Compounds useful as voltage-gated sodium channel inhibitors

Abstract

The present application relates to a kind of compound for being used as voltage-gated sodium channel inhibitor and its preparation method, pharmaceutical composition and application.The described compound has the structural characteristics of formula (I).

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: August 11, 2023; application number: 202311015650.9), and claims priority to Chinese application 202210971471.1 filed on August 12, 2022 and Chinese application 202211124412.7 filed on September 15, 2022. Technical Field

[0002] The present invention relates to a compound used as a voltage-gated sodium channel inhibitor, a preparation method thereof, a pharmaceutical composition and application thereof. The compound has the structural characteristics of formula (I). Background Art

[0003] There are nine main subtypes of human Nav, namely Nav1.1-Nav1.9. Depending on whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), Nav is divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R), and the tissue expression of different subtypes is extremely different.

[0004] Nav1.1, Nav1.2, Nav1.3 are of TTX-S type, Nav1.4, Nav1.6 and Nav1.7 are of TTX-S type, among which Nav1.1, Nav1.2 and Nav1.3 are abundantly expressed in the central nervous system (CNS), Nav1.4 is abundant in skeletal muscle, and Nav1.6 and Nav1.7 are mainly abundant in the central nervous system.

[0005] Nav1.5, Nav1.8 and Nav1.9 are of TTX-R type, among which Nav1.5 is mainly present in cardiomyocytes, while Nav1.8 and Nav1.9 are present in the dorsal root ganglia of the peripheral nervous system (PNS-DRG).

[0006] Table 1 Information of each subtype of Nav

[0007] path Coding genes <![CDATA[TTX IC 50 (nm)]]> Expression tissue Nav1.1 SCN1A 6 central nervous system Nav1.2 SCN2A 13 central nervous system Nav1.3 SCN3A 4 central nervous system Nav1.4 SCN4A 5 skeletal muscle Nav1.5 SCN5A 2000 cardiomyocytes Nav1.6 SCN8A 3 Central nervous system, glia, dorsal root ganglia Nav1.7 SCN9A 4 Central nervous system, dorsal root ganglia Nav1.8 SCN10A 31000 dorsal root ganglion Nav1.9 SCN11A 1500 dorsal root ganglion

[0008] Studies have shown that ion channel changes are the molecular basis for peripheral sensitization, central sensitization, and disinhibition after inflammation or neuropathological damage, and are also an important molecular mechanism for the occurrence of pain. Currently, Nav inhibitors have been proven to be effective. For example, the local anesthetic lidocaine relieves pain by inhibiting Nav. Non-selective Nav inhibitors such as lamotrigine, lacosamide, and mexiletine have been successfully used to treat chronic pain. However, the Nav inhibitors currently used in clinical practice lack subtype selectivity and can inhibit sodium ion channels expressed in the heart and central nervous system. The therapeutic window is narrow and the scope of application is limited.

[0009] Highly selective Nav inhibitors are one of the key research and development directions for voltage-gated sodium channels. Nav1.8 is mainly distributed in the peripheral nervous system and is confined to neurons that sense pain. It is a highly selective target for pain treatment. Therefore, selectively inhibiting Nav1.8 has good prospects for reducing potential toxic side effects.

[0010] Nav1.8 is a subtype of voltage-gated sodium channels (VGSC / Nav).

[0011] NaV1.8 is involved in the conduction and transmission of nociceptive action potentials. Due to its dependence on depolarized voltage, NaV1.8 is the primary mediator of the rising phase of the action potential. At the same time, NaV1.8, because it can quickly recover from inactivation, also contributes to repeated high-frequency emission. By inhibiting the activity of NaV1.8, the spread of pain can be blocked. Furthermore, because NaV1.8 is primarily expressed in neurons that transmit pain signals in the dorsal root ganglia (DRG) of the peripheral nervous system, selectively inhibiting Nav1.8 can also effectively reduce potential toxic side effects.

[0012] There is a need for drugs that are more active as voltage-gated sodium channel inhibitors, especially those that selectively inhibit Nav1.8, to provide therapeutic benefits in the treatment of diseases. Summary of the Invention

[0013] Based on this, the present invention provides a compound used as a voltage-gated sodium channel inhibitor, which has the ability to selectively inhibit the activity of Nav1.8 and is therefore useful for treating a variety of diseases mediated by Nav1.8, especially various pains.

[0014] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:

[0015]

[0016] Wherein, each substituent is as defined in the present invention.

[0017] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it further contains other therapeutic agents.

[0018] In one embodiment, the present application provides the use of a compound as defined in the present application, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for use as a voltage-gated sodium channel inhibitor.

[0019] In one embodiment, the present application provides the use of a compound as defined in the present application, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for use as a voltage-gated sodium channel inhibitor.

[0020] In one embodiment, the present application provides the use of a compound as defined in the present application, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for use as a voltage-gated sodium channel inhibitor.

[0021] In one embodiment, the present application provides the use of a compound as defined in the present application, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for use as a voltage-gated sodium channel inhibitor.

[0022] In one embodiment, the present application provides a method of inhibiting voltage-gated sodium channels in a subject comprising administering to said subject a compound as defined in the present application, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0023] In one embodiment, the present application provides a method of inhibiting voltage-gated sodium channels in a subject comprising administering to said subject a compound as defined in the present application, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0024] The voltage-gated sodium channel inhibitors according to the present invention are useful in treating a disease selected from the group consisting of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or an epileptic disorder, a neurodegenerative disease, a psychiatric disorder such as anxiety and depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe or intractable pain, nociceptive pain, penetrating pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitations, hypertension, migraine, or abnormal gastrointestinal motility.

[0025] In some embodiments, the method is directed to a condition selected from radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain. DETAILED DESCRIPTION

[0026] definition

[0027] The compounds of the present invention, their preparation methods, pharmaceutical compositions, and applications are further described in detail below with reference to specific examples. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive understanding of the present disclosure.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. The terms used herein in the specification are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein means any and all combinations of one or more of the related listed items.

[0029] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0030] The elements involved in the groups and compounds of the present invention include carbon, hydrogen, oxygen, sulfur, nitrogen or halogens, including their isotopes. Furthermore, the elements carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl, 36 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0031] The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group, specifically a saturated hydrocarbon containing primary (normal) carbon atoms, secondary carbon atoms, tertiary carbon atoms, quaternary carbon atoms or a combination thereof. Phrases containing this term, for example, "C 1-6"Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and each occurrence can be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl. In one embodiment, it can include an alkyl group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 10 carbon atoms, and more preferably a lower alkyl group containing 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include: methyl, ethyl, 1-propyl, 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu , i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-propyl-2-yl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-but-2-yl (-C(CH3)2CH2CH3), 3-methyl-but-2-yl (-CH(CH3)CH(CH3)2), 3-methyl-but-1-yl (-CH2CH2CH(C H3)2), 2-methyl-butan-1-yl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), hexan-2-yl (-CH(CH3)CH2CH2CH2CH3), hexan-3-yl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-pentan-2-yl (-C(CH3)2CH2CH2CH3), 3-methyl-pentan-2-yl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-pentan-2-yl (-CH(CH3)CH2CH(CH3)2), 3-methyl-pentan-3-yl (-C(CH3)2CH2CH2CH3), (CH3)(CH2CH3)2), 2-methyl-pentan-3-yl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-butan-2-yl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-butan-2-yl (-CH(CH3)C(CH3)3, octyl (-(CH2)7CH3) and n-nonyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When the alkyl group is substituted, unless otherwise defined, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano and amino.

[0032] "Alkenyl" is an alkyl group as defined herein that contains at least one carbon-carbon double bond. In one embodiment, the alkenyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, or 4-decenyl. When the alkenyl group is substituted, unless otherwise defined, the number of substituents is preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano, and amino.

[0033] "Alkynyl" is an alkyl group as defined herein that contains at least one carbon-carbon triple bond. In one embodiment, the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkynyl groups include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, or 4-decynyl. When the alkynyl group is substituted, unless otherwise specified, the number of substituents is preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0034] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic carbon-containing group. In one embodiment, a cycloalkyl group is a 3-6 membered (C 3-6 ) monocyclic, 3 to 8 membered (C 3-8 ) of a single ring, 3 to 10 members (C 3-10 ) monocyclic, 4 to 12 membered bicyclic (C4- 12 ) or 10 to 15 yuan (C 10-15 ) tricyclic ring system. Carbocyclic rings include bridged rings or spirocycles. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, and the like. Cycloalkyl groups may be optionally substituted. When a cycloalkyl group is substituted, unless otherwise defined, the number of substituents is preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0035] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated monocyclic or polycyclic ring group containing heteroatoms selected from N, O and S. In one embodiment, the heterocyclyl can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system. Preferably, it is a 3-10 membered monocyclic or bicyclic heterocyclyl, more preferably a 5-8 membered monocyclic or bicyclic heterocyclyl, and contains at least one, preferably 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O or S. If present, the heteroatoms N or S in the heterocycle can be oxidized to various oxidation states to form, for example, N-oxides. The heterocycle can be connected to the rest of the molecule through a heteroatom or a carbon atom. Heterocycles include bridged rings or spirocycles. Non-limiting examples of monocyclic heterocycles include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, dithiolanyl, oxanyl, thiazole, azepanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydrothiophenyl, thiooxytetrahydrothiophenyl, etc. Non-limiting examples of bicyclic heterocycles include chromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, octahydrocyclopentapyrrolyl, octahydropyrrolopyrrolyl, octahydropentalenyl, etc. When the heterocyclyl is substituted, unless otherwise defined, the substituents are preferably 1 to 5 and are independently selected from F, Cl, Br, I, =0, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano and amino.

[0036] "Aryl" refers to a substituted or unsubstituted all-carbon monocyclic or fused polycyclic unsaturated group having a conjugated π electron system. In one embodiment, the aryl group is a 6- to 14-membered aromatic ring, preferably a 6- to 10-membered aromatic ring. Non-limiting examples include phenyl or naphthyl; the aryl group may be fused with a heteroaryl, heterocyclic or cycloalkyl group, and the site of attachment to the molecular moiety is on the aryl group. Non-limiting examples of aryl groups include benzene. When the aryl group is substituted, unless otherwise defined, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano and amino.

[0037] "Heteroaryl" refers to a substituted or unsubstituted monocyclic or fused polycyclic unsaturated group containing at least one heteroatom selected from N, O and S. In one embodiment, the heteroaryl group is a 5- to 15-membered heteroaryl ring, a 5- to 14-membered heteroaryl ring, or preferably a 5- to 10-membered heteroaryl ring, or more preferably a 5- to 6-membered heteroaryl ring, wherein the number of heteroatoms is 1 to 4, preferably 1 to 3, and more preferably 1 to 2. Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, N-alkylpyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuran, benzimidazole, benzopyridine or pyrrolopyridine, etc. When the heteroaryl group is substituted, unless otherwise defined, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano and amino.

[0038] "Halogen" refers to F, Cl, Br or I. "Halo" refers to the replacement of one or more hydrogen atoms in a molecule or group with a halogen selected from F, Cl, Br or I.

[0039] In various parts of the present invention, connecting substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represent the alkylene group or arylene group connected respectively. In some specific structures, when an alkyl group is clearly expressed as a linking group, the alkyl group represents the alkylene group connected, for example, the alkyl in the group "-C1-C3 haloalkyl" should be understood as an alkylene group.

[0040] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable, non-toxic salts of acids or bases including salts of inorganic acids or bases or salts of organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts such as salts of Al, Ca, Li, Mg, K, Na, and Zn; salts derived from organic bases include, but are not limited to, salts with primary, secondary, or tertiary amines. The primary, secondary, or tertiary amines include naturally occurring substituted or unsubstituted amines, cyclic amines, and basic ion-exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phenazopyradine, ethylenediamine, glucamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, or polyamine resins; salts derived from inorganic acids and organic acids include, but are not limited to, salts with sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfosalicylic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropanoic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, or trifluoromethanesulfonic acid, and the like.

[0041] The term "solvate" can also be referred to as "solvation compound," "solvate," and refers to a compound that contains a solvent molecule which is combined with the compound molecule in a complex that can include coordination, covalent, van der Waals, ionic, hydrogen-bonding, or other interactions. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the solid-state form. "Solvate" includes both solution-state solvates and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0042] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·xH2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0043] The term "prodrug" refers to any compound that, when administered to an organism, produces a drug, i.e., an active ingredient, as a result of a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and / or metabolic chemical reaction. Prodrugs are therefore covalently modified analogs or latent forms of therapeutically active compounds. Suitable examples include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo compound, phosphoramide, glucoside, ether, acetal, etc. forms of the compound.

[0044] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those of the general formulae or specific compounds described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl, preferably 2 H (i.e., deuterium, D). Compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those incorporating radioactive isotopes (e.g., 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14C isotopes are particularly preferred because they are easy to prepare and detect. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may be preferred in some cases because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when performing the processes disclosed in the following schemes and / or the Examples and Preparations.

[0045] The compounds of the present invention include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0046] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and includes instances where the event or circumstance occurs or does not occur. For example, "aryl is optionally substituted with alkyl" means that the alkyl group may but need not be present, and the term includes instances where the aryl group is substituted with alkyl and instances where the aryl group is not substituted with alkyl.

[0047] A "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the term "pharmaceutically acceptable excipient" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with drug administration. Each excipient must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and maltose. Rice oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0048] The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to one crystalline form being dominant. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0049] Unless otherwise specified, all technical and scientific terms used herein have the standard meanings in the art to which the claimed subject matter belongs. If multiple definitions exist for a term, the definition herein shall prevail. It should be understood that the singular forms used herein, such as "a," "an," and "the" include plural references unless otherwise specified.

[0050] In addition, the terms “include” and “comprising” are open definitions rather than closed definitions, that is, they include the contents specified in the present invention but do not exclude other contents.

[0051] Unless otherwise stated, the present invention uses conventional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to conventional operating steps and conditions in the art.

[0052] Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques for analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical syntheses, chemical analyses, and light-emitting device performance testing.

[0053] Additionally, it should be noted that, unless explicitly stated otherwise, the term "respectively and independently" used in this disclosure should be broadly interpreted to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "respectively and independently" can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.

[0054] The dosage form and administration method of the compound of the present invention or its composition are not particularly limited.

[0055] Representative routes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intraperitoneal, intramuscular or subcutaneous) injection, and / or topical administration.

[0056] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, complex silicates, and sodium carbonate; (e) solvents, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.

[0057] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents (such as water or other solvents), solubilizers, and emulsifiers conventionally used in the art. Specific examples include, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to inert diluents, the composition may also contain adjuvants such as wetting agents, suspending agents, sweeteners, flavoring agents, and spices. For example, a suspension may contain a suspending agent. Specific examples include, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0058] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients are selected from water, ethanol and polyols, or suitable mixtures thereof.

[0059] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants, which are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and preservatives, buffers and / or propellants as needed under sterile conditions.

[0060] The present invention relates to the following embodiments.

[0061] In one embodiment, the present invention relates to a compound of formula (I'), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:

[0062]

[0063] in:

[0064] X is N or CR x ;

[0065] Y is N or CR y ;

[0066] Z is N or CR z ;

[0067] W is N or CR w ;

[0068] G is N or CR g ;

[0069] The condition is that at most two of X, Y and Z are N at the same time;

[0070] R x 、R y and R z Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 and -L1-R1, where R x 、R y and R z At least one of them is -L1-R1, which is optionally substituted with one or more deuterium groups until it is fully deuterated;

[0071] R w and R g Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -OR s1 ,

[0072] The groups are optionally substituted with one or more deuterium groups, up to full deuteration;

[0073] -L1-for-(CR a R b ) m -, where valence permits, -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R a and R b Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[0074] R1 is -S(O) q NR'R", -S(O)(=NR')R4 or -N=S(O)R4R4';

[0075] A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, which are optionally substituted with 3 R2 substituents;

[0076] -L2- is selected from the group consisting of a bond, -O-, -NR'-, -S-, -C(O)- and -(CR c R d) n -, where valence permits, -(CR c R d ) n -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R c and R d Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[0077] R' is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0078] R” is -L3-B;

[0079] B is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, which are optionally substituted with t R5 substituents;

[0080] -L3-for-(CR e R f ) p -, where valence permits, -(CR e R f ) p -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R e and R f Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[0081] R2, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0082] R4 and R4' are each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0083] R5 are each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0084] R6 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0085] R a 、R b 、R c 、R d 、R e and R f Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0086] R s1 and R s2 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0087] m is 0, 1, 2, 3, 4, 5 or 6;

[0088] n is 0, 1, 2, 3, 4, 5 or 6;

[0089] p is 0, 1, 2, 3, 4, 5, or 6;

[0090] t is 1, 2, 3, 4, or 5;

[0091] s is 1, 2, 3, 4, 5, 6, 7, or 8;

[0092] q is 1 or 2.

[0093] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:

[0094]

[0095] in:

[0096] X is N or CR x ;

[0097] Y is N or CR y ;

[0098] Z is N or CR z ;

[0099] W is N or CR w ;

[0100] G is N or CR g ;

[0101] The condition is that at most two of X, Y and Z are N at the same time;

[0102] R x 、R y and R z Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 and -L1-R1, where R x 、R y and R z At least one of them is -L1-R1, which is optionally substituted with one or more deuterium groups until it is fully deuterated;

[0103] R w and R g Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -OR s1 ,

[0104] The group is optionally substituted with one or more deuterium groups, up to full deuteration;

[0105] -L1-for-(CR a R b ) m -, where valence permits, -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R a and R b Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[0106] R1 is -S(O) q NR'R" or -S(O)(=NR')R4;

[0107] A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, which are optionally substituted with s R2 substituents;

[0108] -L2- is selected from the group consisting of a bond, -O-, -NR'-, -S-, -C(O)- and -(CR c R d ) n -, where valence permits, -(CR c R d ) n -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R c and R d Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[0109] R' is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0110] R” is -L3-B;

[0111] B is selected from C3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with t R5substituents;

[0112] -L3- is -(CR e R f ) p -, -(CR e R f ) p any one methylene unit in -L3- is optionally and independently replaced with -NR'-, -O-, -S-, and -C(O)- and / or R e and R f together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3-10 membered heterocyclyl;

[0113] R2, R 3a , R 3b , R 3c and R 3d are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR s1 , -SR s1 , NR s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 , said groups being optionally substituted with one or more deuterium, up to complete deuteration;

[0114] R4is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl, said groups being optionally substituted with one or more deuterium, up to complete deuteration;

[0115] each R5is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR s1 , -SR s1 , NR s1 R s2 , -C(O)Rs1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0116] R6 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0117] R a 、R b 、R c 、R d 、R e and R f Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0118] R s1 and R s2 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0119] m is 0, 1, 2, 3, 4, 5 or 6;

[0120] n is 0, 1, 2, 3, 4, 5 or 6;

[0121] p is 0, 1, 2, 3, 4, 5, or 6;

[0122] t is 1, 2, 3, 4, or 5;

[0123] s is 1, 2, 3, 4, 5, 6, 7, or 8;

[0124] q is 1 or 2.

