referring to the method of Example 4. 1 H NMR(400MHz, MeOD) δ 7.39-7.31 (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] + .

[0216] 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)-tetraol (compound 11) [ka]

[0217] Compound 11 (12.0 mg, yield: 88%) was synthesized by referring to the method of Example 2. 1 H NMR (400 MHz, MeOD) δ 4.12 (s, 1H), 4.04 (s, 2H), 3.99 (d, J = 7.8 Hz, 2H), 3.86-3.80 (m, 1H), 3.78 (d, J = 4.8 Hz, 1H), 3.62-3.50 (m, 1H), 3.09 (d, J = 6.5 Hz, 3H), 2.63 (s, 1H). LCMS(m / z):318.1[M+1] + .

[0218] 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-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 12) [ka]

[0219] Compound 12 (16 mg, yield: 91%) was synthesized by referring to the method of Example 2. 1H NMR (400MHz, MeOD) δ 5.36 (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] + .

[0220] Example 11: ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 13) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-3-ethyl-6,9,11-trihydroxy-9-(hydroxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 14) [ka]

[0221] Step 1: Synthesis of compound S8-A2 [ka]

[0222] Compound S8-A2 was synthesized by referring to the method for compound S8-A1 in Example 6, yielding a grayish-white solid (0.75 g, yield: 48%). LCMS (m / z): 576.3 [M+1] + .

[0223] Step 2: Synthesis of Compound 13 and Compound 14 [ka]

[0224] According to the synthesis method of Example 1, white solid compound 13 (360 mg, yield: 58%) and white solid compound 14 (120 mg, 20%) were obtained. Yield: 78%.

[0225] Compound 13: 1 H NMR (400 MHz, MeOD) δ 7.42-7.21 (m, 5H), 5.35 (d, J = 9.3 Hz, 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 = 9.3 Hz, 1H), 1.10 (t, J = 6.7 Hz, 3H). LCMS(m / z):482.2[M+1] + .

[0226] Compound 14: 1 H NMR (400 MHz, MeOD) δ 7.46-7.14 (m, 5H), 5.37 (s, 1H), 5.12 (d, J = 12.7 Hz, 2H), 4.46 (d, J = 1.9 Hz, 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 = 2.8 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H). LCMS(m / z):464.2[M+1] + .

[0227] Example 12: Synthesis of (4R,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-4,6,9,10,11(10H)-pentanol (compound 15) [ka]

[0228] Compound 15 (16 mg, yield: 77%) was synthesized according to the method of Example 2. LCMS (m / z): 348.2 [M+1] + .

[0229] Example 13: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 16) [ka]

[0230] Compound 16 (24 mg, yield: 12%) was synthesized by referring to the method of Example 4. 1 H NMR (400 MHz, MeOD) δ 7.41-7.23 (m, 5H), 5.10 (s, 2H), 4.14 (s, br, 3H), 4.05-3.79 (m, 4H), 3.77-3.67 (m, 1H), 3.43-3.32 (m, 1H), 3.20-3.05 (m, 1H), 2.47 (dd, J = 12.6, 5.4 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H). LCMS(m / z):466.2[M+1] + .

[0231] 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)-tetraol (compound 17) [ka]

[0232] Compound 17 (12 mg, yield: 72%) was synthesized by referring to the method of Example 2. 1 H NMR (400 MHz, D2O) δ 4.08 (s, 1H), 3.91 (s, 4H), 3.84 (d, J = 8.8 Hz, 2H), 3.47-3.32 (m, 1H), 3.30-3.16 (m, 2H), 2.47 (dd, J = 12.6, 6.3 Hz, 1H), 1.10 (s, 3H). LCMS(m / z):332.1[M+1] + .

[0233] 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-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 18) [ka]

[0234] Compound 18 (13 mg, yield: 99%) was synthesized by referring to the method of Example 2.

[0235] 1H NMR (400 MHz, D2O) δ 5.44 (s, 1H), 4.46 (d, J = 1.9 Hz, 1H), 4.27 (s, 1H), 4.13 (s, 1H), 3.98-3.93 (m, 2H), 3.86 (d, J = 12.1 Hz, 1H), 3.49-3.37 (m, 2H), 2.78 (d, J = 2.9 Hz, 1H), 1.23-1.14 (m, 3H). LCMS(m / z):330.1[M+1] + .

[0236] Example 16: ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 19) and ((4S, Synthesis of 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]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 20) [ka]

[0237] Step 1: Synthesis of compound S8-A6 [ka]

[0238] Compound S8-A6 (380 mg, yield: 66%) was synthesized by referring to the method for compound S8-A1 in Example 6. LCMS (m / z): 602.3 [M+1] + .

[0239] Step 2: Synthesis of Compound 19 and Compound 20

change

[0240] According to the synthesis method of Example 1, white solid compound 19 (160 mg, yield: 50%) and white solid compound 20 (65 mg, yield: 21%) were obtained. Yield: 71%.

[0241] Compound 19: 1 HNMR (400MHz, MeOD) δ 7.49-7.32 (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] + .

[0242] Compound 20: 1 H NMR (400MHz, MeOD) δ 7.43-7.24 (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 = 11.5 Hz, 1H), 3.91 (d, J = 11.5 Hz, 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] + .

[0243] 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) [ka]

[0244] Compound 21 (28 mg, yield: 68%) was synthesized according to the method of Example 2. LCMS (m / z): 374.2 [M+1] + .

[0245] Example 18: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 22) [ka]

[0246] Compound 22 (11 mg, yield: 8%) was synthesized by referring to the method of Example 4.

[0247] 1 H NMR (400MHz, MeOD) δ 7.44-7.22 (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] + .

[0248] 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)-tetraol (compound 23) [ka]

[0249] Compound 23 (7.0 mg, yield: 89%) was synthesized by referring to the method of Example 2.

[0250] 1 H NMR (400MHz, D2O) δ 4.24-4.13 (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), 3.40 (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] + .

[0251] 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-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 24) [ka]

[0252] Compound 24 (45 mg, yield: 100%) was synthesized by referring to the method of Example 2.

[0253] 1 H NMR (400MHz, D2O) δ 5.94 (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 = 10.3 Hz, 4H), 1.89-1.74 (m, 2H). LCMS(m / z):356.1[M+1] + .

[0254] Example 21: ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 25) and ((4S, Synthesis of 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]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 26) [ka]

[0255] Step 1: Synthesis of compound S8-A7 [ka]

[0256] Compound S8-A7 (0.80 g, yield: 49%) was synthesized by referring to the method for compound S8-A1 in Example 6. LCMS (m / z): 602.3 [M+1] + .

[0257] Step 2: Synthesis of Compound 25 and Compound 26 [ka]

[0258] Compound 25 (295 mg, yield: 44%) and compound 26 (280 mg, yield: 43%) were synthesized according to the method of Example 1. Total yield: 87%.

[0259] Compound 25: 1 H NMR (400MHz, MeOD) δ 7.49-7.27 (m, 5H), 5.71-5.62 (m, 1H), 5.26 (d, J = 9.8Hz, 2H), 4.21 (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] + .

[0260] Compound 26: 1H NMR (400 MHz, MeOD) δ 7.47-7.20 (m, 5H), 5.45 (s, 1H), 5.11 (s, 2H), 4.48 (d, J = 2.1 Hz, 1H), 4.39 (s, 1H), 4.18 (dd, J = 3.0, 1.6 Hz, 1H), 4.01 (t, J = 1.8 Hz, 1H), 3.97 (d, J = 11.4 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.43 (dd, J = 14.4, 7.0 Hz, 1H), 3.34 (dd, J = 12.3, 4.8 Hz, 1H), 2.69 (d, J = 2.6 Hz, 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] + .

[0261] 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) [ka]

[0262] Compound 27 (25 mg, yield: 74%) was synthesized by referring to the method of Example 2. 1 H NMR (400 MHz, D2O) δ 5.44 (d, J = 9.6 Hz, 1H), 4.24 (s, 1H), 4.13 (s, 2H), 3.97 (d, J = 12.1 Hz, 2H), 3.92-3.84 (m, 1H), 3.12-2.96 (m, 2H), 2.28 (d, J = 9.5 Hz, 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]+ .

[0263] Example 23: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 28) [ka]

[0264] Compound 28 (14 mg, yield: 12%) was obtained by synthesis following the method of Example 4.

[0265] 1 H NMR (400MHz, MeOD) δ 7.52-7.20 (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] + .

[0266] 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)-tetraol (compound 29) [ka]

[0267] Compound 29 (10 mg, yield: 93%) was synthesized by referring to the method of Example 2.

[0268] 1 H NMR (400 MHz, D2O) δ 4.12-4.02 (m, 2H), 4.00-3.90 (m, 3H), 3.86 (d, J = 6.1 Hz, 2H), 3.44-3.30 (m, 2H), 3.13-3.00 (m, 1H), 2.49 (dd, J = 12.6, 6.2 Hz, 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] + .

[0269] Example 25: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-3-(cyclopropylmethyl)-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 30) [ka]

[0270] Compound 30 (30 mg, yield: 84%) was synthesized by referring to the method of Example 2.

[0271] 1 H NMR(400MHz, D2O) δ 5.52 (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 = 12.1Hz, 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]+ .

[0272] Example 26: ((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-methoxyno[4,5-d]pyrimidine-2-(1H)-ylidene)benzylcarbamate (compound 31) and ((4S, Synthesis of 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]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 32) [ka]

[0273] Step 1: Synthesis of compound S8-A3 [ka]

[0274] Compound S8-A3 was synthesized by referring to the method for compound S8-A1 in Example 6, yielding a white solid compound S8-A3 (0.90 g, yield: 57%). LCMS (m / z): 588.3 [M+1] + .

[0275] Step 2: Synthesis of Compound 31 and Compound 32 [ka]

[0276] Compound 31 (1.35 g, yield: 71%) and compound 32 (200 mg, yield: 11%) were synthesized according to the method of Example 1. Total yield: 88%.

[0277] Compound 31: 1 H NMR (400 MHz, MeOD) δ 7.41-7.27 (m, 5H), 5.43-5.30 (m, 3H), 4.25 (d, J = 1.4 Hz, 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] + .

[0278] Compound 32: LCMS(m / z):476.2[M+1] + .

[0279] 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) [ka]

[0280] Compound 33 (14 mg, yield: 97%) was synthesized by referring to the method of Example 2.

[0281] 1 H NMR (400 MHz, D2O) δ 5.52 (s, 1H), 4.44 (d, J = 2.1 Hz, 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 = 2.7 Hz, 1H), 2.7-2.66 (m, 1H), 0.87 (d, J = 6.6 Hz, 2H), 0.79-0.72 (m, 2H). LCMS(m / z):360.1[M+1]+ .

[0282] Example 28: Synthesis of ((4aR,5R,6S,7S,9S,10S,10aR,11S,E)-3-cyclopropyl6,9,10,11-tetrahydroxy-6-(hydroxymethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 34) [ka]

[0283] Compound 34 (52 mg, yield: 54%) was synthesized by referring to the method of Example 4.

[0284] 1 H NMR (400 MHz, MeOD) δ 7.44-7.23 (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, 5.5 Hz, 1H), 0.88-0.71 (m, 3H), 0.69-0.61 (m, 1H). LCMS(m / z):478.2[M+1] + .

[0285] 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)-tetraol (compound 35) [ka]

[0286] Compound 35 (25 mg, yield: 91%) was synthesized by referring to the method of Example 2.

[0287] 1 H NMR (400 MHz, D2O) δ 4.15 (s, 1H), 4.00 (s, 1H), 3.97 (s, 1H), 3.94 (s, 2H), 3.88 (s, 1H), 3.80 (d, J = 11.9 Hz, 1H), 3.37 (dd, J = 11.5, 6.5 Hz, 1H), 2.73 (s, 1H), 2.54 (dd, J = 12.3, 6.4 Hz, 1H), 0.89 (dd, J = 14.1, 6.5 Hz, 3H), 0.76 (dd, J = 7.4, 4.1 Hz, 1H). LCMS(m / z):344.1[M+1] + .

[0288] Example 30: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-3-cyclopropyl-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 36) [ka]

[0289] Compound 36 (152 mg, yield: 100%) was synthesized by referring to the method of Example 2.

[0290] 1 H NMR (400 MHz, D2O) δ 4.15 (s, 1H), 4.00 (s, 1H), 3.97 (s, 1H), 3.94 (s, 2H), 3.88 (s, 1H), 3.80 (d, J = 11.9 Hz, 1H), 2.73 (s, 1H), 2.54 (dd, J = 12.3, 6.4 Hz, 1H), 0.95-0.85 (m, 3H), 0.76 (dd, J = 7.4, 4.1 Hz, 1H). LCMS(m / z):342.1[M+1] + .

[0291] Example 31: ((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-methyloxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 37) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(hydroxymethyl)-3-isopropyloctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 38) [ka]

[0292] Step 1: Synthesis of compound S8-A4 [ka]

[0293] Compound S8-A4 (0.91 g, yield: 57%) was synthesized by referring to the method for compound S8-A1 in Example 6. LCMS (m / z): 590.3 [M+1] + .

[0294] Step 2: Synthesis of Compound 37 and Compound 38 [ka]

[0295] Compound 37 (330 mg, yield: 46%) and compound 38 (17 mg, yield: 2%) were synthesized according to the method of Example 1. Total yield: 48%.

[0296] Compound 37: 1H NMR (400 MHz, MeOD) δ 7.52-7.28 (m, 5H), 5.79 (s, 1H), 5.30 (s, 2H), 4.59 (d, J = 2.1 Hz, 1H), 4.52 (s, 1H), 4.39-4.31 (m, 1H), 4.30-4.27 (m, 1H), 4.07 (t, J = 1.8 Hz, 1H), 3.98 (d, J = 11.5 Hz, 1H), 3.92 (d, J = 11.5 Hz, 1H), 2.82 (d, J = 2.9 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H), 1.25 (d, J = 6.7 Hz, 3H). LCMS(m / z):496.2[M+1] + .

[0297] Compound 38: LCMS(m / z):478.2[M+1] + .

[0298] 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) [ka]

[0299] Compound 39 (9.8 mg, yield: 90%) was synthesized by referring to the method of Example 2.

[0300] 1H 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, Measured value: 361.35.

[0301] Example 33: Synthesis of ((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]pyrimidine-2-(1H)-ylidene)benzylcarbamate (Compound 40) [ka]

[0302] Compound 40 (17.8 mg, yield: 19%) was synthesized according to the method of Example 4. LCMS (m / z): 480.2 [M+1] + .

[0303] 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)-tetraol (compound 41) [ka]

[0304] Compound 41 (10 mg, yield: 93%) was synthesized by referring to the method of Example 2.

[0305] 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, Measured value: 346.16.

[0306] 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-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 42) [ka]

[0307] Compound 42 (10 mg, yield: 93%) was synthesized by referring to the method of Example 2.

[0308] 1H NMR (400 MHz, D2O) δ 5.74 (s, 1H), 4.54 (d, J = 1.8 Hz, 1H), 4.46 (s, 1H), 4.30 (s, 1H), 4.09 (s, 1H), 4.03-3.96 (m, 1H), 3.93 (d, J = 12.3 Hz, 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), 1.18 (d, J = 6.7 Hz, 3H)。LCMS(m / z):344.1[M+1] + 。

[0309] 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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 43), ((4S,5 aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(hydroxymethyl)-3-(3-hydroxypropyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 44), ((7a R,8S,9S,11S,12S,13R,13aR,13bR,15S,E)-8,9,12,15-tetrahydroxy-12-(hydroxymethyl)octahydro2H,11H-9,13-epoxy-7a,11-methyleneoxy[4',5':4,5]pyrimidino[6,1-b][1,3]oxazine-6(7H)-ylidene)benzylcarbamate (compound 45) and Synthesis of ((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]pyrimidyl[6,1-b][1,3]oxazine-6(7H)-ylidene)benzylcarbamate (compound 46) [ka]

[0310] Step 1: Synthesis of compound S8-A9-a and compound S8-A9-b [ka]

[0311] The compounds were synthesized by referring to the method for compound S8-A1 in Example 6, and a mixture of white solid compounds S8-A9-a and S8-A9-b (0.70 g, 43%) was obtained.

[0312] Compound S8-A9-a: LCMS (m / z): 606.3 [M+H] + .

[0313] Compound S8-A9-b: LCMS (m / z): 844.4 [M+H] + .

[0314] ステップ2: Synthesis of Compound 43, Compound 44, Compound 45 and Compound 46

change

[0315] According to the method of Example 1, 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 as white solids. Yield: 19%.

[0316] Compound 43: 1 H NMR (400 MHz, MeOD) δ 7.38-7.27 (m, 5H), 5.42-5.28 (d, 1H), 5.08 (s, 2H), 4.57 (s, br, 1H), 4.15 (d, J = 8.4 Hz, 2H), 4.04-3.91 (m, 3H), 3.75-3.69 (m, 2H), 3.59-3.53 (m, 2H), 2.68 (d, J = 4.8 Hz, 1H), 2.36 (d, J = 9.6 Hz, 1H), 1.84-1.75 (m, 2H). LCMS(m / z):512.2[M+H] + .

[0317] Compound 44: 1H NMR (400 MHz, MeOD) δ 7.32-7.13 (m, 5H), 5.27 (s, 1H), 5.00 (s, 2H), 4.47 (s, 1H), 4.39 (d, J = 2.0 Hz, 1H), 4.31 (s, 1H), 4.09 (s, 1H), 3.92 (s, 1H), 3.84 (dd, J = 27.0, 11.5 Hz, 2H), 3.67-3.58 (m, 1H), 3.52-3.44 (m, 2H), 3.44-3.33 (m, 1H), 2.61 (d, J = 2.8 Hz, 1H), 1.72-1.61 (m, 2H). LCMS(m / z): 494.2 [M+H] + .

[0318] Compound 45: 1 H NMR (400MHz, MeOD) δ 7.43-7.23 (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] + .

[0319] Compound 46: 1H NMR (400 MHz, MeOD) δ 7.46-7.19 (m, 5H), 5.16 (d, J = 9.5 Hz, 1H), 5.09 (s, 2H), 4.77 (d, J = 14.0 Hz, 1H), 4.56 (s, 1H), 4.46-4.24 (m, 1H), 4.17-3.95 (m, 4H), 3.90 (d, J = 9.2 Hz, 1H), 3.70 (d, J = 11.6 Hz, 1H), 2.85 (t, J = 13.1 Hz, 1H), 2.45 (d, J = 9.4 Hz, 1H), 1.86 (q, J = 12.6 Hz, 1H), 1.58 (d, J = 13.3 Hz, 1H). LCMS(m / z):494.2[M+H] + .

[0320] 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]pyrimidino[6,1-b][1,3]oxazine-8,9,12,15(8H)-tetraol (compound 47) [ka]

[0321] Compound 47 (11 mg, yield: 100%) was synthesized by referring to the method of Example 2.

[0322] 1H NMR (400MHz, D2O) δ 5.01 (d, J = 20.2Hz, 1H), 4.25 (dd, J = 26.7, 13.3Hz, 1H), 4.09 (dd, J = 5.4, 1.6 Hz, 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 = 14.2 Hz, 1H). LCMS(m / z):360.1[M+1] + .

[0323] 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]pyrimidino[6,1-b][1,3]oxazine-8,9,12,15(8H)-tetraol (compound 48) [ka]

[0324] Compound 48 (11 mg, yield: 100%) was synthesized by referring to the method of Example 2.

[0325] 1 H NMR (400 MHz, D2O) δ 5.11 (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 = 11.9 Hz, 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] + .

[0326] 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]pyrimidine-3(4H)-yl)propionic acid (compound 49) and ((7aR,8S Synthesis of 9S,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]pyrimidyl[6,1-b][1,3]oxazine-6(7H)-ylidene)benzylcarbamate (compound 50) [ka]

[0327] Step 1: Synthesis of compound S8-A10 [ka]

[0328] Compound S8-A10 (300 mg, yield: 29%) was synthesized by referring to the method for compound S8-A1 in Example 6. LCMS (m / z): 634.3 [M+1] + .

[0329] Step 2: Synthesis of Compound 49 and Compound 50 [ka]

[0330] Compounds 49 (25.3 mg, yield: 10%) and 50 (65 mg, yield: 27%) were synthesized by referring to the method of Example 1, and were obtained as white solids.

[0331] Compound 49: 1H NMR (400 MHz, MeOD) δ 7.43-7.25 (m, 5H), 5.38 (t, J = 9.1 Hz, 1H), 5.18 (t, J = 9.5 Hz, 2H), 4.40-4.10 (m, 2H), 4.06-3.95 (m, 2H), 3.95-3.65 (m, 4H), 2.76-2.67 (m, 1H), 2.65-2.55 (m, 1H), 2.41 (d, J = 9.5 Hz, 1H). LCMS(m / z):526.2[M+1] + .

