Nav1.8 inhibitor

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 claims the priority of a prior application filed with the China National Intellectual Property Administration on June 22, 2022, with a patent application number of 202210714208.4 and a title of "Nav1.8 Inhibitor". and claims the priority of a prior application filed with the China National Intellectual Property Administration on June 13, 2023, with a patent application number of 202310704035.2 and a title of "Nav1.8 Inhibitor".

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

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

Background Art

[0004] Pain is "a subjective feeling and an unpleasant sensation and emotional feeling caused by actual tissue damage or potential tissue damage". Pain acts as a warning signal to alert the body to potential danger and provides an essential protective function for the normal life activities of the body. At the same time, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, strong pain or long-lasting pain can cause disorders of physiological functions and have a significant impact on the quality of life of the living body. According to statistics, about one in five people worldwide suffers 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. Among them, the acute moderate to severe pain treatment market is expected to continue to grow smoothly at an annual average growth rate of 2.5% in the future, and the chronic pain treatment market is predicted to grow at an annual average growth rate of about 18% in the future. Chronic pain will be the main driving force for the continuous growth of the global pain treatment market in the next decade.

[0005] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings widely distributed throughout the body's skin, muscles, joints, and visceral tissues. They convert the perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), transmit them via afferent nerve fibers to the cell body located in the dorsal root ganglia (DRG), and ultimately reach higher-order nerve centers, causing the sensation of 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, the sodium ion channels are activated, the channels open, sodium ions flow in, the cell membrane further depolarizes, and an action potential is generated. Therefore, inhibiting abnormal sodium ion channel activity is useful for the treatment and alleviation of pain.

[0006] Human sodium ion is a type of transmembrane ion channel protein composed of an α subunit with a molecular weight of 260 kD and β subunits with molecular weights of 30 - 40 kD. It is classified into nine isoforms, Nav1.1 - Nav1.9, respectively, by the α subunit. Nav1.5, Nav1.8, and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Nav1.5 is mainly present in cardiomyocytes, and Nav1.8 and Nav1.9 are present in the peripheral nervous system. Among them, Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective action target for pain treatment.

[0007] The gene encoding Nav1.8 is SCN10A, which is located in the 3p21-22 region of human chromosome and mainly encodes the α subunit. According to research, it has been found that the homology of the Nav1.8 gene between humans and rats reaches 93%. Nav1.8 mainly exists in trigeminal ganglion neurons and DRG neurons and has electrophysiological characteristics of slow inactivation and fast recovery. In neurons expressing Nav1.8, the rise of action potential is mainly due to Nav1.8 current. In a model of neuropathic pain, nerve injury causes an increase in the expression level of Nav1.8 in axons and neuron cell bodies. Using Nav1.8 antisense oligonucleotides can reduce the expression of Nav1.8 and at the same time significantly relieve pain. After injecting carrageenan into the hind paw of rats, the expression of Nav1.8 in DRG neurons increases. Nav1.8 knockout mice cannot exhibit normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene may cause peripheral neuropathic pain. According to a series of animal experiments and human gene evidence, the selective inhibition of Nav1.8 may be a new analgesic therapy and can be used in the treatment of various types of pain such as inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

[0008] The main drawback of several known Nav's inhibitors is their narrow therapeutic range, which may be the result of a lack of isoform selectivity. Since Nav1.8 is mainly limited to neurons that sense pain, selective Nav1.8 blockers are less likely to induce the side effects commonly seen in non-selective Nav's blockers. Therefore, in this technical field, there is still a need to develop new Nav1.8 selective inhibitors, preferably Nav channel inhibitors that are more selective, more effective, have improved metabolic stability, improved solubility, and fewer side effects against Nav1.8.

Summary of the Invention

[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, visceral 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 any optional embodiment of the present invention, the compound represented by formula (I) is the compound represented by formula (II),

[0014]

Chemical formula

[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 any optional embodiment of the present invention, the compound represented by formula (I) is the compound represented by formula (IV),

[0018] [Chemical formula] Among them, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are each independently H, D, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more R 11 、a C2-C6 alkenyl group, a C2-C6 alkenyl group substituted with one or more R 12 、a C2-C6 alkynyl group, a C2-C6 alkynyl group substituted with one or more R 13 、-O-(C1-C6 alkyl group), -O-(C1-C6 alkyl group) substituted with one or more R 14 、-S-(C1-C6 alkyl group), -S-(C1-C6 alkyl group) substituted with one or more R 15 、a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl group substituted with one or more R 16 、a 4- to 8-membered heterocycloalkyl group, a 4- to 8-membered heterocycloalkyl group substituted with one or more R 17 、a 6- to 10-membered aryl group, a 6- to 10-membered aryl group substituted with one or more R 18 、a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryl group substituted with one or more R 19 、-NR 1a R 1b 、halogen, hydroxy group, cyano group, nitro group, -SF5, and when the substituents R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 are plural, the above substituents are the same or different, R 1a and R 1b are each independently H, a C1-C6 alkyl group, one or more R 1a1selected from C1-C6 alkyl groups substituted with, substituent R 1a R 1b R 1a1 when there are a plurality of, 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, amino group, hydroxy group, cyano group, deuterium or nitro group.