[0125] In one embodiment, the present invention relates to a compound of formula (I) or (I') above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (II),

[0126]

[0127] In one embodiment, the present invention relates to a compound of formula (I) or formula (II) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein -L2- is -O-.

[0128] In one embodiment, the present invention relates to a compound of formula (I) or formula (II) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein -L2- is a bond.

[0129] In one embodiment, the present invention relates to the above-mentioned compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein A is selected from phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl and 5-10 membered heterocyclyl.

[0130] In one embodiment, the present invention relates to the above-mentioned compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein A is selected from cyclopentyl, cyclohexyl, azacyclohexyl, oxanyl, thiazole, azepanyl, diazepanyl, octahydrocyclopentapyrrolyl, octahydropyrrolopyrrolyl, octahydropentalenyl, phenyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl and pyridazinyl.

[0131] In one embodiment, the present invention relates to the above-mentioned compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein m is 0.

[0132] In one embodiment, the present invention relates to the above-mentioned compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0133] m is 1, 2, 3, 4 or 5,

[0134] -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -O-, -S- and -C(O)-; and / or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl and 3-5 membered heterocyclic groups;

[0135] Ra Selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0136] R b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0137] In one embodiment, the present invention relates to a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (III),

[0138]

[0139] In one embodiment, the present invention relates to a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (IV)

[0140]

[0141] in:

[0142] X is N or CR x ;

[0143] Y is N or CR y ;

[0144] R x and R y are each independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0145] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0146] R” is -L3-B;

[0147] B is a 5-7 membered heterocyclyl, which is optionally substituted with t R5 substituents;

[0148] -L3-for-(CR e R f ) p -, where valence permits, -(CR e R f ) p- any one methylene unit in - is optionally and independently replaced with -0-, -S-, and -C(O)-;

[0149] R 2a , R 2b , R 2c , R 2d , R 2e , R 3a , R 3b , R 3c , and R 3d are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR s1 , -SR s1 , NR s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 , and -SO2R s1 , said groups being optionally substituted by one or more deuterium up to complete deuteration;

[0150] each R5is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, said groups being optionally substituted by one or more deuterium up to complete deuteriation;

[0151] R e and R f are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl, said groups being optionally substituted by one or more deuterium up to complete deuteriation;

[0152] R s1 and R s2 are independently H, C 1-6 alkyl, or C 1-6 haloalkyl, said groups being optionally substituted by one or more deuterium up to complete deuteriation;

[0153] p is 0, 1, 2, or 3;

[0154] t is 1, 2, or 3.

[0155] In one embodiment, the present application relates to a compound of Formula (IV), as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein:

[0156] X is CR x ;

[0157] Y is N;

[0158] R x Selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0159] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0160] R” is -L3-B;

[0161] B is a 5-6 membered heterocyclyl, which is optionally substituted with t R5 substituents;

[0162] -L3-for-(CR e R f ) p -;

[0163] R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0164] R5 are each independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0165] R e and R f Independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0166] p is 0, 1, 2, or 3;

[0167] t is 1, 2, or 3;

[0168] Preferably, -L3-B is selected from

[0169] In one embodiment, the present invention relates to a compound of formula (IV) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0170] X is CR x ;

[0171] Y is N;

[0172] R x is H or D;

[0173] R' is H;

[0174] R” is -L3-B;

[0175] B is a 5-6 membered heterocyclic group, preferably an azacyclopentyl group or an azacyclohexyl group;

[0176] -L3-for-(CR e R f ) p -, p is 0 or 1;

[0177] R 2a C 1-6 The alkyl group is preferably a methyl group;

[0178] R 2b is H or D;

[0179] R 2c is halogen, preferably F;

[0180] R 2d is H or D;

[0181] R 2e is H or D;

[0182] R 3a is H or D;

[0183] R 3b C 1-6 The haloalkyl group is preferably -CF3;

[0184] R 3c is halogen, preferably Cl;

[0185] R 3d is H or D;

[0186] R e Selected from H, D and C 1-6 alkyl;

[0187] Rf Selected from H, D and C 1-6 alkyl;

[0188] Preferably, -L3-B is selected from

[0189] In one embodiment, the present invention relates to a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (V)

[0190]

[0191] In one embodiment, the present invention relates to a compound of formula (V) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0192] X is N or CR x ;

[0193] Y is N or CR y ;

[0194] R x and R y are independently selected from H, D, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -OR s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0195] -L2- is a bond, -O-, -S- or -NH-;

[0196] A is selected from phenyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl and 5-10 membered heterocyclyl, which are optionally substituted with 3 R2 substituents;

[0197] When valence permits, -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -O-, -S- and -C(O)-;

[0198] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0199] R2, R 3a 、R 3b、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0200] R4 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0201] R a and R b Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0202] or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl and 3-5 membered heterocyclic groups;

[0203] R s1 and R s2 Independently selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0204] m is 0, 1, 2, 3 or 4;

[0205] s is 1, 2, 3, 4, 5, 6, 7, or 8.

[0206] In one embodiment, the present invention relates to a compound of formula (IV) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0207] X is CR x ;

[0208] Y is N or CR y ;

[0209] R x and R y are each independently selected from H, D, halogen and C 1-6 Alkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0210] A is selected from and a 5-8 membered heterocyclyl group, which is optionally substituted with s R2 substituents;

[0211] When valence permits, -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -O-;

[0212] -L2- is a bond or -O-;

[0213] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0214] R2 are each independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0215] R 2a Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR s1a and-SR s1a , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0216] R 2b H or D;

[0217] R 2c H, D, halogen, -OR s1c or -SR s1c ;

[0218] R 2d H or D;

[0219] R 2e H or D;

[0220] R 3a H or D;

[0221] R3b C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0222] R 3c is a halogen;

[0223] R 3d H or D;

[0224] R4 is selected from C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0225] R a and R b Selected from H, D, halogen and C 1-6 Alkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0226] or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0227] R s1 Each independently selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0228] R s1a Selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0229] R s1c Selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0230] m is 1, 2, or 3;

[0231] s is 1 or 2.

[0232] In one embodiment, the present invention relates to a compound of formula (IV) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0233] X is CR x ;

[0234] Y is N or CRy ;

[0235] R x is H;

[0236] R y is a halogen;

[0237] A is selected from and azepanyl, which is substituted with s R2;

[0238] -(CR a R b ) m -selected from -CH2-, -O-CH2-CH2-,

[0239] -L2- is a bond or -O-;

[0240] R' is H;

[0241] R2 are each independently selected from H and halogen, preferably F, said group being optionally substituted with one or more deuteriums, up to full deuteration;

[0242] R 2a H or C 1-6 Alkyl is preferably methyl, said group being optionally substituted by one or more deuterium groups up to full deuteration;

[0243] R 2b is H;

[0244] R 2c Halogen or -OR s1c ;

[0245] R 2d is H;

[0246] R 2e is H;

[0247] R 3a is H;

[0248] R 3b C 1-6 The haloalkyl group is preferably -CF3;

[0249] R 3c is halogen, preferably Cl;

[0250] R 3d is H;

[0251] R4 is C 1-6 The alkyl group is preferably a methyl group;

[0252] R s1c H, C 1-6 Alkyl or C1-6 Haloalkyl, preferably -CF3;

[0253] s is 1 or 2.

[0254] In one embodiment, the present invention relates to a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (VI):

[0255]

[0256] In one embodiment, the present invention relates to a compound of formula (VI) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0257] X is N or CR x ;

[0258] Y is N or CR y ;

[0259] R x and R y are independently selected from H, D, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -OR s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0260] -L2- is a bond, -O-, -S- or -NH-;

[0261] A is selected from phenyl, C 3-8 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, which are optionally substituted with 3 R2 substituents;

[0262] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0263] R2, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, OR s1 SRs1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0264] R4 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0265] R s1 and R s2 Select H and C independently 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0266] s is 1, 2, 3, 4, 5, 6, 7, or 8.

[0267] In one embodiment, the present invention relates to a compound of formula (VI) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0268] A is selected from cyclopentyl, cyclohexyl, azacyclohexyl, oxacyclohexyl, thiacyclohexyl, azepanyl, diazepanyl, octahydrocyclopentapyrrolyl, octahydropyrrolopyrrolyl, octahydropentalenyl, phenyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl. Preferably, A and the substituents thereon are selected from the following:

[0269]

[0270] Among them, R 2a 、R 2b 、R 2c and R 2d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums up to full deuteration.

[0271] In one embodiment, the present invention relates to a compound of formula (VI) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0272] -L2- is -O-;

[0273] A is selected from cyclopentyl and cyclohexyl, and is preferably cyclohexyl.

[0274] In one embodiment, the present invention relates to a compound of formula (VI) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0275] -L2- is a key;

[0276] A is selected from azepanyl, diazepanyl, octahydrocyclopentapyrrolyl, octahydropyrrolopyrrolyl and octahydropentalenyl. Preferably, when A is a nitrogen-containing heterocycle, it is connected to the phenyl group through the nitrogen atom.

[0277] In one embodiment, the present invention relates to a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is formula (VII)

[0278]

[0279] in:

[0280] X is N or CR x ;

[0281] Y is N or CR y ;

[0282] R x and R y are independently selected from H, D, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0283] R' is selected from H, C 1-6 Alkyl and C1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0284] R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0285] R4 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0286] R s1 and R s2 Independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl, said group is optionally substituted with one or more deuterium groups up to full deuteration.

[0287] In one embodiment, the present invention relates to a compound of formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0288] X is N or CR x ;

[0289] Y is N or CR y ;

[0290] R x and R y are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6haloalkyl, which group is optionally substituted with one or more deuterium, up to complete deuteration;

[0291] R' is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to complete deuteration;

[0292] R 2a selected from H, D, halogen, -OR s1a , -SR s1a , NR s1a R s2a , C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to complete deuteration;

[0293] R 2b is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to complete deuteration;

[0294] R 2c selected from H, D, halogen, -OR s1c , -SR s1c , NR s1c R s2c , C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to complete deuteration;

[0295] R 2d is H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to complete deuteration;

[0296] R 2e is H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to complete deuteration;

[0297] R 3a is H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to complete deuteration;

[0298] R 3b selected from H, D, halogen, C 1-6 alkyl and C 1-6haloalkyl, which group is optionally substituted with one or more deuterium, up to per-deuteration;

[0299] R 3c is selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to per-deuteration;

[0300] R 3d is H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to per-deuteration;

[0301] R4is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to per-deuteration;

[0302] R s1a , R s2a , R s1c and R s2c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to per-deuteration.

[0303] In one embodiment, the present application relates to a compound of formula (VII) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0304] X is CR x ;

[0305] Y is N or CR y ;

[0306] R x and R y are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to per-deuteration;

[0307] R’ is H, C 1-6 alkyl or C 1-6 haloalkyl, which group is optionally substituted with one or more deuterium, up to per-deuteration;

[0308] R 2a is -OR s1a , -SR s1a , NR s1a Rs2a , C 1-6 alkyl or C 1-6 haloalkyl, which groups are optionally substituted with one or more deuterium, up to complete deuteriation;

[0309] up to complete deuteriation;

[0310] R 2b is H, D, or halogen;

[0311] R 2c is H, D, halogen, -OR s1c , -SR s1c , or NR s1c R s2c , which groups are optionally substituted with one or more deuterium, up to complete deuteriation;

[0312] R 2d is H, D, or halogen;

[0313] R 2e is H, D, or halogen;

[0314] R 3a is H, D, or halogen;

[0315] R 3b is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, which groups are optionally substituted with one or more deuterium, up to complete deuteriation;

[0316] R 3c is H, D, or halogen;

[0317] R 3d is H, D, or halogen;

[0318] R4is H, C 1-6 alkyl or C 1-6 haloalkyl, which groups are optionally substituted with one or more deuterium, up to complete deuteriation;

[0319] R s1a , R s2a , R s1c , and R s2c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which groups are optionally substituted with one or more deuterium, up to complete deuteriation;

[0320] with the proviso that when Y is N, R 2a is not C 1-6 alkyl or C 1-6 haloalkyl.

[0321] In one embodiment, the present invention relates to a compound of formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0322] X is CR x ;

[0323] Y is N or CR y ;

[0324] R x and R y independently selected from H, D or halogen;

[0325] R' is H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0326] R 2a For-OR s1a 、-SR s1a 、C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0327] R 2b is H, D or halogen;

[0328] R 2c H, D, halogen, -OR s1c or -SR s1c , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0329] R 2d is H or D;

[0330] R 2e is H or D;

[0331] R 3a is H or D;

[0332] R 3b C 1-6 alkyl halide;

[0333] R 3c is a halogen;

[0334] R 3d is H or D;

[0335] R4 is C 1-6 Alkyl or C 1-6 alkyl halide;

[0336] R s1a and R s1cIndependently selected from C 1-6 Alkyl or C 1-6 alkyl halide;

[0337] The condition is that when Y is N, R 2a Not for C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0338] In one embodiment, the present invention relates to a compound of formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0339] X is CR x ;

[0340] Y is N or CR y ;

[0341] R x and R y independently selected from H, D or halogen;

[0342] R' is H;

[0343] R 2a For-OR s1a 、-SR s1a or C 1-6 Alkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0344] R 2b H or D;

[0345] R 2c Halogen, -OR s1c or -SR s1c , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0346] R 2d H or D;

[0347] R 2e H or D;

[0348] R 3a H or D;

[0349] R 3b C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0350] R 3c is a halogen;

[0351] R3d H or D;

[0352] R4 is C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0353] R s1a and R s1c Each independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl, said group is optionally substituted with one or more deuterium groups up to full deuteration.

[0354] In one embodiment, the present invention relates to a compound of formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0355] X is CR x ;

[0356] Y is N or CR y ;

[0357] R x H or D;

[0358] R y is H, D or halogen;

[0359] R' is H;

[0360] R 2a For-OR s1a or -SR s1a , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[0361] R 2b H or D;

[0362] R 2c Halogen, -OR s1c or -SR s1c ;

[0363] R 2d H or D;

[0364] R 2e H or D;

[0365] R 3a H or D;

[0366] R 3b C 1-6 Alkyl or C 1-6haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0367] R 3c is a halogen;

[0368] R 3d is H or D;

[0369] R4 is C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[0370] R s1a and R s1c Independently selected from C 1-6 Alkyl or C 1-6 Haloalkyl, said group is optionally substituted with one or more deuterium groups up to full deuteration.

[0371] In one embodiment, the present invention relates to a compound of formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein:

[0372] X is CR x ;

[0373] Y is N or CR y ;

[0374] R x is H;

[0375] R y is halogen, preferably F;

[0376] R' is H;

[0377] R 2a For-OR s1a , said group is optionally substituted by one or more deuteriums, up to full deuteration, preferably -OCD3;

[0378] R 2b is H;

[0379] R 2c Halogen or -OR s1c , preferably F or -OCF3;

[0380] R 2d is H;

[0381] R 2e is H;

[0382] R 3a is H;

[0383] R 3b C 1-6 The haloalkyl group is preferably -CF3;

[0384] R 3c is a halogen, preferably Cl;

[0385] R 3d is H;

[0386] R4 is C 1-6 alkyl;

[0387] R s1a C 1-6 alkyl;

[0388] R s1c C 1-6 Halogenated alkyl.

[0389] In a specific embodiment, the compound is selected from the following structures:

[0390]

[0391]

[0392]

[0393]

[0394] In a specific embodiment, the present invention relates to a pharmaceutical composition comprising a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.

[0395] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it further contains other therapeutic agents.

[0396] In one embodiment, the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for use as a voltage-gated sodium channel inhibitor.

[0397] In one embodiment, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, or a pharmaceutical composition comprising the same for the preparation of a medicament for use as a sodium ion channel 1.8 (NaV1.8) inhibitor.

[0398] In one embodiment, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same, for use as a voltage-gated sodium channel inhibitor.

[0399] In one embodiment, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same, for use as a sodium ion channel 1.8 (NaV1.8) inhibitor.

[0400] In one embodiment, the present invention provides a method of inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0401] In one embodiment, the present invention provides a method of inhibiting sodium ion channel 1.8 (NaV1.8) in a subject, comprising administering to the subject a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0402] A voltage-gated sodium channel inhibitor as described herein is used to treat a disease selected from the group consisting of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpatic neuralgia, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, bipolar disorders, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpatic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress or exercise induced angina, palpitations, hypertension, migraine or abnormal gastrointestinal motility.

[0403] In some embodiments, the disease to which the present methods are directed is selected from the group consisting of radicular pain, sciatica, back pain, head pain, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain.

[0404] Examples

[0405] Materials and reagents useful herein are either commercially available or are readily prepared by synthetic methods known to those of ordinary skill in the art.

[0406] Example 1

[0407] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(2-(methylamino)ethyl)sulfamoyl)pyridin-4-yl)-4- (trifluoromethyl)benzamide (Compound 1)

[0408]

[0409] First Step: tert-Butyl (2-(benzylsulfanyl)pyridin-4-yl)carbamate

[0410]

[0411] 2-(Benzylthio)-4-bromopyridine (3.7 g, 13.214 mmol) was dissolved in super dry dioxane (37 mL), and tert-butyl carbamate (3.1 g, 26.429 mmol), cesium carbonate (12.9 g, 39.643 mmol), tris(dibenzylideneacetone)dipalladium (Pd2dba3) (1.2 g, 1.321 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (XantPhos) (1.5 g, 2.643 mmol) were added. The atmosphere was replaced with nitrogen and stirred in an oil bath at 100 ° C for 16 hours. The reaction was stopped, the reaction solution was vacuum dried, dichloroethane (40 ml) was added to dissolve it, and the solution was filtered through a sand core funnel filled with diatomaceous earth. The filter cake was rinsed with dichloroethane (80 ml), the filtrate was collected and dried, and the sample was mixed to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain the title compound (3.7 g, yield: 77.6%, colorless oil).

[0412] MS (ESI): m / z 317.2 [M+H] + ;

[0413] Step 2: 2-(Benzylthio)pyridin-4-amine

[0414]

[0415] Dissolve tert-butyl (2-(benzylthio)pyridin-4-yl)carbamate (1 g, 3.16 mmol) in dichloromethane (15 mL). Add trifluoroacetic acid (5 mL) dropwise in an ice bath at 0°C, and stir at room temperature for 1 hour. Stop the reaction, quench the reaction mixture with saturated sodium bicarbonate solution (10 mL), extract the aqueous phase with ethyl acetate (15 mL x 3), and combine the organic phases, wash with saturated brine (10 mL x 2), and dry over anhydrous sodium sulfate. Filter and vacuum-dry the filtrate to obtain the title compound (680 mg, colorless oil), which is directly used in the next reaction.