[0332] Compound 50: 1 H NMR (400 MHz, MeOD) δ 7.43-7.23 (m, 5H), 5.47 (s, 1H), 5.12 (s, 2H), 4.46 (d, J = 2.1 Hz, 1H), 4.37 (s, 1H), 4.17 (dd, J = 2.9, 1.5 Hz, 1H), 4.00 (t, J = 1.7 Hz, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.85-3.76 (m, 1H), 3.71-3.61 (m, 1H), 2.68 (d, J = 2.9 Hz, 1H), 2.62 (dd, J = 15.4, 7.7 Hz, 1H), 2.56-2.46 (m, 1H). LCMS(m / z):508.2[M+1] + .

[0333] 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]pyrimidyl[6,1-b][1,3]oxazin-2-one (compound 51) [ka]

[0334] Compound 51 (15 mg, yield: 67%) was synthesized by referring to the method of Example 2.

[0335] 1 H NMR (400 MHz, D2O) δ 5.50 (s, 1H), 4.52 (d, J = 2.1 Hz, 1H), 4.45 (s, 1H), 4.27 (s, 1H), 4.08 (s, 1H), 3.91 (d, J = 12.2 Hz, 1H), 3.84 (d, J = 12.2 Hz, 1H), 3.71-3.55 (m, 2H), 2.87 (d, J = 2.9 Hz, 1H), 2.51-2.42 (m, 2H). LCMS(m / z):374.1[M+1] + .

[0336] Example 41: ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 52) and ((4S, Synthesis of 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]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 53) [ka]

[0337] Step 1: Synthesis of compound S8-A5 [ka]

[0338] Compound S8-A5 (923 mg, yield: 55.7%) was synthesized by referring to the method for compound S8-A1 in Example 6. LCMS (m / z): 616.3 [M+1] + .

[0339] Step 2: Synthesis of Compound 52 and Compound 53 [ka]

[0340] Compound 52 (300 mg, yield: 39%) and compound 53 (90 mg, yield: 12%) were synthesized according to the method of Example 1. Total yield: 51%.

[0341] Compound 52: 1 H NMR (400 MHz, MeOD) δ 7.51-7.29 (m, 5H), 5.47 (dd, J = 17.2, 9.7 Hz, 1H), 5.28 (d, J = 10.0 Hz, 2H), 4.51-4.31 (m, 1H), 4.20 (d, J = 1.5 Hz, 1H), 4.16 (s, 1H), 4.06-3.95 (m, 3H), 3.91-3.72 (m, 1H), 3.66-3.56 (m, 1H), 2.74 (dd, J = 14.8, 7.3 Hz, 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] + .

[0342] Compound 53: 1H NMR (400 MHz, MeOD) δ 7.47-7.25 (m, 5H), 5.35 (s, 1H), 5.14 (s, 2H), 4.48 (d, J = 2.1 Hz, 1H), 4.39 (s, 1H), 4.18 (dd, J = 3.0, 1.5 Hz, 1H), 4.02 (t, J = 1.8 Hz, 1H), 3.95 (dd, J = 27.9, 11.4 Hz, 2H), 3.60 (dd, J = 14.0, 7.5 Hz, 1H), 3.48 (dd, J = 14.0, 7.3 Hz, 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] + .

[0343] Example 42: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-3-(cyclobutylmethyl)-9-(hydroxymethyl)-2-iminooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 54) [ka]

[0344] Compound 54 (9 mg, yield: 55.8%) was synthesized by referring to the method of Example 2, and was obtained as a nearly white solid.

[0345] 1 H NMR (400 MHz, D2O) δ 5.41 (s, 1H), 4.44 (s, 1H), 4.26 (s, 1H), 4.11 (s, 1H), 4.01-3.77 (m, 3H), 3.41 (d, J = 6.0 Hz, 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] + .

[0346] 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) [ka]

[0347] Compound 55 (35 mg, yield: 47.1%) was synthesized by referring to the method of Example 2, and was obtained as a nearly white solid.

[0348] 1 H NMR (400 MHz, D2O) δ 5.44 (d, J = 8.6 Hz, 1H), 4.35-3.70 (m, 6H), 3.18 (d, J = 5.5 Hz, 2H), 2.49 (d, J = 6.6 Hz, 1H), 2.31 (dd, J = 29.5, 9.2 Hz, 1H), 1.99 (s, 2H), 1.86-1.56 (m, 4H). LCMS(m / z):388.2[M+1] + .

[0349] Example 44: Synthesis of (4aR,5R,6S,7S,9S,10S,10aR,11S)-3-(cyclobutylmethyl)-6-(hydroxymethyl)-2-iminooctanehydro-5,9-epoxy-7,10-methyleneoxy[4,5-d]pyrimidine-6,9,10,11(10H)-tetraol (compound 56) [ka]

[0350] Step 1: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 56-1) [ka]

[0351] Compound 56-1 (50 mg, yield: 51.1%) was synthesized according to the method of Example 4. LCMS (m / z): 506.2 [M+1] + .

[0352] Step 2: Synthesis of Compound 56 [ka]

[0353] Compound 56 (18 mg, yield: 76.6%) was synthesized by referring to the method of Example 2, and was obtained as a nearly white solid.

[0354] 1 H NMR (400 MHz, D2O) δ 4.20-3.70 (m, 6H), 3.55-3.41 (m, 1H), 3.28-3.08 (m, 2H), 2.56 (d, J = 66.2 Hz, 3H), 2.09-1.59 (m, 6H). LCMS(m / z):372.2[M+1] + .

[0355] Example 45: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-3-benzyl-6-(hydroxymethyl)-2-iminooctanehydro-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-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 58) [ka]

[0356] Step 1: Synthesis of compound S8-A8 [ka]

[0357] Compound S8-A8 (0.84 g, yield: 61%) was obtained by synthesizing the compound S8-A8 in reference to the method for compound S8-A1 in Example 6. LCMS (m / z): 604.3 [M+1] + .

[0358] Step 2: Synthesis of Compound 57 and Compound 58 [ka]

[0359] Compounds 57 (13 mg, yield: 2%) and 58 (79 mg, yield: 15%) were synthesized according to the method of Example 1. Total yield: 15%.

[0360] Compound 57: LCMS(m / z):410.2[M+1] + .

[0361] compound 58 1 H NMR (400 MHz, MeOD) δ 7.48-7.29 (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, 11.5 Hz, 2H), 2.77 (d, J = 2.6 Hz, 1H).

[0362] LCMS(m / z):392.1[M+1] + .

[0363] Example 46: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 59) and ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(methoxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 60) [ka]

[0364] Step 1: Synthesis of Compound 59-1 [ka]

[0365] TTX-42 (250 mg, 0.39 mmol) and anhydrous dichloromethane (8 mL) were added to a 50 mL necked flask. The mixture was cooled to approximately 0°C under a nitrogen atmosphere, and 1,8-bismethylaminonaphthalene (251 mg, 1.17 mmol) was added, followed by trimethyloxonium tetrafluoroborate (115 mg, 0.78 mmol). After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred overnight. HPLC was used to detect that most of the starting materials had reacted completely. Saturated sodium bicarbonate solution (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed twice with 0.25 M dilute hydrochloric acid (10 mL x 2), washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by prep-TLC (eluent: petroleum ether / ethyl acetate = 3:1) to obtain compound 59-1 (167 mg, yield: 65.3%), a pale yellow oily substance.

[0366] 1 H NMR (400 MHz, CDCl3) δ 11.60 (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 = 9.8 Hz, 1H), 3.75 (s, 1H), 3.68 (d, J = 10.0 Hz, 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] + .

[0367] Step 2: Synthesis of Compound 59 and Compound 60 [ka]

[0368] The compounds were synthesized according to the method of Example 1, yielding 59 (38.4 mg, yield: 33%) and 60 (23.7 mg, yield: 21%) as white solids. Total yield: 54%.

[0369] Compound 59: 1 H NMR (400 MHz, MeOD) δ 7.43-7.21 (m, 5H), 5.54 (d, J = 9.4 Hz, 1H), 5.05 (s, 2H), 4.51-3.66 (m, 6H), 3.44 (s, 3H), 2.22 (d, J = 9.4 Hz, 1H). LCMS(m / z):468.2[M+1] + .

[0370] Compound 60: 1 H NMR (400 MHz, MeOD) δ 7.40-7.20 (m, 5H), 5.27 (s, 1H), 5.07 (s, 2H), 4.47 (d, J = 1.9 Hz, 1H), 4.42 (s, 1H), 4.17 (s, 1H), 4.01 (s, 1H), 3.84 (d, J = 9.7 Hz, 1H), 3.75 (d, J = 9.7 Hz, 1H), 3.44 (s, 3H), 2.68 (d, J = 2.8 Hz, 1H). LCMS(m / z):450.1[M+1] + .

[0371] 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) [ka]

[0372] The compound was synthesized according to the method of Example 2. After complete reaction, the reaction mixture was filtered, the filtration cake was collected, and deionized water (30 mL) and 2.5% aqueous acetic acid solution (5 mL) were added. The mixture was stirred at room temperature for 1 hour and filtered. This procedure was repeated once more. All filtrates were combined and concentrated to obtain the crude product. Two drops of methanol were added to the crude product to dissolve all the products, then methyl tert-butyl ether (10 mL) was added, the mixture was stirred for 30 minutes, allowed to stand, and the supernatant was aspirated. Then, methyl tert-butyl ether (10 mL) was added again, the mixture was stirred for 30 minutes, allowed to stand, and the supernatant was aspirated. The residue was concentrated to obtain the acetate of compound 61 (12.5 mg, yield: 98%), which was a nearly white solid.

[0373] 1 H NMR (400 MHz, CD3OD+D2O+CD3COOD) δ 5.40 (d, J = 9.2 Hz, 1H), 4.32-3.98 (m, 2H), 3.88-3.47 (m, 4H), 3.32 (s, 3H), 2.12 (d, J = 9.3 Hz, 1H), 1.86 (s, 3H). LCMS(m / z):334.1[M+1] + .

[0374] Example 48: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-2-imino-9-(methoxymethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-6,9,11(5aH)-triol (compound 62) [ka]

[0375] The compound 62 acetate (12 mg, yield: 96%) was synthesized by referring to the method of Example 47, and was a nearly white solid.

[0376] 1H NMR (400 MHz, D2O+CD3COOD) δ 5.45 (s, 1H), 4.54 (d, J = 2.2 Hz, 1H), 4.50 (s, 1H), 4.28 (dd, J = 2.9, 1.6 Hz, 1H), 4.10 (t, J = 1.8 Hz, 1H), 3.84 (d, J = 10.8 Hz, 1H), 3.75 (d, J = 10.8 Hz, 1H), 3.39 (s, 3H), 2.87 (d, J = 2.8 Hz, 1H), 1.95 (s, 3H). LCMS(m / z):316.1[M+1] + .

[0377] Example 49: 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]pyrimidine-2(1H)-ylidene)carbamate (compound 63) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-9-((benzylamino)methyl)-6,9,11-trihydroxyoctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 64) [ka]

[0378] Step 1: Synthesis of Compound 63-1 [ka]

[0379] In a reaction flask, B2 (490 mg, 0.77 mmol, crude product), 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. While stirring, sodium triacetylborohydride (1.83 g, 8.66 mmol) was added, and the mixture was heated to 55°C under a nitrogen atmosphere and reacted for 3 hours. The complete reaction of the starting materials was monitored by HPLC. After cooling the reaction mixture to room temperature, water (40 mL) was added to the reaction mixture, causing a large amount of pale yellow solid to precipitate. The mixture was then stirred for 30 minutes, filtered, and 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 the residue (440 mg). The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 2:1, then changed to dichloromethane / methanol = 40:1 to 10:1) to obtain a crude product (220 mg). The purity was detected by HPLC to be approximately 70%, and further prep-TLC (developing solvent: dichloromethane / methanol = 25:1) yielded compound 63-1 (120 mg, yield: 21.3%) as a pale yellow foamy solid.

[0380] 1 H NMR (400 MHz, CDCl3) δ 11.59 (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 = 2.1 Hz, 1H), 4.61-4.56 (m, 2H), 4.32 (d, J = 8.2 Hz, 1H), 3.94-3.85 (m, 3H), 3.26 (s, 3H), 3.18 (d, J = 12.6 Hz, 1H), 2.94 (d, J = 12.6 Hz, 1H), 1.37 (s, 3H), 1.22 (s, 3H). LCMS(m / z):731.3[M+1] + .

[0381] Step 2: Synthesis of Compound 63 and Compound 64 [ka]

[0382] Compound 63 (7.1 mg, yield: 8.3%) and compound 64 (1.8 mg, yield: 2.2%) were synthesized according to the method of Example 1. Total yield: 10.5%.

[0383] Compound 63: 1 H NMR (400 MHz, MeOD) δ 7.41-7.22 (m, 10H), 5.53 (d, J = 9.5 Hz, 1H), 5.05 (d, J = 3.6 Hz, 2H), 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] + .

[0384] Compound 64: 1 H NMR (400 MHz, MeOD) δ 7.41-7.21 (m, 10H), 5.27 (s, 1H), 5.07 (s, 2H), 4.46 (d, J = 2.1 Hz, 1H), 4.42 (s, 1H), 4.15 (dd, J = 3.0, 1.6 Hz, 1H), 4.03 (d, J = 1.7 Hz, 1H), 3.86 (s, 2H), 3.11 (q, J = 12.7 Hz, 2H), 2.69 (d, J = 2.9 Hz, 1H). LCMS(m / z):525.2[M+1] + .

[0385] Example 50: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-hydroxyazacyclobutan-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 65) and ((4S,5 Synthesis of aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3-hydroxyazacyclobutan-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 174) [ka]

[0386] Step 1: Synthesis of Compound 65-1 [ka]

[0387] Compound 65-1 was synthesized referring to the method for compound 63-1 in Example 49. After the reaction was complete, the reaction mixture was cooled to room temperature, then added to water (30 mL) to precipitate a white solid. The mixture 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] + .

[0388] Step 2: Synthesis of Compound 65 and Compound 174 [ka]

[0389] Compounds 65 (58.8 mg, yield: 21.2%) and 174 (11.9 mg, yield: 4.5%) were synthesized according to the method of Example 1. The total yield was 25.7%.

[0390] Compound 65: 1 H NMR (400 MHz, MeOD) δ 7.49-7.31 (m, 5H), 5.76-5.63 (m, 1H), 5.29 (s, 2H), 4.68 (s, 1H), 4.54 (s, 2H), 4.24 (s, 1H), 4.16 (s, 2H), 4.09 (s, br, 1H), 4.03-3.90 (m, 3H), 3.85 (d, J = 13.2 Hz, 1H), 2.37 (d, J = 9.1 Hz, 1H). LCMS(m / z):509.2[M+1] + .

[0391] Compound 174: 1 H NMR (400 MHz, MeOD) δ 7.39-7.19 (m, 5H), 5.26 (s, 1H), 5.07 (s, 2H), 4.45 (d, J = 2.1 Hz, 1H), 4.41 (s, 1H), 4.36 (t, J = 6.2 Hz, 1H), 4.08 (dd, J = 2.9, 1.5 Hz, 1H), 3.94 (s, 1H), 3.78-3.70 (m, 2H), 3.09 (d, J = 6.0 Hz, 2H), 3.06 (d, J = 4.3 Hz, 1H), 2.97 (d, J = 13.3 Hz, 1H), 2.67 (d, J = 3.0 Hz, 1H). LCMS(m / z): 491.2 [M+1] + .

[0392] Example 51: (4R, 4aR, 5R, 6S, 7S, 9S, 10S, 10aR, 11 S)-6-((3-ヒドロキシアザシクロブタン-1-イル)メチル)-2-イミノオクタン-5,9-エポキシ-7,10a-メチレンオキシ[4,5-d]ピSynthesis of リミジン-4,6,9,10,11(10H)-ペンタノール(Compound 66)

change

[0393] Compound 66 (17 mg, yield: 68%) was synthesized by referring to the method of Example 2.

[0394] 1 H NMR (400 MHz, D2O) δ 5.40 (d, J = 9.5 Hz, 1H), 4.66 (s, 1H), 4.55-4.44 (m, 2H), 4.23 (d, J = 11.2 Hz, 1H), 4.17-3.90 (m, 5H), 3.88-3.67 (m, 2H), 2.27 (d, J = 9.4 Hz, 1H). LCMS(m / z):375.1[M+1] + .

[0395] 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-(epimethanetriyl)-6,10-epoxyoxo[4,3-f][1,3,5]oxydiazepine-9-carboxylic acid (compound 68) [ka]

[0396] Compound 67 (14.7 mg, yield: 21%) and compound 68 (25.0 mg, yield: 37%) were synthesized according to the method of Example 1. Total yield: 58%.

[0397] Compound 67: 1H NMR (400MHz, MeOD) δ 7.50-7.22 (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] + .

[0398] Compound 68: 1 H NMR (400MHz, MeOD) δ 7.46-7.20 (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] + .

[0399] 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) [ka]

[0400] Compound 69 (8.1 mg, yield: 77%) was synthesized by referring to the method of Example 2.

[0401] 1 H NMR (400MHz, D2O) δ 5.44 (d, J = 9.5Hz, 1H), 4.44 (d, J = 66.7Hz, 2H), 4.02 (dd, J = 61.4, 49.6 Hz, 2H), 2.22 (d, J = 9.0Hz, 1H). LCMS(m / z):334.1[M+1] + .

[0402] Example 54: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-iminodecahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-9-carboxylic acid (Compound 70) [ka]

[0403] The compound 70 (12.0 mg, yield: 69%) was synthesized according to the method of Example 2, and a white solid compound was obtained.

[0404] 1 H NMR (400MHz, D2O) δ 5.45 (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] + .

[0405] 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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 71) and ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-9-carbamoyl-6,9,11-trihydroxyoctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 72) [ka]

[0406] Step 1: Synthesis of Compound 71-1 [ka]

[0407] 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'-tetramethylurea hexafluorophosphate (143 mg, 0.38 mmol) were added while stirring. After the addition was complete, the mixture was stirred at room temperature for 16 hours, and the complete reaction of the starting materials was monitored by HPLC. Water (20 mL) was added to the reaction mixture, and it 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 the oily liquid compound 71-1 (195 mg, yield: 96%). LCMS(m / z):655.2[M+1] + .

[0408] Step 2: Synthesis of Compound 71 and Compound 72 [ka]

[0409] Compound 71 (12 mg, yield: 9%) and compound 72 (16 mg, yield: 12%) were synthesized according to the method of Example 1. Total yield: 21%.

[0410] Compound 71: 1 H NMR (400 MHz, MeOD) δ 7.43-7.22 (m, 5H), 5.57 (d, J = 9.5 Hz, 1H), 5.07 (s, 2H), 4.34 (d, J =28.3 Hz, 1H), 4.16 (d, J = 35.0 Hz, 3H), 2.29 (d, J = 9.3 Hz, 1H). LCMS(m / z):467.1[M+1] + .

[0411] Compound 72: 1 H NMR (400 MHz, MeOD) δ 7.43-7.21 (m, 5H), 5.31 (s, 1H), 5.07 (s, 2H), 4.53-4.45 (m, 2H), 4.31 (dd, J = 3.0, 1.6 Hz, 1H), 4.17 (s, 1H), 2.77 (d, J = 3.0 Hz, 1H). LCMS(m / z):449.1[M+1] + .

[0412] 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-formamide (compound 73) [ka]

[0413] Compound 73 (4 mg, yield: 60%) was synthesized by referring to the method of Example 2.

[0414] 1 H NMR (400 MHz, D2O) δ 5.44 (d, J = 9.4 Hz, 1H), 4.51 (s, 1H), 4.32 (s, 1H), 4.24 (s, 1H), 3.92 (s, 1H), 2.30 (d, J = 9.4 Hz, 1H). LCMS(m / z):333.1[M+1] + .

[0415] Example 57: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-iminodecahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-9-formamide (compound 74) [ka]

[0416] Compound 74 (5 mg, yield: 80%) was synthesized by referring to the method of Example 2.

[0417] 1 H NMR (400 MHz, D2O) δ 5.40 (s, 1H), 4.50 (d, J = 2.2 Hz, 1H), 4.48 (s, 1H), 4.45 (dd, J = 3.1, 1.8 Hz, 1H), 4.34 (t, J = 1.9 Hz, 1H), 2.87 (d, J = 3.0 Hz, 1H).

