Nav1.8 inhibitors

Abstract

The present invention provides a Nav1.8 inhibitor. Specifically, the present invention provides a compound represented by Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a method for producing the same, as well as its use in the production of drugs. 【Chemical 1】 JPEG2025520719000179.jpg34169

Description

[Technical Field]

[0001] The present invention Priority rights to a prior application filed with the China National Intellectual Property Administration on June 22, 2022, with patent application number 202210714208.4 and title "Nav1.8 Inhibitor," This application claims priority to a prior application filed with the China National Intellectual Property Administration on June 13, 2023, with patent application number 202310704035.2 and title "Nav1.8 Inhibitor".

[0002] The entire text of the above prior application is incorporated into the present invention by reference.

[0003] This invention belongs to the pharmaceutical field and relates to Nav1.8 inhibitors. Specifically, this invention relates to the use of benzamide compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions thereof as Nav1.8 inhibitors and their use in the manufacture of drugs for treating, alleviating or preventing pain. [Background technology]

[0004] Pain is defined as "a subjective feeling, an unpleasant sensation and emotional feeling caused by actual or potential tissue damage." Pain acts as a warning signal to the body of potential danger and provides essential protective functions for the body's normal life activities. At the same time, pain is a common clinical symptom, and severe or prolonged pain after the external stimulus that caused the pain has disappeared can cause impairment of physiological function and significantly impact the quality of life of the individual. Statistics show that approximately one in five people worldwide suffer from moderate to severe chronic pain. The global analgesic market size was approximately $36 billion in 2018 and is expected to reach $56 billion in 2023. Of this, the market for acute moderate to severe pain treatment is expected to continue growing steadily at a compound annual growth rate of 2.5%, while the chronic pain treatment market is projected to grow at a compound annual growth rate of approximately 18% in the future. Chronic pain will be the main driving force behind the continued growth of the global pain treatment market over the next decade.

[0005] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings widely distributed throughout the skin, muscles, joints, and visceral tissues of the body. They convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are transmitted via afferent nerve fibers to the cell body located in the dorsal root ganglia (DRG), and ultimately to higher-order nerve centers, causing pain. On the other hand, the generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane depolarizes, sodium ion channels are activated and open, allowing sodium ions to flow in, further depolarizing the cell membrane and generating an action potential. Therefore, inhibiting abnormal sodium ion channel activity is useful in treating and alleviating pain.

[0006] Human sodium ion channels are a type of transmembrane ion channel protein consisting of an α-subunit with a molecular weight of 260 kD and a β-subunit with a molecular weight of 30-40 kD. They are classified into nine isoforms, Nav1.1 to Nav1.9, depending on the α-subunit. Nav1.5, Nav1.8, and Nav1.9 are tetrodotoxin (TTX) insensitive sodium channels. Nav1.5 is mainly found in cardiomyocytes, while Nav1.8 and Nav1.9 are found in the peripheral nervous system. Among these, Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for pain treatment.

[0007] The gene encoding Nav1.8 is SCN10A, located in the 3p21-22 region of the human chromosome, and primarily encodes the α subunit. Studies have shown that the Nav1.8 gene homology between humans and rats reaches 93%. Nav1.8 is mainly present in trigeminal ganglion neurons and DRG neurons and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the increase in action potential is mainly due to the Nav1.8 current. In a model of neuropathic pain, nerve injury increases the expression level of Nav1.8 in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides can reduce Nav1.8 expression while simultaneously significantly reducing pain. After intraphalangeal injection of carrageenan into rats, Nav1.8 expression in DRG neurons increases. Nav1.8 knockout mice cannot exhibit normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene can cause peripheral neuropathy. Based on a series of animal studies and human genetic evidence, selective inhibition of Nav1.8 may represent a new analgesic therapy that can be used to treat various types of pain, including inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

[0008] A major drawback of several known Nav's inhibitors is their narrow therapeutic range, which may be a result of a lack of isotype selectivity. Because Nav1.8 is primarily limited to pain-sensing neurons, selective Nav1.8 blockers are less likely to induce the side effects commonly seen with non-selective Nav's blockers. Therefore, there remains a need in the art to develop novel Nav1.8 selective inhibitors, preferably Nav channel inhibitors that are more selective for Nav1.8, more effective, have improved metabolic stability, improved solubility, and fewer side effects. [Overview of the Initiative]

[0009] The present invention aims to provide a Nav1.8 inhibitor for use in the manufacture of a drug for treating, alleviating or preventing pain including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain, etc.

[0010] According to a first aspect of the present invention, the present invention provides a compound represented by formula (I), a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof,

[0011]

Chemical formula

Chemical formula

[0012]

Chemical formula

[0013] In one arbitrary embodiment of the present invention, the compound represented by formula (I) is the compound represented by formula (II),

[0014] [ka] Eventually, X is independently selected from N or CH. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each of these is independently H, D, C1-C6 alkyl, and one or more R 11 A C1-C6 alkyl group, a C2-C6 alkenyl group, or one or more R substituted with 12 A C2-C6 alkenyl group substituted with, a C2-C6 alkynyl group, one or more R 13 A C2-C6 alkynyl group substituted with -O-(C1-C6 alkyl group), one or more R 14 -O-(C1-C6 alkyl group), -S-(C1-C6 alkyl group), one or more R substituted 15 -S-(C1-C6 alkyl group), C3-C6 cycloalkyl group, one or more R substituted with 16 A C3-C6 cycloalkyl group substituted with, a 4- to 8-membered heterocycloalkyl group, one or more R 17 A 4-8 member heterocycloalkyl group substituted with a 6-10 member aryl group, one or more R 18 A 6-10 membered aryl group substituted with a 5-8 membered heteroaryl group, or one or more R 19 A 5- to 8-membered heteroaryl group substituted with -NR 1a R 1b A substituent R is selected from halogen, hydroxyl group, cyano group, nitro group, and -SF5. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18, R 19 When there are a plurality of them, the above substituents are the same or different, R 1a and R 1b are each independently selected from H, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more R 1a1 When there are a plurality of the substituents R 1a , R 1b , R 1a1 the above substituents are the same or different, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 1a1 are each independently selected from halogen, an amino group, a hydroxy group, a cyano group, deuterium or a nitro group.

[0015] In any optional embodiment of the present invention, the compound represented by formula (I) is the compound represented by formula (III),

[0016]

Chemical formula

[0017] In one arbitrary embodiment of the present invention, the compound represented by formula (I) is the compound represented by formula (IV),

[0018] [ka] Eventually, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Each of these is independently H, D, C1-C6 alkyl, and one or more R 11 A C1-C6 alkyl group, a C2-C6 alkenyl group, or one or more R substituted with 12 A C2-C6 alkenyl group substituted with, a C2-C6 alkynyl group, one or more R 13 A C2-C6 alkynyl group substituted with -O-(C1-C6 alkyl group), one or more R 14 -O-(C1-C6 alkyl group), -S-(C1-C6 alkyl group), one or more R substituted 15 -S-(C1-C6 alkyl group), C3-C6 cycloalkyl group, one or more R substituted with 16 A C3-C6 cycloalkyl group substituted with, a 4- to 8-membered heterocycloalkyl group, one or more R 17 A 4-8 member heterocycloalkyl group substituted with a 6-10 member aryl group, one or more R 18 A 6-10 membered aryl group substituted with a 5-8 membered heteroaryl group, or one or more R 19 A 5- to 8-membered heteroaryl group substituted with -NR 1a R 1b A substituent R is selected from halogen, hydroxyl group, cyano group, nitro group, and -SF5. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 If there are multiple substituents, the substituents are homologous or different. R 1a and R 1b Each of these is independently H, a C1-C6 alkyl group, and one or more R 1a1Selected from C1-C6 alkyl groups substituted with substituent R 1a , R 1b , R 1a1 If there are multiple substituents, the substituents are homologous or different. R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 1a1 Each of these is independently selected from halogen, amino group, hydroxyl group, cyano group, deuterium, or nitro group.

[0019] In one arbitrary embodiment of the present invention, the compound represented by formula (I) is the compound represented by formula (V),

[0020] [ka] Eventually, n is independently selected from 0, 1, 2, 3, 4, 5, or 6. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each of these is independently H, D, C1-C6 alkyl, and one or more R 11 A C1-C6 alkyl group, a C2-C6 alkenyl group, or one or more R substituted with 12 A C2-C6 alkenyl group substituted with, a C2-C6 alkynyl group, one or more R 13 A C2-C6 alkynyl group substituted with -O-(C1-C6 alkyl group), one or more R 14 -O-(C1-C6 alkyl group), -S-(C1-C6 alkyl group), one or more R substituted 15 -S-(C1-C6 alkyl group), C3-C6 cycloalkyl group, one or more R substituted with 16A C3-C6 cycloalkyl group substituted with, a 4- to 8-membered heterocycloalkyl group, one or more R 17 A 4-8 member heterocycloalkyl group substituted with a 6-10 member aryl group, one or more R 18 A 6-10 membered aryl group substituted with a 5-8 membered heteroaryl group, or one or more R 19 A 5- to 8-membered heteroaryl group substituted with -NR 1a R 1b A substituent R is selected from halogen, hydroxyl group, cyano group, nitro group, and -SF5. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 If there are multiple substituents, the substituents are homologous or different. R 1a and R 1b Each of these is independently H, a C1-C6 alkyl group, and one or more R 1a1 Selected from C1-C6 alkyl groups substituted with substituent R 1a , R 1b , R 1a1 If there are multiple substituents, the substituents are homologous or different. R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 1a1 Each of these is independently selected from halogen, amino group, hydroxyl group, cyano group, deuterium, or nitro group.

[0021] In one arbitrary embodiment of the present invention, the compound represented by formula (I) is the compound represented by formula (VI),

[0022] [ka] Eventually, R 1 , R 2 , R 3 , R 4 and R 5 Each of these is independently H, D, C1-C6 alkyl, and one or more R 11 A C1-C6 alkyl group, a C2-C6 alkenyl group, or one or more R substituted with 12 A C2-C6 alkenyl group substituted with, a C2-C6 alkynyl group, one or more R 13 A C2-C6 alkynyl group substituted with -O-(C1-C6 alkyl group), one or more R 14 -O-(C1-C6 alkyl group), -S-(C1-C6 alkyl group), one or more R substituted 15 -S-(C1-C6 alkyl group), C3-C6 cycloalkyl group, one or more R substituted with 16 A C3-C6 cycloalkyl group substituted with, a 4- to 8-membered heterocycloalkyl group, one or more R 17 A 4-8 member heterocycloalkyl group substituted with a 6-10 member aryl group, one or more R 18 A 6-10 membered aryl group substituted with a 5-8 membered heteroaryl group, or one or more R 19 A 5- to 8-membered heteroaryl group substituted with -NR 1a R 1b A substituent R is selected from halogen, hydroxyl group, cyano group, nitro group, and -SF5. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 If there are multiple substituents, the substituents are homologous or different. R 1a and R 1b Each of these is independently H, a C1-C6 alkyl group, and one or more R 1a1 Selected from C1-C6 alkyl groups substituted with substituent R 1a , R 1b , R 1a1 If there are multiple substituents, the substituents are homologous or different. R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 1a1 Each of these is independently selected from halogen, amino group, hydroxyl group, cyano group, deuterium, or nitro group.

[0023] In one arbitrary embodiment of the present invention, [ka] teeth, [ka] That is the case.

[0024] In one arbitrary embodiment of the present invention, [ka] teeth, [ka] Selected from, In one arbitrary embodiment of the present invention, [ka] teeth, [ka] That is the case.

[0025] In one arbitrary embodiment of the present invention, [ka] teeth, [ka] They are selected from among them.

[0026] In one arbitrary embodiment of the present invention, R 1 This is either H or a halogen.

[0027] In one arbitrary embodiment of the present invention, R 1 It is either H or F.

[0028] In one arbitrary embodiment of the present invention, R 2 is a halogen, one or more R 11 A C1-C6 alkyl group substituted with, one or more R 12 A C2-C6 alkenyl group substituted with, a C2-C6 alkynyl group, one or more R 15 It is a -S-(C1-C6 alkyl group) substituted with

[0029] In one arbitrary embodiment of the present invention, R 2 Cl,

[0030] [ka] Trifluoromethyl group or [ka] That is the case.

[0031] In one arbitrary embodiment of the present invention, R 3 H, halogen, one or more R 15 -S-(C1-C6 alkyl group) substituted with, one or more R 11 It is a C1-C6 alkyl group substituted with [the specified character].

[0032] In one arbitrary embodiment of the present invention, R 3 is H, Cl, trifluoromethyl group or [ka] That is the case.

[0033] In one arbitrary embodiment of the present invention, R 4 H is H.

[0034] In one arbitrary embodiment of the present invention, R 5 H, D, one or more R 11 A C1-C6 alkyl group substituted with, one or more R 12 A C2-C6 alkenyl group substituted with, one or more R 14 These are -O-(C1-C6 alkyl) and C2-C6 alkynyl groups substituted with .

[0035] In one arbitrary embodiment of the present invention, R 5 H, D, methyl group, [ka] That is the case.

[0036] In one arbitrary embodiment of the present invention, R 6 is a halogen, one or more R 12 A C2-C6 alkenyl group substituted with, one or more R 14 -O-(C1-C6 alkyl group) substituted with, one or more R 15 It is a -S-(C1-C6 alkyl group) substituted with

[0037] In one arbitrary embodiment of the present invention, R6 is F, [ka] That is the case.

[0038] In one arbitrary embodiment of the present invention, R 7 is D or halogen, preferably R 7It is either D or F.

[0039] In one arbitrary embodiment of the present invention, [ka] teeth, [ka] That is the case.

[0040] In one arbitrary embodiment of the present invention, R 1 H is H.

[0041] In one arbitrary embodiment of the present invention, R 2 It is a halogen.

[0042] In one arbitrary embodiment of the present invention, R 2 It is Cl.

[0043] In one arbitrary embodiment of the present invention, R 3 It is a halogen.

[0044] In one arbitrary embodiment of the present invention, R 3 It is Cl.

[0045] In one arbitrary embodiment of the present invention, R 4 H is H.

[0046] In one arbitrary embodiment of the present invention, R 5 H is H.

[0047] In one arbitrary embodiment of the present invention, R 6 is one or more R 14 It is a -O-(C1-C6 alkyl group) substituted with

[0048] In one arbitrary embodiment of the present invention, R 6 teeth, [ka] That is the case.

[0049] In one arbitrary embodiment of the present invention, R 1 It is a halogen, In one arbitrary embodiment of the present invention, R 1 It is F.

[0050] In one arbitrary embodiment of the present invention, R 2 It is a halogen.

[0051] In one arbitrary embodiment of the present invention, R 2 It is Cl.

[0052] In one arbitrary embodiment of the present invention, R 3 is one or more R 11 It is a C1-C6 alkyl group substituted with [the specified character].

[0053] In one arbitrary embodiment of the present invention, R 3 This is a trifluoromethyl group.

[0054] In one arbitrary embodiment of the present invention, R 4 H is H.

[0055] In one arbitrary embodiment of the present invention, R 5 H is H.

[0056] In one arbitrary embodiment of the present invention, R 6 It is a halogen.

