Compounds useful as voltage-gated sodium channel inhibitors

Abstract

The invention relates to a compound used as a voltage-gated sodium channel inhibitor, and a preparation method, a pharmaceutical composition and application thereof. The compound has the structural characteristic of a formula (I). # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese invention patent application (filing date: August 11, 2023; application number: 202311015650.9), claiming the priority of Chinese Application No. 202210971471.1 filed on August 12, 2022 and Chinese Application No. 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, its preparation method, pharmaceutical composition and application. The compound has the structural feature of formula (I). Background Art

[0003] There are mainly 9 subtypes of human Nav, namely Nav1.1 - Nav1.9. According to 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, Nav1.4, Nav1.6 and Nav1.7 are TTX-S types. Among them, Nav1.1, Nav1.2 and Nav1.3 are highly 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 TTX-R types. Among them, Nav1.5 is mainly present in cardiomyocytes, and Nav1.8 and Nav1.9 are present in the dorsal root ganglion of the peripheral nervous system (PNS-DRG).

[0006] Table 1 Information of Each Nav Subtype

[0007] Pathway Coding gene <![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 Cardiomyocyte Nav1.6 SCN8A 3 Central nervous system, glia, dorsal root ganglion Nav1.7 SCN9A 4 Central nervous system, dorsal root ganglion Nav1.8 SCN10A 31000 Dorsal root ganglion Nav1.9 SCN11A 1500 Dorsal root ganglion

[0008] Research shows that ion channel alteration is the molecular basis of peripheral sensitization, central sensitization and disinhibition after inflammation or neuropathic injury, and is also an important molecular mechanism for pain occurrence. Currently, Nav inhibitors have been proven 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 currently used Nav inhibitors in clinical practice have a narrow therapeutic window and limited application scope due to the lack of subtype selectivity and the ability to inhibit sodium ion channels expressed in the heart and central nervous system.

[0009] Highly selective Nav inhibitors are one of the key research directions for voltage-gated sodium channels. Since Nav1.8 is mainly distributed in the peripheral nervous system and is limited to pain-sensing neurons, it is a highly selective target for pain treatment. Therefore, selectively inhibiting Nav1.8 has good prospects for reducing potential 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 depolarization voltage dependence, NaV1.8 is the main mediator in the rising phase of action potentials. At the same time, because NaV1.8 can quickly recover from inactivation, it also contributes to repetitive high-frequency firing. By inhibiting the activity of NaV1.8, the propagation of pain sensation can be blocked. And since NaV1.8 is mainly expressed in neurons that transmit pain signals in the dorsal root ganglion (DRG) of the peripheral nervous system, selectively inhibiting Nav1.8 can also effectively reduce potential side effects.

[0012] Currently, there is a need for drugs with better activity as voltage-gated sodium channel inhibitors, especially those that selectively inhibit Nav1.8, in order 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. It has the activity of selectively inhibiting Nav1.8 and is thus used to treat various diseases mediated by it, especially various pains.

[0014] The present invention provides a compound of general 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, which comprises a compound as defined in the present invention 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.

[0018] In one embodiment, the present invention provides the use of a compound as defined in the present invention 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, in the preparation of a drug for use as a voltage-gated sodium channel inhibitor.

[0019] In one embodiment, the present invention provides the use of a compound as defined in the present invention 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, in the preparation of a drug for use as a sodium channel 1.8 (NaV1.8) inhibitor.

[0020] In one embodiment, the present invention provides a compound as defined in the present invention 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.

[0021] In one embodiment, the present invention provides a compound as defined in the present invention 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 channel 1.8 (NaV1.8) inhibitor.

[0022] In one embodiment, the present invention provides a method for inhibiting voltage-gated sodium channels in a subject, comprising administering to the subject a compound as defined in the present invention 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 invention provides a method for inhibiting sodium channel 1.8 (NaV1.8) in a subject, comprising administering to the subject a compound as defined in the present invention 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 as described in the present invention are used for treating diseases selected from the following: acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy or epileptic disorders, neurodegenerative diseases, mental disorders such as anxiety and depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe or refractory pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitation, hypertension, migraine or abnormal gastrointestinal motility.