[0418] Example 58: ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 75) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(methylcarbamoyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 76) [ka]

[0419] Step 1: Synthesis of Compound 75-1 [ka]

[0420] Referring to the synthesis method for compound 71-1 in Example 55, compound 75-1 (200 mg, yield: 96%) was obtained as an oily liquid. LCMS (m / z): 669.2 [M+1] + .

[0421] Step 2: Synthesis of Compound 75 and Compound 76 [ka]

[0422] Compound 75 (33 mg, yield: 23%) and compound 76 (21 mg, yield: 15%) were synthesized according to the method of Example 1. Total yield: 38%.

[0423] Compound 75: 1 H NMR (400 MHz, MeOD) δ 7.41-7.27 (m, 5H), 5.58 (d, J = 9.4 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):481.2[M+1] + .

[0424] Compound 76: 1 H NMR (400 MHz, MeOD) δ 7.41-7.23 (m, 5H), 5.30 (s, 1H), 5.07 (s, 2H), 4.52-4.46 (m, 2H), 4.31 (dd, J = 3.0, 1.5 Hz, 1H), 4.17 (s, 1H), 2.87 (s, 3H), 2.77 (d, J = 2.9 Hz, 1H). LCMS(m / z):463.1[M+1] + .

[0425] 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-formamide (Compound 77) [ka]

[0426] Compound 77 (15 mg, yield: 72%) was synthesized by referring to the method of Example 2.

[0427] 1 H NMR (400 MHz, D2O) δ 5.62 (d, J = 9.5 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):347.1[M+1] + .

[0428] Example 60: Synthesis of (4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-imino-N-methyldecahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]diaza-9-formamide (compound 78) [ka]

[0429] Compound 78 (10 mg, yield: 61%) was synthesized by referring to the method of Example 2.

[0430] 1 H NMR (400 MHz, D2O) δ 5.59 (s, 1H), 4.70 (d, J = 2.2 Hz, 1H), 4.64 (s, 1H), 4.58 (dd, J = 3.0, 1.7 Hz,1H), 4.47 (s, 1H), 3.05 (d, J = 3.0 Hz, 1H), 2.93 (s, 3H). LCMS(m / z):329.1[M+1] + .

[0431] Example 61: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-6-(dimethylcarbamoyl)-4,6,9,10,11-pentahydroxyoctahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 79) and ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-9-(dimethylcarbamoyl)-6,9,11-trihydroxyoctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 80) [ka]

[0432] Step 1: Synthesis of Compound 79-1 [ka]

[0433] Referring to the synthesis method of compound 71-1 in Example 55, compound 79-1 (200 mg, yield: 95%) was obtained as a nearly white solid. LCMS (m / z): 683.3 [M+1] + .

[0434] Step 2: Synthesis of Compound 79 and Compound 80 [ka]

[0435] Compounds 79 (24 mg, yield: 17%) and 80 (16 mg, yield: 12%) were synthesized according to the method of Example 1, yielding white solids. Total yield: 29%.

[0436] Compound 79: 1H NMR (400 MHz, MeOD) δ 7.42-7.22 (m, 5H), 5.58 (d, J = 9.5 Hz, 1H), 5.05 (s, 2H), 4.64 (d, J= 42.6 Hz, 1H), 4.45 (s, 1H), 4.17 (dd, J = 103.5, 50.7 Hz, 2H), 3.41 (s, 3H), 3.01 (s, 3H), 2.26 (d, J = 9.5 Hz, 1H). LCMS(m / z):495.2[M+1] + .

[0437] Compound 80: 1 H NMR (400 MHz, MeOD) δ 7.43-7.23 (m, 5H), 5.31 (s, 1H), 5.07 (s, 2H), 4.77 (s, 1H), 4.52 (s, 1H), 4.49-4.43 (m, 2H), 3.30-2.85 (m, 6H), 2.76 (d, J = 2.8 Hz, 1H). LCMS(m / z):477.2[M+1] + .

[0438] 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-formamide (Compound 81) [ka]

[0439] Compound 81 (15 mg, yield: 100%) was synthesized by referring to the method of Example 2.

[0440] 1H NMR (400 MHz, D2O) δ 5.45 (t, J = 8.1 Hz, 1H), 4.64 (s, 1H), 4.50 (s, 1H), 4.24 (d, J = 8.3 Hz, 1H),3.91 (d, J = 7.2 Hz, 1H), 3.33-3.16 (m, 3H), 2.92 (s, 3H), 2.32 (t, J = 13.6 Hz, 1H). LCMS(m / z):361.1[M+1] + .

[0441] 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-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]diaza-9-formamide (compound 82) [ka]

[0442] Compound 82 (8 mg, yield: 100%) was synthesized according to the method of Example 2, and was obtained as a white solid.

[0443] 1 H NMR (400 MHz, D2O) δ 5.45 (t, J = 8.1 Hz, 1H), 4.64 (s, 1H), 4.50 (s, 1H), 4.24 (d, J = 8.3 Hz, 1H),3.91 (d, J = 7.2 Hz, 1H), 3.33-3.16 (m, 3H), 2.92 (s, 3H), 2.32 (t, J = 13.6 Hz, 1H). LCMS(m / z):343.1[M+1] + .

[0444] Example 64: Synthesis of ((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-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 83) and (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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 84) [ka]

[0445] Step 1: Synthesis of Compound 83-1 [ka]

[0446] Referring to the synthesis of compound 71-1 in Example 55, compound 83-1 (150 mg, yield: 69%), a pale yellow oily substance, was obtained.

[0447] Step 2: Synthesis of Compound 83 and Compound 84 [ka]

[0448] Compound 83 (6.8 mg, yield: 6%) and compound 84 (15.0 mg, yield: 14%) were synthesized according to the method of Example 1. Total yield: 20%.

[0449] Compound 83: 1H NMR (400 MHz, MeOD) δ 7.39-7.25 (m, 5H), 5.31 (s, 1H), 5.07 (s, 2H), 4.77 (s, 1H), 4.56 (s, 1H), 4.49-4.41 (m, 2H), 4.03-3.90 (m, 1H), 3.67 (d, J = 10.3 Hz, 1H), 3.51 (t, J = 6.5 Hz, 2H), 2.73 (d, J = 2.7 Hz, 1H), 1.99-1.81 (m, 4H). LCMS(m / z):503.2[M+1] + .

[0450] Compound 84: 1 H NMR (400 MHz, MeOD) δ 7.39-7.24 (m, 5H), 5.58 (d, J = 9.3 Hz, 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] + .

[0451] Example 65: ((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-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbama Synthesis of compound 85 / compound 86 and piperidine-1-yl ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-6,9,11-trihydroxy-2-iminodecahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]diaza-9-yl)ketone (compound 87) [ka]

[0452] Step 1: Synthesis of Compound 85-1 [ka]

[0453] Compound 85-1 (215 mg, yield: 95%) was synthesized by referring to the method for compound 71-1 in Example 55. LCMS (m / z): 723.3 [M+1] + .

[0454] Step 2: Synthesis of Compound 85 / Compound 86 and Compound 87 [ka]

[0455] By referring to the method of Example 1, two stereoisomers of compound 85 (31 mg, yield: 21%) and compound 86 (16 mg, yield: 10%), in which the chiral carbon in the reaction equation is in the R or S conformation, were obtained, and simultaneously, compound 87 (16 mg, yield: 15%), a white solid, was also obtained. Total yield: 46%.

[0456] Compound 85: 1 H NMR (400 MHz, MeOD) δ 7.41-7.25 (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 = 2.7 Hz, 1H), 1.76-1.65 (m, 2H), 1.64-1.54 (m, 4H). LCMS(m / z):517.2[M+1] + .

[0457] Compound 86: 1H NMR (400 MHz, MeOD) δ 7.41-7.22 (m, 5H), 5.40 (d, J = 3.6 Hz, 1H), 5.06 (s, 2H), 4.61 (s, 1H),4.48 (d, J = 1.6 Hz, 1H), 4.28 (d, J = 3.5 Hz, 1H), 3.96 (dd, J = 47.3, 13.2 Hz, 2H), 3.39 (d, J = 15.3 Hz,1H), 3.17 (dd, J = 21.6, 12.0 Hz, 1H), 2.90-2.82 (m, 1H), 1.78-1.44 (m, 6H). LCMS(m / z):517.2[M+1] + .

[0458] Compound 87: 1 H NMR (400 MHz, D2O) δ 5.43 (s, 1H), 4.57 (d, J = 1.9 Hz, 1H), 4.51 (s, 1H), 4.48 (s, 1H), 3.80-3.32(m, 5H), 2.92 (d, J = 2.2 Hz, 1H), 1.55 (d, J = 35.9 Hz, 6H).LCMS (m / z):383.2 [M+1] + .

[0459] 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) [ka]

[0460] Compound 88 (21 mg, yield: 93%) was synthesized by referring to the method of Example 2.

[0461] 1H NMR (400 MHz, D2O) δ 5.45-5.39 (m, 1H), 4.29-4.22 (m, 1H), 4.17 (s, 1H), 4.07 (d, J = 12.9 Hz, 1H), 3.93 (dd, J = 14.4, 9.7 Hz, 1H), 3.58-3.36 (m, 2H), 2.27 (dd, J = 9.4, 4.4 Hz, 1H). LCMS(m / z):319.1[M+1] + .

[0462] Example 67: ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 89) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((methylamino)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 90) [ka]

[0463] Step 1: Synthesis of Compound 89-1 Compound 89-1 was synthesized referring to the method for compound 63-1 in Example 49. After the reaction was complete, the reaction mixture was cooled to room temperature, then added to water (30 mL) to precipitate a white solid. The mixture 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] + .

[0464] Step 2: Synthesis of Compound 89 and Compound 90 [ka]

[0465] Compound 89 (77 mg, yield: 72%) and compound 90 (5.2 mg, yield: 5%) were synthesized according to the method of Example 1. Total yield: 77%.

[0466] Compound 89: 1 H NMR (400 MHz, MeOD) δ 7.52-7.35 (m, 5H), 5.73 (d, J = 9.4 Hz, 1H), 5.33 (s, 2H), 4.30 (dd, J =8.5, 7.1 Hz, 2H), 4.06 (s, 2H), 3.66 (s, 2H), 2.82 (d, J = 3.1 Hz, 3H), 2.50-2.36 (m, 1H). LCMS(m / z):467.2[M+1] + .

[0467] Compound 90: 1 H NMR (400 MHz, MeOD) δ 7.34 (d, J = 11.6 Hz, 5H), 5.28 (s, 1H), 5.07 (s, 2H), 4.47 (d, J = 2.0 Hz,1H), 4.43 (s, 1H), 4.15 (d, J = 1.3 Hz, 1H), 4.02 (s, 1H), 3.15 (dd, J = 27.7, 12.7 Hz, 2H), 2.70 (d, J = 3.3Hz, 1H), 2.53 (s, 3H). LCMS(m / z):449.2[M+1] + .

[0468] 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) [ka]

[0469] Compound 91 (31 mg, yield: 79%) was synthesized by referring to the method of Example 2.

[0470] 1 H NMR (400 MHz, D2O) δ 5.46 (dd, J = 14.6, 5.7 Hz, 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 = 9.6 Hz, 1H). LCMS(m / z):333.1[M+1] + .

[0471] Example 69: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 92) [ka]

[0472] Step 1: Synthesis of Compound 92-1 [ka]

[0473] Compound 63-1 was synthesized by following the method in Example 49. After the reaction was complete, the reaction mixture was cooled to room temperature, then added to water (30 mL) to precipitate a white solid. The mixture 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 (175 mg, yield: 100%) as a white solid. LCMS (m / z): 669.3 [M+1] + .

[0474] Step 2: Synthesis of Compound 92 [ka]

[0475] The compound was synthesized according to the method of Example 1, yielding 92 (33 mg, yield: 27.5%) as a white solid.

[0476] 1 H NMR (400 MHz, MeOD) δ 7.48-7.32 (m, 5H), 5.69 (d, J = 9.4 Hz, 1H), 5.27 (s, 2H), 4.26 (d, J = 18.4 Hz, 2H), 4.06 (s, 2H), 3.88-3.62 (m, 2H), 3.00 (s, 6H), 2.40 (d, J = 9.4 Hz, 1H). LCMS(m / z):481.2[M+1] + .

[0477] Example 70: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((dimethylamino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methanooxycyclohepta[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 93) [ka]

[0478] Compound 93 (12 mg, yield: 68%) was synthesized by referring to the method of Example 2.

[0479] 1 H NMR (400 MHz, D2O) δ 5.63 (d, J = 9.2 Hz, 1H), 4.45 (s, 2H), 4.30 (s, 1H), 4.12 (s, 1H), 4.02-3.90 (m, 2H), 2.52 (d, J = 9.7 Hz, 1H), 2.23-2.14 (m, 6H). LCMS(m / z):347.2[M+1] + .

[0480] Example 71: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 94) [ka]

[0481] Step 1: Synthesis of Compound 94-1 [ka]

[0482] Compound 63-1 was synthesized by following the method described in Example 49. After the reaction was complete, the reaction mixture was cooled to room temperature, then added to water (30 mL) to precipitate a white solid. The mixture 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 (95 mg, yield: 85%) as a white solid. LCMS (m / z): 681.3 [M+1] + .

[0483] Step 2: Synthesis of Compound 94 [ka]

[0484] Compound 94 (7 mg, yield: 10%) was synthesized by referring to the method of Example 1.

[0485] 1H NMR (400 MHz, MeOD) δ 7.40-7.23 (m, 5H), 5.52 (d, J = 9.4 Hz, 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] + .

[0486] Example 72: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 95) [ka]

[0487] Step 1: Synthesis of Compound 95-1 [ka]

[0488] Compound 63-1 was synthesized according to the method described in Example 49. After the reaction was complete, the reaction mixture was cooled to room temperature, then added to water (30 mL), extracted with ethyl acetate (15 mL x 3), and washed with saturated sodium chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by flash column chromatography (dichloromethane / methanol = 0%~8%) to obtain a white solid 95-1 (125 mg, yield: 62.5%). LCMS (m / z): 711.3 [M+1] + .

[0489] Step 2: Synthesis of Compound 95 [ka]

[0490] Compound 95 (15 mg, yield: 16.3%) was synthesized by referring to the method of Example 1.

[0491] 1 H NMR (400 MHz, MeOD) δ 7.47-7.40 (m, 5H), 5.73 (d, J = 9.4 Hz, 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] + .

[0492] 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) [ka]

[0493] Compound 96 (5.2 mg, yield: 67.2%) was synthesized by referring to the method of Example 2.

[0494] 1H NMR (400 MHz, D2O) δ 5.44 (d, J = 9.4 Hz, 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, 9.1 Hz, 1H). LCMS(m / z):389.2[M+1] + .

[0495] Example 74: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2-(((1H)-ylidene)benzylcarbamate octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-yl)methyl)alanine (Compound 97) [ka]

[0496] Step 1: Synthesis of Compound 97-1 [ka]

[0497] 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 to a reaction flask, and AcOH (221.2 mg, 3.69 mmol) was added dropwise to the mixture. The reaction mixture was heated at 60°C for 1 hour. Sodium cyanoborohydride (112 mg, 1.76 mmol) was added in installments to the reaction mixture, and the reaction was continued at 60°C for another hour. The completion of the reaction was monitored by HPLC, the reaction was cooled to room temperature, ice water (30 mL) was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the residue. The residue was purified by flash column chromatography (methanol / dichloromethane = 0-8%) to obtain compound 97-1 (128 mg, yield: 57.5%) as a white solid. LCMS (m / z): 712.3 [M+1] + .

[0498] Step 2: Synthesis of Compound 97 [ka]

[0499] Compound 97-1 (123 mg, 0.17 mmol) was synthesized according to the method of Example 1, and the crude product was purified by prep-HPLC (A: 0.1% AcOH, B: MeOH = 0-8%) to obtain a white solid compound 97 (10 mg, yield: 13.6%). LCMS (m / z): 525.2 [M+1] + .

[0500] Example 75: 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]pyrimidine-6-yl)methyl)alanine (compound 98) [ka]

[0501] Compound 98 (5.0 mg, yield: 67.1%) was synthesized according to the method of Example 2. LCMS (m / z): 391.1 [M+1] + .

[0502] Example 76: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(azacyclobutan-1-ylmethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 99) [ka]

[0503] Step 1: Synthesis of Compound 99-1 [ka]

[0504] Compound 63-1 was synthesized by following the method in Example 49. After the reaction was complete, the reaction mixture was cooled to room temperature, then added to water (30 mL) to precipitate a white solid. The mixture 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] + .

[0505] Step 2: Synthesis of Compound 99 [ka]

[0506] Compound 99 (33 mg, yield: 23%) was synthesized according to the method of Example 1, yielding a white solid.

[0507] 1H NMR (400 MHz, MeOD) δ 7.53-7.28 (m, 5H), 5.71 (d, J = 8.9 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):493.2[M+1] + .

[0508] Example 77: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(azacyclobutan-1-ylmethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 100) [ka]

[0509] The compound 100 (17 mg, yield: 78%) was synthesized according to the method of Example 2, and a white solid compound was obtained.

[0510] 1 H NMR (400 MHz, D2O) δ 5.46 (d, J = 9.4 Hz, 1H), 4.44-4.23 (m, 4H), 4.04-3.76 (m, 3H), 3.74-3.42 (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] + .

[0511] Example 78: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-fluoroazacyclobutan-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 101) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3-fluoroazacyclobutan-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 102) [ka]

[0512] Step 1: Synthesis of Compound 101-1 [ka]

[0513] Referring to the synthesis method of compound 97-1 in Example 74, 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] + .

[0514] Step 2: Synthesis of Compound 101 and Compound 102 [ka]

[0515] The compounds were synthesized 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%).

[0516] Compound 101: 1 H NMR (400 MHz, MeOD) δ 7.46-7.26 (m, 5H), 5.62 (d, J = 9.4 Hz, 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 = 9.1 Hz, 1H). LCMS(m / z):511.2[M+1] + .

[0517] Compound 102: 1 H NMR (400 MHz, MeOD) δ 7.50-7.19 (m, 5H), 5.27 (s, 1H), 5.22-5.16 (m, 0.5H), 5.09-5.01 (m, 2.5H), 4.45 (d, J = 2.0 Hz, 1H), 4.41 (s, 1H), 4.10 (d, J = 1.3 Hz, 1H), 3.95 (s, 1H), 3.82-3.69 (m, 2H), 3.39 (dd, J = 9.4, 4.6 Hz, 1H), 3.36-3.32 (m, 1H), 3.11 (d, J = 13.3 Hz, 1H), 3.00 (d, J = 13.3 Hz, 1H), 2.67 (d, J = 3.0 Hz, 1H). LCMS(m / z):493.2[M+1] + .

[0518] Example 79: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((3-fluoroazacyclobutan-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) [ka]

[0519] Compound 103 (10 mg, yield: 90.4%) was obtained by synthesizing the compound according to the method of Example 2 and adding compound 101 (15 mg, 0.03 mmol).

[0520] 1 H NMR (400 MHz, D2O) δ 5.63-5.28 (m, 2H), 4.67-4.42 (m, 4H), 4.33-4.13 (m, 2H), 4.09-3.68 (m, 4H), 2.30 (d, J = 9.5 Hz, 1H). LCMS(m / z):377.1[M+1] + .

[0521] Example 80: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-hydroxypyrrolidine-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 104) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3-hydroxypyrrolidine-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 105) [ka]

[0522] Step 1: Synthesis of Compound 104-1 [ka]

[0523] Compound 63-1 was synthesized by following the method in Example 49. After the reaction was complete, the reaction mixture was cooled to room temperature, then added to water (30 mL) to precipitate a white solid. The mixture 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 as a white solid (145 mg, yield: 87%). LCMS (m / z): 711.3 [M+1] + .

[0524] Step 2: Synthesis of Compound 104 and Compound 105 [ka]

[0525] Compounds 104 (33 mg, yield: 31%) and 105 (3 mg, yield: 3%) were synthesized according to the method of Example 1, yielding white solid compounds.

[0526] Compound 104: 1 H NMR (400 MHz, MeOD) δ 7.57-7.23 (m, 5H), 5.69 (d, J = 7.3 Hz, 1H), 5.29 (s, 2H), 4.59 (s, 1H), 4.29 (s, 1H), 4.23 (s, 1H), 3.97 (d, J = 42.4 Hz, 2H), 3.87-3.76 (m, 1H), 3.63 (t, J = 5.0 Hz, 3H), 3.56-3.39 (m, 2H), 2.41 (d, J = 9.2 Hz, 1H), 2.20 (d, J = 26.9 Hz, 1H), 2.11 (s, 1H). LCMS(m / z):523.2[M+1] + .

[0527] Compound 105: LCMS(m / z):505.2[M+1] + .