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

[0020]

Chemical formula

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

[0022]

Chemical formula

[0023] In any optional embodiment of the present invention,

Chemical formula

Chemical formula

[0024] In any optional embodiment of the present invention,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0025] In any optional embodiment of the present invention,

Chemical formula

[0026] In any optional embodiment of the present invention, R 1 is H or a halogen.

[0027] In any optional embodiment of the present invention, R 1 is H or F.

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

[0029] In any optional embodiment of the present invention, R 2 is Cl,

[0030] [Chemical formula] a trifluoromethyl group or [Chemical formula] is.

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

[0032] In any optional embodiment of the present invention, R 3 is H, Cl, a trifluoromethyl group or [Chemical formula] is.

[0033] In any optional embodiment of the present invention, R 4 is H.

[0034] In any optional embodiment of the present invention, R 5 is H, D, a C1-C6 alkyl group substituted with one or more R 11 , a C2-C6 alkenyl group substituted with one or more R 12 , -O-(C1-C6 alkyl group) substituted with one or more R 14 , or a C2-C6 alkynyl group.

[0035] In any optional embodiment of the present invention, R 5 is H, D, a methyl group, [Chemical formula] is.

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

[0037] In any optional embodiment of the present invention, R6 is F, [Chemical formula] is.

[0038] In any optional embodiment of the present invention, R 7 is D or a halogen, preferably, R 7is D or F.

[0039] In any optional embodiment of the present invention,

Chemical formula

Chemical formula

[0040] In any optional embodiment of the present invention, R 1 is H.

[0041] In any optional embodiment of the present invention, R 2 is halogen.

[0042] In any optional embodiment of the present invention, R 2 is Cl.

[0043] In any optional embodiment of the present invention, R 3 is halogen.

[0044] In any optional embodiment of the present invention, R 3 is Cl.

[0045] In any optional embodiment of the present invention, R 4 is H.

[0046] In any optional embodiment of the present invention, R 5 is H.

[0047] In any optional embodiment of the present invention, R 6 is -O-(C1-C6 alkyl group) substituted with one or more R 14 s.

[0048] In any optional embodiment of the present invention, R 6 is

Chemical formula

[0049] In any optional embodiment of the present invention, R 1 is a halogen, In any optional embodiment of the present invention, R 1 is F.

[0050] In any optional embodiment of the present invention, R 2 is a halogen.

[0051] In any optional embodiment of the present invention, R 2 is Cl.

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

[0053] In any optional embodiment of the present invention, R 3 is a trifluoromethyl group.

[0054] In any optional embodiment of the present invention, R 4 is H.

[0055] In any optional embodiment of the present invention, R 5 is H.

[0056] In any optional embodiment of the present invention, R 6 is a halogen.

[0057] In any optional embodiment of the present invention, R 6 is F.

[0058] In any optional embodiment of the present invention,

Chemical formula

Chemical formula

[0059] In any optional embodiment of the present invention, R 1 is a halogen.

[0060] In any optional embodiment of the present invention, R 1 is F.

[0061] In any optional embodiment of the present invention, R 2 is a halogen.

[0062] In any optional embodiment of the present invention, R 2 is Cl.

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

[0064] In any optional embodiment of the present invention, R 4 is H.

[0065] In any optional embodiment of the present invention, R 5 is a halogen.

[0066] In any optional embodiment of the present invention, R 5 is F.

[0067] In any optional embodiment of the present invention, R 6 is a halogen.

[0068] In any optional embodiment of the present invention, R 6 is F.

[0069] In any optional embodiment of the present invention, R1 is H.

[0070] In any optional embodiment of the present invention, R 2 is halogen.

[0071] In any optional embodiment of the present invention, R 2 is Cl.

[0072] In any optional embodiment of the present invention, R 3 is a C1-C6 alkyl group substituted with one or more Rs 11 .

[0073] In any optional embodiment of the present invention, R 3 is a trifluoromethyl group.

[0074] In any optional embodiment of the present invention, R 4 is H.

[0075] In any optional embodiment of the present invention, R 5 is -O-(C1-C6 alkyl group) substituted with one or more Rs 14 .

[0076] In any optional embodiment of the present invention, R 5 is

Chemical formula

[0077] In any optional embodiment of the present invention, the compound represented by formula (I) is

Chemical formula

[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 tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable pharmaceutical 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 tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above pharmaceutical composition in the manufacture of a related drug for inhibiting and treating voltage-dependent sodium ion channels, wherein the voltage-dependent sodium ion channels to be inhibited include Nav1.1 to Nav1.9, preferably Nav1.8.

[0080] According to a specific embodiment of the present invention, the present invention provides the use of the above compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above pharmaceutical composition in the manufacture of a drug that can be used for the treatment, alleviation or prevention of pain, wherein the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

Advantages of the Invention

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

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

[0083] 2) The compound of the present invention has 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 be understood by the practice of the present invention.

Modes for Carrying Out the Invention

[0085] Definition and Explanation of Terms Unless otherwise specified, the terms and definitions used in the application of the present invention, including the specification and claims of the present application, are as follows.

[0086] As understood by those skilled in the art, based on the conventions used in the art, in the structural formula of the present application,

Chem.

[0087] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable non-toxic acid or base salt, including salts of inorganic acids and bases, 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, and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to a living body.