[0416] MS (ESI): m / z 217.1 [M+H] + ;

[0417] Step 3: N-(2-(Benzylthio)pyridin-4-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)benzamide

[0418]

[0419] 2-(Benzylthio)pyridin-4-amine (680 mg, 3.148 mmol) was dissolved in thionyl chloride (1 mL). After nitrogen substitution three times, the mixture was stirred at 80°C for 2 hours and then dried. 5-Chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (763.6 mg, 3.148 mmol) was dissolved in dichloromethane (8 mL) and N,N-diisopropylethylamine (1.63 g, 12.592 mmol) was added dropwise in an ice bath at 0°C. The reaction mixture, which had been dried at the beginning, was dissolved in dichloromethane (1 mL) and added dropwise to the reaction mixture in an ice bath at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was stopped, dried, and the sample was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 5:1) to obtain the title compound (370 mg, yield: 26.7%, as a colorless oil).

[0420] MS (ESI): m / z 441.1 [M+H] + ;

[0421] Step 4: N-(2-(Benzylthio)pyridin-4-yl)-5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide

[0422]

[0423] N-(2-(Benzylthio)pyridin-4-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (330 mg, 0.749 mmol) was dissolved in N,N-dimethylformamide (3.3 mL). 4-Fluoro-2-methylphenol (94.3 mg, 0.749 mmol) and cesium carbonate (487.8 mg, 1.497 mmol) were added, and the mixture was stirred in an oil bath at 100°C for 1 hour. The reaction was stopped and quenched with water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 5:1) to obtain the title compound (343 mg, yield: 83.9%) as a colorless oil.

[0424] MS (ESI): m / z 547.0 [M+H] + ;

[0425] Step 5: 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride

[0426]

[0427] N-(2-(Benzylthio)pyridin-4-yl)-5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (100 mg, 0.183 mmol) was placed in a three-necked flask and the atmosphere was replaced with nitrogen. Glacial acetic acid: water: dichloromethane = 7:1:2 (2 mL) was added to the flask, followed by 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (108 mg, 0.548 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was stopped and quenched with water (3 ml). The aqueous phase was extracted with dichloromethane (5 ml x 3). The organic phases were combined, washed with saturated brine (3 ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo to afford the title compound (80 mg, crude product, light yellow solid).

[0428] MS (ESI): m / z 523.1 [M+H] + ;

[0429] Step 6: tert-butyl (2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)ethyl)(methyl)carbamate

[0430]

[0431] Dissolve 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (120 mg, 0.229 mmol) in dichloromethane (1 ml). Add a solution of tert-butyl (2-aminoethyl)(methyl)carbamate (39.9 mg, 0.229 mmol) in pyridine (1 mL) dropwise at 0°C. Stir at room temperature for 2 hours. Stop the reaction, quench with saturated sodium bicarbonate solution (3 ml), and extract the aqueous phase with ethyl acetate (5 ml x 3). The combined organic phases are washed with saturated brine (2 ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is vacuum-dried to obtain the crude product. The crude product is isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the title compound (45 mg, yield: 29.8%) as a pale yellow solid.

[0432] MS (ESI): m / z 661.2 [M+H] + ;

[0433] Step 7: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(2-(methylamino))ethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 1)

[0434]

[0435] Dissolve tert-butyl (2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)ethyl)(methyl)carbamate (59 mg, 0.089 mmol) in dichloromethane (3 mL). Add trifluoroacetic acid (1 mL) in an ice bath at 0°C, and stir at room temperature for 1 hour. Stop the reaction, remove the solvent in vacuo, and obtain a crude product. Purify the crude product by reverse-phase preparative chromatography (elution system: ammonia, water, acetonitrile) to obtain the title compound (18.7 mg, yield: 37.5%) as a brown-yellow solid).

[0436] MS (ESI): m / z 561.1 [M+H] + ;

[0437] 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),8.62(d,J=5.4Hz,1H),8.26(d,J=1.4Hz,1H),8.12(s,1H),7.77(d,J=5.3Hz,1H), 7.23–7.17(m,1H),7.10(dd,J=7.1,4.6Hz,3H),2.96(t,J=6.5Hz,2H),2.47(t,J=6.5Hz,2H),2.17(s,3H),2.16(s,3H).

[0438] Example 2

[0439] (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 2)

[0440]

[0441] Step 1: (R)-tert-Butyl 3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)-benzamido)pyridine)-2-sulfonylamino)pyrrolidine-1-carboxylate

[0442]

[0443] 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (300 mg, 0.57 mmol) and (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (107 mg, 0.57 mmol) were dissolved in a mixture of pyridine (2 mL) and dichloromethane (4 mL) and reacted at 0°C for 2 hours. The reaction was stopped, the solvent removed in vacuo, the mixture was diluted with water (10 mL), and the mixture was adjusted to neutral with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The mixture was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (222 mg, yield: 58%) as a yellow solid.

[0444] MS (ESI): m / z 673.2 [M+H] + ;

[0445] Step 2: (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 2)

[0446]

[0447] Dissolve (R)-tert-butyl 3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)-benzamido)pyridine)-2-sulfonamido)pyrrolidine-1-carboxylate (210 mg, 0.312 mmol) in a mixture of trifluoroacetic acid (2 mL) and dichloromethane (6 mL) and allow to react at room temperature for 2 hours. Stop the reaction, remove the solvent in vacuo, dilute with water (10 mL), extract with ethyl acetate (20 mL x 3), and dry over anhydrous sodium sulfate. Filter, evaporate the filtrate to dryness under reduced pressure, and purify by preparative HPLC (elution system: formic acid, water, acetonitrile) to afford the title compound (122.14 mg, yield: 68%) as a white solid.

[0448] MS (ESI): m / z 573.0 [M+H] + ;

[0449] 1H NMR (400MHz, DMSO-d6) δ11.40(s,1H),8.65(d,J=5.4Hz,1H),8.34(d,J=1.7Hz,1H),8.1 2(s,1H),7.80(dd,J=5.4,1.9Hz,1H),7.21(dd,J=9.2,2.3Hz,1H),7.15–7.06(m,3H),4. 05–3.96(m,1H),3.22(dd,J=11.8,6.6Hz,1H),3.15(dd,J=15.2,7.8Hz,1H),3.10–3.05( m,1H),2.96(dd,J=11.8,5.4Hz,1H),2.17(s,3H),2.00–1.93(m,1H),1.81–1.74(m,1H).

[0450] Example 3

[0451] (S)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 3)

[0452]

[0453] Step 1: (S)-tert-Butyl 3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonylamino)pyrrolidine-1-carboxylate

[0454]

[0455] 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (300 mg, 0.57 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (107 mg, 0.57 mmol) were dissolved in a mixture of pyridine (2 mL) and dichloromethane (4 mL) and reacted at 0°C for 2 hours. The reaction was stopped, the solvent was removed in vacuo, the mixture was diluted with water (10 mL), and the mixture was adjusted to neutral with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The title compound (210 mg, yield: 56%) was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (200 mg, yield: 56%) as a yellow solid.

[0456] MS (ESI): m / z 673.3 [M+H] + ;

[0457] Step 2: (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 3)

[0458]

[0459] Dissolve (S)-tert-butyl 3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)pyrrolidine-1-carboxylate (210 mg, 0.312 mmol) in a mixture of trifluoroacetic acid (2 mL) and dichloromethane (6 mL) and allow to react at room temperature for 2 hours. Stop the reaction, remove the solvent in vacuo, dilute with water (10 mL), extract with ethyl acetate (20 mL x 3), and dry over anhydrous sodium sulfate. Purify by preparative HPLC (elution system: formic acid, water, acetonitrile) to obtain the title compound (71.26 mg, yield: 40.0%) as a white solid.

[0460] MS (ESI): m / z 572.9 [M+H] + ;

[0461] 1 H NMR (400MHz, DMSO-d6) δ8.64(d,J=5.4Hz,1H),8.33(s,1H),8.31(d,J=1.8Hz, 1H),8.13(s,1H),7.81(dd,J=5.4,2.0Hz,1H),7.21(dd,J=9.2,2.7Hz,1H),7.1 4–7.05(m,3H),3.96–3.86(m,1H),3.07–2.97(m,2H),2.92(d,J=6.6Hz,1H),2. 77(dd,J=11.6,4.9Hz,1H),2.17(s,3H),1.92–1.87(m,1H),1.67–1.62(m,1H).

[0462] Example 4

[0463] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(piperidin-4-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 4)

[0464]

[0465] Step 1: tert-Butyl 4-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonylamino)piperidine-1-carboxylate

[0466]

[0467] Under stirring at room temperature, tert-butyl 4-aminopiperidin-1-carbamate (76.55 mg, 0.38 mmol) was dissolved in pyridine (2 mL). The temperature was lowered to 0°C, and 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (200 mg, 0.38 mmol) was dissolved in dichloromethane (4 mL) and added dropwise to the reaction mixture. The reaction was stirred at this temperature for 2 hours. The reaction was stopped, poured into water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined extracts were washed with 1N HCl (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:1) to afford the title compound (120 mg, yield: 45.7%) as a white solid.

[0468] MS (ESI): m / z 687.2 [M+H] + ;

[0469] Step 2: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(piperidin-4-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 4)

[0470]

[0471] Under room temperature stirring, tert-butyl 4-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)piperidine-1-carboxylate (120 mg, 0.17 mmol) was placed in a 25 ml single-necked flask and dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added, the mixture was allowed to warm to room temperature, and the reaction was stirred for 1 hour. The reaction was terminated and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by preparative HPLC (elution system: formic acid, water, acetonitrile) to obtain the title compound (87.96 mg, yield: 85.8%) as a white solid.

[0472] MS (ESI): m / z 587.2 [M+H] + ;

[0473] Example 5

[0474] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(piperidin-4-ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 5)

[0475]

[0476] Step 1: tert-Butyl 4-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)piperidine-1-carboxylate

[0477]

[0478] 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (200 mg, 0.38 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (82 mg, 0.38 mmol) were added sequentially to a mixture of pyridine (2 mL) and dichloromethane (4 mL) at 0°C and allowed to react for 2 hours. The reaction was stopped, the solvent removed in vacuo, the mixture was diluted with water (10 mL), and the mixture was adjusted to neutral with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The title compound (110 mg, yield: 41.2%) was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (110 mg, yield: 41.2%) as a yellow solid.

[0479] MS (ESI): m / z 701.1 [M+H] + ;

[0480] Step 2: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(piperidin-4-ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 5)

[0481]

[0482] Dissolve tert-butyl 4-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)piperidine-1-carboxylate (100 mg, 0.143 mmol) in a mixture of trifluoroacetic acid (1 mL) and dichloromethane (3 mL) and allow to react at room temperature for 2 hours. Stop the reaction, remove the solvent in vacuo, dilute with water (10 mL), extract with ethyl acetate (20 mL x 3), and dry over anhydrous sodium sulfate. Filter, evaporate the filtrate to dryness under reduced pressure, and purify by preparative HPLC (elution system: formic acid, water, acetonitrile) to afford the title compound (40.99 mg, 48% yield, as a white solid).

[0483] MS (ESI): m / z 601.0 [M+H] + ;

[0484] 1H NMR (400MHz, DMSO-d6) δ11.39(s,1H),8.63(d,J=5.4Hz,1H),8.29(d,J=1.7Hz,1H ),8.12(s,1H),7.77(dd,J=5.4,1.9Hz,1H),7.21(dd,J=9.2,2.3Hz,1H),7.14–7.0 6(m,3H),3.19(d,J=12.0Hz,2H),2.81(d,J=6.6Hz,2H),2.74(t,J=11.8Hz,2H),2 .16(s,3H),1.76(d,J=13.3Hz,2H),1.63(brs,1H),1.21(dd,J=23.0,10.9Hz,2H).

[0485] Example 6

[0486] (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 6)

[0487]

[0488] Step 1: (R)-tert-Butyl 3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonylamino)methyl)pyrrolidine-1-carboxylate

[0489]

[0490] 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (300 mg, 0.57 mmol) and tert-butyl (S)-3-(aminomethyl)pyrrolidine-1-carboxylate (115 mg, 0.57 mmol) were dissolved in a mixture of pyridine (2 mL) and dichloromethane (4 mL) at 0°C and allowed to react for 2 hours. The reaction was stopped, the solvent removed in vacuo, the mixture was diluted with water (10 mL), and the mixture was adjusted to neutral with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The title compound (256 mg, yield: 65.4%) was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (256 mg, yield: 65.4%) as a yellow solid.

[0491] MS (ESI): m / z 687.3 [M+H] + ;

[0492] Step 2: (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3- ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 6)

[0493]

[0494] (R)-3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)pyridine-2-sulfonamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (240 mg, 0.35 mmol) was dissolved in a mixture solvent of trifluoroacetic acid (2 mL) and dichloromethane (6 mL), and stirred at room temperature for 2 hours. The reaction was stopped, the solvent was removed by vacuum evaporation, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was dried under reduced pressure, and purified by high performance liquid chromatography preparation (elution system: formic acid, water, acetonitrile) to obtain the title compound (112.26 mg, yield: 54.6%, white solid).

[0495] MS (ESI): m / z 587.0 [M+H] + ;

[0496] 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.64 (d, J = 5.5 Hz, 1H), 8.31 (d, J = 1.7 Hz, 1H), 8.11 (s, 1H), 7.77 (dd, J = 5.4, 1.9 Hz, 1H), 7.21 (dd, J = 9.2, 2.4 Hz, 1H), 7.14 - 7.06 (m, 3H), 3.23 - 3.09 (m, 2H), 3.08 - 3.02 (m, 1H), 2.98 (d, J = 7.0 Hz, 2H), 2.81 (dd, J = 11.6, 7.7 Hz, 1H), 2.36 (dt, J = 15.3, 7.6 Hz, 1H), 2.16 (s, 3H), 1.97 - 1.92 (m, 1H), 1.61 - 1.56 (m, 1H).

[0497] Example 7

[0498] (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3- ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 7)

[0499]

[0500] Step 1: (S)-tert-Butyl 3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)pyrrolidine-1-carboxylate

[0501]

[0502] 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (300 mg, 0.57 mmol) and (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (115 mg, 0.57 mmol) were dissolved in a mixture of pyridine (2 mL) and dichloromethane (4 mL) at 0°C and allowed to react for 2 hours. The reaction was stopped, the solvent removed in vacuo, the mixture was diluted with water (10 mL), and the mixture was adjusted to neutral with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The title compound (256 mg, yield: 65.4%) was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (256 mg, yield: 65.4%) as a yellow solid.

[0503] MS (ESI): m / z 687.2 [M+H] + ;

[0504] Step 2: (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 7)

[0505]

[0506] Dissolve (S)-tert-butyl 3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)pyrrolidine-1-carboxylate (240 mg, 0.35 mmol) in a mixture of trifluoroacetic acid (2 mL) and dichloromethane (6 mL) and allow to react at room temperature for 2 hours. Stop the reaction, remove the solvent in vacuo, dilute with water (10 mL), extract with ethyl acetate (20 mL x 3), and dry over anhydrous sodium sulfate. Filter, evaporate the filtrate to dryness under reduced pressure, and purify by preparative HPLC (elution system: formic acid, water, acetonitrile) to afford the title compound (63.06 mg, yield: 30.7%) as a white solid.

[0507] MS (ESI): m / z 586.9 [M+H] + ;

[0508] 1H NMR (400MHz, DMSO-d6) δ8.63(d,J=5.5Hz,1H),8.36(s,1H),8.29(d,J=1.7Hz,1H),8.12(s,1H),7.7 9(dd,J=5.4,1.9Hz,1H),7.21(dd,J=9.2,2.6Hz,1H),7.15–7.05(m,3H),3.12(dd,J=11.3,7.8Hz,1H ),3.09–3.03(m,1H),2.99(d,J=7.8Hz,1H),2.95(d,J=7.1Hz,2H),2.74(dd,J=11.3,7.3Hz,1H),2. 31(dd,J=14.7,7.3Hz,1H),2.16(s,3H),1.88(dt,J=13.0,6.5Hz,1H),1.53(dq,J=15.4,7.8Hz,1H).

[0509] Example 8

[0510] (S)-5-Chloro-N-(2-(N-(1-ethylpyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl))benzamide (Compound 8)

[0511]

[0512] (S)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (102 mg, 0.178 mmol) was dissolved in tetrahydrofuran (1.5 mL), and triethylamine (54 mg, 0.535 mmol) and iodoethane (28 mg, 0.178 mmol) were added. The mixture was sealed and reacted in an oil bath at 70°C for 16 hours. The reaction was stopped, and 1N dilute hydrochloric acid was added to the reaction solution to adjust it to slightly acidic. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure. The product was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 10:1), and then purified by preparative high performance liquid chromatography (elution system: ammonia, water, acetonitrile) to obtain the title compound (21.24 mg, yield: 19.9%, white solid).

[0513] MS (ESI): m / z 601.2 [M+H] + ;

[0514] 1H NMR (400MHz, DMSO-d6) δ11.33(s,1H),8.63(d,J=5.4Hz,1H),8.27(d,J=1.8Hz,1H),8.1 3(s,1H),8.07(d,J=6.8Hz,1H),7.78(dd,J=5.4,1.9Hz,1H),7.20(dd,J=9.1,2.2Hz,1H ),7.14–7.05(m,3H),3.77(brs,1H),2.59(dd,J=9.3,7.3Hz,1H),2.42–2.25(m,4H),2. 22–2.14(m,4H),1.94–1.85(m,1H),1.52(dq,J=8.0,5.9Hz,1H),0.93(t,J=7.2Hz,3H).

[0515] Example 9

[0516] (S)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(1-propylpyrrolidin-3-yl)sulfonylamino)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 9)

[0517]

[0518] At room temperature, (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (80 mg, 0.14 mmol) and propionaldehyde (24.33 mg, 0.42 mmol) were dissolved in dichloromethane (2 mL). Acetic acid (25.13 mg, 0.42 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (NaBH(OAc)3) (88.77 mg, 0.42 mmol) was added, and the reaction was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then isolated and purified by preparative HPLC (elution system: formic acid, water, acetonitrile) to obtain the title compound (27.16 mg, yield: 28.1%) as a white solid.

[0519] MS (ESI): m / z 615.2 [M+H] + ;

[0520] Example 10

[0521] (S)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(1-(2-fluoroethyl)pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 10)

[0522]

[0523] (S)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (70 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 1-fluoro-2-iodoethane (21.25 mg, 0.12 mmol) and potassium carbonate (33.7 mg, 0.24 mmol) were added. The mixture was reacted in an oil bath at 50°C for 16 hours. The reaction was stopped and quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The title compound (28.51 mg, yield: 37.7%) was obtained as a white solid by preparative HPLC (elution system: ammonia, water, acetonitrile).