[0025] In some embodiments, the diseases involved in the present method are selected from radicular pain, sciatica, back pain, headache, neck pain, refractory pain, acute pain, postoperative pain, back pain, tinnitus or cancer pain. Detailed Description of the Invention

[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. On the contrary, these embodiments are provided so that the disclosure of the present invention can be understood more thoroughly and comprehensively.

[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 in the present specification are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein means any one and all combinations of one or more of the related listed items.

[0029] Unless otherwise stated, 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, including carbon, hydrogen, oxygen, sulfur, nitrogen or halogen, all include their isotope situations. Further, 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, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include16 O, 17 O and 18 O. Isotopes of sulfur include 32 S, 33 S, 34 S and 36 S. Isotopes of nitrogen include 14 N and 15 N. Isotopes of fluorine include 19 F. Isotopes of chlorine include 35 Cl, 36 Cl and 37 Cl. Isotopes of bromine include 79 Br and 81 Br.

[0031] The term "alkyl" refers to a saturated straight-chain 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 independently be a C1 alkyl group, C2 alkyl group, C3 alkyl group, C4 alkyl group, C5 alkyl group, or C6 alkyl group. In one embodiment, it may 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-prop-1-yl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-prop-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(CH3)2), 2-methyl-but-1-yl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), hex-2-yl (-CH(CH3)CH2CH2CH2CH3), hex-3-yl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-pent-2-yl (-C(CH3)2CH2CH2CH3), 3-methyl-pent-2-yl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-pent-2-yl (-CH(CH3)CH2CH(CH3)2), 3-methyl-pent-3-yl (-C(CH3)(CH2CH3)2), 2-methyl-pent-3-yl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-but-2-yl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-but-2-yl (-CH(CH3)C(CH3)3, octyl (-(CH2)7CH3), and n-nonyl, and their various branched isomers. The alkyl group may be substituted or unsubstituted. When the alkyl 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.

[0032] "Alkenyl" is an alkyl group defined in the present invention that contains at least one carbon-carbon double bond. In one example, 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, etc. When the alkenyl 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, hydroxy, nitro, cyano, and amino.

[0033] "Alkynyl" is an alkyl group defined in the present invention that contains at least one carbon-carbon triple bond. In one example, 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, etc. When the alkynyl 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, hydroxy, nitro, cyano, and amino.

[0034] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic carbon-containing group. In one embodiment, the cycloalkyl group is a monocyclic ring of 3 to 6 members (C 3-6 ) monocyclic ring of 3 to 8 members (C 3-8 ) monocyclic ring of 3 to 10 members (C 3-10 ) monocyclic ring of 4 to 12 members bicyclic (C4- 12 ) or a 10 to 15 membered (C 10-15 ) tricyclic system. The carbocyclic ring includes bridged rings or spiro rings. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, etc. The cycloalkyl group may be optionally substituted. When the cycloalkyl 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, hydroxy, nitro, cyano, and amino.