[0089] The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the types of the term "excipient" non-exclusively include adhesives, disintegrants, lubricants, flow promoters, stabilizers, fillers, and diluents, etc. Excipients can improve the handling properties of pharmaceutical formulations, that is, by enhancing 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 the functional groups in the compound, and the modification can be removed by ordinary operations or in the body to obtain the parent compound. Prodrugs include compounds formed by bonding any group to a hydroxy group or an amino group in the compound according to the present invention. When a prodrug of the compound according to the present invention is administered to an individual mammal, the prodrug cleaves to form a free hydroxy group and a free amino group, respectively.

[0091] The term "stereoisomer" refers to isomers generated 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 functional group isomers generated by the rapid movement of a certain atom within a molecule between two positions. The compounds according to the present invention can exhibit tautomerism. Tautomeric compounds can have two or more types of interconvertible species. Proton-transfer tautomers are due to the movement of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium state, and when attempting to separate a single tautomer, a mixture is usually produced whose physicochemical properties are consistent with a mixture of compounds. The position of the equilibrium is determined by the chemical characteristics 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 includes all tautomeric forms of the compound.

[0093] Some compounds of the present invention may have an asymmetric 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 illustration methods of racemates, ambiscalemic and scalemic, or enantiomerically pure compounds are shown in J. Chem. Ed. 1985, 62: 114 - 120. Unless otherwise specified, the absolute configuration of the stereocenters is shown by wedge bonds and dashed bonds. When the compounds described in this specification contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, these include E, Z geometric isomers. Similarly, all tautomeric forms are included within the scope of the present invention.

[0095] The compounds according to the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates 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 mixtures enriched in enantiomers or diastereomers belong to the scope of the present invention. Substituents such as alkyl groups may have other asymmetric carbon atoms. All of these isomers and their mixtures are included 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 which the mixture of obtained diastereomers is separated and the base decomposition is assisted to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxy group), an appropriate optically active acid or base forms a diastereomeric salt, and then the diastereomers are resolved by fractional crystallization or chromatography known in the art, and then recovered to obtain the 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 constituted by the 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 term "effective amount" or "therapeutically effective amount" refers 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 medical 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 straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of the above alkyl groups include, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, 2-methylbutyl group, 1-methylbutyl group, 1-ethylpropyl group, 1,2-dimethylpropyl group, neopentyl group, 1,1-dimethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 2-ethylbutyl group, 1-ethylbutyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutyl group or 1,2-dimethylbutyl group, etc. or their isomers. In particular, the above group has 1, 2 or 3 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 that the alkyl group is bonded to the rest of the molecule through an oxygen atom, and among them, "C1-C6 alkyl group" has the above definition. For example, -O-(methyl group), -O-(ethyl group).

[0105] The term "--S-(C1-C6 alkyl group)" should be understood that the alkyl group is bonded to the rest of the molecule through a sulfur atom, and among them, "C1-C6 alkyl group" has the above definition. For example, -S-(methyl group), -S-(ethyl group).

[0106] The term "C2-C6 alkynyl group" represents a straight-chain or branched-chain unsaturated hydrocarbon group having at least one (for example, 1 to 2, preferably 1) triple bond, and examples include 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, 1-methyl-2-propynyl group, etc., but are not limited thereto.

[0107] The term "C2-C6 alkenyl group" should be understood to represent a straight-chain or branched-chain monovalent hydrocarbon group having one or more double bonds and having 2 to 6 carbon atoms, for example 2 or 3 carbon atoms (i.e., a C2-C3 alkenyl group). When the above alkenyl group contains more than one double bond, it should be understood that the double bonds may be separated or conjugated to each other. The above alkenyl group is, for example, a vinyl group, an allyl group, an (E)-2-methylvinyl group, a (Z)-2-methylvinyl group, an (E)-but-2-enyl group, a (Z)-but-2-enyl group, an (E)-but-1-enyl group, a (Z)-but-1-enyl group, a pent-4-enyl group, an (E)-pent-3-enyl group, a (Z)-pent-3-enyl group, an (E)-pent-2-enyl group, a (Z)-pent-2-enyl group, an (E)-pent-1-enyl group, a (Z)-pent-1-enyl group, a hex-5-enyl group, an (E)-hex-4-enyl group, a (Z)-hex-4-enyl group, an (E)-hex-3-enyl group, a (Z)-hex-3-enyl group, an (E)-hex-2-enyl group, a (Z)-hex-2-enyl group, an (E)-hex-1-enyl group, a (Z)-hex-1-enyl group, an isopropenyl group, a 2-methylprop-2-enyl group, a 1-methylprop-2-enyl group, a 2-methylprop-1-enyl group, an (E)-1-methylprop-1-enyl group, a (Z)-1-methylprop-1-enyl group, a 3-methylbut-3-enyl group, a 2-methylbut-3-enyl group, a 1-methylbut-3-enyl group, a 3-methylbut-2-enyl group, an (E)-2-methylbut-2-enyl group, a (Z)-2-methylbut-2-enyl group, an (E)-1-methylbut-2-enyl group, a (Z)-1-methylbut-2-enyl group, an (E)-3-methylbut-1-enyl group, a (Z)-3-methylbut-1-enyl group, an (E)-2-methylbut-1-enyl group, a (Z)-2-methylbut-1-enyl group, an (E)-1-methylbut-1-enyl group, a (Z)-1-methylbut-1-enyl group, a 1,1-dimethylprop-2-enyl group, a 1-ethylprop-1-enyl group, a 1-propylvinyl group, a 1-isopropylvinyl group.