[0057] In one arbitrary embodiment of the present invention, R 6 It is F.

[0058] In one arbitrary embodiment of the present invention, [ka] teeth, [ka] That is the case.

[0059] In one arbitrary embodiment of the present invention, R 1 It is a halogen.

[0060] In one arbitrary embodiment of the present invention, R 1 It is F.

[0061] In one arbitrary embodiment of the present invention, R 2 It is a halogen.

[0062] In one arbitrary embodiment of the present invention, R 2 It is Cl.

[0063] In one arbitrary embodiment of the present invention, R 3 is one or more R 11 A C1-C6 alkyl group substituted with, preferably R 3 This is a trifluoromethyl group.

[0064] In one arbitrary embodiment of the present invention, R 4 H is H.

[0065] In one arbitrary embodiment of the present invention, R 5 It is a halogen.

[0066] In one arbitrary embodiment of the present invention, R 5 It is F.

[0067] In one arbitrary embodiment of the present invention, R 6 It is a halogen.

[0068] In one arbitrary embodiment of the present invention, R 6 It is F.

[0069] In one arbitrary embodiment of the present invention, R1 H is H.

[0070] In one arbitrary embodiment of the present invention, R 2 It is a halogen.

[0071] In one arbitrary embodiment of the present invention, R 2 It is Cl.

[0072] In one arbitrary embodiment of the present invention, R 3 is one or more R 11 It is a C1-C6 alkyl group substituted with [the specified character].

[0073] In one arbitrary embodiment of the present invention, R 3 This is a trifluoromethyl group.

[0074] In one arbitrary embodiment of the present invention, R 4 H is H.

[0075] In one arbitrary embodiment of the present invention, R 5 is one or more R 14 It is a -O-(C1-C6 alkyl group) substituted with

[0076] In one arbitrary embodiment of the present invention, R 5 teeth, [ka] That is the case.

[0077] In one arbitrary embodiment of the present invention, the compound represented by formula (I) is [ka] JPEG0007846262000029.jpg207169 It is selected from the compound JPEG0007846262000030.jpg52169.

[0078] According to a second aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable medicinal carrier, diluent or excipient.

[0079] According to a third aspect of the present invention, the present invention provides the use of the above compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or pharmaceutical compositions in the manufacture of related drugs for inhibiting and treating voltage-gated sodium ion channels, wherein the voltage-gated sodium ion channels to be inhibited include Nav1.1 to Nav1.9, preferably Nav1.8.

[0080] Specific embodiments of the present invention relate to the use of the above compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above pharmaceutical composition in the manufacture of a drug that can be used for the treatment, relief or prevention of pain, wherein the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, bowel pain and idiopathic pain. [Effects of the Invention]

[0081] According to embodiments of the present invention, the present invention has at least one of the following technical effects.

[0082] 1) To provide a Nav1.8 inhibitor having a novel structure, excellent pharmacokinetic properties, and good efficacy or drug discovery potential, which can effectively treat diseases and conditions related to Nav1.8.

[0083] 2) The compounds of the present invention have relatively strong inhibitory activity against the Nav1.8 ion channel.

[0084] Additional aspects and advantages of the present invention are partially shown in the following description, some of which will become apparent from the following description or will be understood through the practice of the present invention. [Modes for carrying out the invention]

[0085] Definitions and explanations of terms Unless otherwise specified, the terms and definitions used in this application of the present invention, including the specification and claims, are as follows:

[0086] As will be understood by those skilled in the art, in accordance with the conventions used in the art, the structural formula of this application is as follows: [ka] The term is used to describe chemical bonds, which are points where a part or substituent is attached to a core or skeletal structure.

[0087] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic acid or base salt, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0088] The term "pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of compounds to a living organism.

[0089] The term "excipient" refers to a pharmaceutically acceptable inert component. Examples of the types of excipients include, but are not limited to, adhesives, disintegrants, lubricants, flow enhancers, stabilizers, fillers, and diluents. Excipients can improve the handling properties of pharmaceutical formulations, i.e., by increasing their fluidity and / or adhesiveness, making the formulations more suitable for direct compression.

[0090] The term "prodrug" refers to a compound according to the present invention that is converted to have biological activity under physiological conditions or by solvolysis. The prodrugs of the present invention are produced by modifying a functional group in the compound, and such modification can be removed by normal procedures or in the body to obtain the parent compound. The prodrugs include compounds formed by bonding a hydroxyl group or an amino group in the compound according to the present invention to any group, and when a prodrug of a compound according to the present invention is administered to a mammalian individual, the prodrug cleaves to form a free hydroxyl group and a free amino group, respectively.

[0091] The term "stereoisomer" refers to isomers that are produced by differences in the spatial arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0092] The term "tautomer" refers to a functional isomer resulting from the rapid movement of an atom within a molecule between two positions. Compounds according to the present invention can exhibit tautomerism. Tautomer compounds can have two or more interconvertible forms. Proton-transfer tautomers are due to the movement of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and when a single tautomer is isolated, a mixture is usually produced whose physicochemical properties match those of a mixture of compounds. The equilibrium position is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form is dominant, while in phenol, the enol form is dominant. The present invention encompasses all tautomer forms of compounds.

[0093] Some of the compounds of the present invention may have a chiral carbon atom (optical center) or a double bond. Exosomes, diastereomers, geometric isomers, and individual isomers are all included within the scope of the present invention.

[0094] In this specification, the method of illustrating racemic, ambiscalemic and scalemic, or enantiomeric pure compounds is shown in J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, the absolute configuration of stereocenters is indicated by wedge-shaped bonds and dashed bonds. Where compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, these include E and Z geometric isomers unless otherwise specified. Similarly, all tautomeric forms are all included within the scope of the present invention.

[0095] The compounds according to the present invention may exist in specific geometric or stereoisomer forms. The present invention intends all compounds including cis-trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, D-isomers, L-isomers, and their racemic mixtures and other mixtures. For example, all mixtures such as enantiomers or diastereomer-enriched mixtures are within the scope of the present invention. Substituents such as alkyl groups may have other chiral carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0096] Optically active (R)- and (S)-isomers and D and L isomers can be produced by chiral synthesis, chiral reagents, or other conventional techniques. To obtain one enantiomer of a certain compound according to the present invention, it can be produced by asymmetric synthesis or by induction with a chiral auxiliary. Among them, the mixture of obtained diastereomers is separated, and the pure desired enantiomer is provided by assisting the resolution of the groups. Alternatively, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), an appropriate optically active acid or base is used to form a diastereomeric salt, and then the diastereomers are separated by fractional crystallization or chromatography known in the art, and then recovered to obtain a pure enantiomer. Note that the separation of enantiomers and diastereomers is generally completed by chromatography, and the above chromatography uses a chiral stationary phase and is optionally combined with a chemical induction method (e.g., generating a carbamate from an amide).

[0097] The compounds according to the present invention may contain non-natural proportions of atomic isotopes in one or more atoms constituting the compound. For example, radioactive isotope-labeled compounds such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C) can be used. All conversions composed of isotopes of the compounds according to the present invention, regardless of the presence or absence of radioactivity, are included in the scope of the present invention.

[0098] In the case of a drug or a pharmacological activator, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. In the case of the oral dosage form of the present invention, the "effective amount" of the active substance in the composition refers to the amount necessary to achieve the desired effect when used in combination with other active substances in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the subject, and also depends on the specific active substance. In some cases, the appropriate effective amount can be determined by those skilled in the art based on general tests.

[0099] The terms "active ingredient", "therapeutic agent", "active substance" or "activating agent" refer to chemical entities that can effectively treat a target disorder, disease or condition.

[0100] The term "substituted" means that any one or more hydrogen atoms at a particular atom are replaced by a substituent, and includes variants of deuterium and hydrogen provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur in aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary as long as they are chemically feasible.

[0101] The term "plurality" refers to two or more, including two, three, four or more.

[0102] The prefix "C u -C v " represents that the following group has u to v carbon atoms. For example, "C1-C6 alkyl group" represents that the alkyl group has 1 to 6 carbon atoms.

[0103] The term "C1-C6 alkyl group" should be understood to represent a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the above group has one, two, or three carbon atoms ("C1-C3 alkyl group"), and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0104] The term "-O-(C1-C6 alkyl group)" should be understood as an alkyl group being bonded to the rest of the molecule via an oxygen atom, where the "C1-C6 alkyl group" has the above definition. Examples include -O-(methyl group) and -O-(ethyl group).

[0105] The term "--S-(C1-C6 alkyl group)" should be understood as an alkyl group being bonded to the rest of the molecule via a sulfur atom, where the "C1-C6 alkyl group" has the above definition. For example, -S-(methyl group) and -S-(ethyl group).

[0106] The term "C2-C6 alkynyl group" refers to a linear or branched unsaturated hydrocarbon group having at least one (e.g., 1-2, preferably 1) triple bond, and includes, but is not limited to, C2-C6 alkynyl groups such as ethynyl group, 1-propynyl group or 2-propynyl group, 1-butynyl group, 2-butynyl group or 3-butynyl group, and 1-methyl-2-propynyl group.

[0107] The term "C2-C6 alkenyl group" should be understood to represent a linear or branched monovalent hydrocarbon group that contains one or more double bonds and has 2 to 6 carbon atoms, for example, 2 or 3 carbon atoms (i.e., a C2-C3 alkenyl group). If the above alkenyl group contains more than one double bond, the above double bonds may be separated or conjugated from each other. The above alkenyl group is, for example, vinyl group, allyl group, (E)-2-methylvinyl group, (Z)-2-methylvinyl group, (E)-buta-2-enyl group, (Z)-buta-2-enyl group, (E)-buta-1-enyl group, (Z)-buta-1-enyl group, penta-4-enyl group, (E)-penta-3-enyl group, (Z)-penta-3-enyl group, (E)-penta-2-enyl group, (Z)-penta-2-enyl group, (E)-penta-1 -enyl group, (Z)-penta-1-enyl group, hexa-5-enyl group, (E)-hexa-4-enyl group, (Z)-hexa-4-enyl group, (E)-hexa-3-enyl group, (Z)-hexa-3-enyl group, (E)-hexa-2-enyl group, (Z)-hexa-2-enyl group, (E)-hexa-1-enyl group, (Z)-hexa-1-enyl group, isopropenyl group, 2-methylpropa-2-enyl group, 1-methylpropa-2 - Enyl group, 2-methylpropa-1-enyl group, (E)-1-methylpropa-1-enyl group, (Z)-1-methylpropa-1-enyl group, 3-methylbuta-3-enyl group, 2-methylbuta-3-enyl group, 1-methylbuta-3-enyl group, 3-methylbuta-2-enyl group, (E)-2-methylbuta-2-enyl group, (Z)-2-methylbuta-2-enyl group, (E)-1-methylbuta-2-enyl group, (Z)-1-methylbuta-2-enyl group These are the rubuta-2-enyl group, (E)-3-methylbuta-1-enyl group, (Z)-3-methylbuta-1-enyl group, (E)-2-methylbuta-1-enyl group, (Z)-2-methylbuta-1-enyl group, (E)-1-methylbuta-1-enyl group, (Z)-1-methylbuta-1-enyl group, 1,1-dimethylpropa-2-enyl group, 1-ethylpropa-1-enyl group, 1-propylvinyl group, and 1-isopropylvinyl group.

[0108] The term "C3-C6 cycloalkyl group" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including condensed or bridging polycyclic systems. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0109] The term "4- to 8-membered heterocycloalkyl group" refers to a monocyclic saturated heterocycle having a total of 4, 5, 6, 7, or 8 ring atoms and containing one or two homologous or heteroatom-containing ring heteroatoms or heteroatom-containing groups, wherein the ring heteroatoms or heteroatom-containing groups are selected from N, NH, O, S, SO, and SO2, and the heterocycloalkyl group can be bonded to the rest of the molecule via any one carbon atom or (if present) a nitrogen atom. The above heterocycloalkyl group may be a four-membered ring such as an azetidinyl group, an oxetanyl group, or a thietanyl group, or a five-membered ring such as a tetrahydrofuranyl group, a 1,3-dioxolanyl group, a thianyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a 1,1-dioxothianyl group, a 1,2-oxazolidinyl group, a 1,3-oxazolidinyl group, or a 1,3-thiazolidinyl group, or a six-membered ring such as a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, a 1,3-dioxanyl group, a 1,4-dioxanyl group, or a 1,2-oxacyclohexyl group.

[0110] The term "6-10 membered aryl group" should be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 10 carbon atoms, particularly a ring having 6 carbon atoms ("C6 aryl group"), such as a phenyl group. When the above 6-10 membered aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, the substitution site is not limited and may be, for example, at the ortho, para, or meta position.

[0111] The term "5-8 membered heteroaryl group" should be understood as a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group having 5-8 ring atoms, particularly 5 or 6 carbon atoms, and containing 1-5 heteroatoms independently selected from N, O, and S. Preferably, it is a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group containing 1-3 heteroatoms independently selected from N, O, and S, and may further be benzo-condensed in each case. In particular, heteroaryl groups are selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., or pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., or synnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenadinyl, phenothiazinyl, phenoxadinyl, etc.

[0112] The terms "halo" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0113] The term "deuterium" ("D" and "d") refers to the isotope of hydrogen (H) that has one proton and one neutron in its nucleus and whose natural abundance is 0.015%.

[0114] The term “one or more” (for example, in the definition of substituents of compounds in the general formula of the present invention) means “one, two, three, four or five, especially one, two, three or four, even more especially one, two or three, most especially one or two.”

[0115] The terms "at their discretion" or "at their discretion" mean that the events or circumstances described thereafter may or may not occur, and the above description includes both cases in which the events or circumstances described occur and cases in which they do not occur.

[0116] Furthermore, unless otherwise specifically stated, the description method of "… independently" used in the present invention should be understood in a broad sense. It should be noted that each of the described individuals is independent of each other and may be specific groups that are independently identical or different. More specifically, the description method of "… independently" means that among the specific options represented by the same symbol in different groups, they do not affect each other, and also means that among the specific options represented by the same symbol in the same group, they do not affect each other.

[0117] [Embodiments for Carrying out the Invention] Hereinafter, embodiments of the present invention will be described in accordance with examples. Those skilled in the art should understand that the following examples are only for explaining the present invention and do not limit the scope of the present invention. When specific technologies or conditions are not described in the examples, they are carried out according to the technologies or conditions described in the literature of this field or according to the product manuals. Reagents or equipment used without the manufacturer's description are all ordinary products available in the market.

[0118] Unless otherwise specified, the structures of the compounds of the present invention are all determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of the NMR shift is 10 -6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0119] The abbreviations of the present invention are defined as follows.

[0120] M is the molar concentration. For example, 1 M hydrochloric acid represents a hydrochloric acid solution of 1 mol / L.

[0121] LC-MS is liquid chromatography mass spectrometry.

[0122] DMSO is dimethyl sulfoxide.

[0123] HATU is N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate.

[0124] DMF is N,N-dimethylformamide.

[0125] DCM is dichloromethane.

[0126] m-CPBA is m-chloroperbenzoic acid.

[0127] DIPEA, also written as DIEA, is diisopropylethylamine, or N,N-diisopropylethylamine.