[0524] MS(ESI):m / z 618.9[M] + ;

[0525] 1 H NMR (400MHz, DMSO-d6) δ11.33 (s, 1H), 8.63 (d, J = 5.4Hz, 1H), 8.27 (s, 1H), 8. 15–8.07(m,2H),7.78(dd,J=5.4,1.7Hz,1H),7.23–7.17(m,1H),7.13–7.09(m ,3H),4.44(dt,J=44.0,4.9Hz,2H),3.79(dd,J=14.4,6.6Hz,1H),2.72–2.58( m,5H),2.34–2.26(m,1H),2.16(s,3H),1.98–1.83(m,1H),1.58–1.51(m,1H).

[0526] Example 11

[0527] (R)-5-Chloro-N-(2-(N-(1-ethylpyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl))benzamide (Compound 11)

[0528]

[0529] (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (80 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2.0 mL), and triethylamine (42.38 mg, 0.42 mmol) and iodoethane (21.78 mg, 0.14 mmol) were added. The mixture was sealed and reacted in an oil bath at 70°C for 16 hours. The reaction was stopped and the reaction mixture was adjusted to slightly acidic by adding 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. The product was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 10:1) and then purified by preparative HPLC (elution system: formic acid, water, acetonitrile) to obtain the title compound (44.72 mg, yield: 42.6%, white solid).

[0530] MS (ESI): m / z 601.1 [M+H] + ;

[0531] Example 12

[0532] (R)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(1-propylpyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 12)

[0533]

[0534] At room temperature, (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (80 mg, 0.14 mmol) and propionaldehyde (24.32 mg, 0.42 mmol) were dissolved in dichloromethane (2 mL). Acetic acid (25.13 mg, 0.42 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (88.77 mg, 0.42 mmol) was added, and the reaction was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was isolated and purified by preparative HPLC (elution system: formic acid, water, acetonitrile) to obtain the title compound (27.36 mg, yield: 25.5%) as a white solid.

[0535] MS (ESI): m / z 615.2 [M+H] + ;

[0536] 1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),8.64–8.62(m,1H),8.28–8.27(m,1H) ),8.15–8.08(m,2H),7.79–7.77(m,1H),7.21–7.19(m,1H),7.13–7.05(m,3 H),3.83–3.76(m,1H),2.69–2.64(m,1H),2.46–2.26(m,5H),2.16(s,3H),1 .95–1.86(m,1H),1.59–1.50(m,1H),1.40–1.31(m,2H),0.83–0.78(m,3H).

[0537] Example 13

[0538] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 13)

[0539]

[0540] Step 1: 2-(Methylthio)pyridin-4-amine

[0541]

[0542] 2-Chloropyridin-4-amine (1 g, 7.8 mmol) was dissolved in NMP (10 mL), and sodium thiomethoxide (1.12 g, 15.6 mmol) was added. The mixture was microwaved at 200°C for 0.5 h. The reaction was stopped and quenched with water (30 ml). The aqueous phase was extracted with chloroform / isopropanol (v:v = 3:1) (40 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the sample was spin-dried. The product was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the title compound (900 mg, crude product), which was directly used in the next reaction.

[0543] MS (ESI): m / z 141.2 [M+H] + ;

[0544] Step 2: 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0545]

[0546] 2-(Methylthio)pyridin-4-amine (400 mg, 2.85 mmol) was dissolved in pyridine (6 mL), and 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (691 mg, 2.85 mmol) was added. Phosphorus oxychloride (1.31 g, 8.55 mmol) was added dropwise at 0°C, and the reaction was stirred for 2 hours. The reaction was stopped, and the reaction solution was slowly added dropwise to ice water (30 mL). The pH was adjusted to 5-6 with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 4:1) to obtain the title compound (720 mg, yield: 69.2%, colorless oil).

[0547] MS (ESI): m / z 364.9 [M+H] + ;

[0548] Step 3: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0549]

[0550] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (200 mg, 0.55 mmol) was dissolved in DMF (2 mL), and 4-fluoro-2-methylphenol (138 mg, 1.097 mmol) and cesium carbonate (357 mg, 1.097 mmol) were added. The mixture was stirred in an oil bath at 100°C for 2 hours. The reaction solution was quenched with water (10 mL), and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and dried under vacuum to afford the crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 4:1) to afford the title compound (273 mg, yield: 92.5%) as a white solid.

[0551] MS (ESI): m / z 471.1 [M+H] + ;

[0552] Step 4: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 13)

[0553]

[0554] Dissolve 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(methylthio)pyridin-4-yl)-4- (trifluoromethyl)benzamide (250 mg, 0.53 mmol) in methanol (3 mL), add ammonium carbonate (153 mg, 1.59 mmol) and iodo-benzene diacetate (683 mg, 2.12 mmol), stir at room temperature for 1 hour. Stop the reaction, spin dry the reaction liquid, separate the product by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1), dissolve the crude product in DMF, and purify by reverse phase preparative chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (75.41 mg, yield: 28.2%, white solid).

[0555] MS (ESI): m / z 502.1 [M+H] + ;

[0556] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.5 Hz, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.77 (d, J = 5.3 Hz, 1H), 7.20 (d, J = 10.0 Hz, 1H), 7.14 - 7.04 (m, 3H), 3.12 (s, 3H), 2.15 (s, 3H).

[0557] Example 14

[0558] 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)- 4-(trifluoromethyl)benzamide (Compound 14)

[0559]

[0560] First step: 1-(benzyloxy)-4-fluoro-2-(methoxy-d3)benzene

[0561]

[0562] Dissolve 2-(benzyloxy)-5-fluorophenol (400 mg, 1.83 mmol) in DMF (4 mL), add potassium carbonate (506 mg, 3.66 mmol), add deuterated iodomethane (319 mg, 2.20 mmol) at 0 °C, seal the tube and stir at room temperature for 16 hours. Stop the reaction, quench the reaction with water (10 ml), extract the aqueous phase with ethyl acetate (15 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, spin dry the filtrate, and purify by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) to obtain the title compound (340 mg, white solid, yield: 79.1%).

[0563] 1 H NMR (400MHz, CDCl3) δ7.44–7.29(m,5H),6.80(dd,J=8.8,5.5Hz,1H),6.65(dd,J=10.2,2.9Hz,1H),6.52(td,J=8.5,2.9Hz,1H),5.10(s,2H).

[0564] Step 2: 4-Fluoro-2-(methoxy-d3)phenol

[0565]

[0566] Dissolve 1-(benzyloxy)-4-fluoro-2-(methoxy-d3)benzene (300 mg, 1.275 mmol) in methanol (9 mL), add Pd(OH)2 (60 mg), and stir at room temperature for 16 h. Stop the reaction, filter the reaction mixture, rinse the filter cake with methanol (9 mL x 3), and spin-dry the filtrate to obtain the title compound (136 mg, yield: 73.5%) as a brown oil.

[0567] Step 3: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0568]

[0569] 4-Fluoro-2-(methoxy-d3)phenol (50 mg, 0.34 mmol) was dissolved in DMF (1 mL), and 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (62.8 mg, 0.17 mmol) was added. Potassium carbonate (47.5 mg, 0.34 mmol) was added, and the mixture was sealed and stirred at 100°C for 2 hours. The reaction was stopped and quenched with water (10 ml). The aqueous phase was extracted with ethyl acetate (15 ml × 3). The organic phases were combined, washed with saturated brine (5 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the title compound (100 mg, yield: 97.7%, white solid).

[0570] MS (ESI): m / z 490.1 [M+H] + ;

[0571] Step 4: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 14)

[0572]

[0573] 5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (85 mg, 0.17 mmol) was dissolved in methanol (1 mL), and ammonium carbonate (50 mg, 0.52 mmol) and iodobenzene diacetate (224 mg, 0.70 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was dried and mixed, and the crude product was separated by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1). The crude product was purified by reverse phase preparative chromatography (elution system: formic acid, water, acetonitrile) to give 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methylimidosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (FZ008-114) (47.93 mg, yield: 52.9%, white solid).

[0574] MS (ESI): m / z 521.1 [M+H] + ;

[0575] 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),8.63(d,J=5.4Hz,1H),8.40(s,1H),8.07(s,1H),7.82(d,J=3.6Hz,1H),7.29(dd ,J=8.8,5.8Hz,1H),7.14(dd,J=10.6,2.8Hz,1H),7.00(s,1H),6.85(td,J=8.6,2.9Hz,1H),4.37(s,1H),3.14(s,3H).

[0576] Separation of chiral isomers of compound 14:

[0577] (S)-5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0578] (R)-5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0579]

[0580] Compound 14 was prepared by chiral separation column (chromatographic column: IC, 250*25 mm, 10 μm; mobile phase: A-Supercritical CO2; B-MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), 50% B ratio elution, flow rate: 100 mL / min, column temperature: room temperature) to separate and obtain single-configuration compound 14E1 (shorter retention time) and compound 14E2 (longer retention time).

[0581] Example 15

[0582] 5-Chloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 15)

[0583]

[0584] Step 1: 5-chloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0585]

[0586] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (78 mg, 0.21 mmol) was dissolved in DMF (1 mL), and 2-(methoxy-d3)-4-(trifluoromethoxy)phenol (90 mg, 0.43 mmol) and potassium carbonate (59 mg, 0.43 mmol) were added. The mixture was stirred in an oil bath at 100°C for 2 hours. The reaction was stopped and quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and dried in vacuo to afford the crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 3:1) to afford the title compound (100 mg, yield: 84.7%) as a white solid.

[0587] MS (ESI): m / z 556.1 [M+H] + ;

[0588] Step 2: 5-chloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 15)

[0589]

[0590] Dissolve 5-chloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (88 mg, 0.16 mmol) in methanol (1 mL). Add ammonium carbonate (45.6 mg, 0.48 mmol) and iodobenzene diacetate (204 mg, 0.63 mmol). Stir at room temperature for 0.5 hour. Stop the reaction, spin dry, and separate the sample by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the crude product. Purify the crude product by reverse-phase preparative chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (57.30 mg, yield: 61.3%) as a white solid.

[0591] MS (ESI): m / z 587.1 [M+H] + ;

[0592] 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),8.62(d,J=5.5Hz,1H),8.38(s,1H),8.09(s,1H),7.80(dd, J=5.4,1.8Hz,1H),7.30(d,J=8.8Hz,1H),7.23–7.12(m,2H),7.00(d,J=8.8Hz,1H),3.14(s,3H).

[0593] Example 16

[0594] 5-Chloro-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 16)

[0595]

[0596] Step 1: 5-chloro-N-(2-(methylthio)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

[0597]

[0598] Dissolve 5-chloro-2-fluoro-N-(2-(methylsulfanyl)pyridin-4-yl)-4- (trifluoromethyl)benzamide (70 mg, 0.192 mmol) and 4-(trifluoromethoxy)phenol (68.5 mg, 0.385 mmol) in N,N-dimethylformamide (2 mL), add potassium carbonate (54 mg, 0.385 mmol), and react at 70 °C in an oil bath for 16 hours. Stop the reaction, add saturated ammonium chloride solution (5 mL) to quench the reaction, extract with ethyl acetate (20 mL x 3), wash the combined organic phase with saturated brine (20 mL x 3), dry over anhydrous sodium sulfate, and separate and purify by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain the title compound (120 mg, yield: 93.02%, white solid).

[0599] MS (ESI): m / z 523.2 [M+H] + ;

[0600] Second Step: 5-chloro-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-2-(4- (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 16)

[0601]

[0602] Dissolve 5-chloro-N-(2-(methylsulfanyl)pyridin-4-yl)-2-(4- (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (100 mg, 0.192 mmol) in methanol (2 mL), add ammonium carbonate (55.3 mg, 0.575 mmol) and iodo-benzene diacetate (247 mg, 0.767 mmol), and react at room temperature for 1 hour. Stop the reaction, remove the solvent by vacuum distillation, separate and purify by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:9), and then purify by high performance liquid chromatography preparation (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (68.69 mg, yield: 64.8%, white solid).

[0603] MS (ESI): m / z 554.0 [M+H] + ;

[0604] 1 H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.15 (s, 1H), 7.76 (dd, J = 5.4, 2.0 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.24 - 7.20 (m, 2H), 4.36 (s, 1H), 3.13 (s, 3H).

[0605] Example 17

[0606] 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 17)

[0607]

[0608] Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-trifluoromethyl)benzamide

[0609]

[0610] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.274 mmol) and 4,4-difluoroazetidine hydrochloride (234 mg, 1.371 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cesium carbonate (625.3 mg, 1.92 mmol) was added and the mixture was reacted in an oil bath at 100°C for 16 hours. The reaction was stopped and quenched with saturated ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The mixture was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (125 mg, yield: 92.6%) as a white solid.

[0611] MS (ESI): m / z 480.1 [M+H] + ;

[0612] Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 17)

[0613]

[0614] 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-trifluoromethyl)benzamide (65 mg, 0.136 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (40 mg, 0.41 mmol) and iodobenzene diacetate (175 mg, 0.543 mmol) were added and allowed to react at room temperature for 1 hour. The reaction was terminated, and the solvent was removed in vacuo. The product was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10), followed by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to afford the title compound (35.02 mg, yield: 50.49%) as a white solid.

[0615] MS (ESI): m / z 511.1 [M+H] + ;

[0616] 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),8.63(d,J=5.3Hz,1H),8.41(s,1H),7.84(d,J=4.7Hz,1H),7.75(s,1H) ,7.35(s,1H),4.37(s,1H),3.39–3.32(m,4H),3.15(s,3H),2.24(brs,2H),2.07–2.04(m,2H),1.79(brs,2H).

[0617] Separation of chiral isomers of compound 17:

[0618] (S)-5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0619] (R)-5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0620]

[0621] Compound 17 was prepared by chiral separation column (chromatographic column: OJ, 250*25mm, 10μm; mobile phase: A-Supercritical CO2; B-MEOH (+0.1% 7.0mol / l Ammonia in MEOH), 25% B ratio elution, flow rate: 70mL / min, column temperature: room temperature) to separate and obtain single-configuration compound 17E1 (shorter retention time) and compound 17E2 (longer retention time).

[0622] Example 18

[0623] 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 18)

[0624]

[0625] Step 1: 5-chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0626]

[0627] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.27 mmol) was dissolved in DMF (3 mL), and (3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole hydrochloride (98.8 mg, 0.54 mmol) and cesium carbonate (536 mg, 1.64 mmol) were added. The atmosphere was purged with nitrogen and the reaction was allowed to proceed at 100°C for 12 hours. The reaction was stopped, and water (15 mL) was added. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 9:1) to obtain the title compound (100 mg, yield: 74.6%) as a white solid.

[0628] MS (ESI): m / z 492.1 [M+H] + ;

[0629] Step 2: 5-chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(2-(S-methylimidesulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 18)

[0630]

[0631] 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.20 mmol) was dissolved in methanol (1.5 mL), and ammonium carbonate (58.6 mg, 0.60 mmol) and iodobenzene oxalate (261.9 mg, 0.81 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped, the reaction solution was spin-dried, and saturated sodium bicarbonate solution (2 ml) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (5 ml × 3), and the organic phases were combined, washed with saturated brine (3 ml × 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was vacuum-dried to give a crude product, which was purified by reverse-phase preparative chromatography (elution system: ammonia water, water, acetonitrile) to give the title compound (10 mg, yield: 9.4%, white solid).

[0632] MS (ESI): m / z 539.8 [M+H] + ;

[0633] 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.62(d,J=4.9Hz,1H),8.42(s,1H),7.82(s,1H),7.72(s,1H),7.16(s,1H) ,4.36(s,1H),3.39(brs,2H),3.19(d,J=9.6Hz,2H),3.14(s,3H),2.85(brs,2H),2.32(brs,2H),1.98(brs,2H).

[0634] Example 19

[0635] 5-Chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 19)

[0636]

[0637] Step 1: 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0638]

[0639] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.274 mmol) and 4,4-difluorocyclohexan-1-ol (150 mg, 1.097 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cesium carbonate (268 mg, 0.823 mmol) was added, and the mixture was reacted in an oil bath at 100°C for 16 hours. The reaction was stopped and quenched with saturated ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (200 mg, yield: 98.1%) as a white solid.

[0640] MS (ESI): m / z 481.0 [M+H] + ;

[0641] Step 2: 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 19)

[0642]

[0643] 5-Chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (190 mg, 0.4 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (114 mg, 1.19 mmol) and iodobenzene diacetate (510 mg, 1.58 mmol) were added and allowed to react at room temperature for 1 hour. The reaction was terminated, and the solvent was removed in vacuo. The product was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10), followed by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to afford the title compound (81.2 mg, yield: 39.8%) as a white solid.

[0644] MS (ESI): m / z 512.1 [M+H] + ;

[0645] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.63(d,J=5.4Hz,1H),8.40(s,1H),7.92(s,1H),7.78 (d,J=5.2Hz,1H),7.66(s,1H),4.96(brs,1H),4.37(s,1H),3.14(s,3H),2.01–1.83(m,8H).

[0646] Example 20

[0647] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(S-methylimidosulfonyl)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 20)

[0648]

[0649] Step 1: 6-(Methylthio)pyridazin-4-amine

[0650]

[0651] Dissolve 6-chloropyridazin-4-amine (1 g, 7.7 mmol) in methanol (10 mL), add sodium thiomethoxide (2.8 g, 38.6 mmol), seal the tube, and stir at 100°C for 16 hours. Stop the reaction, spin dry the reaction mixture, and purify it by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:10) to obtain the title compound (800 mg, white solid, yield: 73.4%).

[0652] MS (ESI): m / z 142.0 [M+H] + ;

[0653] Step 2: 5-chloro-2-fluoro-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide

[0654]

[0655] 6-(Methylthio)pyridazin-4-amine (75 mg, 0.53 mmol) was dissolved in pyridine (2 mL), and 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (129 mg, 0.53 mmol) was added. Phosphorus oxychloride (244 mg, 1.59 mmol) was added dropwise at 0°C, and the reaction was stirred for 2 hours. The reaction was stopped, and the reaction solution was slowly added dropwise to ice water (10 mL). The pH was adjusted to 5-6 with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the title compound (90 mg, yield: 46.6%) as a yellow solid.

[0656] MS (ESI): m / z 365.0 [M+H] + ;

[0657] Step 3: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide

[0658]

[0659] 5-Chloro-2-fluoro-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (80 mg, 0.22 mmol) was dissolved in DMF (1 mL), and 4-fluoro-2-methylphenol (41.4 mg, 0.33 mmol) and cesium carbonate (142.7 mg, 0.44 mmol) were added. The mixture was stirred in an oil bath at 100°C for 2 hours. The reaction was stopped and quenched with water (10 ml). The aqueous phase was extracted with ethyl acetate (15 ml × 3). The organic phases were combined, washed with saturated brine (5 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the title compound (69 mg, yield: 67.0%) as a white solid.