[0035] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated monocyclic or polycyclic ring group containing heteroatoms, and the heteroatoms are selected from N, O, and S. In one embodiment, the heterocyclic group may be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic system. Preferably, it is a 3- to 10-membered monocyclic or bicyclic heterocyclic group, more preferably a 5- to 8-membered monocyclic or bicyclic heterocyclic group, 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 linked to other parts of the molecule through a heteroatom or a carbon atom. The heterocycle includes bridged rings or spiro rings. Non-limiting examples of monocyclic heterocycles include ethylene oxide, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, dithiolanyl, tetrahydropyranyl, thiacyclohexyl, piperidyl, heptamethyleneimine, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dihydropyridyl, tetrahydrothienyl, sulfur-oxidized tetrahydrothienyl, etc. Non-limiting examples of bicyclic heterocyclic groups include benzodihydrofuran, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, octahydrocyclopentapyrrolyl, octahydropyrrolopyrrolyl, octahydroazulenyl, etc. When the heterocyclic group is substituted, unless otherwise defined, the substituents are preferably 1 to 5 and are independently selected from F, Cl, Br, I, =O, 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 is a 6- to 14-membered aromatic ring, preferably a 6- to 10-membered aromatic ring. Non-limiting examples thereof include phenyl or naphthyl; the aryl can be fused with a heteroaryl, heterocyclic group, or cycloalkyl, and the part where it is connected to other parts of the molecule is on the aryl. Non-limiting examples of aryl include benzene. When the aryl 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, hydroxy, 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 is a 5- to 15-membered heteroaryl ring, a 5- to 14-membered heteroaryl group, 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 include pyrrolyl, furyl, thienyl, N-alkylpyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuran, benzimidazole, benzopyridine, or pyrrolopyridine, etc. When the heteroaryl 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, hydroxy, nitro, cyano, and amino.

[0038] "Halogen" refers to F, Cl, Br, or I. "Halogenated" means replacing 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, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", then it should be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively. In some specific structures, when an alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group. For example, the alkyl in the group "-C1-C3 haloalkyl" should be understood as an alkylene group.

[0040] "Pharmaceutically acceptable salts" refer to salts of pharmaceutically acceptable non-toxic acids or bases, including salts formed with inorganic acids or inorganic bases or salts formed with organic acids and organic bases. Salts derived from inorganic bases include, but are not limited to, metal salts formed with Al, Ca, Li, Mg, K, Na, and Zn; salts derived from organic bases include, but are not limited to, salts formed with primary amines, secondary amines, or tertiary amines. The primary amines, secondary amines, 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, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, penicillin G, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, or polyamine resins; salts derived from inorganic acids and organic acids include, but are not limited to, salts formed with the following acids: 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, vinylsulfonic 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, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic 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, etc.

[0041] The term "solvate" may also be referred to as "solvent compound", "solventate", and refers to a compound containing solvent molecules, where the solvent molecules can be combined with the compound molecules in ways including coordination bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds, etc. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. 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 solvates will be able to be separated, for example, when one or more solvent molecules are incorporated into the lattice of the crystalline solid. "Solvate" includes solvates in solution state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0042] The term "hydrate" refers to a compound combined with water. Generally, the number of water molecules contained in the hydrate of a compound is determined by the ratio to the number of molecules of that compound in the hydrate. Thus, the hydrate of a compound can be represented, for example, by the general formula R·xH₂O, 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 = 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrate (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H₂O) and hexahydrate (R·6H₂O)).

[0043] The term "prodrug" refers to any compound that, when administered to an organism, gives rise to a drug, i.e., the active ingredient, by spontaneous chemical reaction, enzyme-catalyzed chemical reaction, photolysis, and / or metabolic chemical reaction. A prodrug is thus a covalently modified analogue or latent form of a therapeutically active compound. Suitable examples include, but are not limited to: carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc. of the compound.

[0044] The present invention also includes isotopically labeled compounds (isotope variants) that are equivalent to those general formulas or specific compounds described in the present application, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be introduced 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 containing the above isotopes and / or other isotopes of other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g., 3 H and 14 C), can be used for drug and / or substrate tissue distribution assays. Tritium, i.e., 3 H and carbon-14, i.e., 14C isotopes are particularly preferred because they are easily prepared and detected. Additionally, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide therapeutic benefits, such as an extended in vivo half-life or reduced dose requirements, due to higher metabolic stability, and is thus preferred in some cases. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents when carrying out the processes and / or the procedures and preparation examples disclosed below.

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

[0046] "Optional" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, including the instances where the event or circumstance occurs or does not occur. For example, "aryl is optionally substituted by alkyl" means that the alkyl may or may not be present, and the term includes the cases where the aryl is substituted by alkyl and the cases where the aryl is not substituted by alkyl.

[0047] "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 the administration of the drug. 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-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn 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 non-toxic compatible substances used in pharmaceutical formulations.