[0528] Example 81: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((3-hydroxypyrrolidine-1-yl)methyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 106) [ka]

[0529] Compound 106 (13 mg, yield: 87%) was synthesized by referring to the method of Example 2.

[0530] 1 H NMR (400 MHz, D2O) δ 5.46 (d, J = 9.4 Hz, 1H), 4.66 (s, 2H), 4.29 (d, J = 6.6 Hz, 2H), 4.13 (s, 1H), 4.05-3.91 (m, 2H), 3.89-3.75 (m, 2H), 3.63-3.35 (m, 2H), 2.35 (d, J = 9.4 Hz, 2H), 2.16-2.03 (m, 1H). LCMS(m / z):389.2[M+1] + .

[0531] Example 82: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-fluoropyrrolidine-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 107) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3-fluoropyrrolidine-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 108) [ka]

[0532] Step 1: Synthesis of Compound 107-1 [ka]

[0533] 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 under a nitrogen atmosphere and stirred for 1 hour. Then, sodium borohydride (222.1 mg, 3.537 mmol) was added in portions and the mixture was reacted for 30 minutes. The reaction was monitored by HPLC until the starting materials were completely reacted. After cooling the reaction system to room temperature, ice water (50 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue of approximately 230 mg. The residue was subjected to flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 107-1 (200 mg, yield: 89.9%).

[0534] Step 2: Synthesis of Compound 107 and Compound 108 [ka]

[0535] Compound 107-1 (200 mg, 0.28 mmol) was added to a reaction flask, water (10 mL) and TFA (10 mL) were added, and the mixture was heated to 60°C under a nitrogen atmosphere and stirred for 18 hours. The reaction mixture was concentrated and dried, and the residue was subjected to flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 107 (30 mg, yield: 20.4%) and compound 108 (6 mg, yield: 4%). Total yield: 24.4%.

[0536] Compound 107: 1 H NMR (400 MHz, MeOD) δ 7.51-7.21 (m, 5H), 5.64 (d, J = 9.3 Hz, 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 = 9.4 Hz, 1H), 2.28-2.01 (m, 2H). LCMS(m / z):525.2[M+1] + .

[0537] Compound 108: LCMS(m / z):507.2[M+1] + .

[0538] Example 83: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((3-fluoropyrrolidine-1-yl)methyl)-2-iminooctanoate-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 109) [ka]

[0539] Compound 107 (20 mg, 0.04 mmol) was dissolved in methanol (5 mL), 10% Pd / C (10 mg) was added, and the mixture was substituted with hydrogen three times. Hydrogen was then introduced into the reaction mixture, and the reaction was allowed to proceed for approximately 3 hours. The reaction was then monitored by HPLC until the reaction of the starting materials was complete. The reaction mixture was filtered, and the filtrate cake was washed with 0.05 M aqueous AcOH solution. The filtrate was concentrated to obtain the crude compound. The crude compound was slurryed with methyl tert-butyl ether (10 mL), allowed to stand, the solvent was absorbed, and the residue was concentrated and dried to obtain compound 109 (10 mg, yield: 67.1%).

[0540] Compound 109: 1H NMR (400 MHz, D2O) δ 5.60-5.38 (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] + .

[0541] Example 84: ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 110) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(morpholinomethyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 111) [ka]

[0542] Step 1: Synthesis of Compound 110-1 [ka]

[0543] 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. Acetic acid (221.8 mg, 3.69 mmol) was then added, and the mixture was heated to 60°C and reacted for 2 hours. Sodium triacetylborohydride (749.6 mg, 3.54 mmol) was then added, and the mixture was reacted for another 1.5 hours. The mixture was then stirred overnight at room temperature. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (3 x 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (developing solvent DCM / MeOH = 30:1) to obtain compound 110-1 (84 mg, yield 32.9%). LCMS(m / z):711.3[M+1] + .

[0544] Step 2: Synthesis of Compound 110 and Compound 111 [ka]

[0545] 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 reacted overnight. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried, 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%). Total yield: 39.8%.

[0546] Compound 110: 1H NMR (400 MHz, MeOD) δ 7.46-7.15 (m, 5H), 5.56 (d, J = 7.4 Hz, 1H), 5.11 (s, 2H), 4.33-3.81 (m, 4H), 3.69 (t, J = 4.5 Hz, 4H), 3.05-2.85 (m, 2H), 2.74-2.58 (m, 4H), 2.27 (d, J = 9.5 Hz, 1H). LCMS(m / z):523.2[M+1] + .

[0547] Compound 111: LCMS(m / z):505.2[M+1] + .

[0548] 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) [ka]

[0549] Compound 110 (9 mg, 0.02 mmol), MeOH (15 mL), and 10% Pd / C (3 mg) were added to a reaction flask, substituted three times with hydrogen, and then hydrogenated under hydrogen balloon pressure for 3 hours. After monitoring by HPLC until the starting materials had completely reacted, 0.2% aqueous acetic acid (5 mL) was added to the reaction mixture, stirred for 30 minutes, filtered, and the filter cake was slurryed twice with 0.2% aqueous acetic acid and filtered again. The filtrates were combined, concentrated and dried, then methanol (2 drops) was added to dissolve the solid, and then methyl tert-butyl ether (10 mL) was added to precipitate a white solid. The mixture was stirred for 15 minutes, allowed to stand, and the supernatant was aspirated. The residue was concentrated and dried, then freeze-dried to obtain the acetate of compound 112 (7.5 mg, yield: 96%).

[0550] 1H NMR (400 MHz, D2O) δ 5.44 (d, J = 9.4 Hz, 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 = 9.4 Hz, 1H), 2.02 (s, 3H). LCMS(m / z):389.2[M+1] + .

[0551] Example 86: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2-(((1H)-ylidene)benzylcarbamate octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-yl)methyl)glycine (Compound 113) [ka]

[0552] Step 1: Synthesis of Compound 113-1 [ka]

[0553] 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 separate additions. After the addition was complete, the reaction was continued at 60°C for another 2 hours with stirring. After the reaction was complete, water was added to quench the mixture, and the organic phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed once with saturated brine, separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was dried by vacuum concentration 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] + .

[0554] Step 2: Synthesis of Compound 113 [ka]

[0555] Compound 113-1 (145 mg, 0.20 mmol) was added to a solvent of water:trifluoroacetic acid = 1:1 and stirred at 65°C for 17 hours. After the reaction was complete, the mixture was concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 0-6.5%) to obtain compound 113 (18 mg, yield: 17.0%).

[0556] 1 HNMR (400 MHz, MeOD) δ 7.38-7.26 (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] + .

[0557] 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]pyrimidine-6-yl)methyl)glycine (compound 114) [ka]

[0558] Compound 113 (10 mg, 0.02 mmol) and 10% Pd / C (5 mg) were added to MeOH (2 mL), substituted with hydrogen, and stirred at 25°C for 4 hours. After the reaction was complete, a 0.5% aqueous acetic acid solution was added and stirred for 0.5 hours, 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] + .

[0559] Example 88: Synthesis of (((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2(1H)-ylidene)benzylcarbamate octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-yl)methyl)pyrrolidine-3-carboxylic acid (Compound 115) [ka]

[0560] Step 1: Synthesis of Compound 115-1 [ka]

[0561] Compound 63-1 was synthesized by following the method in Example 49. Compound B2 (190 mg, 0.30 mmol) was added, and after the reaction was complete, the reaction mixture was cooled to room temperature. Then, it was added to water (30 mL) to precipitate a white solid, which was then filtered. The filtered cake was washed with water (10 mL x 2), collected, and dried to obtain the white solid compound 115-1 (175 mg, yield: 80%). LCMS (m / z): 738.3 [M+1] + .

[0562] Step 2: Synthesis of Compound 115 [ka]

[0563] Compound 115 was synthesized by referring to the method of Example 1, and compound 115-1 (175 mg, 0.24 mmol) was added to obtain compound 115 (29 mg, yield: 22%), which is a white solid.

[0564] 1 H NMR (400 MHz, MeOD) δ 7.50-7.35 (m, 5H), 5.69 (d, J = 9.0 Hz, 1H), 5.27 (s, 2H), 4.28 (d, J = 16.8 Hz, 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] + .

[0565] 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]pyrimidine-6-yl)methyl)pyrrolidine-3-carboxylic acid (Compound 116) [ka]

[0566] Compound 116 (4.5 mg, yield: 54%) was obtained as a white solid by adding compound 115 (11 mg, 0.01 mmol) according to the method of Example 2. LCMS (m / z): 417.2 [M+1] + .

[0567] Example 90: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3-aminopyrrolidine-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 117) [ka]

[0568] Step 1: Synthesis of Compound 117-1 [ka]

[0569] Compound B2 (200 mg, 0.31 mmol) was dissolved in dimethyl sulfoxide (3 mL), and compound 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. The mixture was heated to 60°C under a nitrogen atmosphere and stirred for 1 hour. Then, sodium borohydride cyanohydride (222.1 mg, 3.54 mmol) was added in portions and the mixture was reacted for 30 minutes. The reaction was monitored by HPLC until the reaction of the starting materials was complete. After cooling the reaction mixture to room temperature, 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 obtain 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]+ .

[0570] Step 2: Synthesis of Compound 117 [ka]

[0571] Compound 117-1 (240 mg, 0.3 mmol) was added to a reaction flask, water (15 mL) and TFA (7.5 mL) were added, and the mixture was heated to 60°C under a nitrogen atmosphere and reacted for 18 hours. The reaction mixture was concentrated and dried, and the resulting residue was purified by flash column chromatography (MeOH / DCM = 0-4%) to obtain compound 117 (30 mg, yield: 19.5%). LCMS (m / z): 522.2 [M+1] + .

[0572] Example 91: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((3-aminopyrrolidine-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) [ka]

[0573] Compound 117 (30 mg, 0.06 mmol) was dissolved in methanol (10 mL), 10% Pd / C (30 mg) was added, and the mixture was substituted with hydrogen three times. After introducing hydrogen into the reaction mixture, the reaction was monitored by HPLC until the reaction of the starting materials was complete. The reaction mixture was filtered, and the filter cake was washed with 0.05 M aqueous acetic acid solution. The filtrate was concentrated to obtain the crude compound. The crude compound was slurryed with methyl tert-butyl ether (10 mL), allowed to stand, the supernatant was absorbed, and the residue was concentrated and dried to obtain compound 118 (20 mg, yield: 89.8%).

[0574] 1H NMR (400 MHz, D2O) δ 5.42 (d, J = 9.3 Hz, 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 = 9.1 Hz, 1H), 2.24-2.15 (m, 1H), 1.99 (d, J = 9.8 Hz, 1H). LCMS(m / z):388.2[M+1] + .

[0575] Example 92: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((R)-3-acetamidopyrrolidine-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 119) [ka]

[0576] Step 1: Synthesis of Compound 119-1 [ka]

[0577] 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 mixture in three separate additions. After the addition was complete, the mixture was stirred at 60°C for another 2 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and dried, 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] + .

[0578] Step 2: Synthesis of Compound 119-2 [ka]

[0579] Compound 119-1 (110 mg, 0.14 mmol) was added to a 20 mL mixed solution of water and trifluoroacetic acid in a 1:4 ratio, and the mixture was stirred at 60°C for 17 hours. After the reaction was complete, the mixture was concentrated and dried, and the resulting crude product was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 0-4.5%) to obtain compound 119-2 (15 mg, yield: 19.7%). LCMS (m / z): 522.2 [M+1] + .

[0580] Step 3: Synthesis of Compound 119 [ka]

[0581] Compound 119-2 (15 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2 mL), then acetic anhydride (3.5 mg, 0.03 mmol) was added, and the mixture was stirred at 18°C ​​for 1 hour. After the reaction was complete, the reaction solution was concentrated and dried, and the resulting residue was purified by Prep-HPLC to obtain compound 119 (2.0 mg, yield: 12.3%).

[0582] 1 H NMR (400 MHz, MeOD) δ 7.44-7.17 (m, 5H), 5.53 (d, J = 9.4 Hz, 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, 6.7 Hz, 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] + .

[0583] Example 93: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 120) [ka]

[0584] Step 1: Synthesis of Compound 120-1 [ka]

[0585] 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 borohydride cyanohydride (80 mg, 1.26 mmol) was added to the reaction mixture in three separate additions. After the addition was complete, the reaction was continued at 60°C for another 2 hours with stirring. After the reaction was complete, ice water was added to quench the mixture, and a small amount of solid sodium chloride was added, causing a white solid to precipitate in 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] + .

[0586] Step 2: Synthesis of Compound 120 [ka]

[0587] Compound 120-1 (95 mg, 0.13 mmol) was added to a mixed solution of water and trifluoroacetic acid (1:2, 15 mL) and stirred at 60°C for 17 hours. After the reaction was complete, the reaction solution was concentrated and dried, and the resulting residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 0-7%) to obtain compound 120 (7.5 mg, yield: 10.7%).

[0588] 1 H NMR (400 MHz, MeOD) δ 7.46-7.20 (m, 5H), 5.59 (d, J = 9.0 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):535.2[M+1] + .

[0589] 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) [ka]

[0590] Compound 120 (5 mg, 0.01 mmol) and 10% Pd / C (2.5 mg) were added to methanol (5 mL), purged with hydrogen, and stirred under a hydrogen atmosphere at 25°C for 4 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried, and the resulting residue was freeze-dried to obtain compound 121 (1.62 mg, yield: 43%).

[0591] 1 H NMR (400 MHz, D2O) δ 5.44-5.39 (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] + .

[0592] Example 95: Synthesis of ((((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2-((1H)-ylidene)benzylcarbamate octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-yl)methyl)amino)propionic acid (compound 122) [ka]

[0593] Step 1: Synthesis of Compound 122-1 [ka]

[0594] 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 a nitrogen atmosphere and reacted for 1 hour. Sodium cyanoborohydride (83.4 mg, 1.33 mmol) was added in installments, and the mixture was reacted at 60°C for 30 minutes. The reaction was monitored by HPLC until the starting materials were completely reacted. After cooling the reaction mixture to room temperature, ice water (20 mL) was added and stirred, causing a large amount of solid to precipitate. The mixture was filtered, the filter cake was collected, concentrated and dried to obtain the crude product Compound 122-1 (100 mg, yield: 60%), which was then used in the next reaction.

[0595] Step 2: Synthesis of Compound 122 [ka]

[0596] Crude compound 122-1 (100 mg, 0.14 mmol) was added to a reaction flask, water (10 mL) and TFA (5 mL) were added, and the mixture was heated to 60°C under a nitrogen atmosphere and reacted for 20 hours. The reaction mixture was concentrated and dried, and the residue was purified by flash column chromatography (MeOH / DCM = 0-3%) to obtain compound 122 (25 mg, yield: 34%).

[0597] 1H NMR (400 MHz, MeOD) δ 7.40-7.33 (m, 5H), 5.59 (d, J = 9.3 Hz, 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 = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 2.27 (d, J = 9.3 Hz, 1H). LCMS(m / z):525.2[M+1] + .

[0598] Example 96: 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]pyrimidine-6-yl)methyl)amino)propionic acid (compound 123) [ka]

[0599] Compound 122 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), 10% Pd / C (20 mg) was added, hydrogen was purged, and the mixture was reacted under a hydrogen atmosphere for 3 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was filtered, and the filter cake was washed with 0.05 M aqueous acetic acid solution. The filtrate was concentrated to obtain the crude compound, which was then slurryed with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was aspirated. The residue was concentrated and dried to obtain compound 123 (14 mg, yield: 94%).

[0600] 1H NMR (400 MHz, D2O) δ 5.43 (d, J = 9.2 Hz, 1H), 4.26 (s, 2H), 4.09 (s, 1H), 3.91 (s, 1H), 3.72-3.52 (m, 2H), 3.34 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H), 2.31 (d, J = 9.4 Hz, 1H). LCMS(m / z):391.1[M+1] + .

[0601] Example 97: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 124) [ka]

[0602] Step 1: Synthesis of Compound 124-1 [ka]

[0603] 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 under a nitrogen atmosphere, stirring for 1 hour. Sodium triacetylborohydride (94.2 mg, 1.5 mmol) was added, and stirring continued for another hour. After the reaction was complete, the reaction system was cooled to room temperature, water (2 mL) was added, and a white solid precipitated. After stirring for 5 minutes, the mixture was filtered to obtain compound 124-1 (200 mg, yield: 95.6%) as a grayish-white solid. LCMS (m / z): 705.3 [M+1] + .

[0604] Step 2: Synthesis of Compound 124 [ka]

[0605] Compound 124-1 (200 mg, 0.28 mmol) was dissolved in a TFA:H2O = 2:1 solution (4 mL) and stirred under a nitrogen atmosphere, heated to 60°C for 16 hours. After the reaction was complete, the reaction solution was concentrated and dried, and the residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 5%~8%) to obtain compound 124 (25 mg, yield: 17.1%) as a white solid.

[0606] 1 H NMR (400 MHz, MeOD) δ 7.47-7.29 (m, 5H), 6.13-5.77 (m, 1H), 5.65 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 4.60 (s, 1H), 4.19 (d, J = 17.2 Hz, 2H), 3.97 (s, 2H), 3.27 (s, 1H), 3.12-3.00 (m, 2H), 2.33 (d, J = 9.0 Hz, 1H). LCMS(m / z):517.2[M+1] + .

[0607] Example 98: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((2,2-difluoroethyl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 125) [ka]

[0608] Compound 124 (7.0 mg, 0.013 mmol) was dissolved in methanol (2 mL), 10% Pd / C (1 mg) was added, the mixture was replaced three times with hydrogen, and the reaction was stirred at 25°C for 8 hours. After the reaction was complete, a 1% aqueous acetic acid solution was added, the mixture was stirred for 5 minutes, filtered, and the filter cake was washed three times with a 1% aqueous acetic acid solution. The filtrate was concentrated and dried, and then freeze-dried to obtain a grayish-white solid compound 125 (3.2 mg, yield: 61.8%).

[0609] 1 H NMR (400 MHz, D2O) δ 6.31 (t, J = 53.3 Hz, 1H), 5.42 (d, J = 9.3 Hz, 1H), 4.27 (d, J = 10.7 Hz, 2H), 4.10 (s, 1H), 3.90 (s, 1H), 3.74 (s, 2H), 3.71-3.59 (m, 2H), 2.30 (d, J = 9.6 Hz, 1H). LCMS(m / z):383.1[M+1] + .

[0610] Example 99: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 126) [ka]

[0611] Step 1: Synthesis of Compound 126-1 [ka]

[0612] 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 the mixture was heated to 60°C and reacted for 1 hour. Sodium cyanoborohydride (73.7 mg, 1.17 mmol) was added to the reaction mixture in portions, and the reaction was continued at 60°C for another 1 hour. The reaction was monitored by HPLC until completion. Ice water (15 mL) was added dropwise to the reaction mixture, and a white solid precipitated. 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 and dried. The crude compound 126-1 (161 mg) was obtained by combining it with the filtered cake and used directly in the next reaction. LCMS (m / z): 687.5 [M+1] + .

[0613] Step 2: Synthesis of Compound 126 [ka]

[0614] 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. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (A: 0.1% AcOH, B: MeOH, 0-0.1%) to obtain compound 126 (35 mg, two-step yield: 30%) as a white solid.

[0615] 1H NMR (400 MHz, MeOD) δ 7.45-7.36 (m, 5H), 5.71 (d, J = 9.1 Hz, 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 = 9.3 Hz, 1H). LCMS(m / z):499.2[M+1] + .

[0616] Example 100: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((2-fluoroethyl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 127) [ka]

[0617] Compound 126 (25 mg, 0.05 mmol) was dissolved in MeOH (1.5 mL), Pd / C (2.5 mg) was added, and the mixture was reacted at room temperature under a hydrogen atmosphere for 3 hours. The reaction was monitored by HPLC until the starting materials were completely reacted. Subsequently, 0.5% AcOH / H2O (6 mL) and MeOH (1.5 mL) were added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was washed with 0.5% AcOH / H2O (10 mL) and MeOH (10 mL). The resulting filtrate was concentrated under reduced pressure and then freeze-dried to obtain compound 127 (11.69 mg, yield: 64.0%), which was a nearly white solid.

[0618] 1H NMR (400 MHz, MeOD) δ 5.51 (d, J = 9.4 Hz, 1H), 4.36 (d, J = 7.6 Hz, 2H), 4.19 (s, 1H), 3.99 (s, 2H), 3.78 (d, J = 5.5 Hz, 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, 4.8 Hz, 1H). LCMS(m / z):365.3[M+1] + .