[0128] I C 50 This is the half-inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is reached.

[0129] Example 1: Preparation of target compound I-1 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (Target compound I-1)

[0130] [ka] The synthesis route for compound I-1 was as follows:

[0131] [ka] Step 1: Synthesis of 4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid

[0132] [ka] At room temperature, 4,5-dichloro-2-fluorobenzoic acid (1.0 g, 4.78 mmol), cesium carbonate (4.68 g, 14.35 mmol), and 4-(trifluoromethoxy)phenol (8 mL) were added to a 20 mL microwave tube, the microwave tube was sealed, and the reaction was carried out at 150°C for 1 hour. After cooling to room temperature, water (10 mL) was added to the reaction mixture, and the mixture was extracted with SiO2 (20 mL x 3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and rotated-dried. The crude product was purified by column chromatography (SiO2, PE:EA = 10:1) and 4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid was obtained. acid( 1.0 g was obtained, with a yield of 56.9%.

[0133] Step 2: Synthesis of 4,5-dichloro-N-(pyrimidine-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide

[0134] [ka] 4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid (1.0 g, 2.72 mmol), 5-aminopyrimidine (310.88 mg, 3.27 mmol), and HATU (2.07 g, 5.45 mmol) were added to DMF (10 mL), followed by the addition of DIPEA (1.06 g, 8.17 mmol). After the addition was complete, the reaction mixture was allowed to react at room temperature for 16 hours. LC-MS indicated that the reaction was complete. NH4Cl solution (15 mL) was added to the reaction mixture and extracted with siRNA (20 mL × 3). The organic phases were combined and washed with water (20 mL × 2) and saturated brine (10 mL), respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and rotated-dried. The crude organisms were separated by normal-phase silica gel column chromatography (SiO2, siRNA / PE = 1:1) to obtain 4,5-dichloro-N-(pyrimidine-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (1.10 g, yield 90.9%).

[0135] Step 3: 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (Target compound I-1)

[0136] [ka] At room temperature, 4,5-dichloro-N-(pyrimidine-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (1.0 g, 2.09 mmol) was weighed and dissolved in DCM (10 mL), and m-CPBA (849.89 mg, 4.19 mmol, 85%) was gradually added. The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (20 mL), then washed with saturated sodium bicarbonate aqueous solution (15 mL x 2), the organic phase was dried over Na2SO4, concentrated, and then obtained by preparative high-pressure liquid chromatography (ammonia water - acetonitrile) to obtain 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (86.6 mg, yield 8.38%).

[0137] 1 H NMR (400 MHz, DMSO): δ 8.85-8.84 (m, 2H), 8.43-8.42 (m, 1H), 8.04 (s, 1H), 7.45 (s, 1H), 7.40-7.37 (m, 2H), 7.20-7.18 (m, 2H).

[0138] LC-MS, M / Z (ESI): 458.1 [MH] - Example 2: Preparation of target compound I-2 5-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzoylamino)pyrimidine-1-oxide (Target compound I-2)

[0139] [ka] The synthesis route for compound I-2 was as follows:

[0140] [ka] Step 1: Synthesis of 5-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide

[0141] [ka] In an ice bath, 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (1.60 g, 6.60 mmol) was added to DMF (20 mL), followed by HATU (3.76 g, 9.89 mmol). The mixture was stirred for 10 minutes under these conditions, and then 5-aminopyrimidine (752.83 mg, 7.92 mmol) and DIPEA (2.56 g, 19.79 mmol) were added. After the addition was complete, the reaction mixture was gradually heated to room temperature and allowed to react for 16 hours. LC-MS indicated that the reaction was complete. NH4Cl aqueous solution (30 mL) was added to the reaction mixture and extracted with siRNA (30 mL × 3). The organic phases were combined and washed with water (30 mL × 2) and saturated brine (20 mL), respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and rotary dried. The crude organisms were separated using a normal-phase silica gel preparative plate (siRNA / PE = 1:2) to obtain 5-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (0.17 g, yield 8.06%).

[0142] Step 2: 5-Chloro-N-(pyrimidine-5-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide do synthesis

[0143] [ka] At room temperature, 170 mg, 0.53 mmol of 5-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide, 519.85 mg, 1.60 mmol of cesium carbonate, and 3 mL of 4-(trifluoromethoxy)phenol were added to a 20 mL microwave tube. The microwave tube was sealed, and the mixture was reacted at 150°C for 1 hour. After cooling to room temperature, 10 mL of water was added to the reaction mixture, and it was extracted with RINKAN (20 mL x 3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and rotated-dried. The crude product was purified using a silica gel preparative plate to obtain 0.20 g, yield 78.7% of 5-chloro-N-(pyrimidine-5-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide.

[0144] Step 3: 5-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzoylamino)pyrimidine-1-oxide (Target compound I-2)

[0145] [ka] At room temperature, 5-chloro-N-(pyrimidine-5-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (0.20 mg, 0.42 mmol) was weighed and added to DCM (3 mL), and then m-CPBA (169.98 mg, 0.84 mmol, 85%) was gradually added. The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (10 mL), then washed with saturated sodium bicarbonate aqueous solution (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and then obtained 5-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzoylamino)pyrimidine-1-oxide (10.4 mg, yield 5.03%) by preparative high-pressure liquid chromatography (ammonia water - acetonitrile).

[0146] 1 H NMR (400 MHz, DMSO-d6) :δ 8.84-8.82 (m, 1H), 8.52 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.48 (s, 1H), 7.33-7.31 (m, 2H), 7.09-7.07 (m, 2H).

[0147] LC-MS, M / Z (ESI): 492.0 [MH] - Example 3: Preparation of target compound I-11 3-(3-chloro-2-fluoro-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)-4-trifluoromethyl-benzamide)pyridine 1-oxide (Target compound I-11)

[0148] [ka] The synthesis route for compound I-11 was as follows:

[0149] [ka] Step 1: Synthesis of 2,2-difluorobenzo[d][1,3]dioxol-4-ol (11E-2)

[0150] [ka] Compound 11E-1 (25.0 g, 8.20 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL), then the mixture was evacuated and replaced with nitrogen gas, and this process was repeated three times. Under nitrogen gas protection, the reaction mixture was cooled to -78°C, and sec-butyllithium (134 mL, 173.94 mmol, 1.3 M) was gradually added, maintaining the reaction temperature below -70°C. After the addition was complete, the reaction mixture was allowed to continue reacting at this temperature for 2 hours, and trimethyl borate (19.72 g, 189.75 mmol) was gradually added dropwise, maintaining the temperature below -65°C. After the addition was complete, the reaction mixture was gradually raised to room temperature and allowed to continue reacting for 1 hour. Hydrogen peroxide (10.76 g, 316.25 mmol, 30%) and sodium hydroxide (6.32 g, 158.12 mmol) were then added, respectively. After the addition was complete, the reaction mixture was allowed to continue reacting at room temperature for 16 hours. TLC (PE:EA=5:1) indicated completion of the reaction. The mixture was diluted with water (100 mL), then extracted with SiO (100 mL × 3), the organic phase was combined, washed with 2 N NaOH aqueous solution (50 mL × 2), the aqueous phase was combined, the pH was adjusted to approximately 3 with 2 N HCl aqueous solution, and further extracted with SiO (100 mL × 3), the organic phase was combined, washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and rotary dried, and the crude organisms were separated (SiO / PE=0%~20%) by normal-phase silica gel column chromatography to obtain 2,2-difluorobenzo[d][1,3]dioxol-4-ol (11E-2) (31.6 g).

[0151] Step 2: tert-butyl((2,2-difluorobenzo[d][1,3]dioxol-4-yl)oxy)dimethylsilane(11E-4)

[0152] [ka] 2,2-Difluorobenzo[d][1,3]dioxol-4-ol (31.6 g, 181.50 mmol) was dissolved in anhydrous DMF (300 mL), and then imidazole (29.66 g, 435.60 mmol) and compound 11E-3 (32.83 g, 217.80 mmol) were added. After the addition was complete, the reaction mixture was heated to 80°C and reacted under these conditions for 10 hours. TLC (PE:EA = 3:1) indicated completion of the reaction. The reaction mixture was cooled to room temperature, diluted with water (300 mL), extracted with siRNA (150 mL x 3), the organic phases were combined, washed separately with water (100 mL x 2), washed with saturated brine (100 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and rotary dried, and the crude organisms were separated by normal-phase silica gel column chromatography (siRNA / PE = 0%~20%) to obtain tert-butyl((2,2-difluorobenzo[d][1,3]dioxol-4-yl)oxy)dimethylsilane (11E-4) (34.0 g, yield 64.96%).

[0153] Step 3: tert-butyldimethyl((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)silane(11E-5)

[0154] [ka] Compound 11E-4 (34.0 g, 117.91 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL), then the mixture was evacuated and replaced with nitrogen gas, and this process was repeated three times. Under nitrogen gas protection, the reaction mixture was cooled to -78°C, and n-butyllithium (58.95 mL, 147.38 mmol, 2.5 M) was gradually added, maintaining the reaction temperature below -70°C. After the addition was complete, the reaction mixture was allowed to continue reacting at this temperature for 2 hours, and a solution of NFSI (46.47 g, 147.38 mmol) in tetrahydrofuran (100 mL) was gradually added dropwise, maintaining the temperature below -65°C. After the addition was complete, the reaction mixture was gradually raised to room temperature and allowed to continue reacting for 10 hours. LC-MS revealed a small amount of residual starting material. The reaction was quenched by adding saturated ammonium chloride aqueous solution (100 mL), then extracted with RINKAN (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and rotated-dried, and the crude organisms were separated by normal-phase silica gel column chromatography (RINKAN / PE = 0%~20%) to obtain tert-butyldimethyl((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)silane (11E-5) (32.20 g; yield 89.14%).

[0155] Step 4: 2,2,7-trifluorobenzo[d][1,3]dioxol-4-ol (11E)

[0156] [ka] 32.20 g, 105.11 mmol of tert-butyldimethyl((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)silane was weighed and dissolved in 300 mL of anhydrous ethanol. Then potassium hydroxide (8.85 g, 157.66 mmol) was added, and the reaction mixture was allowed to react at room temperature for 10 hours. TLC (PE:EA = 5:1) indicated that the reaction was complete. The solution was prepared in an ice bath by adding 2 N HCl to adjust the pH to approximately 3, then extracted with RINKAN (150 mL x 3), combined with the organic phase, washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and rotated-dried. The crude organisms were separated by reverse-phase silica gel column chromatography (HCOOH, ACN / H2O = 0%~30%) to obtain 2,2,7-trifluorobenzo[d][1,3]dioxol-4-ol (11E) (18.0 g; yield 89.15%).

[0157] Step 5: 6-Bromo-3-chloro-2-fluoro-N-(pyridine-3-yl)-4-(trifluoromethyl)benzamide(11C)

[0158] [ka] Under ice bath conditions, 6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (11A) (10.0 g, 31.11 mmol) was dissolved in anhydrous DMF (100 mL), then HATU (27.20 g, 62.22 mmol) was added, and after 10 minutes, 3-aminopyridine (3.51 g, 37.33 mmol) and DIPEA (12.06 g, 93.33 mmol) were further added. After the addition was complete, the temperature was raised to room temperature and the mixture was reacted at room temperature for 2 hours. TLC (PE:EA = 3:1) indicated that the reaction was complete. Water (100 mL) was added to the reaction mixture and extracted with siRNA (100 mL × 3). The organic phase was washed with water (100 mL × 2) and saturated brine (50 mL), respectively, dried over Na₂SO₄, filtered, concentrated under reduced pressure, and rotated-dried. The crude organisms were separated by normal-phase silica gel column chromatography (PE / siRNA = 0%~50%) to obtain 6-bromo-3-chloro-2-fluoro-N-(pyridine-3-yl)-4-(trifluoromethyl)benzamide (11C) (9.50 g, yield 76.81%).

[0159] Step 6: 3-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyridine 1-oxide (11D)

[0160] [ka] In an ice bath, 6-bromo-3-chloro-2-fluoro-N-(pyridine-3-yl)-4-(trifluoromethyl)benzamide (11C) (5.0 g, 12.58 mmol) was weighed and dissolved in DCM (50 mL), and then m-CPBA (6.38 g, 85%, 31.44 mmol) was added in several portions. The reaction mixture was allowed to react at room temperature for 2 hours. TLC(siRNA) indicated completion of the reaction. The reaction mixture was diluted with dichloromethane (20 mL), then washed with saturated sodium bicarbonate aqueous solution (30 mL x 2) and saturated saline solution (30 mL). The organic phase was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and rotated-dried. The crude organisms were separated by normal-phase silica gel column chromatography (DCM / MeOH = 0%~10%) to obtain 3-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyridine 1-oxide (11D) (2.50 g, yield 48.07%).

[0161] Step 7: 3-(3-chloro-2-fluoro-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)-4-trifluoromethyl-benzamide)pyridine 1-oxide (Target compound I-11)

[0162] [ka] Under nitrogen gas protection, 3-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyridine 1-oxide (0.50 g, 1.21 mmol) was weighed and dissolved in toluene (5 mL). Then, compound 11E (232.3 mg, 1.21 mmol), cesium carbonate (1.18 g, 3.63 mmol), and cuprous iodide (46.1 mg, 0.24 mmol) were added in sequence. After the addition was complete, the reaction mixture was heated to 100°C and reacted under these conditions for 20 minutes. Reaction completion was indicated by LC-MS. After cooling to room temperature, NH4Cl solution (20 mL) was added to the reaction mixture, and it was extracted with siRNA (30 mL x 3). The organic phase was washed once with saturated brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and rotated dry. The crude organisms were subjected to preparative reverse-phase high-pressure liquid chromatography (NH3). . The compound was purified and separated using H2O to obtain 3-(3-chloro-2-fluoro-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)-4-trifluoromethyl-benzamide)pyridine 1-oxide (target compound I-11) (279 mg, yield 43.9%).

[0163] 1 1H NMR (400 MHz, DMSO) - d6):δ 11.38 (s, 1H), 8.61 (s, 1H), 8.06 (d, 1H, J=4.0 Hz), 7.62 (s, 1H), 7.46-7.39 (m, 2H), 7.31-7.26 (m, 1H), 7.13-7.10 (m, 1H).

[0164] LC-MS, M / Z (ESI): 523.0 [MH] - Example 4: Preparation of target compound I-16 5-(4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (Target compound I-16)

[0165] [ka] The synthesis route for compound I-16 was as follows:

[0166] [ka] Step 1: Synthesis of 1-bromo-3,4-difluoro-2-deuterated methoxybenzene (16C-2)

[0167] [ka] At room temperature, intermediate 16C-1 (1.0 g, 4.8 mmol), potassium carbonate (0.99 g, 7.2 mmol), and deuterated iodomethane (0.69 g, 4.8 mmol) were added to anhydrous acetonitrile (25 mL), heated to 120°C, and reacted overnight. After cooling the reaction mixture to room temperature, water (20 mL) was added to the reaction mixture, and it was extracted with SiO4 (20 mL × 3). The organic phase was washed once with saturated brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and rotated-dried. The crude organism was purified by silica gel column (SiO4 / PE = 1:10) to obtain the yellow liquid 1-bromo-3,4-difluoro-2-deuterated methoxybenzene (16C-2) (0.95 g, yield 87.9%).