[0048] The term "polymorph" refers to a crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors can result in one crystalline form being dominant. The 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 field to which the claimed subject matter pertains. If there are multiple definitions for a term, the definition herein shall prevail. It should be understood that the singular forms used in the present invention, such as "a", include plural referents unless otherwise specified.

[0050] In addition, the terms "comprising", "including" are open-ended and not closed, that is, they include what is specified in the present invention, but do not exclude other aspects.

[0051] Unless otherwise indicated, the compounds of the present invention are identified by conventional methods such as mass spectrometry, nuclear magnetic resonance, and the steps and conditions can refer to the conventional operating steps and conditions in the art.

[0052] Unless otherwise specified, standard nomenclature and standard laboratory procedures and techniques in analytical chemistry, organic synthetic chemistry, and optics are employed in the present invention. In certain cases, standard techniques are used for chemical synthesis, chemical analysis, and detection of the performance of light-emitting devices.

[0053] In addition, it should be noted that, unless otherwise explicitly indicated, the description mode of "… are each independently" adopted in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the description mode of "… are each independently" can either mean that among different groups, the specific options expressed between the same symbols do not affect each other; or it can also mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0054] There is no particular limitation on the dosage form and administration method of the compounds or their compositions of the present invention.

[0055] Representative administration methods 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 calcium phosphate, or is mixed with the following components: (a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxypropylmethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, complex silicates, and sodium carbonate; (e) solvents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 forms may contain inert diluents conventionally used in the art (such as water or other solvents), solubilizers and emulsifiers. Specific examples are, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to the inert diluents, the compositions may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents and fragrances. For example, the suspension may contain a suspending agent. Specific examples are, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures thereof.

[0058] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous 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. They are prepared by mixing the active ingredient under sterile conditions with a pharmaceutically acceptable carrier and preservatives, buffers and / or propellants that may be required as necessary.

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

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

[0062]

[0063] Wherein:

[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 simultaneously;

[0070] R x , R y and R z 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 and -L1-R1, where at least one of R x , R y and R z is -L1-R1, and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0071] R w and R g 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 and -OR s1 ,

[0072] and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0073] -L1- is -(CR a R b ) m -, and where valence permits, any methylene unit in -(CR a R b ) m - 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 form a C 3-8 cycloalkyl or a 3- to 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- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with s R2 substituents;

[0076] -L2- is selected from a bond, -O-,-NR’-,-S-,-C(O)- and -(CR c R d) n - , provided that the valence allows, -(CR c R d ) n - any one of the methylene units 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 form a C 3-8 cycloalkyl or a 3- to 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 groups being optionally substituted by one or more deuteriums up to complete deuteration;

[0078] R” is -L3-B;

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

[0080] -L3- is -(CR e R f ) p - , provided that the valence allows, -(CR e R f ) p - any one of the methylene units 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 form a C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group;

[0081] 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 , wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[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, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[0083] R5 is 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 , wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[0084] R6 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[0085] R a , R b , R c , R d , R e and R f are each independently selected from H, D, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[0086] R s1 and R s2 are each independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[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] Wherein:

[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] Provided that at most two of X, Y and Z are N at the same time;

[0102] R x 、R y and R z 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 and -L1-R1, where at least one of R x 、R y and R z is -L1-R1, and the groups are optionally substituted with one or more deuteriums until fully deuterated;

[0103] R w and R g are 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] wherein said groups are optionally substituted with one or more deuteriums until fully deuterated;

[0105] -L1- is -(CR a R b ) m -, and when valence permits, any methylene unit in -(CR a R b ) m - 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 form C 3-8 cycloalkyl or a 3- to 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, a 3- to 10-membered heterocyclic group, C 6-10 aryl, and a 5- to 10-membered heteroaryl, which is optionally substituted with s R2 substituents;