[0619] Example 101: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 128) [ka]

[0620] Step 1: Synthesis of Compound 128-1 [ka]

[0621] 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) and heated to 60°C under a nitrogen atmosphere, stirring for 1 hour. Sodium triacetylborohydride (94.2 mg, 1.5 mmol) was added, and stirring continued for another hour. After the reaction was complete, the mixture was cooled to room temperature, water (2 mL) was added to the reaction solution, a white solid precipitated, and after stirring for 5 minutes, the mixture was filtered to obtain compound 128-1 (200 mg, yield: 93.7%) as a grayish-white solid. LCMS (m / z): 719.3 [M+1]+ .

[0622] Step 2: Synthesis of Compound 128 [ka]

[0623] Compound 128-1 (200 mg, 0.28 mmol) was dissolved in a TFA:H2O=2:1 aqueous solution (4 mL) and stirred under a nitrogen atmosphere, heated to 60°C for 16 hours. After the reaction was complete, the reaction mixture was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 5%~8%) to obtain compound 128 (32.5 mg, yield: 22.2%) as a white solid.

[0624] 1 H NMR (400 MHz, MeOD) δ 7.48-7.23 (m, 5H), 6.28-5.85 (m, 1H), 5.62 (d, J = 9.4 Hz, 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] + .

[0625] Example 102: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((3,3-difluoropropyl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 129) [ka]

[0626] Compound 128 (7.0 mg, 0.01 mmol) was dissolved in methanol (2 mL), and Pd / C (1 mg) was added. The mixture was replaced three times with hydrogen and stirred at 25°C for 3 hours. After the reaction was complete, a 1% aqueous acetic acid solution was added, the mixture was stirred for 5 minutes, and the solution was filtered. The mixture was washed three times with a 1% aqueous acetic acid solution, the filtrate was concentrated and dried, and then freeze-dried to obtain a grayish-white solid compound 129 (3.5 mg, yield: 67.3%).

[0627] 1 H NMR (400 MHz, D2O) δ 6.06 (tt, J = 55.5, 3.7 Hz, 1H), 5.42 (d, J = 9.4 Hz, 1H), 4.26 (d, J = 5.9 Hz, 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] + .

[0628] Example 103: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 130) [ka]

[0629] Step 1: Synthesis of Compound 124-1 [ka]

[0630] 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), and AcOH (199.5 mg, 3.32 mmol) was 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 to the reaction mixture in portions, and the reaction was continued at 60°C for another 1 hour. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined and washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and then 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] + .

[0631] Step 2: Synthesis of Compound 130-2 [ka]

[0632] Compound 124-1 (130 mg, 0.18 mmol) and KOAc (104.2 mg, 1.06 mmol) were dissolved in MeOH (2 mL), and AcOH (130.8 mg, 2.18 mmol) and 37% formaldehyde aqueous solution (44.9 mg, 0.55 mmol) were added dropwise to the mixture. The reaction was allowed to proceed at room temperature for 1 hour. NaBH3CN (58.0 mg, 0.92 mmol) was added to the reaction mixture in portions, and the reaction was continued at room temperature for another 1 hour. The reaction was monitored by HPLC until completion. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined and washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and then 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]+ .

[0633] Step 3: Synthesis of Compound 130 [ka]

[0634] Compound 130 (11.14 mg, yield: 11.3%) was synthesized by referring to the method of Example 1, and was obtained as a nearly white solid.

[0635] 1 H NMR (400 MHz, MeOD) δ 7.39-7.25 (m, 5H), 6.16-5.83 (m, 1H), 5.54 (d, J = 4.0 Hz, 1H), 5.06 (s, 2H), 4.70-4.50 (m, 1H), 4.21-4.05 (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] + .

[0636] Example 104: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 131) [ka]

[0637] Compound 131 (1.04 mg, yield: 16.83%) was synthesized by referring to the method of Example 2, and was obtained as a nearly white solid.

[0638] 1H NMR (400 MHz, D2O) δ 6.59-6.26 (m, 1H), 5.52 (d, J =6.0 Hz, 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] + .

[0639] Example 105: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((5-oxopyrrolidine-3-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2-(1H)-ylidene)benzylcarbamate (Compound 132) [ka]

[0640] Step 1: Synthesis of Compound 132-1 [ka]

[0641] Compound B2 (150 mg, 0.24 mmol), compound 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) and heated to 60°C under a nitrogen atmosphere, stirring for 2 hours. Sodium triacetylborohydride (562.8 mg, 2.66 mmol) was added, and stirring continued for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, water (30 mL) was added to the reaction solution, a white solid precipitated, and the mixture was stirred for 15 minutes. The mixture was then filtered to obtain a grayish-white solid, compound 132-1 (148 mg, yield: 87%). LCMS (m / z): 724.3 [M+1] + .

[0642] Step 2: Synthesis of Compound 132 [ka]

[0643] Compound 132-1 (148 mg, 0.20 mmol) was dissolved in a TFA:H2O=1:3 aqueous solution (12 mL) and stirred under a nitrogen atmosphere, heated to 60°C for 17 hours. After the reaction was complete, the reaction solution was concentrated and dried, and the resulting residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 0-2%) to obtain compound 132 (21 mg, yield: 19.2%) as a white solid.

[0644] 1 H NMR (400 MHz, MeOD) δ 7.49-7.18 (m, 5H), 5.61 (d, J = 8.5 Hz, 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, 7.5 Hz, 1H), 2.35-2.20 (m, 2H). LCMS(m / z):536.2[M+1] + .

[0645] Example 106: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((5-oxopyrrolidine-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) [ka]

[0646] Compound 132 (10.0 mg, 0.02 mmol) was dissolved in methanol (2 mL), and 10% Pd / C (1 mg) was added. The mixture was replaced three times with hydrogen and stirred at 25°C for 3 hours. After the reaction was complete, 1% aqueous acetic acid was added, the mixture was stirred for 5 minutes, filtered, and the filter cake was washed three times with 1% aqueous acetic acid. The filtrate was concentrated and dried to obtain compound 133 (4.6 mg, yield: 62.2%) as a grayish-white solid.

[0647] 1 H NMR (400 MHz, D2O) δ 5.42 (d, J = 9.4 Hz, 1H), 4.32-4.21 (m, 3H), 4.08 (s, 1H), 3.94-3.81 (m, 2H), 3.68-3.51 (m, 3H), 2.92 (dd, J = 18.1, 9.0 Hz, 1H), 2.60 (dd, J = 18.1, 4.8 Hz, 1H), 2.29 (d, J = 9.5 Hz, 1H). LCMS(m / z):402.2[M+1] + .

[0648] Example 107: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 134) [ka]

[0649] Step 1: Synthesis of Compound 134-1 [ka]

[0650] Compound 63-1 was synthesized by referring to the method in Example 49. Compound B2 (200 mg, 0.31 mmol) was added, and after the reaction was complete, the reaction mixture was cooled to room temperature. Then, it was added to water (30 mL) to precipitate a white solid, which was filtered. The filtered cake was washed with water (10 mL x 2), the filtered cake was collected, and dried to obtain a white solid compound 134-1 (220 mg, yield: 96%). LCMS (m / z): 739.3 [M+1] + .

[0651] Step 2: Synthesis of Compound 134 [ka]

[0652] Compound 134 was synthesized by referring to the method of Example 1, and compound 134-1 (210 mg, 0.28 mmol) was added to obtain compound 134 (30.2 mg, yield: 19%) as a white solid.

[0653] 1 H NMR (400 MHz, MeOD) δ 7.45-7.27 (m, 5H), 5.61 (d, J = 9.0 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):551.2[M+1] + .

[0654] 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) [ka]

[0655] Synthesized by referring to the method of Example 2, 12 mg (0.02 mmol) of Compound 134 was added, and 8 mg (yield: 88%) of Compound 135 as a white solid was obtained.

[0656] 1 H NMR (400 MHz, D2O) δ 5.34 (d, J = 9.4 Hz, 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 = 9.5 Hz, 1H). LCMS (m / z): 417.2 [M+1] + 。

[0657] Example 109: Synthesis of ((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-methylenoxy[4,5-d]pyrimidin-2(1H)-ylidene)benzylcarbamate (Compound 136)

Chemical formula

[0658] Step 1: Synthesis of Compound 136-1

Chemical formula

[0659] Synthesized by referring to the method of Compound 63-1 in Example 49, 190 mg (0.30 mmol) of Compound B2 was added. After the reaction was completed, the reaction solution was cooled to room temperature, then added to water (30 mL) to precipitate a white solid, filtered, the filter cake was washed with water (10 mL × 2), the filter cake was collected and dried to obtain 210 mg (yield: 99%) of Compound 136-1 as a white solid. LCMS (m / z): 712.3 [M+1] + 。

[0660] Step 2: Synthesis of Compound 136 [ka]

[0661] Compound 136 was synthesized by referring to the method of Example 1, and compound 136-1 (210 mg, 0.30 mmol) was added to obtain compound 136 (32 mg, yield: 21%), which is a white solid.

[0662] 1 H NMR (400 MHz, MeOD) δ 7.44-7.30 (m, 5H), 5.64 (d, J = 8.9 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):524.2[M+1] + .

[0663] Example 110: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((2-(methylamino)-2-oxoethyl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 137) [ka]

[0664] Compound 137 (19 mg, yield: 85%) was obtained as a white solid by adding compound 136 (30 mg, 0.06 mmol) according to the method of Example 2.

[0665] 1H NMR (400 MHz, D2O) δ 5.57 (d, J = 9.4 Hz, 1H), 4.42 (d, J = 13.6 Hz, 2H), 4.26 (s, 1H), 4.06 (s, 3H), 3.82-3.70 (m, 2H), 2.87 (s, 3H), 2.45 (d, J = 9.4 Hz, 1H). LCMS(m / z):390.4[M+1] + .

[0666] Example 111: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((6-oxopiperidine-3-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 138) [ka]

[0667] Step 1: Synthesis of Compound 138-1 [ka]

[0668] Compound 63-1 was synthesized according to the synthesis method in Example 49, and compound B2 (180 mg, 0.28 mmol) was added. After the reaction was complete, the reaction mixture was cooled to room temperature, then added to water (30 mL) to precipitate a white solid, filtered, the filter cake was washed with water (10 mL x 2), the filter cake was collected and dried to obtain compound 138-1 (190 mg, yield: 92%) as a white solid. LCMS (m / z): 738.3 [M+1] + .

[0669] Step 2: Synthesis of Compound 138 [ka]

[0670] Synthesized by referring to the method of Example 1, and compound 138-1 (190 mg, 0.26 mmol) was added to obtain compound 138 as a white solid (33 mg, yield: 23%).

[0671] 1 H NMR (400 MHz, MeOD) δ 7.41-7.29 (m, 5H), 5.57 (d, J = 9.5 Hz, 1H), 5.17-5.08 (m, 2H), 4.22 (d, J = 5.9 Hz, 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] + .

[0672] Example 112: Synthesis of (4R,4aR,5R,6S,7S,9S,1QS,10aR,11S)-6-(((6-oxopiperidin-3-yl)amino)methyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methylenedioxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (Compound 139) [Chemical formula]

[0673] Synthesized by referring to the method of Example 2, and compound 138 (30 mg) was added to obtain compound 139 as a white solid (22 mg, yield: 97%).

[0674] 1H NMR (400 MHz, D2O) δ 5.34 (d, J = 9.4 Hz, 1H), 4.18-4.00 (m, 4H), 3.92-3.78 (m, 2H), 3.49 (dd, J = 14.3, 7.3 Hz, 1H), 3.26 (d, J = 13.3 Hz, 1H), 3.15-3.07 (m, 1H), 2.49-2.37 (m, 2H), 2.33-2.24 (m, 1H), 2.19 (t, J = 8.9 Hz, 1H), 1.92-1.89 (m, 1H). LCMS(m / z):416.4[M+1] + .

[0675] Example 113: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((3,3-difluoroazacyclobutan-1-yl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2-(1H)-ylidene)benzylcarbamate (compound 140) and ((4S, Synthesis of 5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-((3,3-difluoroazacyclobutan-1-yl)methyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2-(1H)-ylidene)benzylcarbamate (compound 141) [ka]

[0676] Step 1: Synthesis of Compound 140-1 [ka]

[0677] Compound B2 (250 mg, 0.39 mmol) was dissolved in DMSO (5 mL), and 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 under a nitrogen atmosphere and stirred for 1 hour. Sodium cyanoborohydride (138 mg, 2.2 mmol) was added to the reaction mixture in portions and the mixture was allowed to react for 30 minutes. The reaction was monitored by HPLC until the starting materials had completely reacted. After cooling the reaction mixture to room temperature, 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 solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue of approximately 230 mg. 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] + .

[0678] Step 2: Synthesis of Compound 140 and Compound 141 [ka]

[0679] Compound 140-1 (100 mg, 0.14 mmol) was dissolved in water (7.5 mL) and TFA (7.5 mL), and the reaction was carried out under a nitrogen atmosphere by heating to 60°C for 20 hours. The reaction mixture was concentrated and dried, and the residue was purified by flash column chromatography (MeOH / DCM = 0-4%) to obtain compound 140 (20 mg, yield: 27.2%) and compound 141 (20 mg, yield: 27.3%).

[0680] Compound 140: 1H NMR (400 MHz, MeOD) δ 7.48-7.29 (m, 5H), 5.61 (d, J = 9.1 Hz, 1H), 5.16 (s, 2H), 4.65-4.42 (m, 1H), 4.16 (d, J = 19.5 Hz, 2H), 3.94 (s, 2H), 3.77 (t, J = 12.3 Hz, 4H), 3.17 (d, J = 12.0 Hz, 1H), 2.28 (d, J = 9.3 Hz, 1H). LCMS(m / z):529.2[M+1] + .

[0681] Compound 141: 1 H NMR (400 MHz, MeOD) δ 7.49-7.34 (m, 5H), 5.49 (s, 1H), 5.28 (s, 2H), 4.56 (d, J = 2.1 Hz, 1H), 4.55 (s, 1H), 4.27-4.21 (m, 1H), 4.10-4.03 (m, 1H), 3.77 (t, J = 12.2 Hz, 4H), 3.23 (d, J = 13.3 Hz, 1H), 3.08 (d, J = 13.4 Hz, 1H), 2.88 (d, J = 3.0 Hz, 1H). LCMS(m / z):511.2[M+1] + .

[0682] Example 114: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-((3,3-difluoroazacyclobutan-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) [ka]

[0683] Compound 141 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), 10% Pd / C (15 mg, 0.01 mmol) was added, and the mixture was substituted with hydrogen three times. Hydrogen was then introduced into the reaction mixture, and the reaction was allowed to proceed for approximately 3 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was filtered, and the filter cake was washed with 0.05 M aqueous acetic acid solution. The filtrate was concentrated to obtain the crude compound, which was further slurryed 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%).

[0684] 1 H NMR (400 MHz, D2O) δ 5.47-5.37 (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 = 9.5 Hz, 1H), 1.97 (dt, J = 4.4, 2.2 Hz, 1H). LCMS(m / z):395.1[M+1] + .

[0685] Example 115: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 143) [ka]

[0686] Step 1: Synthesis of Compound 143-1 [ka]

[0687] 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. The mixture was heated to 60°C under a nitrogen atmosphere and stirred for 1 hour. Then, sodium borohydride (138 mg, 2.2 mmol) was added to the reaction mixture in portions, and the mixture was reacted at 60°C for 30 minutes. The reaction was monitored by HPLC until the starting materials were completely reacted. After cooling the reaction mixture to room temperature, 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 brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated and dried to obtain the residue (220 mg). The residue was subjected to flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 143-1 (150 mg, yield: 52.6%). LCMS (m / z): 731.3 [M+1] + .

[0688] Step 2: Synthesis of Compound 143 [ka]

[0689] Compound 143 (150 mg, 0.2 mmol) was dissolved in water (7.5 mL) and TFA (7.5 mL), and the mixture was heated to 60°C under a nitrogen atmosphere and reacted for 20 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried, and the residue was subjected to flash column chromatography (MeOH / DCM = 0-4%) to obtain compound 143 (20 mg, yield: 18%).

[0690] 1H NMR (400 MHz, MeOD) δ 7.43-7.27 (m, 5H), 5.59 (d, J = 9.1 Hz, 1H), 5.15 (s, 2H), 4.30-3.81 (m, 4H), 3.36-3.32 (m, 1H), 3.12 (d, J = 6.8 Hz, 2H), 2.88-2.74 (m, 2H), 2.51-2.34 (m, 2H), 2.28 (d, J = 9.5 Hz, 1H). LCMS(m / z):543.2[M+1] + .

[0691] 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) [ka]

[0692] Compound 143 (15 mg, 0.03 mmol) was dissolved in methanol (10 mL), 10% Pd / C (7.5 mg) was added, and the mixture was substituted with hydrogen. Hydrogen was then introduced into the reaction mixture, and the reaction was allowed to proceed for approximately 3 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was filtered, and the filter cake was washed with 0.05 M aqueous AcOH solution. The filtrate was concentrated to obtain the crude compound, which was slurryed with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was aspirated. The residue was concentrated and dried to obtain compound 144 (8 mg, yield: 70.8%).

[0693] 1H NMR (400 MHz, D2O) δ 5.35 (d, J = 9.4 Hz, 1H), 4.18 (s, 2H), 4.00 (s, 1H), 3.87 -3.69 (m, 2H), 3.57-3.39 (m, 2H), 3.06-2.94 (m, 2H), 2.91-2.78 (m, 2H), 2.22 (d, J = 9.4 Hz, 1H). LCMS(m / z):409.2[M+1] + .

[0694] Example 117: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(piperazine-1-ylmethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 145) [ka]

[0695] Step 1: Synthesis of Compound 145-1 [ka]

[0696] Compound B2 (160 mg, 0.25 mmol), compound 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) and heated to 60°C under a nitrogen atmosphere, stirring for 1 hour. Sodium triacetylborohydride (94.2 mg, 1.5 mmol) was added, and the reaction was continued stirring for another hour. After the reaction was complete, the mixture was cooled to room temperature, water (2 mL) was added, and a white solid precipitated. After stirring for 5 minutes, the mixture was filtered to obtain compound 145-1 (150 mg, yield: 80.2%) as a grayish-white solid. LCMS (m / z): 752.3 [M+1] + .

[0697] Step 2: Synthesis of Compound 145 [ka]

[0698] Compound 145-1 (150 mg, 0.20 mmol) was dissolved in a TFA:H2O=2:1 aqueous solution (4 mL) and stirred under a nitrogen atmosphere, heated to 60°C for 16 hours. After the reaction was complete, the reaction mixture was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 5%~8%) to obtain compound 145 (18.6 mg, yield: 17.9%) as a white solid.

[0699] 1 H NMR (400 MHz, MeOD) δ 7.42-7.22 (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] + .

[0700] Example 118: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((1,3-dihydroxypropane-2-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 146) [ka]

[0701] Step 1: Synthesis of Compound 146-1 [ka]

[0702] Compound B2 (150 mg, 0.23 mmol), 3-aminooxetane (25.73 mg, 0.35 mmol), and KOAc (132.4 mg, 1.35 mmol) were dissolved in anhydrous DMSO (2.5 mL), and then AcOH (166.3 mg, 2.77 mmol) was added dropwise to the mixture. The reaction mixture was heated to 60°C and allowed to react for 1 hour. NaBH3CN (73.7 mg, 1.17 mmol) was added to the reaction mixture in portions, and the reaction was allowed to continue at 60°C for another hour. The reaction was monitored by HPLC until completion. The reaction mixture was diluted with water (25 mL), extracted with ethyl acetate (12 mL x 3), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and then 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] + .

[0703] Step 2: Synthesis of Compound 146 [ka]

[0704] Compound 146-1 (149 mg, 0.21 mmol) was dissolved in TFA (2 mL) and purified water (8 mL), and the mixture was heated to 60°C and stirred for 15 hours. The reaction was monitored by LC-MS until completion. The reaction mixture 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 obtain compound 146 (22.85 mg, yield 20.3%) as a white solid.

[0705] 1H NMR (400 MHz, MeOD) δ 7.43-7.35 (m, 5H), 5.64 (d, J = 9.3 Hz, 1H), 5.21 (s, 2H), 4.26 (d, J = 9.0 Hz, 2H), 4.15-3.96 (m, 2H), 3.84 (dd, J = 11.6, 4.6 Hz, 2H), 3.75 (dd, J = 11.8, 6.3 Hz, 2H), 3.63 (s, 2H), 3.27-3.22 (m, 1H), 2.34 (d, J = 9.4 Hz, 1H). LCMS(m / z):527.2[M+1] + .