[0168] Step 2: Synthesis of 3,4-difluoro-2-deuterated methoxyphenol (16C)

[0169] [ka] Compound 16C-2 (0.95 g, 4.2 mmol) and triisopropyl boronate (0.95 g, 5.0 mmol) were added to THF (10 mL), and the air in the reaction flask was replaced three times with nitrogen gas. After cooling the reaction system to -78°C, n-BuLi (2 mL, 2.5 M, 5.0 mmol) was gradually added dropwise to the reaction flask. The reaction was then gradually heated to room temperature and stirred overnight.

[0170] After lowering the temperature of the reaction system to 0°C, MeOH (20 mL) and H2O2 (30 wt% 10 mL) were added to the reaction mixture, and then aqueous sodium hydroxide solution (10%, 40 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium thiosulfate (20 mL) was added dropwise to quench the reaction, and the mixture was further extracted with siRNA (30 mL × 3). The organic phases were combined and washed with water (20 mL × 2) and saturated brine (20 mL), respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and rotary dried. The crude organisms were separated by normal-phase silica gel column (siRNA / PE = 1:4) to obtain a pale yellow liquid 3,4-difluoro-2-deuterated methoxyphenol (16C) (360 mg, yield 52%).

[0171] 1 H NMR (400 MHz, DMSO-d6): δ 8.89 (s, 1H), 6.76-6.72 (m, 1H), 6.59-6.54 (m, 1H). Step 3: Synthesis of methyl 4,5-dichloro-2-fluorobenzoate (16B)

[0172] [ka] 4,5-Dichloro-2-fluorobenzoic acid (1.0 g, 4.7 mmol) was added to MeOH (20 mL), and concentrated hydrochloric acid (5 drops) was added dropwise to the reaction mixture. The reaction mixture was allowed to react at 50°C for 6 hours. LC-MS indicated completion of the reaction. The reaction mixture was rotated dry, NH4Cl solution (10 mL) was added, and the mixture was extracted with HCl (20 mL × 3). The organic phases were combined and washed with water (20 mL × 2) and saturated brine (10 mL), respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and rotated dry. The crude organisms were separated by normal-phase silica gel column (HCl / PE = 1:20) to obtain a white solid methyl 4,5-dichloro-2-fluorobenzoate (16B) (1.1 g, yield 95.4%).

[0173] Step 4: Synthesis of 4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)methyl benzoate (16D)

[0174] [ka] At room temperature, intermediate 16C (0.16 g, 1 mmol), methyl 4,5-dichloro-2-fluorobenzoate (0.22 g, 1 mmol), cesium carbonate (0.65 g, 2 mmol), and acetonitrile (5 mL) were added to a 25 mL round-bottom flask and reacted at 80°C for 5 hours. After cooling to room temperature, NH4Cl solution (20 mL) was added to the reaction mixture, and it was extracted with siRNA (20 mL × 3). The organic phase was washed once with saturated brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and rotated-dried. The crude organism was purified by silica gel column (siRNA / PE = 1:10) to obtain a pale yellow solid methyl 4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)benzoate (16D) (340.0 mg, yield 90.3%).

[0175] Step 5: Synthesis of 4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)benzoic acid (16E)

[0176] [ka] At room temperature, intermediate 16D (0.34 g, 0.95 mmol), lithium hydroxide monohydrate (0.07 g, 1.5 mmol), and methanol (10 mL) were added to a 25 mL round-bottom flask and reacted for 3 hours. Dilute hydrochloric acid solution (20 mL) was added to the reaction mixture, and the mixture was extracted with siRNA (20 mL × 3). The organic phase was washed once with saturated brine (20 mL), dried over Na₂SO₄, filtered, concentrated under reduced pressure, and rotated-dried. The crude product was purified by silica gel column chromatography (MeOH / DCM = 1:10) to obtain a white solid 4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)benzoic acid (16E) (311.0 mg, yield 95.3%).

[0177] LC-MS: m / z 352.02 [M+H] + .

[0178] Step 6: Synthesis of 4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)-N-(pyrimidine-5-yl)benzamide (16G)

[0179] [ka] Under ice bath conditions, compound 16F (0.086 g, 0.9 mmol), intermediate 16E (0.31 g, 0.89 mmol), DIEA (3.48 g, 2.7 mmol), and HATU (0.51 g, 1.35 mmol) were added to MeCN (10 mL), and the reaction mixture was allowed to react overnight at room temperature. LC-MS indicated completion of the reaction. Water (20 mL) was added to the reaction mixture, and it was further extracted with siRNA (30 mL x 3). The organic phases were combined and washed with water (20 mL x 2) and saturated brine (20 mL), respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and rotated-dried. The crude organisms were separated by normal-phase silica gel column (siRNA / PE = 1:1) to obtain a pale yellow solid 4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)-N-(pyrimidine-5-yl)benzamide (16 G) (305 mg, yield 81.3%).

[0180] LC-MS: m / z 429.04[M+H] + .

[0181] Step 7: Synthesis of 5-(4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (target compound I-16)

[0182] [ka] At room temperature, 16G (100 mg, 0.22 mmol) of intermediate and m-CPBA (75.7 mg, 0.44 mmol) were weighed and added to DCM (10 mL). The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with dichloromethane (20 mL), then washed with saturated sodium bicarbonate aqueous solution (10 mL x 2), the organic phase was dried over Na2SO4, concentrated, and then obtained by preparative high-performance liquid chromatography of 5-(4,5-dichloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (target compound I-16) (31.1 mg, yield 28.9%).

[0183] 1 H NMR (400 MHz, CDCl3) :δ 9.64 (s, 1H), 9.22 (t, J = 1.8 Hz, 1H), 8.76 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.28 (s, 1H), 7.02 (dd, J = 7.7, 4.9 Hz, 2H), 6.91 (s, 1H). LC-MS, M / Z (ESI): 445.04 [M+H] + Example 5: Preparation of target compound I-17 Synthesis of 5-(3-chloro-2-fluoro-6-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide)pyrimidine 1-oxide (I-17)

[0184] [ka] The synthesis route for target compound I was as follows:

[0185] [ka] Step 1: Synthesis of 6-bromo-3-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (17B)

[0186] [ka] At room temperature, 6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (2.00 g, 3.22 mmol) and 3-amidepyrimidine (710 mg, 7.46 mmol) were dissolved in N,N-dimethyl benzoate. Holm The amide was dissolved in 20.0 mL, and N,N-diisopropylethylamine (1.61 g, 12.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (HATU, 3.08 g, 8.08 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in 40.0 mL of water, extracted with ethyl acetate (20.0 mL x 3), washed with saturated sodium chloride solution (40.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The solution was directly concentrated to obtain crude organisms, which were separated by chromatography column (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain the yellow solid 6-bromo-3-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (17B) (1.70 g, yield 68.5%).

[0187] LC-MS, M / Z (ESI): 399.9 [M+H]+ Step 2: Synthesis of 5-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (17C)

[0188] [ka] At 0°C, 6-bromo-3-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (17B) (1.20 g, 3.01 mmol) was dissolved in dichloromethane (24.0 mL), and m-chloroperbenzoic acid (1.83 g, 9.03 mmol) was added in several batches. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in saturated sodium sulfite solution (50.0 mL), extracted with dichloromethane (30.0 mL x 3), washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The mixture was directly concentrated to obtain a crude product, which was purified by chromatography column chromatography (petroleum ether:ethyl acetate = 5:1 to 0:1) to obtain a white solid 5-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (17C) (500 mg, yield 40%).

[0189] LC-MS, M / Z (ESI): 415.9 [M+H] + 1 H NMR (400 MHz, CDCl3-d) δ 9.66 (br s, 1H), 9.15 (br s, 1H), 8.87 (s, 1H), 8.70 (s, 1H), 7.79 (s, 1H). Step 3: Synthesis of 5-(3-chloro-2-fluoro-6-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide)pyrimidine 1-oxide (I-17)

[0190] [ka] At room temperature, 5-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (17C) (400 mg, 965 μmol) and 4-trifluoromethoxyphenol (258 mg, 1.45 mmol) were dissolved in toluene (8.00 mL), and cuprous iodide (36.7 mg, 193 μmol) and cesium carbonate (629 mg, 1.93 mmol) were further added. The reaction mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, water (20.0 mL) was added to the reaction mixture and extracted with ethyl acetate (10.0 mL × 3). The organic phase was washed with saturated sodium chloride solution (20.0 mL), and the organic phase was concentrated to obtain the crude organism. The crude organism was then subjected to preparative reverse phase (YMC-Actus Triart C18 150 × 30 mm × 7 μm, mobile phase [water (0.225% formic acid)-acetonitrile], B% 53%~83%, 10 min) to obtain 5-(3-chloro-2-fluoro-6-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide)pyrimidine 1-oxide (I-17, 95.4 mg, yield 18.5%).

[0191] 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (br s, 1H), 8.89 (d, 1H), 8.82 (t, 1H), 8.37 (d, 1H), 7.40 - 7.46 (m, 3H), 7.26 - 7.31 (m, 2H). LC-MS, M / Z (ESI): 512.1 [M+H] + Example 6: Preparation of target compound I-18 Synthesis of 5-(4,5-dichloro-2-(2-methoxy-4-(trifluoromethoxy)phenoxy)benzamidino)pyrimidine 1-oxide(I-18)

[0192] [ka] The synthesis route for target compound I-18 was as follows:

[0193] [ka] Step 1: 1-Bromo-2-methoxy-4-(trifluoromethoxy)benzene

[0194] [ka] The starting materials 2-bromo-5-(trifluoromethoxy)phenol (5.0 g, 19.45 mmol), iodomethane (4.14 g, 29.18 mmol), and potassium carbonate (8.07 g, 58.36 mmol) were dissolved in DMF (60 mL) and reacted at room temperature for 2 hours. After the reaction was complete, water (50 mL) and ethyl acetate (100 mL) were added, the mixture was separated, the organic phases were combined, and the mixture was washed with brine (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow, oily crude biomass (18B, 5.0 g, yield 94.8%).

[0195] 1 H NMR (400 MHz, cdcl3) δ 7.56 - 7.52 (m, 1H), 6.77 - 6.72 (m, 2H), 3.90 (s, 3H). Step 2: (2-Methoxy-4-(trifluoromethoxy)phenyl)boronic acid

[0196] [ka] The starting material 1-bromo-2-methoxy-4-(trifluoromethoxy)benzene (2.0 g, 7.38 mmol) was dissolved in tetrahydrofuran (20 mL), and under nitrogen gas protection and at -78°C, a solution of n-butyllithium in tetrahydrofuran (2.5 M, 3.5 mL, 8.86 mmol) was gradually added dropwise to the solution. After the addition was complete, stirring was continued at this temperature for 30 minutes. At -78°C, triisopropyl borate (1.94 g, 10.33 mmol) was added dropwise to the reaction mixture and stirring was continued for 2 hours. After the reaction was complete, the pH was adjusted to 4-5 with 1 N hydrochloric acid (10 mL), ethyl acetate (20 mL) was added, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude organisms (18C, 1.7 g, yield 97.6%). Step 3: 2-Methoxy-4-(trifluoromethoxy)phenol

[0197] [ka] The starting material (2-methoxy-4-(trifluoromethoxy)phenyl)boronic acid (1.0 g, 4.24 mmol) was dissolved in ethanol (10 mL), and hydrogen peroxide solution (2.5 mL) was gradually added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, water (10 mL) and ethyl acetate (30 mL) were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This compound was then separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the title compound (18D, 800 mg, 90% yield).

[0198] 1 H NMR (400 MHz, cdcl3) δ 6.91 - 6.87 (m, 1H), 6.78 - 6.73 (m, 2H), 3.90 (s, 3H). Step 4: 4,5-Dichloro-2-(2-methoxy-4-(trifluoromethoxy)phenoxy)-N-(pyrimidine-5-yl)benzamide

[0199] [ka] The starting materials 4,5-dichloro-2-fluoro-N-(pyrimidine-5-yl)benzamide (800 mg, 2.8 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (465 mg, 2.24 mmol), and cesium carbonate (2.73 g, 8.39 mmol) were dissolved in DMF (10 mL), and the reaction mixture was allowed to react at 100°C for 2 hours. After the reaction was complete, water (10 mL) and ethyl acetate (30 mL) were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This compound was then separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the title compound (18F, 200 mg, yield 15%).

[0200] LC-MS, M / Z (ESI): 473.98 [M+H] + . Step 5: 5-(4,5-dichloro-2-(2-methoxy-4-(trifluoromethoxy)phenoxy)benzamidino)pyrimidine 1-oxide(I-18)

[0201] [ka] The starting materials 4,5-dichloro-2-(2-methoxy-4-(trifluoromethoxy)phenoxy)-N-(pyrimidine-5-yl)benzamide (100 mg, 0.210 mmol) and m-CPBA (100 mg, 0.63 mmol) were dissolved in dichloromethane (2 mL) and reacted at room temperature for 10 hours. After the reaction was complete, the mixture was washed with an aqueous solution of sodium bicarbonate, dichloromethane (10 mL) was added, the mixture was separated, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude organism. Next, the compound was purified by preparative reverse-phase high-performance liquid chromatography (column: SunFile™ Prep C18 OBD™ 5 μm 30 mm × 150 mm, mobile phase: A = acetonitrile, B = water, gradient: 1% to 35%, 10 minutes) to obtain the title compound 5-(4,5-dichloro-2-(2-methoxy-4-(trifluoromethoxy)phenoxy)benzamidino)pyrimidine 1-oxide (I-18, 30 mg, yield 29%).

[0202] LC-MS, M / Z (ESI): 490.0 [M+H] + . 1 H NMR (400 MHz, cdcl3) δ 9.73 (s, 1H), 9.21 (t, 1H), 8.77 (d, 1H), 8.31 (d, 1H), 8.30 (s, 1H), 7.28 (d, 1H), 7.01 - 6.97 (m, 2H), 6.88 (s, 1H), 3.87 (s, 3H). Example 7: Preparation of target compound I-19 5-(3,4-dichloro-2-fluoro-6-(4-(trifluoromethoxy)phenoxy)benzamidino)pyrimidine 1-oxide(I-19)

[0203] [ka] The synthesis route for target compound I-19 was as follows:

[0204] [ka] Step 1: Synthesis of 6-bromo-3,4-dichloro-2-fluorobenzoic acid (19B)

[0205] [ka] Under nitrogen gas protection, 5-bromo-1,2-dichloro-3-fluorobenzene (19A) (10.0 g, 41.0 mmol) was dissolved in tetrahydrofuran (100 mL). The reaction mixture was then cooled to -70°C, and a 2 M lithium diisopropylamine solution in tetrahydrofuran (30.7 mL, 61.5 mmol) was gradually added dropwise, while the reaction mixture was stirred at -70°C for 0.5 hours. Next, dry ice (20.0 g) was added to the reaction mixture in several batches, and the reaction mixture was stirred at 25°C for a further 0.5 hours. After the reaction was complete, 1 M hydrochloric acid was added to adjust the pH to 3-4, and the organic phase was concentrated by extraction with ethyl acetate to obtain the crude organism. The crude organism was pulped with petroleum ether (50.0 mL), filtered, and dried with an oil pump to obtain the brown solid 6-bromo-3,4-dichloro-2-fluorobenzoic acid (19B) (10.0 g, yield 84.7%).