[0108] -L2- is selected from a bond, -O-,-NR'-,-S-,-C(O)-, and -(CR c R d ) n -, and when valence permits, any methylene unit in -(CR c R d ) n - is optionally and independently replaced by -NR'-,-O-,-S-,-C(O)- and / or R c and R d together with the carbon atom to which they are attached form C 3-8 cycloalkyl or a 3- to 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, wherein said groups are optionally substituted with one or more deuteriums until fully deuterated;

[0110] R” is -L3-B;

[0111] B is selected from C3-8 Cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, which are optionally substituted with t R5 substituents;

[0112] -L3- is -(CR e R f ) p -, and when valence allows, any one of the methylene units in -(CR e R f ) p - 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 form C 3-8 cycloalkyl or 3- to 10-membered heterocyclic group;

[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 , and the said groups are optionally substituted with one or more deuteriums until completely deuterated;

[0114] R4 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, and the said groups are optionally substituted with one or more deuteriums until completely deuterated;

[0115] Each R5 is 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 ,wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[0116] R6 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[0117] R a 、R b 、R c 、R d 、R e and R f are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[0118] R s1 and R s2 are independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[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’), 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) 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) 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 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- to 6-membered heteroaryl and 5- to 10-membered heterocyclic group.

[0130] In one embodiment, the present invention relates to the above 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, oxacyclohexyl, thiacyclohexyl, azacycloheptyl, diazacycloheptyl, octahydrocyclopentadienopyrrolyl, octahydropyrrolopyrrolyl, octahydrobicyclopentadienyl, phenyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl.

[0131] In one embodiment, the present invention relates to the above 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 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 one of the methylene units 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 form C 3-6 cycloalkyl and 3- to 5-membered heterocyclic group;

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

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

[0137] 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 (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] wherein:

[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 groups being optionally substituted with one or more deuteriums up to complete deuteration;

[0145] R’ is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, said groups being optionally substituted with one or more deuteriums up to complete deuteration;

[0146] R” is -L3-B;

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

[0148] -L3- is -(CR e R f ) p -, and where valence permits, -(CR e R f ) pAny one of the methylene units is optionally and independently replaced by -O-, -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 , and the groups are optionally substituted by one or more deuteriums until fully deuterated;

[0150] Each R5 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, and the groups are optionally substituted by one or more deuteriums until fully deuterated;

[0151] R e and R f are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl, and the groups are optionally substituted by one or more deuteriums until fully deuterated;

[0152] R s1 and R s2 are independently selected from H, C 1-6 alkyl, or C 1-6 haloalkyl, and the groups are optionally substituted by one or more deuteriums until fully deuterated;

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

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

[0155] In one embodiment, the present invention relates to the compound of formula (IV) 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 are 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 is 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) 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- or 6-membered heterocyclic group, preferably azetidinyl or piperidinyl;

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

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

[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 is C 1-6 haloalkyl, preferably -CF3;

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

[0185] R 3d is H or D;

[0186] R e is 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) 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 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 deuteriums up to complete 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 heterocyclic, which are optionally substituted with s R2 substituents;

[0197] Where valence permits, any methylene unit in -(CR a R b ) m - 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 groups being optionally substituted with one or more deuteriums up to complete deuteration;

[0199] 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 , and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0200] R4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0201] R a and R b are selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0202] Or R a and R b together with the carbon atom to which they are attached form C 3-6 cycloalkyl and 3-5 membered heterocyclic group;

[0203] R s1 and R s2 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, and the groups are optionally substituted with one or more deuteriums up to complete 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 the compound of formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope 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, and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0210] A is selected from and 5- to 8-membered heterocyclic groups, which are optionally substituted with s R2 substituents;

[0211] When the valence allows, any one of the methylene units in -(CR a R b ) m - 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, and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0214] R2 are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR s1 and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0215] R 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR s1a and -SR s1a and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[0216] R 2b is H or D;

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

[0218] R 2d is H or D;

[0219] R 2e is H or D;

[0220] R 3a is H or D;

[0221] R3b is C 1-6 haloalkyl, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[0222] R 3c is halogen;

[0223] R 3d is 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 deuteriums up to complete deuteration;

[0225] R a and R b are each independently selected from H, D, halogen and C 1-6 alkyl, said group being optionally substituted with one or more deuteriums up to complete deuteration;

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

[0227] R s1 are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[0228] R s1a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[0229] R s1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[0230] m is 1, 2 or 3;

[0231] s is 1 or 2.