[0660] MS (ESI): m / z 472.0 [M+H] + ;

[0661] Step 4: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(S-methylimidosulfonyl)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 20)

[0662]

[0663] Dissolve 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (60 mg, 0.13 mmol) in methanol (1 mL). Add ammonium carbonate (36.6 mg, 0.39 mmol) and iodobenzene diacetate (164 mg, 0.51 mmol) and stir at room temperature for 1 hour. Stop the reaction, spin dry the reaction mixture, and separate the crude product by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1). Purify the crude product by reverse-phase preparative chromatography (elution system: formic acid, water, acetonitrile) to afford the title compound (17.45 mg, yield: 27.3%) as a white solid.

[0664] MS (ESI): m / z 503.0 [M+H] + ;

[0665] 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H),9.39(s,1H),8.63(d,J=2.0Hz,1H),8.21(s,1H),8.1 4(s,1H),7.24–7.17(m,1H),7.11(d,J=5.3Hz,3H),4.86(s,1H),3.31(s,3H),2.16(s,3H).

[0666] Example 21

[0667] 5-Chloro-N-(6-(S-methyliminosulfonyl)pyridazin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 21)

[0668]

[0669] Step 1: 5-chloro-N-(6-(methylthio)pyridazin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

[0670]

[0671] 5-Chloro-2-fluoro-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (70 mg, 0.192 mmol) and 4-(trifluoromethoxy)phenol (68.3 mg, 0.384 mmol) were dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (53 mg, 0.384 mmol) was added and the mixture was reacted in an oil bath at 70°C for 16 hours. The reaction was stopped and quenched with saturated ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The title compound was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (70 mg, yield: 69.72%) as a white solid.

[0672] MS (ESI): m / z 524.0 [M+H] + ;

[0673] Step 2: 5-chloro-N-(6-(S-methylimidosulfonyl)pyridazin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 21)

[0674]

[0675] 5-Chloro-N-(6-(methylthio)pyridazin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (60 mg, 0.125 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (36.04 mg, 0.375 mmol) and iodobenzene diacetate (161 mg, 0.5 mmol) were added and allowed to react at room temperature for 1 hour. The reaction was terminated, and the solvent was removed in vacuo. The product was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:9), followed by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to afford the title compound (25.42 mg, yield: 36.7%) as a yellow solid.

[0676] MS (ESI): m / z 555.0 [M+H] + ;

[0677] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),9.39(d,J=2.4Hz,1H),8.59(d,J=2.4Hz,1H),8.19(s ,1H),7.55(s,1H),7.41(d,J=8.8Hz,2H),7.23(d,J=9.1Hz,2H),4.87(s,1H),3.29(s,3H).

[0678] Example 22

[0679] 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(S-methyliminosulfonyl)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 22)

[0680]

[0681] Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide

[0682]

[0683] Dissolve 5-chloro-2-fluoro-N-(6-(methylsulfanyl)pyridazin-4-yl)-4- (trifluoromethyl)benzamide (70 mg, 0.192 mmol) and 4,4-difluoroazepane hydrochloride (164 mg, 0.959 mmol) in N,N-dimethylformamide (2 mL), add cesium carbonate (437 mg, 1.342 mmol), and react in an oil bath at 100 °C for 16 hours. Stop the reaction, add saturated ammonium chloride solution (5 mL) to the reaction liquid to quench, extract with ethyl acetate (20 mL x 3), wash the combined organic phases with saturated brine (20 mL x 3), dry over anhydrous sodium sulfate, filter, and then concentrate the filtrate under reduced pressure. Purify by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain the title compound (70 mg, yield: 75.95%, white solid).

[0684] MS (ESI): m / z 481.1 [M+H] + ;

[0685] Second Step: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(S-methyliminosulfonyl)pyridazin-4-yl)-4- (trifluoromethyl)benzamide (Compound 22)

[0686]

[0687] Dissolve 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(methylsulfanyl)pyridazin-4-yl)-4- (trifluoromethyl)benzamide (70 mg, 0.134 mmol) in methanol (2 mL), add ammonium carbonate (39 mg, 0.402 mmol) and iodo phenyl diacetate (172 mg, 0.535 mmol), and react at room temperature for 1 hour. Stop the reaction, remove the solvent under vacuum, purify by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:10), and then purify by high performance liquid chromatography preparation (eluent system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (15.88 mg, yield: 23.2%, white solid).

[0688] MS (ESI): m / z 512.0 [M+H] + ;

[0689] 1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),9.44(s,1H),8.66(s,1H),7.80(s,1H),7.35(s,1H),4.89(s,1H) ,3.42–3.40(m,2H),3.38–3.34(m,2H),3.32(s,3H),2.27(brs,2H),2.08–2.00(m,2H),1.80(brs,2H).

[0690] Example 23

[0691] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 23)

[0692]

[0693] Step 1: 4-Fluoro-3-(methylthio)aniline

[0694]

[0695] 3-Bromo-4-fluoroaniline (1 g, 5.26 mmol) was dissolved in ultra-dry 1,4-dioxane (20 mL). Sodium thiomethoxide (569 mg, 7.89 mmol), Pd2(dba)3 (485 mg, 0.53 mmol), XantPhos (609 mg, 1.05 mmol), and DIEA (2.04 g, 15.78 mmol) were added. The atmosphere was replaced with nitrogen and the mixture was stirred in an oil bath at 110°C for 16 hours. The reaction was terminated, filtered, and the filter cake was rinsed with DCM (30 ml x 3). The filtrate was then dried and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:2) to obtain the title compound (600 mg, colorless oil, yield: 72.6%).

[0696] MS (ESI): m / z 158.0 [M+H] + ;

[0697] Step 2: 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0698]

[0699] 5-Chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (980 mg, 4.04 mmol) was dissolved in thionyl chloride (1.5 mL), the atmosphere was replaced with nitrogen, and the mixture was stirred at 80°C for 2 hours before being dried and set aside. 4-Fluoro-3-(methylthio)aniline (635 mg, 4.04 mmol) was dissolved in ultra-dry DCM (10 mL). Pyridine (1.28 g, 16.16 mmol) was added at 0°C, followed by a dichloromethane solution (2 mL) that had been dried and set aside. The mixture was stirred at room temperature for 2 hours. The reaction mixture was stopped, dried, and the sample was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 10:1) to obtain the title compound (870 mg, yield: 56.4%) as a white solid.

[0700] MS (ESI): m / z 382.0 [M+H] + ;

[0701] Step 3: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0702]

[0703] 5-Chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (300 mg, 0.785 mmol) was dissolved in DMF (4 mL), and 4-fluoro-2-methylphenol (198 mg, 1.571 mmol) and cesium carbonate (512 mg, 1.571 mmol) were added. The mixture was stirred in an oil bath at 100°C for 2 hours. The reaction was stopped and quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-dried to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 5:1) to obtain the title compound (290 mg, yield: 75.7%) as a yellow solid.

[0704] MS (ESI): m / z 488.1 [M+H] + ;

[0705] Step 4: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(S-methylimidosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 23)

[0706]

[0707] Dissolve 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(methylthio)phenyl)-4- (trifluoromethyl)benzamide (290 mg, 0.59 mmol) in methanol (3 mL), add ammonium carbonate (171.3 mg, 1.78 mmol) and iodo-benzene diacetate (766 mg, 2.36 mmol), stir the reaction at room temperature for 1 hour. Stop the reaction, spin dry the reaction mixture and isolate the product by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1 : 10) to give the crude product, which is purified by reverse phase preparative chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to give the title compound (197 mg, yield: 64.3%, white solid).

[0708] MS (ESI): m / z 519.1 [M+H] + ;

[0709] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.25 (dd, J = 6.5, 2.7 Hz, 1H), 8.06 (s, 1H), 7.92 - 7.85 (m, 1H), 7.43 (t, J = 9.3 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.13 - 7.06 (m, 3H), 4.68 (s, 1H), 3.18 (s, 3H), 2.17 (s, 3H).

[0710] Chiral isomer resolution of compound 23:

[0711] (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(S-methylsulfϊnyl)phenyl)-4- (trifluoromethyl)benzamide

[0712] (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(S-methylsulfϊnyl)phenyl)-4- (trifluoromethyl)benzamide

[0713]

[0714] Chiral preparative separation column (chromatography column: AS, 250*25 mm, 10 μm; mobile phase: A-Supercritical CO2; B-MEOH (+0.1% 7.0 mol / 1 Ammonia in MEOH), elution with 30% B ratio, flow rate: 70 mL / min, column temperature: room temperature) to give single configuration compound 23E1 (shorter retention time) and compound 23E2 (longer retention time).

[0715] Example 24

[0716] 5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 24)

[0717]

[0718] Step 1: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0719]

[0720] 4-Fluoro-2-(methoxy-d3)phenol (95 mg, 0.654 mmol) and 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (50 mg, 0.131 mmol) were dissolved in N,N-dimethylformamide (1 mL). Potassium carbonate (36.2 mg, 0.262 mmol) was added, and the mixture was sealed and reacted in an oil bath at 100°C for 2 hours. The reaction was stopped and quenched with saturated ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (80 mg, yield: 98.2%) as a white solid.

[0721] MS (ESI): m / z 507.1 [M+H] + ;

[0722] Step 2: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 24)

[0723]

[0724] 5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (70 mg, 0.138 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (40 mg, 0.415 mmol) and iodobenzene diacetate (178 mg, 0.553 mmol) were added and allowed to react at room temperature for 1 hour. The reaction was terminated, and the solvent was removed in vacuo. The product was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), followed by preparative high-performance liquid chromatography (elution system: formic acid, water, acetonitrile) to afford the title compound (39.21 mg, yield: 52.7%) as a white solid.

[0725] MS (ESI): m / z 538.0 [M+H] + ;

[0726] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.28(dd,J=6.4,2.6Hz,1H),8.01(s,1H),7.96–7.90(m,1H),7.44(t,J=9.3Hz,1H),7. 28(dd,J=8.8,5.9Hz,1H),7.14(dd,J=10.6,2.8Hz,1H),6.98(s,1H),6.85(td,J=8.5,2.9Hz,1H),4.69(s,1H),3.18(s,3H).

[0727] Example 25

[0728] 5-Chloro-N-(4-fluoro-3-(S-methylsulfonimide)phenyl)-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 25)

[0729]

[0730] Step 1: 5-chloro-N-(4-fluoro-3-(methylthio)phenyl)-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

[0731]

[0732] 5-Chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (60 mg, 0.157 mmol) and 2-(methoxy-d3)-4-(trifluoromethoxy)phenol (66.4 mg, 0.314 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). Potassium carbonate (43.4 mg, 0.314 mmol) was added and the mixture was reacted in an oil bath at 100°C for 2 hours. The reaction was stopped and quenched with saturated ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (80 mg, yield: 89.79%) as a white solid.

[0733] MS (ESI): m / z 572.8 [M+H] + ;

[0734] Step 2: 5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 25)

[0735]

[0736] 5-Chloro-N-(4-fluoro-3-(methylthio)phenyl)-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (60 mg, 0.105 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (30.3 mg, 0.315 mmol) and iodobenzene diacetate (135.15 mg, 0.42 mmol) were added and allowed to react at room temperature for 1 hour. The reaction was terminated, and the solvent was removed in vacuo. The product was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), followed by preparative high-performance liquid chromatography (elution system: formic acid, water, acetonitrile) to afford the title compound (16.02 mg, yield: 25.4%) as a white solid.

[0737] MS (ESI): m / z 604.1 [M+H] + ;

[0738] 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.25 (dd, J = 6.4, 2.6 Hz, 1H), 8.03 (s, 1H), 7.91 (dd, J = 8.3, 3.6 Hz, 1H), 7.43 (t, J = 9.3 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.13 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 4.68 (s, 1H), 3.18 (s, 3H).

[0739] Example 26

[0740] 5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-2-(4- (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 26)

[0741]

[0742] First Step: 5-chloro-N-(4-fluoro-3-(methylthio)phenyl)-2-(4- (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

[0743]

[0744] Dissolve 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4- (trifluoromethyl)benzamide (100 mg, 0.26 mmol) in DMF (2 mL), add 4- (trifluoromethoxy)phenol (93.3 mg, 0.52 mmol), add cesium carbonate (170 mg, 0.52 mmol), stir at 100 °C in an oil bath for 2 hours. Stop the reaction, quench the reaction with water (10 ml), extract the aqueous phase with ethyl acetate (15 ml x 3), combine the organic phases, wash with saturated brine (5 ml x 2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate to obtain a crude product. Purify the crude product by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (100 mg, yield: 71.4%, white solid).

[0745] MS (ESI): m / z 540.0 [M+H] + ;

[0746] Second Step: 5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-2-(4- (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 26)

[0747]

[0748] Dissolve 5-chloro-N-(4-fluoro-3-(methylthio)phenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (87 mg, 0.16 mmol) in methanol (1 mL). Add ammonium carbonate (46.4 mg, 0.48 mmol) and iodobenzene diacetate (206 mg, 0.64 mmol) and stir at room temperature for 0.5 hour. Stop the reaction, spin dry the reaction mixture, and separate the crude product by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1). Purify the crude product by reverse-phase preparative chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (28.96 mg, yield: 31.5%) as a white solid.

[0749] MS (ESI): m / z 571.0 [M+H] + ;

[0750] 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 7.86 (s, 1H), 7.71 (d, J = 23.3Hz, 2H), 7.48(d,J=8.0Hz,3H),7.34(s,2H),7.02(s,1H),4.75(s,1H),3.13(s,3H).

[0751] Example 27

[0752] 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 27)

[0753]

[0754] Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0755]

[0756] 4,4-Difluoroazepane hydrochloride (80 mg, 0.58 mmol) was dissolved in DMF (2 mL), and 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (80 mg, 0.20 mmol) and cesium carbonate (210 mg, 0.64 mmol) were added. The mixture was stirred in an oil bath at 100°C for 12 hours. The reaction was stopped and quenched with water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and dried in vacuo to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 3:1) to obtain the title compound (45 mg, yield: 43.2%) as a yellow solid.

[0757] MS (ESI): m / z 497.1 [M+H] + ;

[0758] Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-formimidosulfonyl)phenyl)-4-trifluoromethylbenzamide (Compound 27)

[0759]

[0760] 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (45 mg, 0.09 mmol) was dissolved in methanol (1.5 mL). Ammonium bicarbonate (27 mg, 0.28 mmol) and iodobenzene diacetate (118 mg, 0.36 mmol) were added and stirred at room temperature for 1 hour. The reaction was stopped, the reaction solution was spin-dried, and quenched with water (2 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain the crude product. The crude product was purified by reverse-phase preparative chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (2.85 mg, yield: 0.59%) as a white solid.

[0761] MS (ESI): m / z 539.0 [M+H] + ;

[0762] 1H NMR(400MHz, DMSO-d6)δ10.87(s,1H),8.27(dd,J=6.4,2.5Hz,1H),8.01–7.90(m,1H),7.69(s,1H),7.46(t,J=9 .3Hz,1H),7.34(s,1H),4.70(s,1H),3.40(brs,4H),3.20(s,3H),2.25(brs,2H),2.07(brs,2H),1.81(brs,2H).

[0763] Separation of chiral isomers of compound 27:

[0764] (S)-5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-formimidosulfonyl)phenyl)-4-trifluoromethylbenzamide

[0765] (R)-5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-formimidosulfonyl)phenyl)-4-trifluoromethylbenzamide

[0766]

[0767] Compound 27 was prepared by chiral separation column (chromatographic column: AS, 250*25 mm, 10 μm; mobile phase: A-Supercritical CO2; B-MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), 45% B ratio elution, flow rate: 70 mL / min, column temperature: room temperature) to separate and obtain single-configuration compound 27E1 (shorter retention time) and compound 27E2 (longer retention time).

[0768] Example 28

[0769] 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 28)

[0770]

[0771] Step 1: 5-chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0772]

[0773] (3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole hydrochloride (100 mg, 0.681 mmol) was dissolved in DMF (1 mL), and 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (130 mg, 0.340 mmol) and cesium carbonate (322 mg, 1.021 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was stirred in an oil bath at 100°C for 16 hours. The reaction was stopped and quenched with water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and vacuum-dried to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 2:1) to obtain the title compound (100 mg, yield: 57.8%) as a yellow solid.

[0774] MS(ESI):m / z 510.1[M+H] + ;

[0775] Step 2: 5-chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 28)

[0776]

[0777] 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (100 mg, 0.196 mmol) was dissolved in methanol (1.5 mL), and ammonium carbonate (56.6 mg, 0.589 mmol) and iodobenzene oxalate (253.1 mg, 0.785 mmol) were added, and the reaction was stirred at room temperature for 1 hour. The reaction was stopped, the reaction solution was spin-dried, and saturated sodium bicarbonate solution (2 ml) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (5 ml × 3), and the organic phases were combined, washed with saturated brine (3 ml × 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was vacuum-dried to give a crude product, which was purified by reverse-phase preparative chromatography (elution system: ammonia water, water, acetonitrile) to give the title compound (10 mg, yield: 9.4%, white solid).

[0778] MS(ESI):m / z 539.8[M+H] + ;

[0779] 1H NMR(400MHz, DMSO-d6)δ10.88(s,1H),8.29(d,J=3.8Hz,1H),8.01–7.85(m,1H),7.65(s,1H),7.45(t,J=9.3Hz,1H),7 .14(s,1H),4.68(s,1H),3.39(d,J=7.0Hz,2H),3.23–3.19(m,5H),2.84(brs,2H),2.39–2.25(m,2H),1.96(brs,2H).

[0780] Example 29

[0781] 5-Chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 29)

[0782]

[0783] Step 1: 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0784]

[0785] 5-Chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (80 mg, 0.21 mmol) and 4,4-difluorocyclohexan-1-ol (114 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cesium carbonate (205 mg, 0.63 mmol) was added and the mixture was reacted in an oil bath at 100°C for 1 hour. The reaction was stopped and quenched with saturated ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The title compound was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (120 mg, yield: 92.3%) as a white solid.

[0786] MS(ESI):m / z 498.1[M+H] + ;

[0787] Step 2: 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 29)

[0788]

[0789] 5-Chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (105 mg, 0.211 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (61 mg, 0.634 mmol) and iodobenzene diacetate (272.2 mg, 0.845 mmol) were added and allowed to react at room temperature for 1 hour. The reaction was terminated, and the solvent was removed in vacuo. The product was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), followed by preparative high-performance liquid chromatography (elution system: formic acid, water, acetonitrile) to afford the title compound (71.14 mg, yield: 64.1%) as a white solid.

[0790] MS(ESI):m / z 529.1[M+H] + ;

[0791] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.27(s,1H),7.86(s,2H),7.64(s,1H),7 .44(t,J=9.1Hz,1H),4.94(brs,1H),4.68(s,1H),3.18(s,3H),1.88(brs,8H).