[0706] Example 119: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(((1,3-dihydroxypropane-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) [ka]

[0707] Compound 146 (17 mg, 29.01 μmol) was dissolved in MeOH (8 mL), 10% Pd / C (5 mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere for 2 hours. The reaction was monitored by HPLC 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 washed with MeOH / H2O = 1:1 (20 mL). The filtrate was concentrated under reduced pressure and then freeze-dried to obtain compound 147 (7.39 mg, yield: 58.3%) as a white solid.

[0708] 1H NMR (400 MHz, D2O) δ 5.39 (dd, J = 9.5, 3.1 Hz, 1H), 4.24 (d, J = 1.8 Hz, 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 = 9.5 Hz, 1H). LCMS(m / z):393.2[M+1] + .

[0709] Example 120: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 148) [ka]

[0710] Compound B3 (120 mg, 0.19 mmol) was dissolved in TFA (2 mL) and H2O (2 mL), and the mixture was heated to 60°C and reacted for 48 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried, 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%).

[0711] 1 H NMR (400 MHz, MeOD) δ 7.53-7.30 (m, 5H), 5.73 (d, J = 9.3 Hz, 1H), 5.32 (s, 2H), 4.28 (d, J = 10.8 Hz, 2H), 4.04 (d, J = 6.7 Hz, 2H), 3.62-3.52 (m, 2H), 2.43 (d, J = 9.3 Hz, 1H). LCMS(m / z):453.2[M+1] + .

[0712] Example 121: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 149) [ka]

[0713] Step 1: Synthesis of Compound 149-1 [ka]

[0714] 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. The mixture was heated to 60°C under a nitrogen atmosphere and reacted for 1 hour. Sodium borohydride cyanohydride (110.8 mg, 1.77 mmol) was added to the reaction mixture in portions and reacted at 60°C for 30 minutes. The reaction was monitored by HPLC until the starting materials were completely reacted. After cooling the reaction mixture to room temperature, ice water (20 mL) was added and stirred, causing a large amount of solid to precipitate. The mixture was filtered, the filter cake was collected, and the filter cake was concentrated and dried 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] + .

[0715] Step 2: Synthesis of Compound 149 [ka]

[0716] Compound 149-1 (180 mg, 0.25 mmol) was dissolved in water (10 mL) and TFA (5 mL), and reacted under a nitrogen atmosphere by heating to 60°C for 20 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried, and the residue was purified by flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 149 (30 mg, yield: 22.6%).

[0717] 1 H NMR (400 MHz, MeOD) δ 7.49-7.26 (m, 5H), 5.66 (d, J = 9.3 Hz, 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 = 9.4 Hz, 2H). LCMS(m / z):525.2[M+1]+.

[0718] 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) [ka]

[0719] Compound 149 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), 10% Pd / C (20 mg) was added, and the mixture was substituted with hydrogen. Hydrogen was then introduced into the reaction mixture, and the reaction was allowed to proceed for 3 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was filtered, and the filter cake was washed with 0.05 M aqueous AcOH solution. The filtrate was concentrated to obtain the crude compound, which was slurryed with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was aspirated. The residue was concentrated and dried to obtain the acetate of compound 150 (15 mg, yield: 100%).

[0720] 1 H NMR (400 MHz, D2O) δ 5.42 (d, J = 9.4 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):391.2[M+1] + .

[0721] Example 123: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-2(1H)-ylidene)benzylcarbamate octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-6-carboxylate methyl ester (Compound 151) [ka]

[0722] Compound 67 (44 mg, 0.09 mmol), 18-crown ether-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 reacted with stirring at room temperature for 17 hours. After the reaction was complete, the mixture was concentrated into a crude product, which was purified using a reversed-phase column (methanol / 0.1% aqueous acetic acid solution = 0-4%) to obtain compound 151 (4.2 mg, yield: 9.3%).

[0723] 1 H NMR (400 MHz, MeOD) δ 7.44-7.19 (m, 5H), 5.32 (s, 1H), 5.07 (s, 2H), 4.65 (dd, J = 3.0, 1.7 Hz, 1H), 4.53 (t, J = 1.9 Hz, 1H), 4.47-4.40 (m, 2H), 3.81 (s, 3H), 2.68 (d, J = 2.8 Hz, 1H). LCMS(m / z):482.1[M+1] + .

[0724] Example 124: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(3-fluoroazacyclobutane-1-formyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 152) [ka]

[0725] 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 under a nitrogen atmosphere at 25°C for 1 hour. After the reaction was complete, the reaction mixture was purified by reverse-phase column chromatography (methanol / 5% aqueous acetic acid solution = 0%~10%) to obtain compound 152 (11.3 mg, yield: 31.4%) as a grayish-white solid.

[0726] 1 H NMR (400 MHz, MeOD) δ 7.45-7.17 (m, 5H), 5.57 (d, J = 9.4 Hz, 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 = 7.3 Hz, 1H). LCMS(m / z):525.2[M+1] + .

[0727] Example 125: Synthesis of ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(3-fluoroazacyclobutane-1-formyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 153) [ka]

[0728] 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 under a nitrogen atmosphere at 25°C for 1 hour. After the reaction was complete, the reaction mixture was purified by reverse-phase column chromatography (methanol / 5% aqueous acetic acid solution = 0%~10%) to obtain compound 153 (10.5 mg, yield: 37.3%) as a grayish-white solid.

[0729] 1 H NMR (400 MHz, MeOD) δ 7.44-7.22 (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), 4.45 (d, J = 3.1 Hz, 1H), 4.43 (d, J = 2.0 Hz, 1H), 4.39-4.27 (m, 1H), 4.22-3.97 (m, 1H), 2.70 (d, J = 2.9 Hz, 1H). LCMS(m / z):507.1[M+1] + .

[0730] Example 126: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(3-fluoroazacyclobutane-1-formyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 154) [ka]

[0731] Compound 152 (7.0 mg, 0.01 mmol) was dissolved in methanol (2 mL), Pd / C (1 mg) was added, the mixture was replaced three times with hydrogen, and the reaction was stirred at 25°C for 3 hours. After the reaction was complete, a 1% aqueous acetic acid solution was added, the mixture was stirred for 5 minutes, filtered, washed three times with a 1% aqueous acetic acid solution, the filtrate was concentrated and dried, and freeze-dried to obtain compound 154 (3.4 mg, yield: 65.3%) as a grayish-white solid.

[0732] 1H NMR (400 MHz, D2O) δ 5.48-5.24 (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, 9.8 Hz, 1H). LCMS(m / z):391.1[M+1] + .

[0733] Example 127: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 155) [ka]

[0734] Step 1: Synthesis of Compound 155-1 [ka]

[0735] Compound B1 (150 mg, 0.23 mmol) was dissolved in DCM (10 mL), then 3-fluorocyclobutane-1-amine hydrochloride (43 mg, 0.34 mmol) and HATU (130 mg, 0.34 mmol) were added, and TEA (69.4 mg, 0.69 mmol) was added dropwise. The reaction was carried out overnight at room temperature under a nitrogen atmosphere. 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, and concentrated to obtain the 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] + .

[0736] Step 2: Synthesis of Compound 155 [ka]

[0737] Compound 155-1 (120 mg, 0.17 mmol) was dissolved in water (10 mL) and TFA (5 mL), and reacted under a nitrogen atmosphere by heating to 60°C for 20 hours. The reaction mixture was concentrated and dried, and the residue was purified by reverse-phase column chromatography (MeOH / H2O = 0-15%) to obtain compound 155 (20 mg, yield: 22.5%).

[0738] 1 H NMR (400 MHz, MeOD) δ 7.57-7.12 (m, 5H), 5.58 (d, J = 9.3 Hz, 1H), 5.09 (s, 2H), 4.8-4.68 (m, 1H), 4.64-4.47 (m, 1H), 4.38 (s, 1H), 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] + .

[0739] 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) [ka]

[0740] Compound 155 (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), 10% Pd / C (20 mg) was added, and the mixture was substituted with hydrogen. Hydrogen was then introduced into the reaction mixture, and the reaction was allowed to proceed for 3 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was filtered, and the filter cake was washed with 0.05 M aqueous AcOH solution. The filtrate was concentrated to obtain the crude compound, which was slurryed with methyl tert-butyl ether (10 mL), allowed to stand, and the supernatant was aspirated. The residue was concentrated and dried to obtain the acetate of compound 156 (15 mg, yield: 100%).

[0741] 1 H NMR (400 MHz, D2O) δ 5.42 (d, J = 9.5 Hz, 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] + .

[0742] Example 129: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate ((Compound 157)) [ka]

[0743] Step 1: Synthesis of Compound 157-1 [ka]

[0744] 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 the mixture was reacted at room temperature for 3 hours.

[0745] The reaction was monitored by LC-MS until completion. The solution was diluted with dichloromethane (40 mL), washed with saturated sodium chloride (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the 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. LC-MS (m / z): 725.3 [M+1] + .

[0746] Step 2: Synthesis of Compound 157 [ka]

[0747] Compound 157-1 (120 mg, 0.17 mmol) was dissolved in TFA (5 mL) and purified water (10 mL), and the mixture was heated to 60°C and reacted for 18 hours. The reaction was monitored by MS until completion. The reaction mixture 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 obtain compound 157 (13 mg, yield: 25.9%) as a white solid.

[0748] 1 H NMR (400 MHz, MeOD) δ 7.45-7.37 (m, 5H), 5.71 (d, J = 9.4 Hz, 1H), 5.30 (s, 2H), 4.48-4.38 (m, 3H), 4.24 (d, J = 8.4 Hz, 2H), 4.02 (s, 1H), 2.48-2.24 (m, 5H). LCMS(m / z):537.2[M+1] + .

[0749] 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) [ka]

[0750] Compound 157 (17 mg, 0.03 mmol) and 10% palladium-carbon (2 mg) were added to methanol (10 mL), substituted three times with hydrogen, and reacted at room temperature for 2 hours. The reaction was monitored by HPLC until completion. The reaction mixture was concentrated under reduced pressure and lyophilized to obtain compound 158 (10 mg, yield: 78.4%) as a white solid.

[0751] 1 H NMR (400 MHz, D2O) δ 5.45 (d, J = 9.4 Hz, 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] + .

[0752] Example 131: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 159) [ka]

[0753] Step 1: Synthesis of Compound 159-1 [ka]

[0754] 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 the reaction was complete, water was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed once with saturated brine, separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated and dried, 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] + .

[0755] Step 2: Synthesis of Compound 159 [ka]

[0756] Compound 159-1 (161 mg, 0.22 mmol) was added to water:trifluoroacetic acid = 1:1 (16 mL) and stirred at 65°C for 17 hours. After the reaction was complete, the mixture was concentrated into a crude product, which was purified using a reversed-phase column (methanol / 0.1% aqueous acetic acid solution = 0-7%) to obtain compound 159 (14 mg, yield: 11.8%).

[0757] 1H NMR (400 MHz, MeOD) δ 7.46-7.25 (m, 5H), 5.99 (tt, J = 56.2, 4.1 Hz, 1H), 5.62 (d, J = 9.4 Hz, 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, 4.1 Hz, 2H), 2.33 (d, J = 9.5 Hz, 1H). LCMS(m / z):531.2[M+1] + .

[0758] 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) [ka]

[0759] Compound 159 (6 mg, 0.01 mmol) and 10% Pd / C (3 mg) were added to methanol (5 mL), purged with hydrogen, and stirred under a hydrogen atmosphere at 25°C for 4 hours. After the reaction was complete, a 1% aqueous acetic acid solution was added and stirred for 0.5 hours. The mixture was then filtered, the filtrate was collected, and concentrated under reduced pressure to obtain compound 160 (2.1 mg, yield: 46.9%).

[0760] 1 H NMR (400 MHz, D2O) δ 6.15-5.80 (m, 1H), 5.45 (d, J = 9.4 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):397.1[M+1] + .

[0761] Example 133: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(cyclopropanecarboxamidemethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 161) [ka]

[0762] Step 1: Synthesis of Compound 161-1 [ka]

[0763] A 25 mL necked flask was taken, and 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. The mixture was stirred under a nitrogen atmosphere for 30 minutes, and then monitored by HPLC until most of the starting materials had completely reacted. Water (10 mL) was added to the reaction mixture, and it was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified using a positive-phase column (dichloromethane / methanol = 20:1) to obtain the white solid compound 161-1 (150 mg, yield: 97.3%). LCMS (m / z): 709.3 [M+1] + .

[0764] Step 2: Synthesis of Compound 161 [ka]

[0765] A 25 mL reaction flask was prepared, and compound 161-1 (140 mg, 0.20 mmol) was dissolved in trifluoroacetic acid:water = 2:1 (5 mL). The mixture was heated to 60°C and reacted overnight. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried to obtain the crude product. The crude product was purified by prep-HPLC to obtain compound 161 (24.5 mg, yield: 23.5%).

[0766] 1 H NMR (400 MHz, MeOD) δ 7.49-7.31 (m, 5H), 5.62 (d, J = 9.4 Hz, 1H), 5.13 (s, 2H), 4.35-3.84 (m, 6H), 2.28 (d, J = 9.7 Hz, 1H), 1.79-1.72 (m, 1H), 0.99-0.83 (m, 4H). LCMS(m / z):521.2[M+1] + .

[0767] Example 134: Synthesis of (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(cyclopropanecarboxamidemethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 162) [ka]

[0768] A 25 mL necked flask was taken, compound 161 (10.0 mg, 0.02 mmol) was dissolved in methanol (2 mL), 10% palladium-carbon (2 mg) was added, and the mixture was replaced three times with hydrogen. The hydrogenation reaction was carried out under hydrogen balloon pressure for 3 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was filtered, the filter cake was collected, deionized water (10 mL) and 2.5% aqueous acetic acid solution (5 mL) were added, the mixture was stirred at room temperature for 1 hour, and then filtered. This procedure was repeated once more. All the filtrates were combined, concentrated and dried, and washed twice with methanol to obtain the crude product. Two drops of methanol were added to the crude product to dissolve all the products, then methyl tert-butyl ether (2 mL) was added, the mixture was stirred for 5 minutes, allowed to stand, and the supernatant was aspirated. Then, methyl tert-butyl ether (2 mL) was added again, the mixture was stirred for 5 minutes, allowed to stand, and the supernatant was aspirated. The residue was concentrated and dried to obtain compound 162 (5.2 mg, yield: 69.4%), a white solid.

[0769] 1 H NMR (400 MHz, D2O) δ 5.47 (d, J = 9.4 Hz, 1H), 4.43 (s, 1H), 4.25 (d, J = 9.0 Hz, 1H), 4.17 (s, 1H), 4.00 (s, 1H), 3.95 (d, J = 7.6 Hz, 1H), 3.84 (s, 1H), 2.31 (d, J = 9.4 Hz, 1H), 1.71-1.63 (m, 1H), 0.85 (d, J = 6.2 Hz, 4H). LCMS(m / z):387.1[M+1] + .

[0770] Example 135: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 163) [ka]

[0771] Step 1: Synthesis of Compound 163-1 [ka]

[0772] A 25 mL necked flask was taken, and compound B3 (150 mg, 0.23 mmol) and acetic acid (16.8 mg, 0.28 mmol) were dissolved in anhydrous dichloromethane (5 mL). The mixture was cooled to 0°C, and HATU (106 mg, 0.28 mmol) and triethylamine (59 mg, 0.59 mmol) were added to the reaction mixture. The mixture was stirred under a nitrogen atmosphere for 30 minutes. The reaction was monitored by HPLC until most of the starting materials had reacted. Water (10 mL) was added to the reaction mixture, and it was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried 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] + .

[0773] Step 2: Synthesis of Compound 163 [ka]

[0774] A 25 mL reaction flask was prepared, and compound 163-1 (135 mg, 0.20 mmol) was dissolved in trifluoroacetic acid:water = 2:1 (5 mL). The mixture was heated to 60°C and reacted overnight. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried to obtain the crude product. The crude product was purified by prep-HPLC to obtain compound 163 (24.5 mg, yield: 23.5%).

[0775] 1H NMR (400 MHz, MeOD) δ 7.41-7.26 (m, 5H), 5.56 (d, J = 9.3 Hz, 1H), 5.08 (s, 2H), 4.30-3.75 (m, 6H), 2.22 (d, J = 9.3 Hz, 1H), 1.96 (s, 3H). LCMS(m / z):495.2[M+1] + .

[0776] 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) [ka]

[0777] A 25 mL necked flask was taken, compound 163 (7.1 mg, 0.01 mmol) was dissolved in methanol (2 mL), 10% palladium-carbon (1 mg) was added, the mixture was replaced three times with hydrogen, and the hydrogenation reaction was carried out under hydrogen balloon pressure for 3 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was filtered, the filter cake was collected, deionized water (10 mL) and 2.5% aqueous acetic acid solution (5 mL) were added, the mixture was stirred at room temperature for 1 hour, and then filtered. The above procedure was repeated once. All the filtrates were combined, concentrated and dried, and washed twice with methanol to obtain the crude product. Two drops of methanol were added to the crude product to dissolve all the products, then methyl tert-butyl ether (2 mL) was added, the mixture was stirred for 5 minutes, allowed to stand, and the supernatant was aspirated. Then, methyl tert-butyl ether (2 mL) was added again, the mixture was stirred for 5 minutes, allowed to stand, and the supernatant was aspirated. The residue was concentrated and dried to obtain compound 164 (4.1 mg, yield: 82.7%), a white solid.

[0778] 1H NMR (400 MHz, D2O) δ 5.52 (dd, J = 8.8, 3.6 Hz, 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 = 9.5 Hz, 1H), 2.08 (s, 3H). LCMS(m / z):361.1[M+1] + .

[0779] 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]pyrimidine-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-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)acetamide (compound 166) [ka]

[0780] Step 1: Synthesis of Compound 165-2 [ka] Compound 165-1 (1 g, 5.26 mmol) was dissolved in DCM (3 mL), diisopropylethylamine (0.7 g, 5.43 mmol) was added, the temperature was lowered to 0 °C under a nitrogen atmosphere, acetic anhydride (0.54 g, 5.32 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours. The reaction solution was poured into water (100 mL) and extracted with DCM (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (EA / PE = 0 - 30%) to obtain liquid compound 165-2 as a colorless oil (1.1 g, yield: 90.2%).

[0781] HRMS(ESI + ):C9H 16 N2O3S([M+H] + ): Calculated value: 233.09, Measured value: 232.30.

[0782] Step 2: Synthesis of compound 165-3

Chemical Structure

[0783] Compound S8 (200 mg, 0.54 mmol) was dissolved in acetonitrile (10 mL), compound 165-2 (150 mg, 0.65 mmol) and triethylamine (272 mg, 2.7 mmol) were added, the temperature was lowered to 0 °C under a nitrogen atmosphere, and silver trifluoromethanesulfonate (277.5 mg, 1.08 mmol) was added. After the addition was completed, the temperature was gradually raised to room temperature and the reaction was carried out 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 as a white foamy solid (225 mg, yield: 75.2%).

[0784] HRMS(ESI+):C 25 H 37 N3O 11 ([M+H] + ): Calculated value: 556.24, Measured value: 556.58.

[0785] Step 3: Synthesis of Compound 165 and Compound 166 [ka]

[0786] Compound 165-3 (220 mg, 0.40 mmol) was dissolved in water (10 mL) and TFA (10 mL), and reacted under a nitrogen atmosphere by heating to 60°C for 18 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried, and the residue was purified by Prep-HPLC to obtain formate of compound 165 (22 mg, yield: 15%) and formate of compound 166 (12 mg, yield: 8.2%). Total yield: 23.2%.

[0787] Compound 165: 1 H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 5.66 (d, J = 8.7 Hz, 1H), 4.28-4.12 (m, 2H), 4.06-3.92 (m, 4H), 2.34 (d, J = 9.6 Hz, 1H), 2.16 (s, 3H). LCMS(m / z):362.1[M+1] + .

[0788] Compound 166: 1 H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 5.39 (s, 1H), 4.52 (d, J = 1.9 Hz, 1H), 4.50 (s, 1H), 4.21 (s, 1H), 4.04 (s, 1H), 3.97 (d, J = 11.4 Hz, 1H), 3.91 (d, J = 11.4 Hz, 1H), 2.79 (d, J = 2.8 Hz, 1H), 2.12 (s, 3H). LCMS(m / z):344.1[M+1] + .

[0789] Example 138: Synthesis of ((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]pyrimidine-2(1H)-ylidene)carbamate cyclopentyl ester (compound 167) [ka]

[0790] Step 1: Synthesis of Compound 167-2 [ka]

[0791] 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), cooled to 0°C under a nitrogen atmosphere, 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. The reaction mixture was diluted with dichloromethane (50 mL), washed with saturated sodium chloride (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the 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] + .