[0232] In one embodiment, the present invention relates to the compound of formula (IV) 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 R2s;

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

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

[0240] R’ is H;

[0241] Each R2 is independently selected from H and a halogen, preferably F, and the group is optionally substituted with one or more deuteriums until fully deuterated;

[0242] R 2a is H or C 1-6 alkyl, preferably methyl, and the group is optionally substituted with one or more deuteriums until fully deuterated;

[0243] R 2b is H;

[0244] R 2c is a halogen or -OR s1c ;

[0245] R 2d is H;

[0246] R 2e is H;

[0247] R 3a is H;

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

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

[0250] R 3d is H;

[0251] R4 is C 1-6 alkyl, preferably methyl;

[0252] R s1c is H, C 1-6 alkyl or C1-6 Halogenoalkyl, preferably -CF3;

[0253] s is 1 or 2.

[0254] In one embodiment, the present invention relates to a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, 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) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, 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 each independently selected from H, D, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenoalkyl and -OR s1 , said groups being optionally substituted with one or more deuteriums up to complete 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 heterocyclic group, which is optionally substituted with s R2 substituents;

[0262] R' is selected from H, C 1-6 alkyl and C 1-6 halogenoalkyl, said groups being optionally substituted with one or more deuteriums up to complete deuteration;

[0263] 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 halogenoalkyl, 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 , wherein said group is optionally substituted with one or more deuteriums until fully deuterated;

[0264] R4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, wherein said group is optionally substituted with one or more deuteriums until fully deuterated;

[0265] R s1 and R s2 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said group is optionally substituted with one or more deuteriums until fully deuterated;

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

[0267] In one embodiment, the present invention relates to the compound of formula (VI) 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, azacycloheptyl, diazacycloheptyl, octahydrocyclopentadienopyrrolyl, octahydropyrrolopyrrolyl, octahydrobicyclopentadienyl, phenyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl. Preferably, A and the substituents thereon are selected from the following:

[0269]

[0270] wherein, R 2a 、 R 2b 、 R 2c and R 2d 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 , wherein said group is optionally substituted with one or more deuteriums up to complete deuteration.

[0271] In one embodiment, the present invention relates to a compound of formula (VI) 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, preferably cyclohexyl.

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

[0275] -L2- is a bond;

[0276] A is selected from azepanyl, diazepanyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[1,2-a]pyrrolyl and octahydrospiro[4.5]decanyl, and preferably, when A is a nitrogen-containing heterocycle, it is linked to the phenyl group through a 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 of formula (VII)

[0278]

[0279] wherein:

[0280] X is N or CR x ;

[0281] Y is N or CR y ;

[0282] 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, wherein said group is optionally substituted with one or more deuteriums up to complete deuteration;

[0283] R’ is selected from H, C 1-6 alkyl and C1-6 A haloalkyl group, optionally substituted with one or more deuteriums up to full deuteration;

[0284] 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 , the groups optionally being 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, the groups optionally being substituted with one or more deuteriums up to full deuteration;

[0286] R s1 and R s2 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, the groups optionally being substituted with one or more deuteriums 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 each independently are selected from H, D, halogen, C 1-6 alkyl or C 1-6A haloalkyl group, said group being optionally substituted with one or more deuteriums up to complete deuteration;

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

[0292] R 2a is 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 deuteriums up to complete deuteration;

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

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

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

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

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

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

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

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

[0301] R4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, optionally substituted with one or more deuteriums up to complete deuteration;

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

[0303] 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:

[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, optionally substituted with one or more deuteriums up to complete deuteration;