[0108] The term "C3-C6 cycloalkyl group" should be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic systems. For example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group.

[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 identical or different 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 remainder of the molecule via any one carbon atom or (if present) nitrogen atom. The heterocycloalkyl group may be a 4-membered ring such as azetidinyl group, oxetanyl group or thietanyl group, or a 5-membered ring such as tetrahydrofuranyl group, 1,3-dioxolanyl group, thianyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, 1,1-dioxothianyl group, 1,2-oxazolidinyl group, 1,3-oxazolidinyl group or 1,3-thiazolidinyl group, or a 6-membered ring such as tetrahydropyranyl group, tetrahydrothiopyranyl group, piperidinyl group, morpholinyl group, dithianyl group, thiomorpholinyl group, piperazinyl group, 1,3-dioxanyl group, 1,4-dioxanyl group or 1,2-oxazacyclohexyl group.

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

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

[0112] The term "halo" or "halogen" means fluorine, chlorine, bromine and iodine.

[0113] The term "deuterium" ("D" and "d") refers to an isotope of hydrogen (H) having one proton and one neutron in the deuterium atomic nucleus and a natural abundance ratio of 0.015% for that isotope.

[0114] The term "one or more" (for example, in the definition of substituents of the compounds of the general formula of the present invention) means "1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, and most particularly 1 or 2".

[0115] The term "optionally" or "optionally" means that the event or situation described thereafter may or may not occur, and the above description includes the case where the described event or situation occurs and the case where the described event or situation does not occur.

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

[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 in this field or according to the product manuals. Reagents or equipment used without the manufacturer's description are all ordinary products available on 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 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 denoted as DIEA, is diisopropylethylamine, i.e., N,N-diisopropylethylamine.

[0128] IC 50 is the half-maximal inhibitory concentration, referring to the concentration when half of the maximum inhibitory effect is reached.

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

[0130]

Chem.

[0131]

Chem.

[0132]

Chem.

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

[0134]

Chemical formula

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

[0136]

Chem.

[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 [M - H] - 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]

Chem.

[0140]

Chemical formula

[0141]

Chemical formula

[0142] Step 2: Synthesis of 5-chloro-N-(pyrimidin-5-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (5)

[0143]

Chemical formula

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

[0145]

Chemical Structure

[0146] 1 1H 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 [M-H] - 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]

Chem.

[0149]

Chem.

[0150]

Chem.

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

[0152]

Chemical formula

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

[0154]

Chemical formula

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

[0156]

Chemical Structure

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

[0158]

Chemical formula

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

[0160]

Chemical formula

[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]

Chemical Structure

[0163] 1 H 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 [M-H] - 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]

Chemical formula

[0166]

Chem.

[0167]

Chem.

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

[0169]

Chem.

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

[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]

Chemical formula

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

[0174]

Chem.

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

[0176]

Chem.

[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-(pyrimidin-5-yl)benzamide (16G)

[0179]

Chemical formula

[0180] LC-MS: m / z 429.04 [M+H] + 。

[0181] Step 7: Synthesis of 5-(4,5-dichloro-2-(3,4-difluoro-2-(deuteromethoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (Target Compound I-16)

[0182]

Chemical Structure

[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]

Chem.

[0185]

Chem.

[0186]

Chem.

[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]

Chem.

[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]

Chem.

[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)benzamidine)pyrimidine 1-oxide (I-18)

[0192]

Chemical Structure

[0193]

Chem.

[0194]

Chem.

[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]

Chem.

[0197]

Chemical formula

[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-(pyrimidin-5-yl)benzamide

[0199] [Chemical formula] The raw materials 4,5-dichloro-2-fluoro-N-(pyrimidin-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 solution was reacted at 100 °C for 2 h. After the reaction was completed, water (10 mL) and ethyl acetate (30 mL) were added for liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, which was separated and purified by a chromatography column (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] [Chemical formula] The raw materials 4,5-dichloro-2-(2-methoxy-4-(trifluoromethoxy)phenoxy)-N-(pyrimidin-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 h. After the reaction was completed, an aqueous solution of sodium hydrogen carbonate was added for washing, dichloromethane (10 mL) was added, and liquid separation was carried out. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and a crude product was obtained. Next, it was purified by preparative reverse-phase high performance liquid chromatography (column: SunFileTM Prep C18 OBDTM 5 μm 30 mm×150 mm, mobile phase: A = acetonitrile, B = water, gradient: 1% - 35%, for 10 minutes) to obtain the title compound 5-(4,5-dichloro-2-(2-methoxy-4-(trifluoromethoxy)phenoxy)benzamidinio)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 the target compound I-19 5-(3,4-Dichloro-2-fluoro-6-(4-(trifluoromethoxy)phenoxy)benzamidinio)pyrimidine 1-oxide (I-19)

[0203]

Chemical formula

[0204]

Chemical formula

[0205]

Chem.