[0792] Example 30

[0793] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 30)

[0794]

[0795] 第一步:(4-溴吡啶-2-基)甲醇

[0796]

[0797] Dissolve methyl 4-bromopyridine-2-carboxylate (2 g, 9.258 mmol) in ethanol (50 mL), add sodium borohydride (771 mg, 20.381 mmol), and react at room temperature for 16 hours after nitrogen substitution. Stop the reaction, remove the solvent in vacuo, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the title compound (1.23 g, yield: 70.7%) as a white solid.

[0798] MS(ESI):m / z 188.0[M+H] + ;

[0799] 第二步:4-溴-2-(氯甲基)吡啶

[0800]

[0801] Dissolve (4-bromopyridin-2-yl)methanol (9.7 g, 51.59 mmol) in dichloromethane (60 mL). Slowly add thionyl chloride (9.21 mg, 77.414 mmol) dropwise at 0°C. Allow to react at room temperature for 3 hours. Stop the reaction and quench with saturated sodium bicarbonate solution (100 mL). Extract with dichloromethane (100 mL x 3), dry over anhydrous sodium sulfate, filter, and remove the solvent from the filtrate in vacuo. Purify the mixture by column chromatography (silica gel, petroleum ether:ethyl acetate = 9:1) to obtain the title compound (10 g, yield: 85.1%) as a yellow oil.

[0802] MS(ESI):m / z 206.0[M+H] + ;

[0803] 第三步:4-溴-2-((甲硫基)甲基)吡啶

[0804]

[0805] 4-Bromo-2-(chloromethyl)pyridine (10 g, 48.433 mmol) was dissolved in N,N-dimethylformamide (80 mL). Sodium thiomethoxide (4.07 mg, 58.076 mmol) was slowly added at 0°C and allowed to react for 2 hours. The reaction was stopped and the reaction solution was poured into water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. The filtrate was filtered and the solvent was removed by vacuum centrifugation. The title compound was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain the title compound (9.3 g, yield: 88.1%) as a yellow oil.

[0806] MS(ESI):m / z 218.1[M+H] + ;

[0807] Step 4: 4-Bromo-2-((methylsulfinyl)methyl)pyridine

[0808]

[0809] Dissolve 4-bromo-2-((methylthio)methyl)pyridine (4 g, 18.34 mmol) in a mixture of methanol (50 mL) and water (10 mL). Slowly add sodium periodate (3.93 g, 18.34 mmol) at 0°C. Allow to react at room temperature for 5 hours. Stop the reaction, remove the solvent in vacuo, and purify by column chromatography (silica gel, dichloromethane:methanol = 9:1) to obtain the title compound (4.1 g, yield: 96.47%) as a white solid.

[0810] MS(ESI):m / z 234.0[M+H] + ;

[0811] Step 5: N-(((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 -硫亚基)-2,2,2-三氟乙酰胺

[0812]

[0813] Dissolve 4-bromo-2-((methylsulfinyl)methyl)pyridine (2 g, 8.584 mmol) in dichloromethane (20 mL), add 2,2,2-trifluoroacetamide (1.94 g, 17.17 mmol), magnesium oxide (1.34 g, 34.33 mmol), rhodium acetate (190 g, 0.43 mmol), and iodobenzene acetate (5.53 g, 17.17 mmol). After nitrogen substitution, react at room temperature for 16 hours. Stop the reaction, remove the solvent in vacuo, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (1.18 g, yield: 40.2%, yellow oil).

[0814] MS(ESI):m / z 345.0[M+H] + ;

[0815] Step 6: ((4-bromopyridin-2-yl)methyl)(imino)(methyl)-λ 6 -亚砜

[0816]

[0817] N-(((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 Dissolve (1.13 g, 3.285 mmol) of (-sulfylidene)-2,2,2-trifluoroacetamide in methanol (10 mL) and add potassium carbonate (2.27 g, 16.424 mmol). Allow to react at room temperature for 1 hour. Stop the reaction, remove the solvent in vacuo, and purify by column chromatography (silica gel, dichloromethane:methanol = 8:1) to obtain the title compound (660 mg, yield: 81.08%) as a yellow oil.

[0818] MS(ESI):m / z 249.0[M+H] + ;

[0819] Step 7: (((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 -硫亚基)氨基甲酸苄基酯

[0820]

[0821] ((4-bromopyridin-2-yl)methyl)(imino)(methyl)-λ 6 Dissolve 2-(2-methyl-1-thiophene)-sulfoxide (660 mg, 2.66 mmol) in dichloromethane (10 mL), add pyridine (632 mg, 8 mmol), cool to 0°C, slowly add benzyl chloroformate (1.09 g, 6.4 mmol), and react at room temperature for 3 hours. Stop the reaction, remove the solvent in vacuo, dilute with water (10 mL), adjust to slightly acidic with 1N dilute hydrochloric acid, and extract with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (900 mg, yield: 88.58%) as a yellow oil.

[0822] MS(ESI):m / z 383.1[M+H] + ;

[0823] Step 8: (1-(4-bromopyridin-2-yl)cyclopropyl)(imino)(methyl)-λ 6 -亚砜

[0824]

[0825] (((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 Benzyl (2-(2-(2-thio)-1-yl)carbamate (680 mg, 1.78 mmol) was dissolved in tetrahydrofuran (12.8 mL), and tetrabutylammonium bromide (57.4 mg, 0.178 mmol) and 1,2-dibromoethane (1.34 g, 7.12 mmol) were added. Sodium hydroxide solution (50%, 3.2 mL) was slowly added dropwise, and the temperature was then raised to 60°C for 16 hours. The reaction was stopped, the solvent was removed in vacuo, the mixture was diluted with water (10 mL), and the mixture was adjusted to slightly acidic with 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the title compound (400 mg, yield: 81.96%) as a yellow solid.

[0826] MS(ESI):m / z 275.0[M+H] + ;

[0827] Step 9: ((1-(4-bromopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -硫亚基)氨基甲酸苄基酯

[0828]

[0829] (1-(4-bromopyridin-2-yl)cyclopropyl)(imino)(methyl)-λ 6 -sulfoxide (400 mg, 1.46 mmol) was dissolved in dichloromethane (6 mL), and pyridine (346 mg, 4.38 mmol) was added. After cooling to 0°C, benzyl chloroformate (623 g, 3.65 mmol) was slowly added dropwise, and the mixture was allowed to react at room temperature for 3 hours. The reaction was stopped, the solvent was removed in vacuo, and the mixture was diluted with water (10 mL). The mixture was adjusted to slightly acidic with 1N dilute hydrochloric acid, and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (400 mg, yield: 67.11%) as a yellow oil.

[0830] MS(ESI):m / z 409.0[M+H] + ;

[0831] Step 10: ((1-(4-((diphenylmethylene)amino)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -硫亚基)氨基甲酸苄基酯

[0832]

[0833] ((1-(4-bromopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6-sulfylidene) benzyl carbamate (330 mg, 0.81 mmol) and benzhydryl imine (220 mg, 1.21 mmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (18.2 mg, 0.08 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (94 mg, 0.162 mmol) and cesium carbonate (790 mg, 2.43 mmol) were added. After nitrogen replacement, the reaction was carried out in an oil bath at 100 ° C for 2 hours. The reaction was stopped and quenched by adding saturated ammonium chloride solution (10 mL) to the reaction solution. The solution was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:2) to give the title compound (400 mg, yield: 97.08%, yellow oil).

[0834] MS(ESI):m / z 510.5[M+H] + ;

[0835] Step 11: ((1-(4-aminopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -硫亚基)氨基甲酸苄基酯

[0836]

[0837] ((1-(4-((diphenylmethylene)amino)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 Dissolve benzyl (420 mg, 0.825 mmol) (-sulfylidene) carbamate in tetrahydrofuran (4 mL) and slowly add 1N dilute hydrochloric acid (4 mL) dropwise. Allow to react at room temperature for 1 hour. Stop the reaction, remove the solvent in vacuo, adjust the solution to a slightly alkaline state with 1N sodium hydroxide solution, and extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated brine (20 mL x 3) and dried over anhydrous sodium sulfate. After filtration, remove the solvent from the filtrate in vacuo to yield the title compound (270 mg, yield: 68.4%) as a white solid.

[0838] MS(ESI):m / z 346.1[M+H] + ;

[0839] Step 12: ((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -硫亚基)氨基甲酸苄基酯

[0840]

[0841] ((1-(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 - sulfanyl)benzylcarbamate (205 mg, 0.594 mmol) and 5-chloro-2-fluoro-4- (trifluoromethyl)benzoic acid (144.1 mg, 0.594 mmol) were dissolved in pyridine (4 mL), after nitrogen replacement, cooled to -10 °C with ice-salt bath, slowly added phosphorus oxychloride (274 mg, 1.783 mmol), reacted at room temperature for 2 hours. The reaction solution was poured into ice water (30 mL), adjusted to slightly acidic with 1 N dilute hydrochloric acid, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, and column chromatography (silica gel, petroleum ether: ethyl acetate = 1:4) was used to separate and purify to obtain the title compound (300 mg, yield: 88.76%, yellow solid).

[0842] MS (ESI): m / z 570.0 [M+H] + ;

[0843] Thirteenth step: ((1-(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 - sulfanyl)benzylcarbamate

[0844]

[0845] ((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2- yl)cyclopropyl)(methyl)(oxo)-λ 6 - sulfanyl)benzylcarbamate (75 mg, 0.132 mmol) and 4-fluoro-2-methylphenol (20 mg, 0.158 mmol) were dissolved in N,N-dimethylformamide (2 mL), cesium carbonate (86 mg, 0.264 mmol) was added, and the reaction was heated to 100 °C for 2 hours. The reaction was stopped, saturated ammonium chloride solution (10 mL) was added to the reaction solution to quench, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 3), the organic phase was collected and dried over anhydrous sodium sulfate, and column chromatography (silica gel, petroleum ether: ethyl acetate = 1:3) was used to separate and purify to obtain the title compound (110 mg, yield: 93.2%, yellow oil).

[0846] MS (ESI): m / z 676.1 [M+H] + ;

[0847] Step 14: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(1-(S-methylsulfonimidoyl)cyclopropyl)pyridin-4-yl)-4- (trifluoromethyl)benzamide (Compound 30)

[0848]

[0849] ((1-(4-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 Benzyl ((1-(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ

[0850] MS (ESI): m / z 542.0 [M+H] + ;

[0851] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.60 (dd, J = 5.5, 1.9 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.11 - 7.08 (m, 3H), 3.71 (s, 1H), 2.91 (s, 3H), 2.16 (s, 3H), 1.81 - 1.73 (m, 1H), 1.48 - 1.41 (m, 1H), 1.31 - 1.20 (m, 2H).

[0852] Example 31

[0853] 5-chloro-N-(2-(1-(S-methylsulfonimidoyl)cyclopropyl)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide (Compound 31)

[0854]

[0855] ((1-(4-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6benzyl (sulfinyl)carbamate

[0856]

[0857] ((1-(4-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 benzyl (sulfinyl)carbamate (70 mg, 0.102 mmol) was dissolved in trifluoroacetic acid (1.5 mL), and the reaction was warmed to 60 °C for 3 h. The reaction was stopped, and the solvent was removed under vacuum. The reaction was made slightly basic with 1 N NaOH solution, extracted with ethyl acetate (2 mL x 3), and the organic phases were combined and washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The title compound was purified by preparative high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) (39.27 mg, yield: 68.42%, white solid).

[0858] MS (ESI): m / z 728.0 [M+H] + ;

[0859] Second Step: 5-chloro-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-2-(4- (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 31)

[0860]

[0861] ((1-(4-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 benzyl (sulfinyl)carbamate (70 mg, 0.102 mmol) was dissolved in trifluoroacetic acid (1.5 mL), and the reaction was warmed to 60 °C for 3 h. The reaction was stopped, and the solvent was removed under vacuum. The reaction was made slightly basic with 1 N NaOH solution, extracted with ethyl acetate (2 mL x 3), and the organic phases were combined and washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The title compound was purified by preparative high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) (39.27 mg, yield: 68.42%, white solid).

[0862] MS (ESI): m / z 728.0 [M+H] + ;

[0863] 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.44(d,J=5.6Hz,1H),8.12(s,1H),7.83(d,J=1.5Hz,1H),7.57(dd,J=5.5,1.8Hz,1H),7. 50(s,1H),7.40(d,J=8.5Hz,2H),7.24–7.19(m,2H),3.71(s,1H),2.90(s,3H),1.76(brs,1H),1.44(brs,1H),1.30–1.19(m,2H).

[0864] Example 32

[0865] 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 32)

[0866]

[0867] Step 1: ((1-(4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfylidene)carbamic acid benzyl ester

[0868]

[0869] ((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 Benzyl (4,4-difluoro-1,4-difluoro-1,4-difluoro-2-nitropropane) carbamate (75 mg, 0.132 mmol) and 4,4-difluoro-1,4-difluoro-2-nitropropane hydrochloride (113 mg, 0.66 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (300 mg, 0.923 mmol) was added. The temperature was raised to 100°C and the reaction mixture was reacted for 16 hours. The reaction was stopped and quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3) to obtain the title compound (80 mg, yield: 88%) as a yellow oil.

[0870] MS (ESI): m / z 685.1 [M+H] + ;

[0871] Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 32)

[0872]

[0873] ((1-(4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 Benzyl (2-(2-(2-thio)-1,3-dimethylamino)-1-thio-1-yl)carbamate (70 mg, 0.102 mmol) was dissolved in trifluoroacetic acid (1.5 mL) and heated to 60°C for 3 hours. The reaction was stopped, and the solvent was removed in vacuo. The mixture was adjusted to a slightly alkaline state with 1N sodium hydroxide solution and extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purification by preparative HPLC (elution system: ammonium bicarbonate, water, acetonitrile) afforded the title compound (19.21 mg, yield: 34.12%) as a white solid.

[0874] MS (ESI): m / z 551.1 [M+H] + ;

[0875] 1 H NMR(400MHz, DMSO-d6)δ10.97(s,1H),8.47(d,J=5.5Hz,1H),7.85(s,1H),7.73–7.67(m,2H),7.36(s,1H),3.69(s,1H), 3.42–3.33(m,4H),2.92(s,3H),2.24(brs,2H),2.11–2.00(m,2H),1.79(brs,3H),1.49–1.43(m,1H),1.31–1.21(m,2H).

[0876] Example 33

[0877] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(2-(S-methyliminosulfonyl)ethoxy)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 33)

[0878]

[0879] Step 1: 4-Bromo-2-(2-(methylthio)ethoxy)pyridine

[0880]

[0881] 2-(Methylthio)ethan-1-ol (3.14 g, 34.10 mmol) was dissolved in N,N-dimethylformamide (60 mL). Sodium hydroxide (1.70 g, 42.60 mmol) was added at 0°C and allowed to react for 0.5 hours. 4-Bromo-2-fluoropyridine (5.00 g, 28.40 mmol) was added under nitrogen and allowed to react at 0°C for another 2 hours. The reaction was stopped and quenched by the slow addition of water (250 mL). The aqueous phase was extracted with ethyl acetate (250 mL x 3). The combined organic phases were washed with saturated brine (250 mL x 2), dried over anhydrous sodium sulfate, and vacuum-dried to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 97:3) to obtain the title compound (5.00 g, yield: 71.0%) as a colorless oil.

[0882] MS (ESI): m / z 247.9 [M+H] + ;

[0883] Step 2: (2-((4-bromopyridin-2-yl)oxy)ethyl)(imino)(methyl)-λ 6 -sulfoxide

[0884]

[0885] 4-Bromo-2-(2-(methylthio)ethoxy)pyridine (4.5 g, 18.13 mmol) was dissolved in methanol (50 mL). Ammonium carbonate (5.2 g, 54.40 mmol) was added, followed by iodobenzene diacetate (23.3 g, 72.53 mmol) under ice-cooling. The atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for 2 hours. The reaction was stopped and quenched with water (200 mL). The aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, and vacuum-dried to obtain a crude product. The crude product was separated and purified by reverse-phase column chromatography (mobile phase: water:methanol = 85:15) to obtain the title compound (900 mg, yield: 17.7%, yellow oil).

[0886] MS (ESI): m / z 279.0 [M+H] + ;

[0887] Step 3: ((2-((4-bromopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfylidene)carbamic acid benzyl ester

[0888]

[0889] (2-((4-bromopyridin-2-yl)oxy)ethyl)(imino)(methyl)-λ 6-sulfoxide (700 mg, 2.50 mmol) was dissolved in DCM (10 mL), and pyridine (297 mg, 3.76 mmol) was added. The atmosphere was replaced with nitrogen, and CbzCl (513 mg, 3.00 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction was stopped and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and dried under vacuum to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the title compound (800 mg, yield: 77.2%, colorless oil).

[0890] MS (ESI): m / z 415.0 [M+H] + ;

[0891] Step 4: ((2-((4-((diphenylmethylene)amino)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfylidene)carbamic acid benzyl ester

[0892]

[0893] ((2-((4-bromopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 Benzyl (9,9-dimethyl-9H-xanthene-4,5-diyl) carbamate (700 mg, 1.69 mmol) was dissolved in dioxane (10 mL), and diphenylimine (458 mg, 2.54 mmol), tris(dibenzylideneacetone)dipalladium (154 mg, 0.16 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (195 mg, 0.33 mmol) and cesium carbonate (1654 mg, 5.08 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was stirred at 100 ° C for 1.5 hours. The reaction was stopped, and the reaction solution was cooled and water (100 mL) was added. The aqueous phase was extracted with ethyl acetate (100 ml × 3). The organic phases were combined, washed with saturated brine (3 ml × 2), dried over anhydrous sodium sulfate, and dried under vacuum to give a crude product. The crude product was purified by thin layer chromatography (developing solvent system: ethyl acetate) to give the title compound (550 mg, yield: 63.2%, yellow solid).

[0894] MS (ESI): m / z 514.2 [M+H] + ;

[0895] Step 5: ((2-((4-aminopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfylidene)carbamic acid benzyl ester

[0896]

[0897] ((2-((4-((diphenylmethylene)amino)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 Benzyl 2-thiophenylamine (500 mg, 0.97 mmol) was dissolved in tetrahydrofuran (2 mL), and water (1 mL) and hydrochloric acid (1 mL) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at room temperature for 1.5 hours. The crude title compound (400 mg, white solid) was obtained by vacuum drying. The crude product was directly used for the next reaction.

[0898] MS (ESI): m / z 350.1 [M+H] + ;

[0899] Step 6: ((2-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamide)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfylidene)carbamic acid benzyl ester

[0900]

[0901] ((2-((4-aminopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 Benzyl (450 mg, 1.16 mmol) (-sulfylidene) carbamate was dissolved in pyridine (15 mL) and 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (283 mg, 1.16 mmol) was added. The atmosphere was replaced with nitrogen and phosphorus oxychloride (536 mg, 3.50 mmol) was added under ice-cooling. The reaction was allowed to react at room temperature for 2 hours. The reaction was stopped and water (100 mL) was added to the reaction solution under ice-cooling. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and vacuum-dried to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the title compound (450 mg, yield: 67.0%), as a yellow solid.