[0206] LC-MS, M / Z (ESI): 301.0 [MH] - 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (d, 1H). Step 2: Synthesis of 6-bromo-3,4-dichloro-2-fluoro-N-(pyrimidine-5-yl)benzamide (19C)

[0207] [ka] At room temperature, 6-bromo-3,4-dichloro-2-fluorobenzoic acid (3.00 g, 10.4 mmol) and 3-amidopyrimidine (1.19 g, 12.5 mmol) were dissolved in N,N-dimethyl HolmThe amide was dissolved in 30.0 mL, and N,N-diisopropylethylamine (2.69 g, 20.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (HATU, 5.15 g, 13.5 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in 50.0 mL of water, extracted with ethyl acetate (30.0 mL x 3), washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The solution was directly concentrated to obtain crude compounds, which were separated by chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain a yellow solid 6-bromo-3,4-dichloro-2-fluoro-N-(pyrimidine-5-yl)benzamide (19C) (2.60 g, yield 68.4%).

[0208] LC-MS, M / Z (ESI): 365.9 [M+H] + Step 3: Synthesis of 5-(6-bromo-3,4-dichloro-2-fluorobenzoylamino)pyrimidine 1-oxide (19D)

[0209] [ka] At 0°C, 6-bromo-3,4-dichloro-2-fluoro-N-(pyrimidine-5-yl)benzamide (2.40 g, 6.58 mmol) was dissolved in dichloromethane (48.0 mL), and m-chloroperbenzoic acid (2.67 g, 13.2 mmol) was added in several batches. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in saturated sodium sulfite solution (50.0 mL), extracted with dichloromethane (30.0 mL x 3), washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The mixture was directly concentrated to obtain a crude product, which was then purified by chromatography column chromatography (petroleum ether:ethyl acetate = 5:1 to 0:1) to obtain a white solid 5-(6-bromo-3,4-dichloro-2-fluorobenzoylamino)pyrimidine 1-oxide (19D) (700 mg, yield 27.9%).

[0210] LC-MS, M / Z (ESI): 381.9 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (br s, 1H), 8.92 (s, 2H), 8.44 (d, 1H), 8.14 (d, 1H). Step 4: Synthesis of 5-(3,4-dichloro-2-fluoro-6-(4-(trifluoromethoxy)phenoxy)benzamidino)pyrimidine 1-oxide (I-19)

[0211] [ka] At room temperature, 5-(6-bromo-3,4-dichloro-2-fluorobenzoylamino)pyrimidine 1-oxide (650 mg, 1.71 mmol) and 4-trifluoromethoxyphenol (365 mg, 2.05 mmol) were dissolved in N,N-dimethylformamide (14.0 mL), and cuprous iodide (65.0 mg, 341 μmol) and cesium carbonate (1.11 mg, 3.41 mmol) were further added. The reaction mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was added to water (50.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (50.0 mL), and the organic phase was concentrated to obtain the crude organism. The crude organism was then subjected to preparative reverse phase (Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase [water (0.225% formic acid)-acetonitrile], B% 45%~75%, 10 min) to obtain 5-(3,4-dichloro-2-fluoro-6-(4-(trifluoromethoxy)phenoxy)benzamidino)pyrimidine 1-oxide (I-19, 200 mg, yield 24.3%).

[0212] LC-MS, M / Z (ESI): 478.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.30 - 11.71 (m, 1H), 8.87 (d, 1H), 8.83 (t, 1H), 8.38 (d, 1H), 7.42 (d, 2H), 7.33 (d, 1H), 7.23 - 7.28 (m, 2H). Example 8: Preparation of target compound I-20 Synthesis of 5-(2-fluoro-6-(4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide)pyrimidine 1-oxide(I-20)

[0213] [ka] The synthesis route for target compound I-20 was as follows:

[0214] [ka] Step 1: Synthesis of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (20B)

[0215] [ka] Under nitrogen gas protection, 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (4.00 g, 16.4 mmol) was dissolved in tetrahydrofuran (40.0 mL). The reaction mixture was then cooled to -70°C, and a 2 M lithium diisopropylamine solution in tetrahydrofuran (9.84 mL, 19.6 mmol) was gradually added dropwise. The reaction mixture was stirred at -70°C for 1 hour. Next, dry ice (30.0 g) was added to the reaction mixture in several batches, and the reaction mixture was stirred at 25°C for another 1 hour. After the reaction was complete, 1 M hydrochloric acid was added to adjust the pH to 3-4. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude compound. The crude compound was pulped with petroleum ether (50.0 mL), filtered, and dried with an oil pump to obtain a brown solid 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (20B) (3.20 g, yield 67.8%).

[0216] LC-MS, M / Z (ESI): 284.9 [MH] - 1 H NMR (400 MHz, CDCl3) δ 9.05 (br s, 1H), 7.53 (d, 2H). Step 2: Synthesis of 6-bromo-2-fluoro-N-(pyrimidine-5-yl)-3-(trifluoromethyl)benzamide (20C)

[0217] [ka] At room temperature, 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (3.00 g, 10.4 mmol) and 3-amidopyrimidine (1.19 mg, 12.5 mmol) were dissolved in N,N-dimethyl Holm The amide was dissolved in 30.0 mL, and N,N-diisopropylethylamine (2.70 g, 20.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (HATU, 5.16 g, 13.6 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in 50.0 mL of water, extracted with ethyl acetate (30.0 mL x 3), washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The mixture was directly concentrated to obtain crude organisms, which were separated by chromatography column (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain the yellow solid 6-bromo-2-fluoro-N-(pyrimidine-5-yl)-3-(trifluoromethyl)benzamide (20C) (3.20 g, yield 84.2%).

[0218] LC-MS, M / Z (ESI): 364.0 [M+H] + Step 3: Synthesis of 5-(6-bromo-2-fluoro-3-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (20D)

[0219] [ka] At 0°C, 6-bromo-2-fluoro-N-(pyrimidine-5-yl)-3-(trifluoromethyl)benzamide (2.50 g, 6.87 mmol) was dissolved in dichloromethane (50.0 mL), and m-chloroperbenzoic acid (4.18 g, 19.8 mmol) was added in several batches. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in saturated sodium sulfite solution (50.0 mL), extracted with dichloromethane (30.0 mL x 3), washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The mixture was directly concentrated to obtain a crude product, which was then purified by chromatography column chromatography (petroleum ether:ethyl acetate = 5:1 to 0:1) to obtain a white solid 5-(6-bromo-2-fluoro-3-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (20D) (650 mg, yield 24.9%).

[0220] LC-MS, M / Z (ESI): 380.0 [M+H] + Step 4: Synthesis of 5-(2-fluoro-6-(4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide)pyrimidine 1-oxide (I-20)

[0221] [ka] At room temperature, 5-(6-bromo-2-fluoro-3-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (400 mg, 1.05 mmol) and 4-trifluoromethoxyphenol (281 mg, 1.58 mmol) were dissolved in toluene (8.00 mL), and cuprous iodide (40.1 mg, 210 μmol) and cesium carbonate (685 mg, 2.10 mmol) were further added. The reaction mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was added to water (50.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (50.0 mL), and the organic phase was concentrated to obtain the crude organism. The crude organism was then subjected to preparative reverse phase (YMC-Actus Triart C18 150 × 30 mm × 7 μm, mobile phase [water (0.225% formic acid)-acetonitrile], B% 50%~80%, 10 min) to obtain 5-(2-fluoro-6-(4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide)pyrimidine 1-oxide (I-20, 155 mg, yield 30.7%).

[0222] LC-MS, M / Z (ESI): 478.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.86 - 8.92 (m, 2H), 8.43 (d, 1H), 7.91 (t, 1H), 7.49 (d, 2H), 7.32 - 7.38 (m, 2H), 6.94 (d, 1H). Example 9: Preparation of target compound I-21 Synthesis of 5-(4,5-dichloro-2-(4-fluoro-2-(trihydrogenated methoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (I-21)

[0223] [ka] The synthesis route for target compound I-21 was as follows:

[0224] [ka] Step 1: Synthesis of 4,5-dichloro-2-fluoro-nitrogen-(pyrimidine-5-yl)benzamide(21C)

[0225] [ka] The starting materials 4,5-dichloro-2-fluorobenzoic acid (3.0 g, 14.35 mmol), 5-aminopyrimidine (1.64 g, 17.23 mmol), N,N-diisopropylethylamine (5.57 g, 43.06 mmol), and HATU (10.9 g, 28.7 mmol) were dissolved in DMF (30 mL) and reacted overnight at room temperature. After the reaction was complete, water (20 mL) and ethyl acetate (50 mL) were added, the mixture was separated, the organic phases were combined, and the mixture was washed with brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was pulped with (petroleum ether:ethyl acetate (V / V) = 1:1) and filtered. The resulting filtration cake was the title compound (21C, 4.0 g, yield 97.4%).

[0226] LC-MS, M / Z (ESI): 285.6 [M+H] + Step 2: Synthesis of 4,5-dichloro-2-(4-fluoro-2-(trihydrogenated methoxy)phenoxy)-nitrogen-(pyrimidine-5-yl)benzamide (21F)

[0227] [ka] The starting materials 4,5-dichloro-2-fluoro-nitrogen-(pyrimidine-5-yl)benzamide (1.0 g, 3.5 mmol), 4-fluoro-2-(trihydrogenated methoxy)phenol, and cesium carbonate (761 mg, 5.24 mmol) were dissolved in DMF (10 mL), and the reaction was carried out at 100°C for 2 hours. After the reaction was complete, the mixture was separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the title compound (21F, 300 mg, yield 56%).

[0228] LC-MS, M / Z (ESI): 411.0 [M+H] + Step 3: Synthesis of 5-(4,5-dichloro-2-(4-fluoro-2-(trihydrogenated methoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (target compound I-21)

[0229] [ka] The starting materials 4,5-dichloro-2-(4-fluoro-2-(trihydrogenated methoxy)phenoxy)-nitrogen-(pyrimidine-5-yl)benzamide (100 mg, 0.243 mmol) and m-CPBA (62.9 mg, 0.364 mmol) were dissolved in dichloromethane (2 mL) and reacted at 25°C for 10 hours. After the reaction was complete, the mixture was washed with an aqueous solution of sodium bicarbonate, dichloromethane (5 mL) was added, the mixture was separated, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude organism. Next, the compound was purified by preparative reverse-phase high-performance liquid chromatography (column: SunFile™ Prep C18 OBD™ 5 μm 30 mm × 150 mm, mobile phase: A = acetonitrile, B = water, gradient: 1% to 25%, 8 minutes) to obtain the title compound 5-(4,5-dichloro-2-(4-fluoro-2-(trihydrogenated methoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (I-21) (20 mg, yield 19.2%).

[0230] LC-MS, M / Z (ESI): 426.6 [M+H]+ 1 H NMR (400 MHz, cdcl3) δ 9.80 (s, 1H), 9.21 (t, 1H), 8.77 (d, 1H), 8.31 (d, 1H), 8.28 (s, 1H), 7.22 (dd, 1H), 6.85 (td, 2H), 6.82 - 6.79 (m, 1H). Example 10: Preparation of target compound I-22 3-(4,5-dichloro-2-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide)-pyridine 1-oxide (Target compound I-22)

[0231] [ka] The synthesis route for compound I-22 was as follows:

[0232] [ka] Step 1: Synthesis of methyl 4,5-dichloro-2-fluorobenzoate (22B)

[0233] [ka] 4,5-Dichloro-2-fluorobenzoic acid (1.0 g, 4.7 mmol) was added to MeOH (20 mL), and concentrated hydrochloric acid (5 drops) was added dropwise to the reaction mixture. The reaction mixture was allowed to react at 50°C for 6 hours. LC-MS indicated completion of the reaction. The reaction mixture was rotated dry, NH4Cl solution (10 mL) was added, and the mixture was extracted with HCl (20 mL × 3). The organic phases were combined and washed with water (20 mL × 2) and saturated brine (10 mL), respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and rotated dry. The crude organisms were separated by normal-phase silica gel column (HCl / PE = 1:20) to obtain a white solid methyl 4,5-dichloro-2-fluorobenzoate (22B) (1.1 g, yield 95.4%).

[0234] Step 2: Synthesis of 4,5-dichloro-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)methyl benzoate (22D)

[0235] [ka] At room temperature, intermediate 22C (0.19 g, 1 mmol), methyl 4,5-dichloro-2-fluorobenzoate (0.22 g, 1 mmol), cesium carbonate (0.65 g, 2 mmol), and acetonitrile (5 mL) were added to a 25 mL round-bottom flask and reacted at 80°C for 8 hours. After cooling to room temperature, NH4Cl solution (20 mL) was added to the reaction mixture, and the mixture was extracted with SiO4 (20 mL × 3). The organic phase was washed once with saturated brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and rotated-dried. The crude organism was purified by silica gel column chromatography (SiO4 / PE = 1:10) and was a pale yellow solid. 4,5-Dichloro-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)methyl benzoate (22D) (364.0 mg, yield 92.3%) was obtained.

[0236] Step 3: Synthesis of 4,5-dichloro-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzoic acid (22E)

[0237] [ka] 4,5-Dichloro-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)methyl benzoate (364 mg, 0.93 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and methanol (1 mL). Then, lithium hydroxide monohydrate (0.12 g, 2.77 mmol) was weighed and added to water (2 mL), and then added to the above solution. After the addition was complete, the reaction mixture was allowed to react at room temperature for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was extracted with siRNA (15 mL × 3), the organic phase was combined, washed twice with water (10 mL × 2), the aqueous phase was combined, the pH was adjusted to 1 with 6 N hydrochloric acid, then extracted with siRNA (15 mL × 3), the organic phase was combined, washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and rotary dried. (4,5-Dichloro-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzoic acid (22E) (320 mg, crude organism) was obtained, and the crude organism was used directly in the next step.

[0238] Step 4: Synthesis of 4,5-dichloro-N-(pyridine-3-yl)-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide (22G)

[0239] [ka] Under ice bath conditions, (4,5-Dichloro-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzoic acid(320 mg, 0.84 mmol) was dissolved in acetonitrile (10 mL), then TCFH (0.35 g, 1.27 mmol) and NMI (0.26 g, 3.09 mmol) were added, and after 10 minutes, intermediate 6 (0.08 g, 0.84 mmol) was added, the temperature was raised to room temperature, and the mixture was reacted for 10 hours. Water (10 mL) was added to the reaction mixture, and it was extracted with SiO (20 mL × 3). The organic phase was washed once with saturated saline (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and rotated-dried. The crude organism was purified by normal-phase silica gel column (SiO / PE = 1:1) to obtain a pale yellow solid 4,5-dichloro-N-(pyridine-3-yl)-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide (22 G) (0.29 g, yield 75.5%).