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

[0207]

Chem.

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

[0209]

Chemical formula

[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]

Chemical Structure

[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)benzamido)pyrimidine 1-oxide (I-20)

[0213]

Chemical Structure

[0214]

Chem.

[0215]

Chem.

[0216] LC-MS, M / Z (ESI): 284.9 [M-H] - 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-(pyrimidin-5-yl)-3-(trifluoromethyl)benzamide (20C)

[0217]

Chem.

[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]

Chemical Structure

[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]

Chemical Structure

[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-(trideuteriomethoxy)phenoxy)benzoylamino)pyrimidine 1-oxide (I-21)

[0223]

Chemical formula

[0224] [Chemical formula] Step 1: Synthesis of 4,5-dichloro-2-fluoro-N-(pyrimidin-5-yl)benzamide (21C)

[0225] [Chemical formula] The raw 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 completed, water (20 mL) and ethyl acetate (50 mL) were added, and the mixture was separated. The organic phases were combined, washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product, slurried with (petroleum ether:ethyl acetate (V / V) = 1:1), and the filter cake obtained by filtration 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-(trideuteriomethoxy)phenoxy)-N-(pyrimidin-5-yl)benzamide (21F)

[0227] [Chemical formula] The raw materials 4,5-dichloro-2-fluoro-N-(pyrimidin-5-yl)benzamide (1.0 g, 3.5 mmol), 4-fluoro-2-(methoxyd3)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 h. After the reaction was completed, it was separated and purified by a chromatography column (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-(methoxyd3)phenoxy)benzoylamino)pyrimidine 1-oxide (target compound I-21)

[0229]

Chemical Structure

[0230] LC-MS, M / Z (ESI): 426.6 [M+H]+ 1 1H 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]

Chem.

[0232]

Chem.

[0233]

Chem.

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

[0235]

Chemical formula

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

[0237]

Chem.

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

[0239]

Chem.

[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]

Chemical formula

[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]

Chemical Structure

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

[0245] [Chemical formula] At room temperature, 4,5-dichloro-2-fluorobenzoic acid (2.00 g, 9.57 mmol) and 3-aminopyrimidine (1.09 g, 11.5 mmol) were dissolved in N,N-dimethylformamide (20.0 mL), N,N-diisopropylethylamine (2.47 g, 19.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 3.08 g, 12.4 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. After completion of the reaction, it was quenched by adding to water (40.0 mL), extracted with ethyl acetate (20.0 mL × 3), the organic phase was washed with saturated sodium chloride solution (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4,5-dichloro-2-fluoro-N-(pyrimidin-5-yl)benzamide (24B) (2.50 g, crude product) as a yellow solid.

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

[0247] [Chemical formula] At room temperature, 2-bromo-5-(trifluoromethoxy)phenol (5.00 g, 19.4 mmol) was dissolved in N,N-dimethylformamide (50.0 mL), potassium carbonate (5.38 g, 38.9 mmol) and iodomethane-d (5.52 g, 38.9 mmol) were further added, and the reaction mixture was stirred at 25 °C for 12 hours. After completion of the reaction, it was quenched by adding to water (100 mL), extracted with ethyl acetate (30.0 mL × 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 1-bromo-2-deuteromethoxy-4-(trifluoromethoxy)benzene (24C-2) (4.60 g, crude product).

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

[0249]

Chemical formula

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

[0251]

Chem.

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

[0253]

Chem.

[0254] LC-MS, M / Z (ESI): 477.1 [M+H] + 1 1H 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-deuteratedmethoxy-4-(trifluoromethoxy)phenoxy]benzoylamino}pyrimidine N-oxide (I-24)

[0255]

Chemical Structure

[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)benzamido)pyrimidine 1-oxide (I-25).

[0257]

Chemical Structure

[0258]

Chemical formula

[0259]

Chemical formula

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

[0262] 1 1H 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-(pyrimidin-5-yl)-4-(trifluoromethyl)benzamide (25B)

[0263] [Chemistry] 6-Bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (10.0 g, 31.1 mmol) was dissolved in N,N-dimethylformamide (100 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (15.4 g, 40.4 mmol) was added, and the reaction mixture was stirred at 25 °C for 0.5 h. Next, pyrimidin-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 h. After completion of the reaction, water (200 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with water (200 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product as a yellow liquid. The crude product was separated and purified by column chromatography (silica, petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain 6-bromo-3-chloro-2-fluoro-N-(pyrimidin-5-yl)-4-(trifluoromethyl)benzamide (8.70 g, yield 70.1%) as a yellow solid.