[0902] MS (ESI): m / z 574.1 [M+H] + ;

[0903] Step 7: ((2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfylidene)carbamic acid benzyl ester

[0904]

[0905] benzyl ((2-((4-(5-chloro-2-(4-fluoro-2-methoxyphenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 benzyl ((2-((4-(5-chloro-2-(4-fluoro-2-methoxyphenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ

[0906] MS (ESI): m / z 680.1 [M+H] + ;

[0907] Step 8: 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-(2-(S-methylsulfonimidoyl)ethoxy)pyridin-4-yl)-4- (trifluoromethyl)benzamide (Compound 33)

[0908]

[0909] benzyl ((2-((4-(5-chloro-2-(4-fluoro-2-methoxyphenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 benzyl ((2-((4-(5-chloro-2-(4-fluoro-2-methoxyphenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ

[0910] MS (ESI): m / z 546.0 [M+H] + ;

[0911] 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.06(s,1H),7.67(d,J=7.5Hz,1H),7.22(d,J=9.0Hz,1H),7.09(d,J=5.8Hz,3H),6.82(d,J= 1.9Hz,1H),6.42(dd,J=7.5,2.2Hz,1H),4.21(t,J=6.8Hz,2H),3.88(s,1H),3.43(td,J=6.8,2.7Hz,2H),2.91(s,3H),2.16(s,3H).

[0912] Example 34

[0913] 2-(4-Acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 34)

[0914]

[0915] Step 1: 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide

[0916]

[0917] 5-Chloro-2-fluoro-N-(2-methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-(1,4-diazepan-1-yl)ethan-1-one (140.8 mg, 0.99 mmol) and cesium carbonate (322.7 mg, 0.99 mmol) were added. The atmosphere was purged with nitrogen and the reaction mixture was allowed to react at 100°C for 16 hours. The reaction was stopped, and water was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was then freed of solvent in vacuo. The title compound was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3) to obtain the title compound (90 mg, yield: 56.3%) as a white solid.

[0918] MS (ESI): m / z 487.0 [M+H] + ;

[0919] Step 2: 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-trifluoromethylbenzamide (Compound 34)

[0920]

[0921] Dissolve 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide (90 mg, 0.18 mmol) in methanol (1 mL), then add ammonium carbonate (18 mg, 0.54 mmol) and iodobenzene acetate (60.3 mg, 0.72 mmol). Allow to react at room temperature for 1 hour. Stop the reaction, remove the solvent in vacuo, and purify by column chromatography (silica gel, dichloromethane:methanol = 20:1), followed by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (2 mg, yield: 2.1%) as a white solid.

[0922] MS (ESI): m / z 518.1 [M+H] + ;

[0923] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),8.62(d,J=5.4Hz,1H),8.40(d,J=3.2Hz,1H),7.84(d,J=5.5Hz,1H),7.73(d,J=17.0H z,1H),7.37(d,J=10.9Hz,1H),4.38(s,1H),3.62–3.54(m,2H),3.49–3.34(m,6H),3.15(s,3H),1.89(s,3H),1.74(brs,2H).

[0924] Example 35

[0925] 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 35)

[0926]

[0927] Step 1: 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0928]

[0929] 5-Chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-trifluoromethylbenzamide (100 mg, 0.262 mmol) and 1-(1,4-diazepan-1-yl)ethan-1-one (75 mg, 0.525 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cesium carbonate (171 mg, 0.525 mmol) was added and the mixture was reacted in an oil bath at 100°C for 16 hours. The reaction was stopped and quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (116 mg, yield: 88%) as a yellow oil.

[0930] MS (ESI): m / z 504.1 [M+H] + ;

[0931] Step 2: 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 35)

[0932]

[0933] Dissolve 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (96 mg, 0.19 mmol) in methanol (2 mL), add ammonium carbonate (54.78 mg, 0.57 mmol) and iodobenzene diacetate (244.8 mg, 0.76 mmol), and allow to react at room temperature for 1 hour. The reaction was terminated, and the solvent was removed in vacuo. The product was isolated and purified by column chromatography (silica gel, ethyl acetate), followed by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to afford the title compound (15.76 mg, yield: 14.85%) as a white solid.

[0934] MS (ESI): m / z 535.1 [M+H] + ;

[0935] 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.28(d,J=4.3Hz,1H),8.03–7.91(m,1H),7.67(d,J=16.7Hz,1H),7.45(t ,J=9.3Hz,1H),7.35(d,J=9.6Hz,1H),4.70(s,1H),3.62–3.35(m,8H),3.20(s,3H),1.90(s,3H),1.76(brs,2H).

[0936] Example 36

[0937] 5-Chloro-2-(4-(2,2-difluoroethyl)-1,4-diazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0938]

[0939] Step 1: tert-Butyl 4-(4-chloro-2-((2-(methylthio)pyridin-4-yl)carbamoyl)-5-(trifluoromethyl)phenyl)-1,4-diazepane-1-carboxylate

[0940]

[0941] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide (200 mg, 0.55 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (220.2 mg, 1.1 mmol) were dissolved in N,N-dimethylformamide (3 mL). Cesium carbonate (358.4 mg, 1.1 mmol) was added and the mixture was reacted in an oil bath at 100°C for 16 hours. The reaction was stopped and quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 7:3) to obtain the title compound (215 mg, yield: 72%) as a yellow oil.

[0942] MS (ESI): m / z 545.1 [M+H] + ;

[0943] Step 2: 5-chloro-2-(1,4-diazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0944]

[0945] Dissolve tert-butyl 4-(4-chloro-2-((2-(methylthio)pyridin-4-yl)carbamoyl)-5-(trifluoromethyl)phenyl)-1,4-diazepane-1-carboxylate (205 mg, 0.377 mmol) in dichloromethane (6 mL). Add trifluoroacetic acid (2 mL) and allow to react at room temperature for 1 hour. Stop the reaction and remove the solvent in vacuo to obtain the title compound (337 mg, 98% yield, as a yellow oil).

[0946] MS (ESI): m / z 445.1 [M+H] + ;

[0947] Step 3: 5-chloro-2-(4-(2,2-difluoroethyl)-1,4-diazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0948]

[0949] Dissolve 5-chloro-2-(1,4-diazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (337 mg) and 2,2-difluoroethyl trifluoromethanesulfonate (96.34 mg, 0.45 mmol) in tetrahydrofuran (1.5 mL). Add triethylamine (91.5 μl) and react in an oil bath at 50°C for 16 hours. Stop the reaction, remove the solvent in vacuo, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 6.5:3.5) to obtain the title compound (148 mg, yield: 44.85%) as a yellow oil.

[0950] MS (ESI): m / z 509.1 [M+H] + ;

[0951] Step 4: 5-chloro-2-(4-(2,2-difluoroethyl)-1,4-diazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 36)

[0952]

[0953] 5-Chloro-2-(4-(2,2-difluoroethyl)-1,4-diazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (114 mg, 0.212 mmol) was dissolved in methanol (1 mL), followed by the addition of ammonium carbonate (11.31 mg, 0.118 mmol) and iodobenzene acetate (50.25 mg, 0.156 mmol). The mixture was allowed to react at room temperature for 1 hour. The reaction was terminated, and the solvent was removed in vacuo. The product was isolated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 6.5:3.5), followed by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to afford the title compound (91 mg, yield: 67.4%) as a yellow oil.

[0954] MS (ESI): m / z 540.1 [M+H] + ;

[0955] Example 37

[0956] 5-Chloro-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-4-(trifluoromethyl)benzamide (Compound 37)

[0957]

[0958] Step 1: 5-chloro-N-(2-(methylthio)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-4-(trifluoromethyl)benzamide

[0959]

[0960] Dissolve 5-chloro-2-(1,4-diazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide (100 mg, 0.23 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (208.89 mg, 0.9 mmol) in tetrahydrofuran (2.5 mL). Add triethylamine (186.19 mg, 1.84 mmol) and react in an oil bath at 50°C for 16 hours. Stop the reaction, remove the solvent in vacuo, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 7:3) to obtain the title compound (68 mg, yield: 56.7%, yellow oil).

[0961] MS (ESI): m / z 527.1 [M+H] + ;

[0962] Step 2: 5-chloro-N-(2-(S-methylimidesulfonyl)pyridin-4-yl)-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-4-(trifluoromethyl)benzamide 2,2,2 (Compound 37)

[0963]

[0964] 5-Chloro-N-(2-(methylthio)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-4-(trifluoromethyl)benzamide (45 mg, 0.086 mmol) was dissolved in methanol (1 mL). Ammonium carbonate (24.7 mg, 0.257 mmol) and iodobenzene acetate (110.8 mg, 0.344 mmol) were then added and allowed to react at room temperature for 1 hour. The reaction was terminated, the solvent removed in vacuo, and the product was isolated and purified by column chromatography (silica gel, pure ethyl acetate), followed by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to afford the title compound (57 mg, yield: 92.3%) as a yellow oil.

[0965] MS (ESI): m / z 558.1 [M+H] + ;

[0966] Example 38

[0967] 5-chloro-N-(2-((dimethyl(oxo)-λ 6 -sulfylidene)amino)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (Compound 38)

[0968]

[0969] Step 1: Dimethyl (4-nitropyridin-2-yl) imine)-λ 6 -6-Sulfanone

[0970]

[0971] Dissolve 2-chloro-4-nitropyridine (1000 mg, 6.31 mmol) in anhydrous 1,4-dioxane (20 mL), add dimethylsulfenyl imide (881 mg, 9.46 mmol), cesium carbonate (6.2 g, 18.93 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (730 mg, 1.26 mmol), and tris(dibenzylideneacetone)dipalladium(0) (577 mg, 0.63 mmol), and heat to 100°C under nitrogen and stir overnight. Stop the reaction, spin dry the reaction solution, and purify it by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (1.2 g, yield: 88%) as a yellow solid.

[0972] MS (ESI): m / z 216.1 [M+H] + ;

[0973] Step 2: ((4-aminopyridin-2-yl)imino)dimethyl-λ 6 -Thiolanone

[0974]

[0975] Dimethyl (4-nitropyridin-2-yl) imino)-λ 6 6-Thiolanone (600 mg, 2.79 mmol) was dissolved in anhydrous methanol (10 mL), and palladium on carbon (180 mg) was added. After hydrogen substitution, the mixture was allowed to react at room temperature for 16 hours. The reaction was terminated, filtered, and the solvent removed by vacuum centrifugation. The filtrate was then purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (460 mg, yield: 89%) as a white solid.

[0976] MS (ESI): m / z 186.2 [M+H] + ;

[0977] Step 3: 5-chloro-N-(2-((dimethyl(oxo)-λ 6 -sulfylidene)amino)pyridin-4-yl)-2-fluoro-4-(trifluoromethyl)benzamide

[0978]

[0979] ((4-aminopyridin-2-yl)imino)dimethyl-λ 61-Thiolanone (120 mg, 0.648 mmol) and 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (157.17 mg, 0.648 mmol) were dissolved in pyridine (2 mL). After nitrogen replacement, the temperature was cooled to -10°C, and phosphorus oxychloride (248.64 mg, 1.62 mmol) was added. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction was stopped and quenched with ice water (5 mL). The solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was then freed of solvent in a vacuum spin-drying cycle. The title compound was isolated and purified by column chromatography (silica gel, dichloromethane:anhydrous methanol = 9:1) to obtain the title compound (263.7 mg, yield: 98%) as a yellow oil.

[0980] MS (ESI): m / z 410.0 [M+H] + ;

[0981] Step 4: 5-chloro-N-(2-((dimethyl(oxo)-λ 6 -sulfylidene)amino)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (Compound 38)

[0982]

[0983] 5-chloro-N-(2-((dimethyl(oxo)-λ 6 To a solution of 2-fluoro-4-(trifluoromethyl)benzamide (132 mg, 0.324 mmol) and 4-fluoro-2-methylphenol (81.64 mg, 0.65 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (316.7 mg, 0.972 mmol). The mixture was reacted in an oil bath at 100°C for 2 hours. The reaction was terminated, the reaction solution was filtered, and then purified by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to afford the title compound (38.25 mg, yield: 22.9%) as a white solid.

[0984] MS (ESI): m / z 516.1 [M+H] + ;

[0985] 1H NMR (400MHz, DMSO-d6) δ10.71(s,1H),8.03(s,1H),7.99(d,J=5.7Hz,1H),7.21(d,J=9.0Hz,1H) ,7.10–7.08(m,4H),7.03(d,J=5.7Hz,1H),6.93(s,1H),3.34(s,3H),3.32(s,3H),2.16(s,3H).

[0986] Example 39

[0987] 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-((dimethyl(oxo)-λ 6 -sulfonylidene)amino)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 39)

[0988]

[0989] 5-chloro-N-(2-((dimethyl(oxo)-λ 6 To a solution of 2-(trifluoromethyl)-2-nitro-1,3-difluoro-4-(thio)amino)pyridin-4-yl)-2-fluoro-4-(trifluoromethyl)benzamide (132 mg, 0.324 mmol) and 4,4-difluoroazepane hydrochloride (322.4 mg, 1.944 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (1.056 g, 3.24 mmol). The mixture was reacted in an oil bath at 100°C for 16 hours. The reaction was terminated, the reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to afford the title compound (39.52 mg, yield: 23.3%) as a yellow solid.

[0990] MS (ESI): m / z 525.1 [M+H] + ;

[0991] 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),7.99(d,J=5.5Hz,1H),7.64(s,1H),7.33(s,1H),7.03 (d,J=8.8Hz,2H),3.41–3.34(m,10H),2.23(brs,2H),2.10–2.01(m,2H),1.80–1.78(m,2H).

[0992] Biological test evaluation

[0993] Test Example A: Blocking activity of the compounds of the present invention on sodium ion channel 1.8 (NaV1.8)

[0994] Experimental purpose: Determination of the inhibitory rate of compounds on human Nav1.8 ion channels stably expressed in CHO cells

[0995] Experimental methods:

[0996] DMSO-dissolved compounds were prepared as stock solutions and diluted with extracellular solution (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH2PO4 2H2O, pH = 7.4 (NaOH)) to specific concentrations for manual patch clamp testing.

[0997] Use a microelectrode puller to pull a capillary glass tube into a recording electrode. Under an inverted microscope, manipulate the microelectrode manipulator to bring the recording electrode into contact with the cell, apply negative pressure and suction to form a GΩ seal. After the GΩ seal is formed, perform rapid capacitance compensation, and then continue to apply negative pressure to break the cell membrane and form a whole-cell recording mode. Then perform slow capacitance compensation and record the membrane capacitance and series resistance. No leakage compensation is given. When the Nav1.8 current recorded in the whole cell stabilizes, start drug administration. After each drug concentration acts for 5 minutes (or the current stabilizes), detect the next concentration. Two concentrations are detected for each test compound.

[0998] The voltage stimulation protocol for whole-cell patch clamp recording of Nav1.8 sodium current is as follows: after the whole-cell seal is formed, the cell voltage is clamped at -120mV for 30ms. The clamping voltage is depolarized to 0mV and maintained for 50ms, and then the voltage is restored to -50mV (the specific voltage refers to the half-inactivation voltage of the IV test) and maintained for 8s. The cell membrane potential is then restored to -120mV and maintained for 20ms, and then depolarized to 0mV again and maintained for 50ms, and finally restored to the clamping voltage of -120mV and maintained for 30ms. Data collection is repeated every 20s. The effect of the drug on the peak of the sodium current is observed. The experimental data are collected by an EPC-10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0999] Experimental results:

[1000]

[1001]

[1002] Test Example B: Pharmacokinetic evaluation of the compound of the present invention by intravenous injection or oral gavage in rats

[1003] Experimental purpose: The purpose of this test example is to evaluate the pharmacokinetic properties of the compounds of the present invention

[1004] The inventors conducted a pharmacokinetic evaluation of the compound of the present invention in rats. Detailed animal information is shown in Table 2.

[1005] Table 2: Information of the test animals of the present invention

[1006] germline grade gender weight age source SD rats SPF male 180-220g 6-8 weeks Shanghai Xipu-Bikai Experimental Animal Co., Ltd.

[1007] Experimental methods:

[1008] The compound of the present invention was administered to the test animals in the form of a 5% DMSO + 5% tween80 + 90% saline solution. The animals were fasted for 12 hours before administration and had free access to water. For the intravenous injection group, the dosage was 1 mg / kg; for oral administration, the dosage was 10 mg / kg. Blood was collected venously at the following time points after administration (blood volume approximately 0.3 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours. EDTA-K2 was pre-added to the blood collection tube as an anticoagulant. The blood samples were centrifuged at 6800g for 6 minutes, and the plasma was collected and stored at -80°C.

[1009] Sample preparation for LC-MS / MS analysis: 20 μL of plasma sample was protein precipitated with 400 μL of methanol containing 100 ng / mL IS (IS = tolbutamide). The mixture was vortexed for 1 minute and then centrifuged at 18,000 g for 7 minutes. 400 μL of the supernatant was transferred to a 96-well plate. 2 μL of the supernatant was subjected to LC-MS / MS analysis. The results showed that the compounds of this invention exhibited favorable pharmacokinetic properties in rats.

[1010]

[1011] Test Example C: Pharmacokinetic evaluation of the compound of the present invention by intravenous injection or oral gavage in mice

[1012] Experimental purpose: The purpose of this test example is to evaluate the pharmacokinetic properties of the compounds of the present invention

[1013] The inventors conducted a pharmacokinetic evaluation of the compound of the present invention in mice. Detailed animal information is shown in Table 3.

[1014] Table 3: Information of the test animals of the present invention

[1015] germline grade gender weight age source ICR mice SPF male 26-32g 6-8 weeks Shanghai Xipu-Bikai Experimental Animal Co., Ltd.

[1016] Experimental methods:

[1017] The compound of the present invention was administered to the test animals in the form of 5% DMSO + 5% tween80 + 90% normal saline solution. The animals were fasted for 12 hours before administration and had free access to water. For the intravenous injection group, the dosage was 1 mg / kg; for oral administration, the dosage was 10 mg / kg. After administration, blood was collected from the animals at the following time points (blood volume approximately 0.3 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 24 hours. EDTA-K2 was pre-added to the blood collection tube as an anticoagulant. The blood samples were centrifuged at 6800g for 6 minutes, and the plasma was collected and stored at -80°C.

[1018] Sample preparation for LC-MS / MS analysis: 15 μL of plasma sample was protein precipitated with 300 μL of methanol containing 100 ng / mL IS (IS = tolbutamide). The mixture was vortexed for 1 minute and then centrifuged at 18,000 g for 10 minutes. 300 μL of the supernatant was transferred to a 96-well plate. 2 μL of the supernatant was subjected to LC-MS / MS analysis. The results showed that the compounds of this invention exhibited favorable pharmacokinetic properties in mice.