[0240] LC-MS, M / Z (ESI): 457.00 [M+H] + Step 5: Synthesis of 3-(4,5-dichloro-2-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide)-pyridine 1-oxide (target compound I-22)

[0241] [ka] In an ice bath, 4,5-dichloro-N-(pyridine-3-yl)-2-(2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide Do (0.29 g, 0.63 mmol) was weighed and dissolved in DCM (10 mL), then m-CPBA (274.5 mg, 1.27 mmol) was added. The reaction mixture was allowed to react at room temperature for 10 hours. LC-MS indicated that the reaction was incomplete and some starting materials remained. The reaction mixture was diluted with dichloromethane (20 mL), then washed with saturated sodium bicarbonate aqueous solution (10 mL x 2), the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and rotated-dried, and after concentration, preparative high-pressure liquid chromatography yielded 3-(4,5-dichloro-2-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide)-pyridine 1-oxide (target compound I-22) (122.1 mg, yield 40.9%).

[0242] 1 H NMR (400 MHz, DMSO-d6) :δ 10.92 (s, 1H), 8.61 (s, 1H), 8.10 - 7.92 (m, 2H), 7.61 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.24 (t, J = 9.7 Hz, 1H), 7.00 (dd, J = 9.5, 3.6 Hz, 1H). LC-MS, M / Z (ESI): 472.99 [M+H] + Example 11: Preparation of target compound I-24 Synthesis of 5-(4,5-dichloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)benzamidino)pyrimidine 1-oxide(I-24)

[0243] [ka] The synthesis route for target compound I-24 was as follows:

[0244] [ka] Step 1: Synthesis of 4,5-dichloro-2-fluoro-N-(pyrimidine-5-yl)benzamide (24B)

[0245] [ka] At room temperature, 4,5-dichloro-2-fluorobenzoic acid (2.00 g, 9.57 mmol) and 3-amidopyrimidine (1.09 g, 11.5 mmol) were dissolved in N,N-dimethyl Holm The amide was dissolved in 20.0 mL, and N,N-diisopropylethylamine (2.47 g, 19.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (HATU, 3.08 g, 12.4 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in 40.0 mL of water, extracted with ethyl acetate (20.0 mL x 3), washed with saturated sodium chloride solution (40.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the yellow solid 4,5-dichloro-2-fluoro-N-(pyrimidine-5-yl)benzamide (24B) (2.50 g, crude biomass).

[0246] LC-MS, M / Z (ESI): 286.0 [M+H] + Step 2: Synthesis of 1-bromo-2-deuterated methoxy-4-(trifluoromethoxy)benzene (24C-2)

[0247] [ka] At room temperature, 2-bromo-5-(trifluoromethoxy)phenol (5.00 g, 19.4 mmol) is dissolved in N,N-dimethyl HolmThe amide was dissolved in 50.0 mL, and potassium carbonate (5.38 g, 38.9 mmol) and deuterated iodomethane (5.52 g, 38.9 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in 100 mL of water, extracted with ethyl acetate (30.0 mL x 3), washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the yellow liquid 1-bromo-2-deuterated methoxy-4-(trifluoromethoxy)benzene (24C-2) (4.60 g, crude biomass).

[0248] Step 3: Synthesis of [2-(deuterated)methoxy-4-(trifluoromethoxy)phenyl]boronic acid (24C-3)

[0249] [ka] At room temperature, 1-bromo-2-deuterated methoxy-4-(trifluoromethoxy)benzene (4.00 g, 14.6 mmol) and triisopropyl borate were dissolved in tetrahydrofuran (40.0 mL). The reaction mixture was cooled to -70°C, and then n-butyllithium tetrahydrofuran solution (7.01 mL, 17.5 mmol, 2.5 M) was gradually added dropwise. After the addition was complete, the reaction was gradually heated to 25°C and stirred for 12 hours. After the reaction was complete, the mixture was quenched in saturated ammonium chloride solution (40 mL), the pH was adjusted to 3-4 with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate (20.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the yellow liquid [2-(deuterated)methoxy-4-(trifluoromethoxy)phenyl]boronic acid (24C-3) (3.85 g, crude biomass).

[0250] Step 4: Synthesis of 2-(deuterated)methoxy-4-(trifluoromethoxy)phenol (24C)

[0251] [ka] At room temperature, [2-(deuterated)methoxy-4-(trifluoromethoxy)phenyl]boronic acid (3.80 g, 15.9 mmol) was dissolved in dioxane (38.0 mL). The reaction mixture was cooled to 0°C, and 30% hydrogen peroxide solution (4.58 g, 47.7 mmol) was gradually added dropwise. After the addition was complete, the reaction was gradually heated to 25°C and stirred for 12 hours. After the reaction was complete, the mixture was gradually added to saturated sodium thiosulfate solution (50.0 mL) and quenched. The mixture was extracted with ethyl acetate (30.0 mL x 3), the organic phase was washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the yellow liquid 2-(deuterated)methoxy-4-(trifluoromethoxy)phenol (24C) (3.20 g, crude biomass).

[0252] Step 5: Synthesis of 4,5-dichloro-2-[2-(deuterated)methoxy-4-(trifluoromethoxy)phenoxy]-N-(pyrimidine-5-yl)benzamide (24D)

[0253] [ka] At room temperature, 4,5-dichloro-2-fluoro-N-(pyrimidine-5-yl)benzamide (1.00 g, 3.50 mmol) and 2-(deuterated)methoxy-4-(trifluoromethoxy)phenol (886 mg, 4.19 mmol) were dissolved in N,N-dimethyl HolmThe amide was dissolved in 10.0 mL, cesium carbonate (2.28 g, 6.99 mmol) was added, and the reaction mixture was stirred at 80°C for 12 hours. After the reaction was complete, the mixture was quenched in 20.0 mL of water, extracted with ethyl acetate (10.0 mL x 3), washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The crude organism was separated by chromatography column (silica, petroleum ether:ethyl acetate = 5:1~1:1) to obtain the yellow solid 4,5-dichloro-2-[2-(deuterated)methoxy-4-(trifluoromethoxy)phenoxy]-N-(pyrimidine-5-yl)benzamide (24D) (140 mg, yield 8.38%).

[0254] LC-MS, M / Z (ESI): 477.1 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 9.60 (br s, 1H), 9.07 (br s, 2H), 9.00 (s, 1H), 8.32 (s, 1H), 7.25 (d, 1H), 6.94 - 7.00 (m, 2H), 6.88 (s, 1H). Step 6: Synthesis of 5-{4,5-dichloro-2-[2-deuterated methoxy-4-(trifluoromethoxy)phenoxy]benzoylamino}pyrimidine nitrogen oxide (I-24)

[0255] [ka] At 0°C, 4,5-dichloro-2-[2-(deuterated)methoxy-4-(trifluoromethoxy)phenoxy]-N-(pyrimidine-5-yl)benzamide (140 mg, 293 μmol) was dissolved in dichloromethane (4.00 mL), and m-chloroperbenzoic acid (71.5 mg, 352 μmol) was added in several portions. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in saturated sodium sulfite solution (5.00 mL), extracted with dichloromethane (5.00 mL x 3), washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The compound was directly concentrated to obtain a crude product, and preparative reverse-phase chromatography (column: Phenomenex Luna C18 150×25 mm×10 μm, mobile phase: [water (0.225% formic acid)-acetonitrile], B%: 58%~88%, 7 min) yielded 5-(4,5-dichloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)benzamidino)pyrimidine 1-oxide (I-24) (20.5 mg, yield 13.9%).

[0256] LC-MS, M / Z (ESI): 492.9 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.90 (s, 1H), 8.86 (d, 1H), 8.47 (d, 1H), 7.99 (s, 1H), 7.28 (d, 1H), 7.19 (d, 1H), 7.07 (s, 1H), 6.99 (dd, 1H). Example 12: Preparation of target compound I-25 5-(3-chloro-6-(4-(difluoromethoxy)phenoxy)-2-fluoro-4-(trifluoromethyl)benzamide)pyrimidine 1-oxide(I-25).

[0257] [ka] The synthesis route for target compound I-25 was as follows:

[0258] [ka] Step 1: 1-(benzyloxy)-4-(difluoromethoxy)benzene(25D-2)

[0259] [ka] 4-(benzyloxy)phenol (5.00 g, 24.9 mmol) and 2-chloro-2,2-difluoroacetate sodium salt (5.71 g, 37.4 mmol) were dissolved in N,N-dimethylformamide (50.0 mL), then cesium carbonate (16.3 g, 49.9 mmol) was added, and the reaction mixture was stirred at 100°C for 3 hours under nitrogen gas protection. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (50.0 mL × 3) and water (100 mL), the organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily crude organism. The crude organism was separated and purified by column chromatography (silica, petroleum ether:ethyl acetate = 20:1~10:1) to obtain a white solid (1-(benzyloxy)-4-(difluoromethoxy)benzene (2.40 g, yield 38.4%).

[0260] 1 H NMR (400 MHz, DMSO-d6) δ 7.43 - 7.48 (m, 2 H) 7.36 - 7.42 (m, 2 H) 7.30 - 7.36 (m, 1 H) 7.27 - 7.29 (m, 1 H) 7.10 - 7.15 (m, 2 H) 7.09 (s, 1 H) 7.02 - 7.08 (m, 2 H) 6.90 (s, 1 H) 5.06 - 5.14 (m, 2 H). Step 2: 4-(difluoromethoxy)phenol (25D)

[0261] [ka] (1-(benzyloxy)-4-(difluoromethoxy)benzene (1.00 g, 4.00 mmol) was dissolved in methanol (5.00 mL), then wet palladium carbon (127 mg, 119 μmol, 10% purity) was added, the reaction flask was purged three times with hydrogen gas, and the mixture was stirred at 25°C for 12 hours under a flow of hydrogen gas (50 Psi). After the reaction was complete, the mixture was concentrated by suction filtration to obtain a black semi-oily substance, 4-(difluoromethoxy)phenol (530 mg, yield 82.8%).

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (br s, 1 H) 6.74 - 7.20 (m, 6 H). Step 3: 6-Bromo-3-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide(25B)

[0263] [ka] 6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (10.0 g, 31.1 mmol) was dissolved in N,N-dimethylformamide (100 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (15.4 g, 40.4 mmol) was added. The reaction mixture was stirred at 25°C for 0.5 hours. Next, pyrimidine-5-amine (3.55 g, 37.3 mmol) and N,N-diisopropylethylamine (8.04 g, 62.2 mmol) were added, and the reaction mixture was stirred at 25°C for 2.5 hours. After the reaction was complete, water (200 mL) was added to the reaction mixture, then extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with water (200 mL) and saturated sodium chloride solution (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude organism, which was a yellow liquid. The crude organism was separated and purified by column chromatography (silica, petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain a yellow solid 6-bromo-3-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (8.70 g, yield 70.1%).

[0264] LC-MS, M / Z (ESI): 499.9 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.38 - 11.55 (m, 1 H) 9.09 (s, 2 H) 9.03 (s, 1 H) 8.17 - 8.24 (m, 1 H) 2.69 (s, 2 H). Step 4: 5-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide(25C)

[0265] [ka] 6-Bromo-3-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (5.00 g, 12.5 mmol) was dissolved in N,N-dimethylformamide (50.0 mL), and then m-chloroperbenzoic acid (10.2 g, 50.2 mmol, 85% purity) was added at 0°C under nitrogen gas protection. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, anhydrous sodium sulfite solution (150 mL) and sodium bicarbonate solution (150 mL) were added to the reaction mixture, and then ethyl acetate (50.0 mL × 3) The organic phase was extracted, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude organism, which was a yellow liquid. The crude organism was separated and purified by column chromatography (silica, petroleum ether:ethyl acetate = 5:1 to 0:1) to obtain a pale white solid 5-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (700 mg, yield 13.5%).

[0266] LC-MS, M / Z (ESI): 415.9 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1 H) 8.94 (d, J=1.75 Hz, 1 H) 8.90 - 8.93 (m, 1 H) 8.44 (d, J=2.00 Hz, 1 H) 8.22 (d, J=1.13 Hz, 1 H). Step 5: 5-(3-chloro-6-(4-(difluoromethoxy)phenoxy)-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide(I-25)

[0267] [ka] 5-{3-chloro-6-[4-(difluoromethoxy)phenoxy]-2-fluoro-4-(trifluoromethyl)benzoylamino}pyrimidine-1-cation-1-alcohol anion (100 mg, 240 μmol) and 4-(difluoromethoxy)phenol (42.4 mg, 264 μmol) were dissolved in N,N dimethylformamide (2.00 mL). Then, cesium carbonate (157 mg, 482 μmol) and cuprous iodide (4.60 mg, 24.1 μmol) were added, and the reaction mixture was stirred at 100°C for 10 minutes. After the reaction was complete, the mixture was filtered to obtain the crude organic phase. The crude organism was separated and purified by reverse-phase high-performance liquid chromatography (column: YMC-Actus Triart C18 150×30 mm×7 μm, mobile phase: [water (formic acid)-acetonitrile], gradient: 48%~78% B over 7 min) to obtain 5-(3-chloro-6-(4-(difluoromethoxy)phenoxy)-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (33.6 mg, yield 27.7%).

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 11.55 - 11.65 (m, 1 H) 8.89 (d, J=1.75 Hz, 1 H) 8.85 (t, J=1.94 Hz, 1 H) 8.40 (d, J=2.00 Hz, 1 H) 7.39 (s, 1 H) 7.26 (s, 5 H) 7.21 (s, 1 H) 7.03 (s, 1 H). Example 13: Preparation of target compound I-26 5-Chloro-(5-Chloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)-4-(trifluoromethyl)benzamide)pyrimidine 1-oxide (Target compound I-26)

[0269] [ka] The synthesis route for compound I-26 was as follows:

[0270] [ka] Step 1: Synthesis of 5-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (26C)

[0271] [ka] Under ice bath conditions, compound 26A (0.5 g, 2 mmol), compound 26B (0.22 g, 2.2 mmol), DIEA (0.78 g, 6 mmol), and HATU (1.14 g, 3 mmol) were added to acetonitrile (20 mL), and the reaction mixture was allowed to react overnight at room temperature. LC-MS indicated completion of the reaction. Water (20 mL) was added to the reaction mixture, and it was further extracted with SiO (30 mL × 3). The organic phases were combined and washed with water (20 mL × 2) and saturated saline (20 mL), respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and rotary dried. Crude organisms were separated by normal-phase silica gel column (SiO / PE = 1:1) to obtain a pale yellow solid (5-chloro-2-fluoro-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (26C) (0.48 g, yield 76.3%).

[0272] LC-MS, M / Z (ESI): 320.0 [M+H] + .

[0273] Step 2: Synthesis of 5-chloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (26E)

[0274] [ka] At room temperature, intermediate 26C (0.48 g, 1.5 mmol), intermediate 26D (0.25 g, 1.5 mmol), cesium carbonate (0.73 mg, 2.25 mmol), and acetonitrile (10 mL) were added to a 25 mL round-bottom flask and reacted at 80°C for 5 hours. After cooling to room temperature, water (10 mL) was added to the reaction mixture and extracted with siRNA (20 mL × 3). The organic phase was washed once with saturated brine (20 mL), dried over Na₂SO₄, filtered, concentrated under reduced pressure, and rotated-dried. The crude organisms were separated by normal-phase silica gel column (siRNA / PE = 1:1) to obtain the pale yellow solid 5-chloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)-N-(pyrimidine-5-yl)-4-(trifluoromethyl)benzamide (26E) (70.0 mg, yield 22.24%).