[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]

Chemical Structure

[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]

Chemical Structure

[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 the 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]

Chemical Structure

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

[0271] [Chemistry] 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 solution was reacted at room temperature overnight. Completion of the reaction was indicated by LC-MS. Water (20 mL) was added to the reaction solution, and it was further extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with water (20 mL × 2) and saturated brine (20 mL) respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and rotary evaporated. The crude product was separated by a normal phase silica gel column (EtOAc / PE = 1:1) to obtain a pale yellow solid, 5-chloro-2-fluoro-N-(pyrimidin-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-(pyrimidin-5-yl)-4-(trifluoromethyl)benzamide (26E)

[0274] [Chemistry] 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 eggplant flask and reacted at 80 °C for 5 h. After cooling to room temperature, water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (20 mL×3). The organic phase was washed once with saturated brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and rotary evaporated. The crude product was separated by normal-phase silica gel column (EtOAc / PE = 1:1) to obtain 5-chloro-2-(3,4-difluoro-2-(deuterated methoxy)phenoxy)-N-(pyrimidin-5-yl)-4-(trifluoromethyl)benzamide (26E), a pale yellow solid (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]

Chemical formula

[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]

Chemical formula

[0280]

Chemical formula

[0281]

Chemical formula

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

[0283]

Chemical formula

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

[0285]

Chemical formula

[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] [Chemical formula] 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-dimethylamide (3.00 mL), cuprous iodide (13.7 mg, 72.3 μmol) and cesium carbonate (235 mg, 723 μmol) were added, and then the reaction was stirred at 100 °C for 10 minutes. After completion of the reaction, preparative reverse phase (column: C18 150×30 mm, mobile phase: [water (formic acid)-acetonitrile], gradient: 48% - 78% B over 7 min) was used to obtain 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] [Chemical formula] The synthetic route of the target compound I-31 was as follows.

[0290]

Chem.

[0291]

Chem.

[0292] LC-MS, M / Z (ESI): 441.9 [M+H] + 11H 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]

Chem.

[0294]

Chem.

[0295]

Chem.

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

[0297]

Chemical formula

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

[0299]

Chemical formula

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

[0301]

Chemical formula

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

[0303]

Chemical formula

[0304] 1 H 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]

Chemical formula

[0307]

Chemical formula

[0308]

Chem.

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

[0310]

Chem.

[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]

Chemical Structure

[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 with reference to the synthesis methods of Examples 1 - 17

[0314]

Table 1

[0315] The test compounds were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9 mM. On the day of the test, they were redissolved in the extracellular solution and adjusted to the desired concentration.

[0316] The electrophysiological experimental procedure was as follows.

[0317] The cells were transferred to a perfusion chamber and perfused with extracellular fluid. The intracellular fluid was thawed on the day of the experiment. The electrodes were pulled with a PC-10 (Narishige, Japan). For whole-cell patch-clamp recording, the noise was filtered at one-fifth of the sampling frequency. Intracellular fluid equal to one-fourth of the electrode tube length was added into the electrode, and the electrode was attached to the probe. The necessary Protocol was set, the interface was set to Membrane test, and the Stage was set 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 aspiration device was set to the three-way state, 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 to form a current path. The suction filtration device and the valve of the extracellular fluid were opened for perfusion, the cell current was observed, and administration was started after the cell current was stable (the current curves of at least three sweeps overlapped). When administering from a low concentration to a high concentration, the administration time for each concentration was 2 min or more, and the concentration was changed for administration after the current was stable.

[0318] The test sample was administered by perfusion using a perfusion system that utilized its own weight. During the initial recording period, it was observed for at least 1 minute until the peak current amplitude was stable. During this period, in order to eliminate the up-and-down fluctuations of the initial current, the CV% of all peak current amplitudes needed to be less than 10%. The average value of the peak current amplitudes recorded in the last 10 times during the initial recording period was used as the current peak value of the negative control. After the initial current was stable, the test sample was administered from a low concentration until the peak current recorded 10 times became stable again or until the 5-min administration was continued, and there was "no change" in the peak current before and after administration. 1) When the absolute average value of the peak current scanned continuously 10 times exceeded 200 pA and the CV value was less than 10%, 2) or when the average value of the peak current scanned continuously 10 times was between 200 pA and 50 pA and the CV value was less than 30%, it was defined as "stable" or "no change". Next, a detection at a higher concentration was given.

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

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

[0321] Data processing and fitting Sample collection and analysis were performed using pCLAMP 10 (Molecular Devices, Union City, CA). The current being stable means that the change in current over time is within a finite range. By plotting the dose - effect relationship between the gradient dilution series concentrations of the drug and the stable current values generated by its action on HEK293 / Nav1.8, further, the inhibitory activity (IC 50 ) of the drug against the Nav1.8 ion channel was calculated.

[0322]

Table 2

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

[0324]

Table 3

[0325] Test Example 3: Spinal nerve ligation nerve injury pain model in rats After anesthetizing male SD rats weighing 180 - 220 g, they were placed on the operating table in the ventral recumbent position, incised along the spine near the ilium of the animal, and the fascia and muscles were separated. The L5 transverse process was carefully nipped off with forceps, the L5 nerve was separated with a glass dissecting needle, and the L5 nerve was ligated with a 5-0 ligature. The muscles and skin were sutured and disinfected with iodophor. 14 days after modeling, the animals were divided into different groups of 10 each, different compounds were administered orally by gavage, and the mechanical pain threshold of the animals was detected with a Von-Frey fiber at different time points after administration. The specific dosage and detection time are shown in detail in Table 3 below.