[1019]

[1020] Specifically, the present invention relates to the following technical solutions:

[1021] 1. A compound of formula (I'), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:

[1022]

[1023] in:

[1024] X is N or CR x ;

[1025] Y is N or CR y ;

[1026] Z is N or CR z ;

[1027] W is N or CR w ;

[1028] G is N or CR g ;

[1029] The condition is that at most two of X, Y and Z are N at the same time;

[1030] R x 、R y and R zEach independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 and -L1-R1, where R x 、R y and R z At least one of them is -L1-R1, which is optionally substituted with one or more deuterium groups until it is fully deuterated;

[1031] R w and R g Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -OR s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1032] -L1-for-(CR a R b ) m -, where valence permits, -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R a and R b Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[1033] R1 is -S(O) q NR'R", -S(O)(=NR')R4 or -N=S(O)R4R4';

[1034] A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, which are optionally substituted with s R2 substituents;

[1035] -L2- is selected from the group consisting of a bond, -O-, -NR'-, -S-, -C(O)- and -(CR c R d ) n -, where valence permits, -(CR c R d ) n-Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R c and R d Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[1036] R' is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1037] R” is -L3-B;

[1038] B is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, which are optionally substituted with t R5 substituents;

[1039] -L3-for-(CR e R f ) p -, where valence permits, -(CR e R f ) p -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R e and R f Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[1040] R2, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1041] R4 and R4' are each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1042] R5 are each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1043] R6 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1044] R a 、R b 、R c 、R d 、R e and R f Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1045] R s1 and R s2 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1046] m is 0, 1, 2, 3, 4, 5 or 6;

[1047] n is 0, 1, 2, 3, 4, 5 or 6;

[1048] p is 0, 1, 2, 3, 4, 5, or 6;

[1049] t is 1, 2, 3, 4, or 5;

[1050] s is 1, 2, 3, 4, 5, 6, 7, or 8;

[1051] q is 1 or 2.

[1052] 2. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:

[1053]

[1054] in:

[1055] X is N or CR x ;

[1056] Y is N or CR y ;

[1057] Z is N or CR z ;

[1058] W is N or CR w ;

[1059] G is N or CR g ;

[1060] The condition is that at most two of X, Y and Z are N at the same time;

[1061] R x 、R y and R z Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 and -L1-R1, where R x 、R y and R z At least one of them is -L1-R1, which is optionally substituted with one or more deuterium groups until it is fully deuterated;

[1062] R w and R g Each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -OR s1, said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1063] -L1-for-(CR a R b ) m -, where valence permits, -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R a and R b Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[1064] R1 is -S(O) q NR'R" or -S(O)(=NR')R4;

[1065] A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, which are optionally substituted with s R2 substituents;

[1066] -L2- is selected from the group consisting of a bond, -O-, -NR'-, -S-, -C(O)- and -(CR c R d ) n -, where valence permits, -(CR c R d ) n -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R c and R d Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[1067] R' is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1068] R” is -L3-B;

[1069] B is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, which are optionally substituted with t R5 substituents;

[1070] -L3-for-(CRe R f ) p -, where valence permits, -(CR e R f ) p -Any methylene unit in is optionally and independently replaced by -NR'-, -O-, -S- and -C(O)- and / or R e and R f Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl or 3-10 membered heterocyclic group;

[1071] R2, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1072] R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1073] R5 are each independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1, said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1074] R6 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1075] R a 、R b 、R c 、R d 、R e and R f Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1076] R s1 and R s2 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1077] m is 0, 1, 2, 3, 4, 5 or 6;

[1078] n is 0, 1, 2, 3, 4, 5 or 6;

[1079] p is 0, 1, 2, 3, 4, 5, or 6;

[1080] t is 1, 2, 3, 4, or 5;

[1081] s is 1, 2, 3, 4, 5, 6, 7, or 8;

[1082] q is 1 or 2;

[1083] Preferably, it is of formula (II),

[1084]

[1085] Preferably, wherein -L2- is -O-;

[1086] Preferably, wherein -L2- is a bond;

[1087] Preferably, wherein A is selected from phenyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl and 5-10 membered heterocyclyl;

[1088] Preferably, wherein A is selected from cyclopentyl, cyclohexyl, azacyclohexyl, oxacyclohexyl, thiacyclohexyl, azepanyl, diazepanyl, octahydrocyclopentapyrrolyl, octahydropyrrolopyrrolyl, octahydropentalenyl, phenyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl;

[1089] Preferably, wherein m is 0;

[1090] Preferably, wherein:

[1091] m is 1, 2, 3, 4 or 5,

[1092] -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -O-, -S- and -C(O)-; and / or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl and 3-5 membered heterocyclic groups;

[1093] R a Selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[1094] R b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[1095] 3.2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (III),

[1096]

[1097] Preferably, it is of formula (IV)

[1098]

[1099] in:

[1100] X is N or CR x ;

[1101] Y is N or CR y ;

[1102] R x and R y are independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1103] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1104] R” is -L3-B;

[1105] B is a 5-7 membered heterocyclyl, which is optionally substituted with t R5 substituents;

[1106] -L3-for-(CR e R f ) p -, where valence permits, -(CR e R f ) p -Any methylene unit in is optionally and independently replaced by -O-, -S- and -C(O)-;

[1107] R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1108] R5 are each independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1109] R e and R f Independently selected from H, D, C 1-6 Alkyl and C1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1110] R s1 and R s2 Select H and C independently 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1111] p is 0, 1, 2, or 3;

[1112] t is 1, 2, or 3;

[1113] Preferably, wherein:

[1114] X is CR x ;

[1115] Y is N;

[1116] R x Selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1117] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1118] R” is -L3-B;

[1119] B is a 5-6 membered heterocyclyl, which is optionally substituted with t R5 substituents;

[1120] -L3-for-(CR e R f ) p -;

[1121] R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1122] R5 are each independently selected from H, D, C 1-6 Alkyl and C 1-6haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1123] R e and R f Independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1124] p is 0, 1, 2, or 3;

[1125] t is 1, 2, or 3;

[1126] Preferably, -L3-B is selected from

[1127] Preferably, wherein:

[1128] X is CR x ;

[1129] Y is N;

[1130] R x H or D;

[1131] R' is H;

[1132] R” is -L3-B;

[1133] B is a 5-6 membered heterocyclic group, preferably an azacyclopentyl group or an azacyclohexyl group;

[1134] -L3-for-(CR e R f ) p -, p is 0 or 1;

[1135] R 2a C 1-6 The alkyl group is preferably a methyl group;

[1136] R 2b H or D;

[1137] R 2c is halogen, preferably F;

[1138] R 2d H or D;

[1139] R 2e H or D;

[1140] R 3a H or D;

[1141] R 3b C 1-6 The haloalkyl group is preferably -CF3;

[1142] R 3c is H or D;

[1143] R 3d is H or D;

[1144] R e is selected from H, D, and C 1-6 alkyl;

[1145] R f is selected from H, D, and C 1-6 alkyl;

[1146] Preferably, -L3-B is selected from

[1147] 4.2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, is of Formula (V)

[1148]

[1149] Preferably, wherein:

[1150] X is N or CR x ;

[1151] Y is N or CR y ;

[1152] R x and R y are each independently selected from H, D, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and -OR s1 , said groups being optionally substituted with one or more deuterium, up to complete deuteration;

[1153] -L2- is a bond, -O-, -S-, or -NH-;

[1154] A is selected from phenyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl, optionally substituted with s R2substituents;

[1155] Any of the methylene units in -(CR a R b ) m are optionally and independently replaced with -O-, -S-, and -C(O)-;

[1156] R’ is selected from H, C 1-6 alkyl, and C1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1157] R2, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1158] R4 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1159] R a and R b Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1160] or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl and 3-5 membered heterocyclic groups;

[1161] R s1 and R s2 Independently selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1162] m is 0, 1, 2, 3 or 4;

[1163] s is 1, 2, 3, 4, 5, 6, 7, or 8;

[1164] Preferably, wherein:

[1165] X is CRx ;

[1166] Y is N or CR y ;

[1167] R x and R y are each independently selected from H, D, halogen and C 1-6 Alkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1168] A is selected from and a 5-8 membered heterocyclyl group, which is optionally substituted with s R2 substituents;

[1169] When valence permits, -(CR a R b ) m -Any methylene unit in is optionally and independently replaced by -O-;

[1170] -L2- is a bond or -O-;

[1171] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1172] R2 are each independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1173] R 2a Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR s1a and-SR s1a , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1174] R 2b H or D;

[1175] R 2c H, D, halogen, -OR s1c or -SR s1c ;

[1176] R 2d H or D;

[1177] R 2e H or D;

[1178] R 3a H or D;

[1179] R 3b C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1180] R 3c is a halogen;

[1181] R 3d H or D;

[1182] R4 is selected from C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1183] R a and R b Selected from H, D, halogen and C 1-6 Alkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1184] or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[1185] R s1 Each independently selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1186] R s1a Selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1187] R s1c Selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1188] m is 1, 2, or 3;

[1189] s is 1 or 2;

[1190] Preferably, wherein:

[1191] X is CR x ;

[1192] Y is N or CR y ;

[1193] R xH;

[1194] R y halogen;

[1195] A is selected from and azepanyl, which is substituted with s R2;

[1196] -(CR a R b ) m - is selected from -CH2-, -O-CH2-CH2-,

[1197] L2is a bond or -O-;

[1198] R’ is H;

[1199] R2is each independently selected from H and halogen, preferably F, said group being optionally substituted with one or more deuterium, up to complete deuteration;

[1200] R 2a is H or C 1-6 alkyl, preferably methyl, said group being optionally substituted with one or more deuterium, up to complete deuteration;

[1201] R 2b is H;

[1202] R 2c is halogen or -OR s1c ;

[1203] R 2d is H;

[1204] R 2e is H;

[1205] R 3a is H;

[1206] R 3b is C 1-6 haloalkyl, preferably -CF3;

[1207] R 3c is halogen, preferably Cl;

[1208] R 3d is H;

[1209] R4is C 1-6 alkyl, preferably methyl;

[1210] R s1c is H, C 1-6 alkyl or C 1-6 haloalkyl, preferably -CF3;

[1211] s is 1 or 2.

[1212] 5.2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (VI):

[1213]

[1214] Preferably, wherein:

[1215] X is N or CR x ;

[1216] Y is N or CR y ;

[1217] R x and R y are independently selected from H, D, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -OR s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1218] -L2- is a bond, -O-, -S- or -NH-;

[1219] A is selected from phenyl, C 3-8 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, which are optionally substituted with 3 R2 substituents;

[1220] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1221] R2, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, OR s1 SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1, said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1222] R4 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1223] R s1 and R s2 Select H and C independently 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1224] s is 1, 2, 3, 4, 5, 6, 7, or 8;

[1225] Preferably, wherein:

[1226] A is selected from cyclopentyl, cyclohexyl, azacyclohexyl, oxacyclohexyl, thiacyclohexyl, azepanyl, diazepanyl, octahydrocyclopentapyrrolyl, octahydropyrrolopyrrolyl, octahydropentalenyl, phenyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl. Preferably, A and the substituents thereon are selected from the following:

[1227]

[1228] Among them, R 2a 、R 2b 、R 2c and R 2d Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR s1 、-SR s1 NR s1 R s2 、-C(O)R s1 、-C(O)OR s1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1229] Preferably, wherein:

[1230] -L2- is -O-;

[1231] A is selected from cyclopentyl and cyclohexyl, preferably cyclohexyl;

[1232] Preferably, wherein:

[1233] - L2- is a bond;

[1234] A is selected from azepanyl, diazepanyl, octahydrocyclopenta pyrrolyl, octahydropyrrolopyrrolyl and octahydropentalenyl, preferably, in case A is a nitrogen containing heterocycle, attached to the phenyl group via the nitrogen atom.

[1235] 6.2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, is of formula (VII)

[1236]

[1237] wherein:

[1238] X is N or CR x ;

[1239] Y is N or CR y ;

[1240] R x and R y are each independently selected from H, D, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl, said groups being optionally substituted with one or more deuterium, up to complete deuteration;

[1241] R’ is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, said groups being optionally substituted with one or more deuterium, up to complete deuteration;

[1242] R 2a , R 2b , R 2c , R 2d , R 2e , R 3a , R 3b , R 3c and R 3d are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR s1 , -SR s1 , NR s1 R s2 , -C(O)R s1 , -C(O)ORs1 、-C(O)NR s1 R s2 、-SOR s1 and-SO2R s1 , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1243] R4 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1244] R s1 and R s2 Independently selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1245] Preferably, wherein:

[1246] X is N or CR x ;

[1247] Y is N or CR y ;

[1248] R x and R y are each independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1249] R' is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1250] R 2a Selected from H, D, halogen, -OR s1a 、-SR s1a NR s1a R s2a 、C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1251] R 2b H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1252] R 2c Selected from H, D, halogen, -ORs1c 、-SR s1c NR s1c R s2c 、C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1253] R 2d H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1254] R 2e H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1255] R 3a H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1256] R 3b Selected from H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1257] R 3c Selected from H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1258] R 3d H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1259] R4 is selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1260] R s1a 、R s2a 、R s1c and R s2c Each independently selected from H, C 1-6 Alkyl or C 1-6haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1261] Preferably, wherein:

[1262] X is CR x ;

[1263] Y is N or CR y ;

[1264] R x and R y Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1265] R' is H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1266] R 2a For-OR s1a 、-SR s1a NR s1a R s2a 、C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium,

[1267] Until complete deuteration;

[1268] R 2b is H, D or halogen;

[1269] R 2c H, D, halogen, -OR s1c 、-SR s1c or NR s1c R s2c , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1270] R 2d is H, D or halogen;

[1271] R 2e is H, D or halogen;

[1272] R 3a is H, D or halogen;

[1273] R 3b H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1274] R 3c is H, D or halogen;

[1275] R 3d is H, D or halogen;

[1276] R4 is H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1277] R s1a 、R s2a 、R s1c and R s2c Each independently selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1278] The condition is that when Y is N, R 2a Not for C 1-6 Alkyl or C 1-6 alkyl halide;

[1279] Preferably, wherein:

[1280] X is CR x ;

[1281] Y is N or CR y ;

[1282] R x and R y independently selected from H, D or halogen;

[1283] R' is H, C 1-6 Alkyl or C 1-6 alkyl halide;

[1284] R 2a For-OR s1a 、-SR s1a 、C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1285] R 2b is H, D or halogen;

[1286] R 2c H, D, halogen, -OR s1c or -SR s1c , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1287] R2d is H or D;

[1288] R 2e is H or D;

[1289] R 3a is H or D;

[1290] R 3b C 1-6 alkyl halide;

[1291] R 3c is a halogen;

[1292] R 3d is H or D;

[1293] R4 is C 1-6 Alkyl or C 1-6 alkyl halide;

[1294] R s1a and R s1c Independently selected from C 1-6 Alkyl or C 1-6 alkyl halide;

[1295] The condition is that when Y is N, R 2a Not for C 1-6 Alkyl or C 1-6 alkyl halide;

[1296] Preferably, wherein:

[1297] X is CR x ;

[1298] Y is N or CR y ;

[1299] R x and R y independently selected from H, D or halogen;

[1300] R' is H;

[1301] R 2a For-OR s1a 、-SR s1a or C 1-6 Alkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1302] R 2b is H or D;

[1303] R 2c Halogen, -OR s1c or -SR s1c , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1304] R 2d is H or D;

[1305] R 2e is H or D;

[1306] R 3a is H or D;

[1307] R 3b C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1308] R 3c is a halogen;

[1309] R 3d is H or D;

[1310] R4 is C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1311] R s1a and R s1c Each independently selected from H, C 1-6 Alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuterium groups up to full deuteration;

[1312] Preferably, wherein:

[1313] X is CR x ;

[1314] Y is N or CR y ;

[1315] R x is H or D;

[1316] R y is H, D or halogen;

[1317] R' is H;

[1318] R 2a For-OR s1a or -SR s1a , said group is optionally substituted with one or more deuteriums, up to full deuteration;

[1319] R 2b is H or D;

[1320] R 2c Halogen, -OR s1c or -SR s1c ;

[1321] R 2d is H or D;

[1322] R 2e is H or D;

[1323] R 3a is H or D;

[1324] R 3b is C 1-6 alkyl or C 1-6 haloalkyl, which groups are optionally substituted with one or more deuterium, up to complete deuteration;

[1325] R 3c is halogen;

[1326] R 3d is H or D;

[1327] R4is C 1-6 alkyl or C 1-6 haloalkyl, which groups are optionally substituted with one or more deuterium, up to complete deuteration;

[1328] R s1a and R s1c are independently selected from C 1-6 alkyl or C 1-6 haloalkyl, which groups are optionally substituted with one or more deuterium, up to complete deuteration;

[1329] Preferably, wherein:

[1330] X is CR x ;

[1331] Y is N or CR y ;

[1332] R x is H;

[1333] R y is halogen, preferably F;

[1334] R’ is H;

[1335] R 2a is -OR s1a , which group is optionally substituted with one or more deuterium, up to complete deuteration, preferably -OCD3;

[1336] R 2b is H;

[1337] R 2c is halogen or -OR s1c , preferably F or -OCF3;

[1338] R 2d is H;

[1339] R 2e is H;

[1340] R 3a is H;

[1341] R 3b C 1-6 The haloalkyl group is preferably -CF3;

[1342] R 3c is a halogen, preferably Cl;

[1343] R 3d is H;

[1344] R4 is C 1-6 alkyl;

[1345] R s1a C 1-6 alkyl;

[1346] R s1c C 1-6 Halogenated alkyl.

[1347] 7. The compound of 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein the compound is selected from:

[1348]

[1349]

[1350]

[1351]

[1352] 8. A pharmaceutical composition comprising a compound according to any one of 1 to 7 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.

[1353] 9. Use of a compound according to any one of 1 to 7 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for use as a voltage-gated sodium channel inhibitor;

[1354] Preferably, the voltage-gated sodium channel inhibitor is a sodium ion channel 1.8 (NaV1.8) inhibitor;

[1355] Preferably, the voltage-gated sodium channel inhibitor is used to treat a disease selected from the group consisting of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or an epileptic disorder, a neurodegenerative disease, a psychiatric disorder such as anxiety and depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe or intractable pain, nociceptive pain, penetrating pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitations, hypertension, migraine, or abnormal gastrointestinal motility;

[1356] Preferably, the disease is selected from radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus or cancer pain.

Claims

1. A compound having the structure: or a pharmaceutically acceptable salt thereof.

2. A compound having the structure: or a pharmaceutically acceptable salt thereof.

3. A compound having the structure: or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

5. A pharmaceutical composition comprising the compound according to claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

6. A pharmaceutical composition comprising the compound according to claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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