[0792] Step 2: Synthesis of Compound 167-3 [ka]

[0793] 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 a nitrogen atmosphere for 16 hours. The reaction mixture was quenched with saturated sodium chloride (1 mL), diluted with ethyl acetate (30 mL), washed with saturated sodium chloride (2 × 10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0%~20%) to obtain compound 167-3 (0.35 g, yield: >100%) as a white solid. LCMS (m / z): 626.3 [M+1] + .

[0794] Step 3: Synthesis of Compound 167 [ka]

[0795] 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), and the mixture was heated to 60°C under a nitrogen atmosphere and stirred for 18 hours. The reaction mixture was concentrated to obtain the residue. The residue was purified by reverse-phase purification to obtain compound 167 (31 mg, yield: 30%) as a white solid.

[0796] 1 H NMR (400 MHz, MeOD) δ 5.66 (d, J = 9.4 Hz, 1H), 5.23-5.17 (m, 1H), 4.22 (d, J = 20.6 Hz, 2H), 4.01 (d, J = 22.7 Hz, 4H), 2.36 (d, J = 9.4 Hz, 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] + .

[0797] Example 139: Synthesis of ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 168) and ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-cyanooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 169) [ka]

[0798] Step 1: Synthesis of Compound 168-2 [ka]

[0799] 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 mixture was stirred at room temperature under a nitrogen atmosphere and allowed to react overnight. The reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product Compound 168-2 (220 mg, yield: 108%), which was used directly in the next reaction. LCMS (m / z): 637.2 [M+1] + .

[0800] Step 2: Synthesis of Compound 168 and Compound 169 [ka]

[0801] Compound 168-2 (220 mg, 0.35 mmol) was dissolved in (10 mL) and TFA (10 mL), and the mixture was heated to 60°C under a nitrogen atmosphere, stirred, and allowed to react overnight. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried to obtain the 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%).

[0802] Compound 168: 1 H NMR (400 MHz, MeOD) δ 7.41-7.25 (m, 5H), 5.58 (d, J = 9.3 Hz, 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 = 8.0 Hz, 1H). LCMS(m / z):449.1[M+1] + .

[0803] Compound 169: 1 H NMR (400 MHz, MeOD) δ 7.49-7.11 (m, 5H), 5.36 (s, 1H), 5.09 (s, 2H), 4.52-4.46 (m, 2H), 4.41 (d, J = 2.1 Hz, 1H), 4.34 (s, 1H), 2.71 (d, J = 2.9 Hz, 1H). LCMS(m / z):431.1[M+1] + .

[0804] Example 140: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((5-methyl-1,2,4-oxydiazepine-3-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 170), ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10, Synthesis of 11-pentahydroxy-6-(ureidomethyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 171) and (4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-6-(ureidomethyl)-2-iminooctanoic acid-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-4,6,9,10,11(10H)-pentanol (compound 172) [ka]

[0805] Step 1: Synthesis of Compound B3-1 [ka]

[0806] 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 carry out the reaction. After the reaction was complete, water was added to the reaction mixture, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain compound B3-1 (70 mg, yield: 67.4%) as a white solid.

[0807] Step 2: Synthesis of Compound 170-1 and Compound 171-1 [ka]

[0808] Compound B3-1 (240 mg, 0.36 mmol) and potassium carbonate (149 mg, 1.08 mmol) were added to ethanol (12 mL), followed by the addition of hydroxylamine hydrochloride (30.1 mg, 0.43 mmol), and the mixture was stirred at room temperature. After the reaction was complete, water (40 mL) was added to the system, and the mixture was extracted with dichloromethane (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to 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.

[0809] Step 3: Synthesis of Compound 170-2 [ka]

[0810] Compound 170-1 (95 mg, 0.14 mmol) was dissolved in DCM (5 mL), and the temperature was controlled to 0°C in an ice bath. Acetyl chloride (13.5 mg, 0.171 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Then, 1,2-dichloroethane (15 mL) was added, and the mixture was heated to 80°C and stirred for 2 hours. After the starting materials had completely reacted, the system was concentrated and dried to obtain the 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%).

[0811] Step 4: Synthesis of Compound 170 [ka]

[0812] Compound 170-2 (70 mg, 0.10 mmol) was dissolved in a mixed solution of water (3.2 mL) and TFA (0.8 mL) and stirred at 60°C for 16 hours. The reaction mixture was then concentrated and dried to obtain the crude product. The crude product was purified by wet-loading reverse-phase column chromatography and freeze-dried to obtain a white solid compound 170 (16 mg, yield: 30.9%). LCMS (m / z): 535.2 [M+1] + .

[0813] Step 5: Synthesis of Compound 171 [ka]

[0814] Compound 171-1 (49 mg, 0.07 mmol) was dissolved in a mixed solution of water (4 mL) and TFA (1 mL) and stirred at 60°C for 16 hours. The reaction system was then concentrated and dried to obtain the crude product. The crude product was purified by reverse-phase column chromatography with wet loading and freeze-dried to obtain compound 171 (14 mg, yield: 39.4%) as a white solid.

[0815] 1 H NMR (400MHz, MeOD) δ 7.39 (dt, J = 19.2, 6.5Hz, 5H), 5.66 (d, J = 9.4Hz, 1H), 5.24 (d, J = 12.5 Hz, 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] + .

[0816] Step 6: Synthesis of Compound 172 [ka]

[0817] Compound 171 (11 mg, 0.02 mmol) was dissolved in methanol (3 mL), 10% palladium-carbon (4 mg) was added, the mixture was purged with hydrogen, and the reaction was stirred for 3 hours under hydrogen balloon pressure. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to obtain compound 172 (7 mg, yield: 87.3%) as a white solid.

[0818] 1 H NMR (400 MHz, D2O) δ 5.40 (d, J = 9.5 Hz, 1H), 4.27-4.05 (m, 2H), 3.90 (d, J = 26.2 Hz, 2H), 3.65 (s, 2H), 2.24 (d, J = 9.4 Hz, 1H). LCMS(m / z):362.1[M+1] + .

[0819] Example 141: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((E)-2-hydroxyguanidinyl)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 173) [ka]

[0820] Step 1: Synthesis of Compound 173-1 [ka]

[0821] Compound 170-1 (95 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and the temperature was controlled to 0°C in an ice bath. Trifluoroacetic anhydride (36 mg, 0.17 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Subsequently, 1,2-dichloroethane (15 mL) was added, and the mixture was heated to 80°C and stirred for 2 hours. After the starting materials had completely reacted, the system was concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 0-35%), concentrated, and obtained the crude product Compound 173-1 (50 mg, yield: 47.3%). LCMS (m / z): 777.2 [M+1] + .

[0822] Step 2: Synthesis of Compound 173 [ka]

[0823] Compound 173-1 (50 mg, 0.06 mmol) was dissolved in a mixed solution of water (2.4 mL) and TFA (0.6 mL) and the reaction was stirred at 60°C for 16 hours. The reaction system was then rotate-dried to obtain the crude product, which was purified by reverse-phase column chromatography with wet loading and freeze-dried to obtain compound 173 (7 mg, yield: 21.3%) as a white solid.

[0824] 1 H NMR (400 MHz, MeOD) δ 7.38-7.25 (m, 5H), 5.52 (dd, J = 17.6, 8.1 Hz, 1H), 5.06 (s, 2H), 4.17 (s, 1H), 4.10 (d, J = 9.8 Hz, 2H), 3.96 (s, 1H), 3.76 (d, J = 14.8 Hz, 2H), 2.22 (d, J = 9.4 Hz, 1H). LCMS(m / z):511.2[M+1] + .

[0825] Example 142: ((4S,5aS,6S,8R,9S,10S,11S,11aR,12R)-9-((3-hydroxyazacyclobutan-1-yl)methyl)-2-iminooctahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]diaza-9-yl)methyl ketone (compound 175) [ka]

[0826] The compound 175 acetate (4.8 mg, yield: 66%) was synthesized by referring to the method of Example 2.

[0827] 1 H NMR (400 MHz, D2O) δ 5.49 (s, 1H), 4.60-4.52 (m, 4H), 4.33-4.28 (m, 1H), 4.20-4.08 (s, 4H), 3.88 (d, J = 14.1 Hz, 1H), 3.76 (d, J = 14.1 Hz, 1H), 2.95 (d, J = 2.8 Hz, 1H), 1.91 (s, 3H). LCMS(m / z):357.1[M+1] + .

[0828] Example 143: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(benzylcarbamoyl)octahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 176) and ((4S,5 Synthesis of aS,6S,8R,9S,10S,11S,11aR,12R,E)-6,9,11-trihydroxy-9-(benzylcarbamoyl)octahydro-4,8,11a-(epimethanetriyl)-6,10-epoxyoxyno[4,3-f][1,3,5]oxydiazepine-2(1H)-ylidene)benzylcarbamate (compound 177) [ka]

[0829] Step 1: Synthesis of Compound 176-1 [ka]

[0830] Compound B1 (50 mg, 0.08 mmol) and benzylamine (9.5 mg, 0.09 mmol) were dissolved in dichloromethane (4 mL). HATU (36 mg, 0.09 mmol) and triethylamine (24 mg, 0.24 mmol) were then added, and the mixture was stirred at room temperature for 16 hours. After the starting materials had completely reacted, water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain compound 176-1 (60 mg, yield >100%) as a white solid. LCMS (m / z): 745.3 [M+1] + .

[0831] Step 2: Synthesis of Compound 176 and Compound 177 [ka]

[0832] Compound 176-1 (60 mg, 0.08 mmol) was dissolved in a mixed solution 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 and dried to obtain the crude product. The crude product was purified by high-performance liquid chromatography to obtain compound 176 (12 mg, yield: 28.3%) as a white solid and compound 177 (6 mg, yield: 14.1%) as a white solid. Total yield: 42.4%.

[0833] Compound 176: 1H NMR (400 MHz, MeOD) δ 7.39-7.21 (m, 10H), 5.56 (d, J = 9.4 Hz, 1H), 5.05 (s, 2H), 4.54 (d, J = 3.1 Hz, 2H), 4.37 (s, 1H), 4.21 (s, 2H), 4.08 (d, J = 14.2 Hz, 1H), 2.29 (d, J = 9.4 Hz, 1H). LCMS(m / z):557.2[M+1] + .

[0834] Compound 177: 1 H NMR (400 MHz, MeOD) δ 7.43-7.20 (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 = 2.8 Hz, 1H). LCMS(m / z):539.2[M+1] + .

[0835] Example 144: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(((4,5-dihydro-1H-imidazole-2-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 178) [ka]

[0836] Step 1: Synthesis of Compound 178-1 [ka]

[0837] Compound B3 (80 mg, 0.12 mmol) and compound 2-(methylthio)-4,5-dihydro-1H-imidazole (36.5 mg, 0.15 mmol) were dissolved in pyridine (2 mL) and stirred under a nitrogen atmosphere at a temperature of 50°C for 16 hours. After the reaction was complete, the reaction mixture was concentrated and dried to obtain the residue. The residue was purified by reverse-phase column chromatography (methanol / 5% aqueous acetic acid solution = 5%~20%) to obtain compound 178-1 (60 mg, yield: 67.8%) as a grayish-white solid. LCMS (m / z): 709.3 [M+1] + .

[0838] Step 2: Synthesis of Compound 178 [ka]

[0839] Compound 178-1 (60 mg, 0.08 mmol) was dissolved in a mixed solution of TFA:H2O = 2:1 (4 mL). The mixture was heated to 60°C under a nitrogen atmosphere and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated and dried to obtain the residue. The residue was purified by reverse-phase column chromatography (methanol:0.1% aqueous acetic acid solution = 5%~8%) to obtain compound 178 (7.5 mg, yield: 17%) as a white solid.

[0840] 1 H NMR (400 MHz, MeOD) δ 7.47-7.22 (m, 5H), 5.55 (d, J = 8.7 Hz, 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 = 9.6 Hz, 1H). LCMS(m / z):521.2[M+1] + .

[0841] Example 145: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S)-4,6,9,10,11-pentahydroxy-6-(((4,5-dihydro-1H-imidazole-2-yl)amino)methyl)octahydro-5,9-epoxy-7,10a-methyleneoxy[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 179) [ka]

[0842] Compound 178 (7.5 mg, 0.01 mmol) was dissolved in methanol (2 mL), and 10% Pd / C (1 mg) was added. The mixture was replaced three times with hydrogen and stirred at 25°C for 8 hours. After the reaction was complete, a 1% aqueous acetic acid solution was added, the mixture was stirred for 5 minutes, filtered, and then washed 2-3 times with a 1% aqueous acetic acid solution. The solution was frozen and dried to obtain compound 179 (3.2 mg, yield: 57.3%) as a grayish-white solid.

[0843] 1 H NMR (400 MHz, D2O) δ 5.41 (d, J = 9.3 Hz, 1H), 4.27-4.19 (m, 1H), 4.15 (s, 1H), 3.97 (s, 1H), 3.91 (d, J = 8.5 Hz, 1H), 3.68-3.61 (m, 6H), 2.27 (d, J = 9.4 Hz, 1H). LCMS(m / z):387.2[M+1] + .

[0844] Example 146: ((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]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 180) [ka]

[0845] Step 1: Synthesis of Compound 180-1 [ka]

[0846] 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. The mixture was heated to 50°C under a nitrogen atmosphere and stirred for 16 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried to obtain the 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] + .

[0847] Step 2: Synthesis of Compound 180 [ka]

[0848] Compound 180-1 (180 mg, 0.2 mmol) was dissolved in a mixed solution of water (10 mL) and TFA (5 mL), and the mixture was heated to 60°C under a nitrogen atmosphere and stirred for 20 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was concentrated and dried to obtain the residue. The residue was purified by flash column chromatography (MeOH / DCM = 0-4%) to obtain compound 180 (37.5 mg, yield: 37.2%).

[0849] 1H NMR (400 MHz, MeOD) δ 7.47-7.25 (m, 5H), 5.64 (d, J = 8.8 Hz, 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 = 9.5 Hz, 1H). LCMS(m / z):495.2[M+1] + .

[0850] 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]pyrimidine-6-yl)methyl)guanidine (compound 181) [ka]

[0851] Compound 180 (30 mg, 0.06 mmol) was dissolved in methanol (10 mL), 10% Pd / C (15 mg) was added, and the mixture was substituted with hydrogen. Hydrogen was then introduced into the reaction mixture and the reaction was allowed to proceed for 3 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. The reaction mixture was filtered, and the filtered cake was washed with 0.05 M HOAc aqueous solution. The filtrate was concentrated and dried to obtain the crude compound. The crude compound was slurryed with methyl tert-butyl ether (10 mL), allowed to stand, the supernatant was absorbed, and the residue was concentrated and dried to obtain compound 181 (20 mg, yield: 91.5%).

[0852] 1 H NMR (400 MHz, D2O) δ 5.42 (d, J = 9.3 Hz, 1H), 4.23 (s, 1H), 4.17 (s, 1H), 3.98 (s, 1H), 3.90 (s, 1H), 3.79 (d, J = 15.1 Hz, 1H), 3.70 (d, J = 15.1 Hz, 1H), 2.28 (d, J = 9.2 Hz, 1H). LCMS(m / z):361.1[M+1]+ .

[0853] Example 148: ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(methylsulfonylamidemethyl)octahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 182) [ka]

[0854] Step 1: Synthesis of Compound 182-1 [ka]

[0855] Compound B3 (140 mg, 0.22 mmol), methylsulfonic 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 the reaction was complete, the mixture was concentrated and dried to obtain the crude product of compound 182-1 (157 mg, yield: 100%). LCMS (m / z): 719.2 [M+1] + .

[0856] Step 2: Synthesis of Compound 182 [ka]

[0857] Compound 182-1 (157 mg, 0.22 mmol) was dissolved in a 1:1 water:trifluoroacetic acid mixture (6 mL) and heated to 65°C, stirring for 17 hours. After the reaction was complete, the mixture was concentrated and dried to obtain the crude product. The crude product was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 0-7%) to obtain compound 182 (14 mg, yield: 12%).

[0858] 1 H NMR (400 MHz, MeOD) δ 7.41-7.27 (m, 5H), 5.59 (d, J = 8.8 Hz, 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 = 9.1 Hz, 1H). LCMS(m / z):531.1[M+1] + .

[0859] 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]pyrimidine-6-yl)methyl)methanesulfonamide (Compound 183) [ka]

[0860] Compound 182 (6 mg, 0.01 mmol) was dissolved in methanol (2 mL), 10% Pd / C (3 mg) was added, and the mixture was replaced with hydrogen and stirred at 28°C for 4 hours. After the reaction was complete, a 0.5% aqueous acetic acid solution was added and the mixture was stirred for 0.5 hours. The mixture was filtered, the filtrate was concentrated and dried, and then freeze-dried to obtain compound 183 (3 mg, yield: 67%). LCMS (m / z): 397.1 [M+1] + .

[0861] Example 150: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-((N-methylmethylsulfonamide)methyl)octahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 184) [ka]

[0862] Step 1: Synthesis of Compound 89-1 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), heated to 60°C under a nitrogen atmosphere, and reacted for 30 minutes. Then, sodium triacetylborohydride (450 mg, 2.12 mmol) was added in portions, and the reaction was continued for 3 hours. The reaction was monitored by HPLC until the starting materials were completely reacted. After the reaction was complete, the reaction mixture was cooled to room temperature and then added to water (30 mL). A white solid precipitated, which 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 (140 mg, yield: >100%) as a white solid. LCMS(m / z):655.3[M+1] + .

[0863] Step 2: Synthesis of Compound 184-2 [ka]

[0864] Compound 89-1 (170 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), triethylamine (105 mg, 1.04 mmol) was added, and under temperature control in an ice bath, methanesulfonic anhydride (68 mg, 0.39 mmol) was added 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, concentrated, and dried to obtain the 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] + .

[0865] Step 3: Synthesis of Compound 184 [ka]

[0866] Compound 184-2 (150 mg, 0.20 mmol) was dissolved in a mixed solution of water (8 mL) and TFA (2 mL), and the mixture was heated to 60°C and stirred for 16 hours. The reaction system was concentrated and dried to obtain the crude product. The crude product was purified by reverse-phase column chromatography with wet loading, and freeze-dried to obtain compound 184 (25 mg, yield: 22%) as a white solid.

[0867] 1 H NMR (400MHz, MeOD) δ 7.49-7.36 (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] + .

[0868] 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]pyrimidine-6-yl)methyl)methanesulfonamide (Compound 185) [ka]

[0869] Compound 184 (20 mg, 0.04 mmol) was dissolved in methanol (3 mL), 10% palladium-carbon (3 mg) was added, and the mixture was replaced three times with hydrogen and stirred for 3 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried to obtain compound 185 (15 mg, yield: 99%), a white solid.

[0870] 1H NMR (400 MHz, D2O) δ 5.40 (dd, J = 9.3, 6.0 Hz, 1H), 4.16 (d, J = 5.2 Hz, 2H), 4.08 (s, 1H), 3.90 (dd, J = 14.3, 5.5 Hz, 3H), 3.12 (s, 3H), 2.75-2.68 (m, 1H), 2.09 (d, J = 4.9 Hz, 3H). LCMS(m / z):411.1[M+1] + .

[0871] Example 152: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(guanidinomethyl)octahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 186) [ka]

[0872] Step 1: Synthesis of Compound 186-1 [ka]

[0873] 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 reaction was stirred at 17°C for 1.5 hours. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated and dried to obtain the 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] + .

[0874] Step 2: Synthesis of Compound 186 [ka]

[0875] Compound 186-1 (145 mg, 0.19 mmol) was dissolved in a 10 mL mixed solution of water and trifluoroacetic acid in a 1:2 ratio, and the mixture was heated to 60°C and stirred for 20 hours. After the reaction was complete, the reaction solution was concentrated and dried to obtain the residue. The residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 0-7%) to obtain compound 186 (17.1 mg, yield: 15.6%).

[0876] 1 H NMR (400 MHz, MeOD) δ 7.40-7.29 (m, 5H), 5.59 (d, J = 10.0 Hz, 1H), 5.09 (s, 2H), 4.18 (s, 2H), 3.94 (s, 2H), 3.84 (d, J = 14.1 Hz, 2H), 2.26 (d, J = 9.2 Hz, 1H). LCMS(m / z):585.1[M+1] + .

[0877] 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]pyrimidine-6-yl)methyl)methanesulfonamide (compound 187) [ka]

[0878] Compound 186 (8 mg, 0.014 mmol) was dissolved in methanol (5 mL), 10% Pd / C (4 mg) was added, the mixture was purged with hydrogen, and the reaction was stirred at 25°C for 4 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried, and then freeze-dried to obtain compound 187 (4.0 mg, yield: 64.9%).