[0326] Method for detecting mechanical pain threshold: After the plantar surface of the hind limb of a test animal was continuously stimulated using a Von-Frey fiber to bend the fiber, the animal's foot withdrawal response was observed. The test animals were stimulated one by one in ascending order of the gram number of the fiber, and each fiber with a specific gram number was stimulated continuously 5 times. If the number of positive reactions that occurred was less than 3 times, the above operation was repeated using a larger fiber. When positive reactions occurred 3 times or more for the first time in the test, the fiber was taken as the pain threshold of the animal (each animal was tested 3 times and the average value was taken). The gram numbers of the fibers were 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0, and the cut-off value was 15.0 g.

[0327]

Table 4

[0328] Test Example 4: Incision pain model of rats After male SD rats weighing 200 - 250 g were anesthetized, they were fixed in the ventral position, the plantar surface of the hind limb on one side was flattened upward, the toes were fixed with surgical tape, and then disinfected. At a position 0.5 cm from the heel of the plantar surface of the animal, the skin and fascia were incised with a scalpel at the tip of the claw, and a longitudinal incision of about 1 cm was made. After lifting the short flexor muscle of the foot with a surgical curved forceps, a longitudinal incision was made in the muscle abdomen with a scalpel, but the muscle was not completely cut. The skin was sutured and disinfected. On the day after modeling, the animals were divided into different groups of 8 each, and different compounds were orally administered into the stomach. The mechanical pain threshold of the animals was detected with Von-Frey fibers at different time points after administration. The specific grouping, dosage, and detection time are shown in detail in Table 4 below.

[0329] Method for detecting mechanical pain threshold: After testing the plantar surface of the hind limb of a test animal using a Von-Frey fiber, the fiber was continuously stimulated to bend, and the foot withdrawal response of the animal was observed. The test animals were stimulated one by one in ascending order of the gram number of the fiber, and each fiber with a specific gram number was stimulated 5 times continuously. When the number of positive reactions that occurred was less than 3 times, the above operation was repeated using a larger fiber. When positive reactions occurred 3 times or more for the first time in the test, the fiber was taken as the pain threshold of the animal (each animal was tested 3 times and the average value was taken). The gram numbers of the fibers were 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0, and the cut-off value was 15.0 g.

[0330]

Table 5

[0331] As described above, the embodiments of the technical solution of the present disclosure have been exemplarily described. It should be understood that the claims of the present disclosure are not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the scope of not departing from the gist and principles of the present disclosure should all be included within the scope of the claims of this application.

Claims

1. A compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein 【Chemical 1】 among them, X is independently N or CR A selected from R A is H, D, C 1 -C 6 an alkyl group or C 3 -C 6 selected from cycloalkyl groups, Y is independently -NH- or 【Chemical 2】 selected from, ring A is independently [Chemical Formula 3] selected from, 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 are each independently H, D, C 1 -C 6 alkyl group, C 11 -C 1 alkyl group substituted with one or more Rs 6 -C 2 alkenyl group, C 6 -C 12 alkenyl group substituted with one or more Rs 2 -C 6 alkynyl group, C 2 -C 6 alkynyl group substituted with one or more Rs 13 -O-(C 2 -C 6 alkyl group), -O-(C 1 -C 6 alkyl group) substituted with one or more Rs 14 -S-(C 1 -C 6 alkyl group), -S-(C 1 -C 6 alkyl group) substituted with one or more Rs 15 -C 1 -C 6 cycloalkyl group, C 3 -C 6 cycloalkyl group substituted with one or more Rs 16 4- to 8-membered heterocycloalkyl group, C 3 -C 6 4- to 8-membered heterocycloalkyl group substituted with one or more Rs, 6- to 10-membered aryl group, C 17 6- to 10-membered aryl group substituted with one or more Rs, 5- to 8-membered heteroaryl group, C 18 5- to 8-membered heteroaryl group substituted with one or more Rs, -NR 19 R 1a R 1b 、halogen, hydroxy group, cyano group, nitro group, -SF 5 selected from, substituent R 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 substituents are the same or different, R 1a and R 1b are each independently H, C 1 -C 6 alkyl group, C 1a1 substituted with one or more R 1 -C 6 alkyl group, and when the substituents R 1a , R 1b , R 1a1 are plural, the 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 a halogen, an amino group, a hydroxy group, a cyano group, deuterium or a nitro group compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

2. The compound represented by the formula (I) is a compound represented by the formula (II) to (VI) respectively, characterized in that the compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug. 【Chemical 4】

3. In formula (II), said [Chemical Formula 5] is 【Chemical Formula 6】 characterized in that it is the compound according to claim 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

4. In formula (II), 【Chemical Formula 7】 is 【Chemical Formula 8】 and and / or, R 1 is H or halogen, preferably, R 1 is H or F, and / or, R 2 is halogen, C 12 substituted with one or more R 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 11 substituted with one or more R 1 -C 6 alkyl group, C 15 substituted with one or more R 1 -S-(C 6 alkyl group), and preferably, R 2 is Cl, 【Chemical Formula 9】 the trifluoromethyl group or 【Chemical Formula 10】 is and / or, R 3 is H, halogen, -S-(C 15 substituted with one or more R 1 -C 6 alkyl group), C 11 substituted with one or more R 1 -C 6 alkyl group, and preferably, R 3 is H, Cl, trifluoromethyl group or 【Chemical 11】 and and / or, R 4 is H, and / or, R 5 is H, D, one or more R 11 substituted C 1 -C 6 alkyl group, one or more R 12 substituted C 2 -C 6 alkenyl group, one or more R 14 substituted -O-(C 1 -C 6 alkyl group), C 2 -C 6 alkynyl group, and preferably, R 5 is H, D, methyl group, 【Chemical Formula 12】 and and / or, R 6 is halogen, C 12 substituted with one or more R 2 -C 6 alkenyl group, -O-(C 14 substituted with one or more R 1 -C 6 alkyl group), -S-(C 15 substituted with one or more R 1 -C 6 alkyl group), and preferably, R 6 is F, 【Chemical 13】 and and / or, R 7 is D or halogen, preferably, R 7 is D or F, characterized in that the compound according to claim 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