[0275] LC-MS, M / Z (ESI): 463.07 [M+H] + .

[0276] Step 3: Synthesis of 5-chloro-(5-chloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)-4-(trifluoromethyl)benzamide)pyrimidine-1-oxide (target compound I-26)

[0277] [ka] In an ice bath, intermediate 26E (100 mg, 0.22 mmol) was weighed and dissolved in DCM (3 mL), then m-CPBA (91.5 mg, 0.45 mmol) was added. The reaction mixture was allowed to react at room temperature for 10 hours. LC-MS indicated that the reaction was incomplete and some starting materials remained. The reaction mixture was diluted with dichloromethane (20 mL), then washed with saturated sodium bicarbonate aqueous solution (10 mL x 2), the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and rotated-dried, and after concentration, preparative high-pressure liquid chromatography yielded 5-chloro-(5-chloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)-4-(trifluoromethyl)benzamide)pyrimidine-1-oxide (target compound I-26) (26.1 mg, yield 24.7%).

[0278] 1 H NMR (400 MHz, CDCl3): δ 9.69 (s, 1H), 9.23 (t, J = 1.9 Hz, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.35 - 8.30 (m, 2H), 7.13 (s, 1H), 7.07 - 6.99 (m, 2H). LC-MS, M / Z (ESI): 479.06 [M+H] + Example 14: Preparation of target compound I-28 Synthesis of 5-(3-chloro-6-(4,5-difluoro-2-(methoxy-d3)phenoxy)-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (I-28)

[0279] [ka] The synthesis route for target compound I-28 was as follows:

[0280] [ka] Step 1: Synthesis of 1-bromo-4,5-difluoro-2-(methoxy-d3)benzene (28B-2)

[0281] [ka] At room temperature, 2-bromo-4,5-difluorophenol (1.00 g, 4.78 mmol) was dissolved in N,N-dimethyl Holm The amide was dissolved in 10.0 mL, then potassium carbonate (793 mg, 5.74 mmol) and deuterated iodomethane (815 mg, 5.74 mmol) were added, and the reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched in water (20.0 mL) at 0°C, extracted with ethyl acetate (10.0 mL x 3), washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily product, 1-bromo-4,5-difluoro-2-(methoxy-d3)benzene (800 mg, crude biomass).

[0282] Step 2: Synthesis of (4,5-difluoro-2-(methoxy-d3)phenyl)boronic acid (28B-3)

[0283] [ka] At room temperature, 1-bromo-4,5-difluoro-2-(methoxy-d3)benzene (700 mg, 3.10 mmol) and trimethyl boronic acid (640 mg, 3.41 mmol) were dissolved in tetrahydrofuran (14.0 mL). The reaction was then cooled to -70°C, and n-butyllithium (2.50 M, 1.49 mL) was gradually added dropwise. The reaction was then heated to 25°C and stirred for 12 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 3-4 with hydrochloric acid (1.00 M, 5.00 mL) at 0°C, extracted with ethyl acetate (10.0 mL x 3), washed the organic phase with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily product (4,5-difluoro-2-(methoxy-d3)phenyl)boronic acid (530 mg, crude biomass).

[0284] Step 3: Synthesis of 4,5-difluoro-2-(methoxy-d3)phenol (28B)

[0285] [ka] At room temperature, (4,5-difluoro-2-(methoxy-d3)phenyl)boronic acid (500 mg, 2.62 mmol) was dissolved in dioxane (5.00 mL). The reaction was then cooled to 0°C, and hydrogen peroxide (890 mg, 7.86 mmol) was gradually added dropwise. After the addition was complete, the reaction was gradually heated to 25°C and stirred for 2 hours. After the reaction was complete, the mixture was quenched in sodium sulfite solution (20.0 mL) at 0°C, and further extracted with ethyl acetate (10.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily product, 4,5-difluoro-2-(methoxy-d3)phenol (400 mg, crude biomass).

[0286] Step 4: Synthesis of 5-(3-chloro-6-(4,5-difluoro-2-(methoxy-d3)phenoxy)-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (I-28)

[0287] [ka] At room temperature, 5-(6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (150 mg, 361 μmol) and 4,5-difluoro-2-(methoxy-d3)phenol (147 mg, 904 μmol) were dissolved in N,N-dimethyl Holm The amide was dissolved in 3.00 mL, and cuprous iodide (13.7 mg, 72.3 μmol) and cesium carbonate (235 mg, 723 μmol) were added. The reaction was then stirred at 100°C for 10 minutes. After the reaction was complete, preparative reverse-phase analysis (column: C18 150 × 30 mm, mobile phase: [water (formic acid)-acetonitrile], gradient: 48%~78% B over 7 min) yielded 5-(3-chloro-6-(4,5-difluoro-2-(methoxy-d3)phenoxy)-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (I-28) (50.0 mg, yield 27.8%).

[0288] LC-MS, M / Z (ESI): 497.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1 H) 8.91 (d, J = 1.88 Hz, 1 H) 8.87 - 8.90 (m, 1 H) 8.44 (d, J = 2.00 Hz, 1 H) 7.48 - 7.55 (m, 1 H) 7.42 (dd, J = 12.44, 7.69 Hz, 1 H) 7.05 (s, 1 H) Example 15: Preparation of target compound I-31 Synthesis of 5-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide(I-31)

[0289] [ka] The synthesis route for target compound I-31 was as follows:

[0290] [ka] Step 1: Synthesis of 5-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (I-31)

[0291] [ka] At room temperature, 5-(5-chloro-2-fluoro-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (25.0 mg, 74.4 μmol) (see Example 5 for synthesis) and 4-fluoro-2-methylphenol (12.2 mg, 96.8 μmol) were mixed with N,N-dimethyl Holm The amide was dissolved in 1.00 mL, then cesium carbonate (48.5 mg, 148 μmol) was added, and the reaction was stirred at 120°C for 12 hours. After the reaction was complete, 5-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoylamino)pyrimidine 1-oxide (I-31) (11.7 mg, yield 35.6%) was obtained by preparative reverse-phase analysis (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (formic acid)-acetonitrile], gradient: 45%~75% B over 10 min).

[0292] LC-MS, M / Z (ESI): 441.9 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.23 (br s, 1 H) 8.86 - 8.92 (m, 2 H) 8.45 (d, J = 1.63 Hz, 1 H) 8.10 (s, 1 H) 7.22 (br d, J = 8.88 Hz, 1 H) 7.13 (s, 1 H) 7.08 - 7.11 (m, 2 H) 2.17 (s, 3 H) Example 16: Preparation of target compound I-32 3-(3,4-dichloro-2-fluoro-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide)pyridine-1-oxide (Target compound I-32)

[0293] [ka] The synthesis route for compound I-32 was as follows:

[0294] [ka] Step 1: Synthesis of methyl 6-bromo-3,4-dichloro-2-fluorobenzoate (32C)

[0295] [ka] 5-Bromo-1,2-dichloro-3-fluorobenzene (2.0 g, 8.20 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), then the system was evacuated and purged with nitrogen gas, and this process was repeated three times. Under nitrogen gas protection, the reaction mixture was cooled to -78°C, and LDA (4.51 mL, 9.02 mmol, 2.0 M) was added. After the addition was complete, the reaction mixture was allowed to continue reacting at the same temperature for 30 minutes, and methyl chloroformate (0.92 g, 9.84 mmol) was gradually added dropwise, maintaining the temperature below -65°C. After the addition was complete, the reaction mixture was gradually raised to room temperature and allowed to continue reacting for 10 hours. TLC (PE:EA = 5:1) indicated completion of the reaction. The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL), diluted with water (20 mL), then extracted with RINKAN (25 mL x 3), the organic phases were combined, washed with saturated brine (25 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and rotated-dried, and the crude organisms were separated by normal-phase silica gel column chromatography (RINKAN / PE = 0%~20%) to obtain methyl 6-bromo-3,4-dichloro-2-fluorobenzoate (32C) (2.20 g, yield 88.9%).

[0296] Step 2: 6-Bromo-3,4-dichloro-2-fluorobenzoic acid (32D)

[0297] [ka] Methyl 6-bromo-3,4-dichloro-2-fluorobenzoate (1.0 g, 3.31 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) and methanol (1 mL). Then, lithium hydroxide monohydrate (0.42 g, 9.93 mmol) was weighed and added to water (3 mL), and this was added to the above solution. After the addition was complete, the reaction mixture was allowed to react at room temperature for 16 hours. TLC (PE:EA = 3:1) indicated completion of the reaction. The reaction mixture was extracted with ELISA (15 mL x 3), the organic phase was combined, washed twice with water (10 mL x 2), the aqueous phase was combined, the pH was adjusted to 1 with 6 N hydrochloric acid, then extracted with ELISA (15 mL x 3), the organic phase was combined, washed with saturated saline (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and rotary dried to obtain 6-bromo-3,4-dichloro-2-fluorobenzoic acid (32D) (0.50 g, crude organism), which was used directly in the next step.

[0298] Step 3: 6-Bromo-3,4-dichloro-2-fluoro-N-(pyridine-3-yl)benzamide (32F)

[0299] [ka] Under ice bath conditions, 6-bromo-3,4-dichloro-2-fluorobenzoic acid (32D) (0.50 g, 1.74 mmol) was dissolved in anhydrous DMF (5 mL), then HATU (0.99 g, 2.61 mmol) was added, and after 10 minutes, 3-aminopyridine (0.20 g, 2.08 mmol) and DIPEA (0.67 g, 5.21 mmol) were further added. After the addition was complete, the temperature was raised to room temperature and the mixture was reacted at room temperature for 2 hours. TLC (PE:EA = 3:1) indicated that the reaction was complete. Water (10 mL) was added to the reaction mixture and extracted with siRNA (20 mL x 3). The organic phase was washed once with saturated brine (20 mL), dried over Na₂SO₄, filtered, concentrated under reduced pressure, and rotated-dried. The crude organisms were separated by normal-phase silica gel column chromatography (PE / siRNA = 0%~50%) to obtain 6-bromo-3,4-dichloro-2-fluoro-N-(pyridine-3-yl)benzamide (32F) (0.60 g, yield 94.91%).

[0300] Step 4: 3,4-Dichloro-2-fluoro-N-(pyridine-3-yl)-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide (32H)

[0301] [ka] Under nitrogen gas protection, 6-bromo-3,4-dichloro-2-fluoro-N-(pyridine-3-yl)benzamide (0.15 g, 0.41 mmol) was weighed and dissolved in ACN (3 mL). Then, 32 g of compound (85.8 mg, 0.41 mmol), potassium carbonate (170.1 mg, 1.24 mmol), and cuprous iodide (15.7 mg, 0.08 mmol) were added in sequence. After the addition was complete, the reaction mixture was heated to 80°C and reacted under these conditions for 2 hours. Reaction completion was indicated by LC-MS. The mixture was cooled to room temperature, NH4Cl solution (20 mL) was added to the reaction mixture, and extracted with siRNA (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and rotated-dried. The crude organisms were purified and separated using a silica gel preparative plate ((DCM:MeOH=10:1):(PE:siRNA=10:1)=3:1). 3,4-Dichloro-2-fluoro-N-(pyridine-3-yl)-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide(32H) (140 mg, yield 71.5%) was obtained.

[0302] Step 5: 3-(3,4-dichloro-2-fluoro-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide)pyridine-1-oxide (Target compound I-32)

[0303] [ka] At room temperature, 3,4-Dichloro-2-fluoro-N-(pyridine-3-yl)-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide (0.14 g, 0.29 mmol) were weighed and dissolved in DCM (3 mL), then m-CPBA (0.15 g, 85%, 0.74 mmol) was added. The reaction mixture was allowed to react at room temperature for 2 hours. Completion of the reaction was indicated by TLC(siRNA). The reaction mixture was diluted with dichloromethane (20 mL), then washed with saturated sodium bicarbonate aqueous solution (10 mL x 2), the organic phase was dried over Na2SO4, concentrated, and then obtained by preparative high-pressure liquid chromatography of 3-(3,4-dichloro-2-fluoro-6-((2,2,7-trifluorobenzo[d][1,3]dioxol-4-yl)oxy)benzamide)pyridine 1-oxide (target compound I-32) (30.7 mg, yield 21.2%).

[0304] 1 1H NMR (400 MHz, DMSO) - d6):δ 11.29 (s, 1H), 8.62 (s, 1H), 8.04 (d, 1H, J=8.0 Hz), 7.53 (s, 1H), 7.47-7.45 (m, 2H), 7.42-7.32 (m, 1H), 7.29-7.09 (m, 1H).

[0305] LC-MS, M / Z (ESI): 491.1[M+H] + Example 17: Preparation of target compound I-33 3-Cyclopropyl-5-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoylamino)pyridine 1-oxide(I-33).

[0306] [ka] The synthesis route for target compound I-33 was as follows:

[0307] [ka] Step 1: 4,5-Dichloro-N-(5-cyclopropylpyridine-3-yl)-2-fluorobenzamide(33B)

[0308] [ka] 4,5-Dichloro-2-fluorobenzoic acid (300 mg, 1.44 mmol) and N,N-dimethylformamide (10.5 mg, 143 μmol) were dissolved in dichloromethane (6.00 mL), and then oxalyl chloride (364 mg, 2.87 mmol) was added dropwise at 0°C. After stirring the reaction mixture at 0°C for 1 hour, it was directly concentrated, and then dichloromethane (3.00 mL) was added. Then, triethylamine (217 mg, 2.15 mmol) and 5-cyclopropylpyridine-3-amine (211 mg, 1.58 mmol) were added to the reaction mixture at 0°C. After substituting with nitrogen gas three times, the reaction mixture was stirred at 25°C for 11 hours. After the reaction was complete, it was directly concentrated to obtain a crude yellow oily substance, which was separated and purified by column chromatography (silica, petroleum ether:ethyl acetate = 1:1). Pure 4,5-dichloro-N-(5-cyclopropylpyridine-3-yl)-2-fluorobenzamide (300 mg, yield 64.3%) was obtained.

[0309] LC-MS, M / Z (ESI): 325.1 (M+H + ) Step 2: 4,5-Dichloro-N-(5-Cyclopropylpyridine-3-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide(33C)

[0310] [ka] 4,5-Dichloro-N-(5-cyclopropylpyridine-3-yl)-2-fluorobenzoyl (150 mg, 461 μmol) and 4-trifluoromethoxyphenol (106 mg, 599 μmol) were dissolved in N,N-dimethylformamide (3.00 mL), then cesium carbonate (300 mg, 922 μmol) was added, and the reaction mixture was stirred at 80°C for 12 hours. After the reaction was complete, the mixture was diluted with water (30.0 mL), then extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated sodium chloride solution (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude organism. The crude product was separated and purified by column chromatography (silica, petroleum ether:ethyl acetate = 1:1), and after purification, the pure product 4,5-dichloro-N-(5-cyclopropylpyridine-3-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (200 mg, yield 89.7%) was obtained.