[0879] 1 H NMR (400 MHz, D2O) δ 5.42 (d, J = 9.5 Hz, 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 = 9.4 Hz, 1H). LCMS(m / z):451.1[M+1] + .

[0880] Example 154: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(propylsulfonamidemethyl)octahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (compound 188) [ka]

[0881] Step 1: Synthesis of Compound 188-1 [ka]

[0882] 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 under a nitrogen atmosphere at 25°C for 3 hours. After the reaction was complete, water (5 mL) was added to the reaction mixture, and the mixture was extracted with DCM (5 mL x 3). The organic phases were combined and concentrated to obtain the residue. The residue was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 5%~30%) to obtain compound 188-1 (140 mg, yield: 92.6%) as a grayish-white solid. LCMS (m / z): 747.3 [M+1] + .

[0883] Step 2: Synthesis of Compound 188 [ka]

[0884] 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 under a nitrogen atmosphere and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated and dried to obtain the residue. The residue was purified by reverse-phase column chromatography (methanol / 0.1% aqueous acetic acid solution = 5-8%) to obtain compound 188 (24.3 mg, yield: 23.1%) as a white solid.

[0885] 1 H NMR (400 MHz, MeOD) δ 7.44-7.15 (m, 5H), 5.57 (d, J = 9.3 Hz, 1H), 5.09 (s, 2H), 4.58 (d, J = 6.7 Hz, 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 = 9.5 Hz, 1H), 1.88-1.76 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). LCMS(m / z):559.2[M+1] + .

[0886] 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]pyrimidine-6-yl)methyl)propane-1-sulfonamide (compound 189) [ka]

[0887] Compound 188 (10 mg, 0.02 mmol) was dissolved in methanol (2 mL), 10% Pd / C (1 mg) was added, and the mixture was replaced three times with hydrogen and stirred at 25°C for 8 hours. After the reaction was complete, 1% aqueous acetic acid was added, and the mixture was stirred for 5 minutes. Pd / C was removed by filtration, and the filtrate cake was washed three times with 1% aqueous acetic acid. The filtrate was concentrated and dried, then freeze-dried to obtain compound 189 (4.6 mg, yield: 60.6%) as a grayish-white solid. LCMS (m / z): 425.1 [M+1] + .

[0888] Example 156: Synthesis of ((4R,4aR,5R,6S,7S,9S,10S,10aR,11S,E)-4,6,9,10,11-pentahydroxy-6-(cyclohexanesulfonamidemethyl)octahydro-5,9-epoxy-7,10a-methoxyno[4,5-d]pyrimidine-2(1H)-ylidene)benzylcarbamate (Compound 190) [ka]

[0889] Step 1: Synthesis of Compound 190-1 [ka]

[0890] Compound B3 (140 mg, 0.22 mmol) was dissolved in DCM (8 mL), pyridine (69.2 mg, 0.33 mmol) and 4-dimethylaminopyridine (DMAP) (13.6 mg, 0.11 mmol) were added, and under temperature control in an ice bath, cyclohexanesulfonyl chloride (60 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by HPLC until the starting materials had completely reacted. Water was added to the reaction mixture, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried to obtain the 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] + .

[0891] Step 2: Synthesis of Compound 190 [ka]

[0892] Compound 190-1 (125 mg, 0.16 mmol) was dissolved in water (4 mL), dioxane (1.5 mL), and TFA (1 mL), and the mixture was heated to 60°C and reacted for 16 hours. The reaction mixture was concentrated and dried, purified by wet loading reverse-phase column chromatography, and freeze-dried to obtain compound 190 (13 mg, yield: 14%) as a white solid.

[0893] 1 HNMR (400MHz, MeOD) δ 7.43-7.26 (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]+ .

[0894] 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]pyrimidine-6-yl)methyl)guanidine (compound 191) [ka]

[0895] Compound 190 (11 mg, 0.02 mmol) was dissolved in methanol (3 mL), 10% palladium-carbon (3 mg) was added, and the mixture was replaced three times with hydrogen, followed by a stirring reaction for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to obtain compound 191 (8 mg, yield: 94%) as a white solid.

[0896] 1 HNMR (400MHz, MeOD) δ 5.51 (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...

Claims

1. A compound or a pharmaceutically acceptable derivative thereof, wherein the compound has the structure of formula (I), 【Chemistry 1】 During the ceremony, X does not exist or -(CH ２ ) ｍ - and 【Chemistry 2】 Selected from, the -CH ２ The - can be optionally replaced with an -O- or carbonyl group, or at least one R Ｘ It is arbitrarily replaced with, Y １ and Y ２ Each is independently selected from a methylene group, O, S, and NH, and the methylene group and NH are at least one R Ｘ It is arbitrarily replaced with, R １ and R ３ are each independently hydrogen, a hydroxyl group, an amino group, a cyano group, C １～８ alkyl group, C ３～８ cycloalkyl group, C １～８ alkyl-C ３～８ cycloalkyl group, C ３～８ heterocyclyl group, C １～８ alkyl-C ３～８ heterocyclyl group, C ６～１０ aryl group, C １～８ alkyl-C ６～１０ aryl group, C ５～１０ heteroaryl group and C １～８ alkyl-C ５～１０ heteroaryl group, and are selected from, and the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally substituted with at least one R Ｘ ; R ２ C is a hydrogen group, a hydroxyl group, an amino group, a formyl group, an acetyl group, and C １～８ alkyl group, C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, -(C=O)OR １０ and -O(C=O)R １１ Selected from, the formyl group, acetyl group, alkyl group, cycloalkyl group and heterocyclyl group are at least one R Ｘ It is arbitrarily replaced with, Each R ４ These are, independently, hydrogen, deuterium, hydroxyl group, halogen, and -OR. １２ and C １～８ Selected from alkyl groups, Or, R ３ and R ４ These, together with the atoms bonded to them, form a 5-12 member heteroring, and the heteroring has at least one R Ｘ It is arbitrarily replaced with, R ５ is hydrogen, deuterium, tritium, hydroxyl group, halogen, C １～８ alkyl group, C ３～８ Cycloalkyl groups and -OR １３ Selected from, R ６ These are hydroxyl groups, mercapto groups, amino groups, azide groups, halogens, cyano groups, and C １～１２ alkyl group, C ２～８ Alkenyl group, -O-C １～１２ alkyl group, C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, C ６～１０ Aryl group, C ５～１０ Heteroaryl group, -(C=O)-R １４ , guanidyl group, ureido group, -(OCH ２ CH ２ ) ｎ -OH, 【Transformation 3】 Selected from, the alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, guanidyl group and ureido group are at least one R Ｘ It is arbitrarily replaced with, Or, R ５ and R ６ These, together with the atoms bonded to them, form a 3- to 12-membered heteroring, and the heteroring has at least one R Ｘ It is arbitrarily replaced with, R ７ is hydrogen, deuterium, tritium, hydroxyl group, halogen, C １～４ Alkyl alkyl group, -O-C １～４ alkyl group, C ３～８ Cycloalkyl groups and C ３～８ Selected from heterocyclyl groups, the alkyl group, cycloalkyl group and heterocyclyl group have at least one R Ｘ It is arbitrarily replaced with, R ８ is hydrogen, deuterium, tritium, hydroxyl group, halogen, C １～８ alkyl group, C ３～８ Cycloalkyl groups and -OR １５ Selected from, Or, R ４ and R ８ These, together with the atoms bonded to them, form a 5-12 membered heteroring, and the heteroring has at least one R Ｘ It is arbitrarily replaced with, R ９ is hydrogen, deuterium, tritium, hydroxyl group, C １～８ alkyl group, C ３～８ Cycloalkyl groups and -OR １６ Selected from, R １０ and R １１ Each of them is independent of C １～８ alkyl group, C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, C ６～２０ Aryl group, C １～８ Alkyl-C ６～２０ Aryl group, C ５～２０ Heteroaryl group and C １～８ Alkyl-C ５～２０ Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R Ｘ It is arbitrarily replaced with, Each R １２ 、R １３ 、R １４ 、R １５ and R １６ is, independently of one another, a C １～８ alkyl group, a C ２～８ alkenyl group, a C ３～８ cycloalkyl group, a C １～８ alkyl-C ３～８ cycloalkyl group, a C ３～８ heterocyclyl group, a C １～８ alkyl-C ３～８ heterocyclyl group, a C ６～１０ aryl group, a C １～８ alkyl-C ６～１０ aryl group, a C ５～１０ heteroaryl group and a C １～８ alkyl-C ５～１０ heteroaryl group, selected from, and the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally substituted with at least one R Ｘ . R ６’ C is hydrogen, hydroxyl group, amino group, cyano group, C １～８ alkyl group, C ３～８ Cycloalkyl groups, C １～８ Alkyl-C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, C １～８ Alkyl-C ３～８ Heterocyclyl group, C ６～１０ Aryl group, C １～８ Alkyl-C ６～１０ Aryl group, C ５～１０ Heteroaryl group and C １～８ Alkyl-C ５～１０ Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R Ｘ It is arbitrarily replaced with, R ６’’ These are hydroxyl groups, mercapto groups, amino groups, halogens, and C １～１２ alkyl group, C ２～８ Alkenyl group, -O-C １～１２ alkyl group, C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, C ６～１０ Aryl group and C ５～１０ Selected from heteroaryl groups, the alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R Ｘ It is arbitrarily replaced with, Each R Ｘ These are independently hydrogen, halogen, hydroxyl group, carboxyl group, amino group, cyano group, formyl group, and C １～８ Alkyl alkyl group, -O-C １～８ alkyl group, C ２～８ Alkenyl group, C ３～２０ Cycloalkyl groups, C １～８ Alkyl-C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, C １～８ Alkyl-C ３～８ Heterocyclyl group, C ６～１０ Aryl group, C １～８ Alkyl-C ６～１０ Aryl group, C ５～１０ Heteroaryl group, C １～８ Alkyl-C ５～１０ heteroaryl group, 【Chemistry 4】 Selected from, the amino group, formyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are at least one R Ｙ It is arbitrarily replaced with, Each R Ｙ These are independently hydrogen, halogen, hydroxyl group, amino group, carboxyl group, formyl group, acetyl group, and C １～８ Alkyl alkyl group, -O-C １～８ alkyl group, C ３～８ Cycloalkyl groups, -O-C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, -O-C ３～８ Heterocyclyl group, C １～８ Alkyl-C ３～８ Heterocyclyl group, C ６～１０ Aryl group, -O-C ６～１０ Aryl group, C １～８ Alkyl-C ６～１０ Aryl group, C ５～１０ Heteroaryl group, -O-C ５～１０ Heteroaryl group and C １～８ Alkyl-C ５～１０ Selected from heteroaryl groups, the formyl group, acetyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group each have at least one halogen, hydroxyl group, or R Ｙ１ It can be arbitrarily selected, Each R Ｙ１ These are, independently, an amino group, C １～８ alkyl group, C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, C ６～１０ Aryl group and C ５～１０ Selected from heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group have at least one R Ｙ２ It is arbitrarily replaced with, Each R Ｙ２ These are, independently, an amino group, C １～８ alkyl group, C ３～８ Cycloalkyl groups, C ３～８ Heterocyclyl group, C ６～１０ Aryl group and C ５～１０ Selected from heteroaryl groups, X is a methylene group and R １ , R ２ and R ３ If R is also hydrogen, ４ , R ５ , R ６ , R ７ , R ８ and R ９ It is not possible for both to be a hydroxyl group at the same time. m is an integer selected from 0 to 6. n is an integer selected from 1 to 12. t is an integer selected from 0 to 4, which is a compound or a pharmaceutically acceptable derivative thereof.

2. The aforementioned X is a methylene group, a carbonyl group and 【Transformation 5】 A compound according to claim 1 or a pharmaceutically acceptable derivative thereof, selected from the above.

3. The aforementioned R １ The compound according to claim 1 or 2 or a pharmaceutically acceptable derivative thereof, wherein is hydrogen.

4. The aforementioned R ２ These are hydrogen, acetyl group and -(C=O)OR １０ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable derivative thereof, selected from among.

5. R １０ The compound according to claim 4 or a pharmaceutically acceptable derivative thereof, selected from a benzyl group and a cyclopentyl group.

6. R ３ is hydrogen, C １～８ alkyl group, C ３～８ Cycloalkyl groups, C １～８ Alkyl-C ３～８ Cycloalkyl groups and C １～８ Alkyl-C ６～１０ Selected from aryl groups, the alkyl group, cycloalkyl group and aryl group have at least one R Ｘ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable derivative thereof, which is optionally substituted with.

7. R Ｘ The compound according to claim 6 or a pharmaceutically acceptable derivative thereof, selected from a hydroxyl group and a carboxyl group.

8. The aforementioned R ３ It consists of hydrogen, methyl group, ethyl group, isopropyl group, 【Transformation 6】 Selected from, preferably hydrogen and 【Transformation 7】 The compound according to claim 6 or a pharmaceutically acceptable derivative thereof.

9. The aforementioned R ４ is a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable derivative thereof, selected from hydrogen, deuterium, and a hydroxyl group.

10. The aforementioned R ３ and R ４ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable derivative thereof, wherein the compounds form a six-membered heterocycle together with the atoms bonded thereto.

11. The aforementioned R ３ and R ４ And the heterocycles formed together with the atoms bonded to them are 【Transformation 8】 A compound according to claim 10 or a pharmaceutically acceptable derivative thereof, selected from the above.

12. The aforementioned R ５ The compound according to any one of claims 1 to 11, wherein is a hydroxyl group, or a pharmaceutically acceptable derivative thereof.

13. R ６ These are hydroxyl group, amino group, cyano group, -O-C １～１２ Alkyl group, guanidyl group, ureido group, C ３～８ Heterocyclyl group and 【Chemistry 9】 Selected from, the amino group, alkyl group, guanidyl group and heterocyclyl group are at least one R Ｘ A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable derivative thereof, which is optionally substituted with.

14. R Ｘ These are halogens, hydroxyl groups, amino groups, formyl groups, and C １～８ alkyl group, C ３～２０ Cycloalkyl groups, C １～８ Alkyl-C ６～１０ Aryl group, C ３～８ Heterocyclyl group and 【Chemistry 10】 Selected from, the amino group, formyl group, alkyl group, cycloalkyl group and heterocyclyl group are at least one R Ｙ The compound according to claim 13 or a pharmaceutically acceptable derivative thereof, which is optionally substituted with.

15. R Ｙ These are halogens, hydroxyl groups, carboxyl groups, formyl groups, acetyl groups, and C １～８ Selected from alkyl groups, the formyl group is a hydroxyl group or R Ｙ１ It is arbitrarily replaced by the R Ｙ１ is selected from amino groups, and the amino group is R Ｙ２ It is arbitrarily replaced by the R Ｙ２ C １～８ A compound according to claim 14, or a pharmaceutically acceptable derivative thereof, selected from alkyl groups.

16. R ６’ The compound according to claim 13 or a pharmaceutically acceptable derivative thereof, selected from hydrogen and a methyl group.

17. The aforementioned R ６’’ C １～１２ alkyl group, C ３～８ Cycloalkyl groups, C ６～１０ Aryl group and C ５～１０ Selected from heteroaryl groups, the alkyl group, cycloalkyl group, aryl group and heteroaryl group have at least one R Ｘ The compound according to claim 13 or a pharmaceutically acceptable derivative thereof, which is optionally substituted with.

18. The aforementioned R Ｘ is halogen, C １～８ Alkyl alkyl group, -O-C １～８ alkyl group, C ３～２０ Cycloalkyl groups and C ６～１０ Selected from aryl groups, the alkyl group, cycloalkyl group and aryl group have at least one R Ｙ The compound according to claim 17 or a pharmaceutically acceptable derivative thereof, which is optionally substituted with.

19. The aforementioned R Ｙ The compound according to claim 18 or a pharmaceutically acceptable derivative thereof, wherein is a halogen, and the halogen is fluorine.

20. The aforementioned R ６’’ These include methyl groups, trifluoromethyl groups, propyl groups, isopropyl groups, 【Chemistry 11】 A compound according to claim 17 or a pharmaceutically acceptable derivative thereof, selected from the above.

21. The aforementioned R ６ These include hydroxyl groups, halogens, cyano groups, amino groups, azide groups, methoxy groups, methylamino groups, tert-butyl groups, propenyl groups, guanidyl groups, ureido groups, 【Chemistry 12-1】 【Chemistry 12-2】 Selected from, Preferably, a hydroxyl group, an amino group, a methoxy group, a methylamino group, a guanidyl group, or a ureido group. 【Chemistry 13】 And, More preferably, a hydroxyl group, an amino group, a methylamino group, a guanidyl group, a ureido group, 【Chemistry 14】 The compound according to claims 13 to 20 or a pharmaceutically acceptable derivative thereof.

22. The aforementioned R ７ The compound according to any one of claims 1 to 21, wherein is a hydroxyl group, or a pharmaceutically acceptable derivative thereof.

23. The aforementioned R ８ The compound according to any one of claims 1 to 22, wherein is a hydroxyl group, or a pharmaceutically acceptable derivative thereof.

24. The aforementioned R ４ and R ８ They form heterocycles together with the atoms bonded to them, 【Chemistry 15】 It has the following structure, In the formula, X, Y １ , Y ２ , R １ , R ２ , R ３ , R ５ , R ６ , R ７ and R ９ The compound according to any one of claims 1 to 23 or a pharmaceutically acceptable derivative thereof, wherein is as defined in any one of claims 1 to 23, and t' is an integer selected from 0 to 3.

25. The aforementioned R ４ and R ８ They form heterocycles together with the atoms bonded to them, 【Chemistry 16】 It has the following structure, In the formula, X, R １ , R ２ , R ３ , R ５ , R ６ , R ７ and R ９ The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable derivative thereof, wherein is as defined in any one of claims 1 to 24.

26. The aforementioned R ９ The compound according to any one of claims 1 to 25, wherein is a hydroxyl group, or a pharmaceutically acceptable derivative thereof. 【Request Item 27】 【Chemistry 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 【Chemistry 17-4】 【Chemistry 17-5】 【Chemistry 17-6】 【Chemistry 17-7】 【Chemistry 17-8】 【Chemistry 17-9】 【Chemistry 17-10】 【Chemistry 17-11】 [Chemistry 17-12] [Chemistry 17-13] [Chemistry 17-14] 【Chemistry 17-15】 [Chemistry 17-16] Preferably, 【Chemistry 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 more, 【Chemistry 19-1】 【Chemistry 19-2】 A compound or a pharmaceutically acceptable derivative thereof having the following structure.

28. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof according to any one of claims 1 to 27 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 manufacture of a drug for the treatment or analgesia of a disease or condition related to sodium ion channels.

30. The diseases or conditions related to the aforementioned sodium ion channels include pain such as neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy-induced pain, traumatic pain, surgical pain, postoperative pain, childbirth pain, labor pains, chronic pain, persistent pain, peripheral pain, central pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, HIV-related pain, acute pain, multiple sclerosis (MS)-related pain, familial rectal pain, and fibromyalgia, or depression, cardiovascular disease, neurogenic cystitis, ulcerative colitis, respiratory disease, mental illness, peripheral neuropathy, HIV treatment-induced neuropathy, heat sensitivity, sarcoidosis, and irritable bowel syndrome. This includes pain caused by the following conditions: syndromes, 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 disorders, schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, epilepsy, epileptic encephalopathy, focal and generalized tonic seizures, restless legs syndrome, arrhythmias, tachyarrhythmias, atrial fibrillation, or ventricular fibrillation. The pain targeted for analgesia includes neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy-induced pain, traumatic pain, surgical pain, postoperative pain, childbirth pain, labor pains, chronic pain, persistent pain, peripheral pain, central pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, HIV-related pain, acute pain, multiple sclerosis (MS)-related pain, familial rectal pain, and fibromyalgia, or pain associated with depression, cardiovascular disease, neurogenic cystitis, ulcerative colitis, respiratory disease, mental illness, peripheral neuropathy, HIV treatment-induced neuropathy, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, and muscular atrophy. The use according to claim 29, including pain caused by the following conditions: degenerative 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 disorder, schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, epilepsy, epileptic encephalopathy, focal and generalized tonic epileptic seizures, restless legs syndrome, arrhythmia, tachyarrhythmia, atrial fibrillation, or ventricular fibrillation.

31. Having the structure of formula (II), 【Chemistry 20】 During the ceremony, X, R ６ This is as defined in any one of claims 1 to 27, Pg １ Pg ２ Each of these compounds is independently selected from an acetyl group, a triphenylmethyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a cyclopentyloxycarbonyl group, and a 9-fluorenylmethyloxycarbonyl group (Fmoc). 【Request Item 32】 【Chemistry 21】 The compound according to claim 31, having the following structure.

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