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

[0308] R 2a is -OR s1a 、-SR s1a 、NR s1a Rs2a , C 1-6 alkyl or C 1-6 haloalkyl, said group optionally substituted with one or more deuteriums,

[0309] up to full deuteration;

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

[0311] R 2c is H, D, halogen, -OR s1c , -SR s1c or NR s1c R s2c , said group optionally substituted with one or more deuteriums, up to full deuteration;

[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, said group optionally substituted with one or more deuteriums, up to full deuteration;

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

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

[0318] R4 is H, C 1-6 alkyl or C 1-6 haloalkyl, said group optionally substituted with one or more deuteriums, up to full deuteration;

[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, said group optionally substituted with one or more deuteriums, up to full deuteration;

[0320] provided 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 are independently selected from H, D or halogen;

[0325] R’ is H, C 1-6 alkyl or C 1-6 haloalkyl;

[0326] R 2a is -OR s1a , -SR s1a , C 1-6 alkyl or C 1-6 haloalkyl, said groups optionally being substituted with one or more deuteriums up to complete deuteration;

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

[0328] R 2c is H, D, halogen, -OR s1c or -SR s1c , said groups optionally being substituted with one or more deuteriums up to complete 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 is C 1-6 haloalkyl;

[0333] R 3c is halogen;

[0334] R 3d is H or D;

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

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

[0337] Provided that when Y is N, R 2a is not C 1-6 alkyl or C 1-6 haloalkyl.

[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 are independently selected from H, D or halogen;

[0342] R' is H;

[0343] R 2a is -OR s1a 、-SR s1a or C 1-6 alkyl, the group being optionally substituted with one or more deuteriums up to complete deuteration;

[0344] R 2b is H or D;

[0345] R 2c is halogen, -OR s1c or -SR s1c ,the group being optionally substituted with one or more deuteriums up to complete deuteration;

[0346] R 2d is H or D;

[0347] R 2e is H or D;

[0348] R 3a is H or D;

[0349] R 3b is C 1-6 alkyl or C 1-6 haloalkyl, the group being optionally substituted with one or more deuteriums up to complete deuteration;

[0350] R 3c is halogen;

[0351] R3d is H or D;

[0352] R4 is C 1-6 alkyl or C 1-6 haloalkyl, said group optionally substituted with one or more deuteriums up to complete deuteration;

[0353] R s1a and R s1c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, said group optionally substituted with one or more deuteriums up to complete 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 is H or D;

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

[0359] R’ is H;

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

[0361] R 2b is H or D;

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

[0363] R 2d is H or D;

[0364] R 2e is H or D;

[0365] R 3a is H or D;

[0366] R 3b is C 1-6 alkyl or C 1-6A haloalkyl group, optionally substituted with one or more deuteriums 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, optionally substituted with one or more deuteriums up to full deuteration;

[0370] R s1a and R s1c are independently selected from C 1-6 alkyl or C 1-6 haloalkyl, optionally substituted with one or more deuteriums 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 a halogen, preferably F;

[0376] R’ is H;

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

[0378] R 2b is H;

[0379] R 2c is a 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 is 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 is C 1-6 alkyl;

[0388] R s1c is C 1-6 haloalkyl.

[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 in the present invention 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.

[0395] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined in the present invention 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 in the present invention 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, in the preparation of a drug for use as a voltage-gated sodium channel inhibitor.

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

[0398] In one embodiment, the present invention provides a compound as defined in the present invention or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, 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 in the present invention or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same, for use as a sodium channel 1.8 (NaV1.8) inhibitor.

[0400] In one embodiment, the present invention provides a method of inhibiting voltage-gated sodium channels in a subject, comprising administering to the subject a compound as defined in the present invention or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, 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 channel 1.8 (NaV1.8) in a subject, comprising administering to the subject a compound as defined in the present invention or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0402] The voltage-gated sodium channel inhibitors as described in the present invention are used for treating diseases selected from the following: acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy or epileptic disorders, neurodegenerative diseases, mental disorders such as anxiety and depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radiculopathy, sciatica, back pain, headache, neck pain, severe or refractory pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitation, hypertension, migraine, or abnormal gastrointestinal activity.