[0311] LC-MS, M / Z (ESI): 483.2 (M+H + ) Step 3: 3-Cyclopropyl-5-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoylamino)pyridine 1-oxide(I-33)

[0312] [ka] 4,5-Dichloro-N-(5-cyclopropylpyridine-3-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (200 mg, 413 μmol) was dissolved in dichloromethane (4.00 mL), then m-chloroperbenzoic acid (168 mg, 827 μmol, 85%) was added at 0°C, and the reaction mixture was stirred at 25°C for 16 hours. After the reaction was complete, the mixture was quenched with sodium sulfite (20 mL) at 0°C, then extracted with dichloromethane (10 mL × 3), washed with saturated sodium bicarbonate solution (20 mL × 3), then washed with saturated sodium chloride solution (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude organism was separated and purified by reverse-phase high-performance liquid chromatography (column: YMC Triart 30×150 mm×7 μm, mobile phase: [water (formic acid)-acetonitrile], gradient: 55%~85% B over 8 min), and after purification, 3-cyclopropyl-5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoylamino)pyridine 1-oxide (51.2 mg, yield 24.5%) was obtained.

[0313] 1 H NMR (400 MHz, DMSO-d6)δ 10.7 - 10.9 (m, 1 H) 7.99 - 8.23 ​​(m, 2 H) 7.63 - 7.78 (m, 1 H) 7.33 - 7.59 (m, 4 H) 7.01 (br s, 1 H) 6.90 (s, 1 H) 1.78 - 2.01 (m, 1 H) 0.98 (br d, J=6.64 Hz, 2 H) 0.51 - 0.78 (m, 2 H) Example 18: Obtained by referring to the synthesis methods of Examples 1 to 17.

[0314] [Table 1] JPEG0007846262000138.jpg220169 JPEG0007846262000139.jpg252169 JPEG0007846262000140.jpg186169 Test Example 1: Detection of the inhibitory activity of a compound against the Nav1.8 ion channel All reagents used in the acid-base titration, except for NaOH and KOH, were purchased from Sigma (St. Louis, MO). The final concentrations of the test compounds were prepared on the same day and redissolved in extracellular fluid. The extracellular fluid (mM) consisted of 137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose, with a pH of 7.4 (titrated with NaOH). All test and control compound solutions contained 1 μM TTX. The intracellular fluid (mM) consisted of 140 mM aspartic acid, 2 mM magnesium chloride, 11 mM ethylene glycol tetraacetic acid (EGTA), and 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). The pH was adjusted to 7.4 with cesium hydroxide.

[0315] The test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9 mM. On the day of the test, it was redissolved in extracellular fluid to adjust to the desired concentration.

[0316] The electrophysiological experimental procedure was as follows:

[0317] Cells were transferred to a perfusion tank and perfused with extracellular fluid. Intracellular fluid was thawed on the day of the experiment. Electrodes were marked using a PC-10 (Narishige, Japan). Whole cell patch-clamp recordings were performed, and noise was filtered at 1 / 5 of the sampling frequency. 1 / 4 the length of the electrode tube of intracellular fluid was added to the electrode, and the electrode was attached to the probe. The necessary protocol was set, with the interface set to Membrane test and the Stage to Bath. A positive voltage was applied to the electrode, the tip of the electrode was brought into contact with the cell, the three-way valve of the insulator was set to the three-way position, and then a negative voltage was applied to the electrode to form a high-resistance seal between the electrode and the cell. The Stage was set to Patch, the leak was controlled within -200 pA, and a negative voltage was continuously applied to rupture the cell membrane and form an electrical pathway. The suction filter and the valve for extracellular fluid were opened to perfuse, and the cell current was observed. Administration was started after the cell current stabilized (at least three sweep current curves overlapped). When administering from low to high concentrations, the administration time for each concentration was 2 minutes or longer, and the concentration was changed and administered only after the current had stabilized.

[0318] The sample was administered using a gravity-based perfusion system. During the initial recording period, observation was performed for at least 1 minute until the peak current amplitude stabilized. During this period, the CV% of all peak current amplitudes needed to be less than 10% to eliminate fluctuations in the initial current. The average of the last 10 peak current amplitudes recorded during the initial recording period was used as the current peak value for the negative control. After the initial current stabilized, the test sample was administered at a low concentration until the peak currents recorded 10 times stabilized again, or until administration was continued for 5 minutes, and the peak currents before and after administration were "unchanged". "Stable" or "unchanged" was defined as: 1) the absolute mean of the peak currents scanned 10 times consecutively exceeds 200 pA and the CV value is less than 10%, or 2) the average of the peak currents scanned 10 times consecutively is between 200 pA and 50 pA and the CV value is less than 30%. Next, detection at higher concentrations was given.

[0319] The average of the peak currents from the last 10 scans for each concentration was used as the peak current for that concentration and was used for data analysis. If a stable state could not be reached within 5 minutes, the average of the peak currents from the last 10 scans at that time was used as the peak current for that concentration and was used for data analysis. At the same time, the cells were discarded without being reused for detection of higher concentrations. At least two cells were tested for each concentration of the compound.

[0320] Voltage pulse program: The cells were clamped to -80 mV and then depolarized to 10 mV with a square wave lasting 10 milliseconds to obtain a NaV1.8 current. This program was repeated every 5 seconds. The maximum square wave-induced current was detected, and after it stabilized, the test compound was perfused. After the reaction stabilized, the cutoff strength was calculated.

[0321] Data processing and fitting Sample collection and analysis were performed using pCLAMP 10 (Molecular Devices, Union City, CA). Current stability refers to the time-dependent change of the current being within a finite range. By plotting the dose-effect relationship between the gradient dilution series concentration of a drug and the stable current value generated by its action on HEK293 / Nav1.8, the inhibitory activity (IC) of the drug on the Nav1.8 ion channel could be further determined. 50 ) was calculated.

[0322] [Table 2] The test results showed that the compound of the present invention has relatively strong inhibitory activity against the Nav1.8 ion channel.

[0323] Test Example 2: Pharmacokinetic Study in Mice In the mouse pharmacokinetic study, three male ICR mice were fasted overnight and administered 10 mg / kg orally via gastric injection. Blood samples were collected before administration, at 15, 30 minutes, and at 1, 2, 4, 6, 8, and 24 hours after administration. Blood samples were centrifuged at 8000 rpm at 4°C for 6 minutes to collect plasma, which was then stored at -20°C. Plasma samples were taken at each time point, mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4°C for 10 minutes, and 3 times the volume of water was added to the supernatant and mixed. An appropriate volume of the mixture was taken and analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0324] [Table 3] The test results showed that the compound of the present invention has good pharmacokinetic properties.

[0325] Test Example 3: A rat model of neuropathic pain using spinal nerve ligation. Male SD rats weighing 180-220 g were anesthetized and placed prone on an operating table. An incision was made along the spine near the pelvis, and the fascia and muscle were separated. The L5 transverse process was carefully bitten off with forceps, the L5 nerve was isolated with a glass dissecting needle, and the L5 nerve was ligated with a 5-0 ligament. The muscle and skin were sutured and disinfected with iodine. After 14 days of modeling, the animals were divided into two groups of 10 each, and different compounds were administered orally and intragastricly to each group. The mechanical pain thresholds of the animals were detected using a Von-Frey fiber at different time points after administration. Specific doses and detection times are detailed in Table 3 below.

[0326] Method for detecting mechanical pain threshold: The plantar of the hind limb to be tested was continuously stimulated using a Von-Frey fiber in test animals to flex the fiber, and the animal's foot contraction response was observed. Test animals were stimulated one by one, starting with the smallest fiber weight and progressing to the largest, and each fiber weight was stimulated five times consecutively. If fewer than three positive responses occurred, the above procedure was repeated using a larger fiber, and if three or more positive responses occurred for the first time in the test, that fiber was set as the pain threshold for that animal (each animal was tested three times, and the average value was taken). The fiber weights were 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, and 15.0 g, and the cutting value was 15.0 g.

[0327] [Table 4] The test results showed that the compound of the present invention can significantly improve the reduction in the mechanical pain threshold in animals caused by rat spinal nerve ligation modeling, and that it has excellent analgesic efficacy.

[0328] Test Example 4: Rat model of incision pain Male SD rats weighing 200-250 g were anesthetized, fixed in a prone position, and their hind limbs were flattened with the soles of their feet facing upwards. The toes were secured with surgical tape and disinfected. A dermal fascia was incised at the tip of the claw 0.5 cm from the heel of the animal's foot using a scalpel, followed by a longitudinal incision of approximately 1 cm. After lifting the short flexor muscle of the foot with surgical curved forceps, a longitudinal incision was made in the muscle belly with a scalpel, without completely severing the muscle. The skin was sutured and disinfected. The day after modeling, the animals were divided into two different groups of eight each, and different compounds were administered orally and intragastricly to each group. The animals' mechanical pain thresholds were detected using a Von-Frey fiber at different time points after administration. The specific group divisions, dosages, and detection times are detailed in Table 4 below.

[0329] Method for detecting mechanical pain threshold: The plantar of the hind limb to be tested was continuously stimulated using a Von-Frey fiber in test animals to flex the fiber, and the animal's foot contraction response was observed. Test animals were stimulated one by one, starting with the smallest fiber weight and progressing to the largest, and each fiber weight was stimulated five times consecutively. If fewer than three positive responses occurred, the above procedure was repeated using a larger fiber, and if three or more positive responses occurred for the first time in the test, that fiber was set as the pain threshold for that animal (each animal was tested three times, and the average value was taken). The fiber weights were 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, and 15.0 g, and the cutting value was 15.0 g.

[0330] [Table 5] The test results showed that the compound of the present invention can significantly improve the reduction in the mechanical pain threshold in animals caused by rat incision pain modeling, and that it has excellent analgesic efficacy.

[0331] The embodiments of the technical proposal described herein have been explained exemplarily. The claims of this disclosure should be understood to be not limited to the embodiments described above. Any modifications, equivalent substitutions, or improvements made by those skilled in the art, without departing from the gist and principles of this disclosure, should all be included within the claims of this application.

Claims

1. A compound represented by formula (II) or (IV), a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, 【Chemistry 1】 Eventually, X is N, R 1 、 R 2 、 R 3 、 R 4 、 R 5 、 R 6 and R 7 are each independently H, D, C 1 -C 6 alkyl group, C 11 substituted with one or more R 1 -C 6 alkyl group, -O-(C 1 -C 6 alkyl group), -O-(C 14 substituted with one or more R 1 -C 6 alkyl group), -S-(C 1 -C 6 alkyl group), -S-(C 15 substituted with one or more R 1 -C 6 alkyl group) and halogen, and when the substituents R 11 , R 14 and R15 are plural, the substituents are the same or different. R 11 , R 14 And R15 are each independently selected from halogen or deuterium. Compounds, their tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

2. In the compound shown in formula (II), 【Chemistry 2】 teeth, 【Transformation 3】 And, And / or, R 1 is H or halogen, And / or, R 2 is a halogen, or one or more R 11 C replaced by 1 -C 6 It is an alkyl group, And / or, R 3 This is H, halogen, or one or more R 11 C replaced by 1 -C 6 It is an alkyl group, And / or, R 4 H is, And / or, R 5 H, D, one or more R 11 C replaced by 1 -C 6 Alkyl group or one or more R 14 -O-(C) substituted 1 -C 6 It is an alkyl group, And / or, R 6 is a halogen, or one or more R 14 -O-(C) substituted 1 -C 6 It is an alkyl group, And / or, R 7 It is characterized by being D or halogen, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

3. In the compound represented by formula (II), R1 is either H or F. And / or, R2 is Cl or a trifluoromethyl group. And / or, R 3 is H, Cl, or a trifluoromethyl group. And / or, R 5 is H, D, methyl group, 【Chemistry 4】 And, And / or, R 6 is F, 【Transformation 5】 And, And / or, R 7 is characterized by being D or F, The compound according to claim 2, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

4. In the compound shown in formula (II), 【Transformation 6】 teeth, 【Transformation 7】 Selected from, And / or, 【Transformation 8】 teeth, 【Chemistry 9】 Characterized by being selected from, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

5. In the compound shown in formula (II), 【Chemistry 10】 teeth, 【Chemistry 11】 And, And / or, R 1 is H or halogen, And / or, R 2 It is a halogen, And / or, R 3 is a halogen, or one or more R 11 C replaced by 1 -C 6 It is an alkyl group, And / or, R 4 H is, And / or, R 5 H is, And / or, R 6 is a halogen, or one or more R 14 -O-(C) substituted 1 -C 6 Characterized by being an alkyl group, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

6. In a compound represented by formula (II), 【Chemistry 12】 teeth, 【Chemistry 13】 And, R1 is either H or F. And / or, R2 is Cl, And / or, R 3 is Cl or a trifluoromethyl group. And / or, R 4 is H, And / or, R 5 is H, And / or, R 6 is F, or 【Chemistry 14】 Characterized by, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

7. In the compound shown in formula (IV), R 1 is H or halogen, And / or, R 2 is a halogen or one or more R 11 C replaced by 1 -C 6 It is an alkyl group, And / or, R 3 is a halogen or one or more R 11 C replaced by 1 -C 6 It is an alkyl group, And / or, R 4 H is, And / or, R 5 H is, And / or, R 6 It is characterized by being a halogen, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

8. In the compound represented by formula (IV), R1 is either H or F. And / or, R2 is Cl or a trifluoromethyl group. And / or, R 3 is Cl or a trifluoromethyl group. And / or, R 4 is H, And / or, R 5 is H, And / or, R 6 is characterized by being F, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

9. In the compound shown in formula (IV), 【Chemistry 15】 teeth, 【Chemistry 16】 Characterized by being selected from, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

10. In the compound shown in formula (IV), R 1 It is a halogen, And / or, R 2 It is a halogen, And / or, R 3 is one or more R 11 C replaced by 1 -C 6 It is an alkyl group, And / or, R 4 H is, And / or, R 5 H is, And / or, R 6 It is characterized by being a halogen, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

11. In a compound represented by formula (IV), 【Chemistry 17】 teeth, [Chemistry 18] Characterized by being selected from, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

12. In a compound represented by formula (IV), R1 is F, And / or, R2 is Cl, And / or, R 3 is a trifluoromethyl group, And / or, R 4 is H, And / or, R 5 is H, And / or, R 6 is characterized by being F, The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

13. The aforementioned compound, 【Chemistry 19】 It is characterized by being selected from the following compounds: The compound described in claim 1, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

14. The compound is 【Chemistry 20】 It is characterized by being selected from the following compounds: The compound according to claim 8, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. Use of a compound according to any one of claims 1 to 14, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt in the manufacture of a voltage-gated sodium ion channel inhibitor.

17. The voltage-gated sodium ion channel is characterized by being Nav1.

8. The use described in claim 16.

18. Use of a compound according to any one of claims 1 to 14, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof in the manufacture of a drug for treating, relieving, or preventing pain.

19. The aforementioned pain is characterized by including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, bowel pain, and idiopathic pain. The use described in claim 18.

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