5. In formula (II), 【Chemical 14】 is 【Chemical Formula 15】 selected from, and / or, 【Chemical 16】 is 【Chemical 17】 selected from, characterized in that the compound according to claim 4, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

6. In formula (II), 【Chemical 18】 is 【Chemical 19】 and and / or, R 1 is H or halogen, preferably, R 1 is H or F, and / or, R 2 is halogen, C 12 substituted with one or more R 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, one or more R 15 substituted -S-(C 1 -C 6 alkyl group), preferably, R 2 is Cl, 【Chemical 20】 and and / or, R 3 is halogen, -S-(C 15 substituted with one or more R 1 -C 6 alkyl group), C 11 substituted with one or more R 1 -C 6 alkyl group, and preferably, R 3 is Cl, a trifluoromethyl group or 【Chemical 21】 and and / or, R 4 is H, and / or, R 5 is H, one or more Rs 12 substituted C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, and preferably, R 5 is H, 【Chemical 22】 and and / or, R 6 is halogen, C 12 substituted with one or more R 2 -C 6 -alkenyl group, -O-(C 14 substituted with one or more R 1 -C 6 -alkyl group), -S-(C 15 substituted with one or more R 1 -C 6 -alkyl group), and preferably, R 6 is F, 【Chemical 23】 characterized in that it is the compound according to claim 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

7. In formula (III), 【Chemical 24】 is 【Chemical 25】 and and / or, R 1 is H, and / or, R 2 is a halogen, preferably, R 2 is Cl, and / or, R 3 is a halogen, preferably, R 3 is Cl, and / or, R 4 is H, and / or, R 5 is H, and / or, R 6 is one or more Rs 14 substituted -O-(C 1 -C 6 alkyl group), preferably, R 6 is 【Chemical 26】 characterized in that it is the compound according to claim 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

8. In formula (IV), R 1 is H or halogen, preferably, R 1 is H or F, and / or, R 2 is a halogen or a C 11 substituted with one or more R 1 -C 6 alkyl group, preferably, R 2 is a Cl or trifluoromethyl group, and / or, R 3 is halogen or a C 11 -alkyl group substituted with one or more R 1 -C 6 alkyl group, preferably, R 3 is a Cl or trifluoromethyl group, and / or, R 4 is H, and / or, R 5 is H, and / or, R 6 is a halogen, preferably, R 6 is F, characterized in that the compound according to claim 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

9. In formula (IV), 【Chemical 27】 is 【Chemical Formula 28】 selected from, characterized in that the compound according to claim 8, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

10. In formula (IV), R 1 is a halogen, and preferably, R 1 is F, and / or, R 2 is a halogen, preferably, R 2 is Cl, And / or, R 3 is one or more Rs 11 substituted C 1 -C 6 alkyl group, preferably, R 3 is a trifluoromethyl group, and / or, R 4 is H, and / or, R 5 is H, and / or, R 6 is a halogen, preferably, R 6 is F, characterized by the compound according to claim 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

11. In formula (V), 【Chemical 29】 is 【Chemical Formula 30】 wherein and / or, R 1 is a halogen, preferably, R 1 is F, and / or, R 2 is a halogen, preferably, R 2 is Cl, and / or, R 3 is one or more Rs 11 substituted C 1 -C 6 is an alkyl group, preferably, R 3 is a trifluoromethyl group and / or, R 4 is H, and / or, R 5 is a halogen, preferably, R 5 is F, and / or, R 6 is a halogen, preferably, R 6 is F, characterized by The compound according to claim 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

12. In formula (VI), R 1 is H, and / or, R 2 is a halogen, preferably, R 2 is Cl, And / or, R 3 is one or more Rs 11 substituted C 1 -C 6 alkyl group, preferably, R 3 is a trifluoromethyl group and / or, R 4 is H, and / or, R 5 is one or more Rs 14 substituted -O-(C 1 -C 6 alkyl group), preferably, R 5 is 【Chemical 31】 characterized in that The compound according to claim 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

13. The compound is 【Chemical 32】 【Chem.】 selected from the compounds of The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable excipient.

15. Use of the compound according to any one of claims 1 to 13, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the composition according to claim 14, in the manufacture of a voltage-dependent sodium ion channel inhibitor drug.

16. Characterized in that the voltage-dependent sodium ion channel is Nav1.8, The use according to claim 15.

17. Use of the compound according to any one of claims 1 to 13, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the composition according to claim 14, in the manufacture of a drug for treating, alleviating or preventing pain.

18. Characterized in that the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain, The use according to claim 17.

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