[0403] In some embodiments, the diseases involved in the method are selected from radiculopathy, sciatica, back pain, headache, neck pain, refractory pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain.

[0404] Examples

[0405] The materials or reagents used herein are commercially available or prepared by synthetic methods commonly known 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-(benzylthio)pyridin-4-yl)carbamate

[0410]

[0411] Dissolve 2-(benzylthio)-4-bromopyridine (3.7 g, 13.214 mmol) in ultradry dioxane (37 mL), add 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), displace with nitrogen, and stir at 100 °C in an oil bath for 16 hours. Stop the reaction, rotary evaporate the reaction solution to dryness under vacuum, dissolve it in dichloroethane (40 ml), filter it through a sintered funnel filled with diatomaceous earth, wash the filter cake with dichloroethane (80 ml), collect the filtrate, rotary evaporate it to dryness and mix the sample to obtain the crude product. The crude product is 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 solution (15 mL), add trifluoroacetic acid (5 mL) dropwise at 0 °C in an ice bath, and stir at room temperature for 1 hour. Stop the reaction, quench the reaction solution with saturated sodium bicarbonate solution (10 ml), extract the aqueous phase with ethyl acetate (15 ml×3), combine the organic phases, wash with saturated brine (10 ml×2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate to dryness under vacuum to obtain the title compound (680 mg, colorless oil), which is directly used in the next step of the 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] Dissolve 2-(benzylthio)pyridin-4-amine (680 mg, 3.148 mmol) in thionyl chloride (1 mL). After purging with nitrogen three times, stir at 80 °C for 2 hours, then evaporate to dryness for later use. Dissolve 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (763.6 mg, 3.148 mmol) in dichloromethane (8 mL). Dropwise add N,N-diisopropylethylamine (1.63 g, 12.592 mmol) at 0 °C in an ice bath. Dissolve the reaction solution that was evaporated to dryness earlier in dichloromethane (1 mL) and dropwise add it to the above reaction solution at 0 °C in an ice bath. Stir at room temperature for 16 hours. Stop the reaction, evaporate the reaction solution to dryness and mix the sample. Purify by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 5:1) to obtain the title compound (370 mg, yield: 26.7%, 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] Dissolve N-(2-(benzylthio)pyridin-4-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (330 mg, 0.749 mmol) in N,N-dimethylformamide (3.3 mL). Add 4-fluoro-2-methylphenol (94.3 mg, 0.749 mmol) and cesium carbonate (487.8 mg, 1.497 mmol). Stir and react in an oil bath at 100 °C for 1 hour. Stop the reaction, quench the reaction solution with water (5 ml), extract the aqueous phase with ethyl acetate (10 ml × 3), combine the organic phases, wash with saturated brine (5 ml × 2), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under vacuum to obtain the crude product. Purify the crude product by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 5:1) to obtain the title compound (343 mg, yield: 83.9%, 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] Place N-(2-(benzylthio)pyridin-4-yl)-5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (100 mg, 0.183 mmol) in a three-necked flask, displace the air with nitrogen, add (glacial acetic acid: water: dichloromethane = 7:1:2) (2 mL) into the flask, add 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (108 mg, 0.548 mmol), and stir at room temperature for 3 hours. Stop the reaction, quench the reaction mixture with water (3 mL), extract the aqueous phase with dichloromethane (5 mL × 3), combine the organic phases, wash with saturated brine (3 mL × 2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under vacuum to obtain the title compound (80 mg, crude product, pale 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)pyridin-2-yl)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), and then dropwise add it into a pyridine (1 mL) solution of tert-butyl (2-aminoethyl)(methyl)carbamate (39.9 mg, 0.229 mmol) at 0 °C, and stir at room temperature for 2 hours. Stop the reaction, quench the reaction mixture with saturated sodium bicarbonate solution (3 mL), extract the aqueous phase with ethyl acetate (5 mL × 3), combine the organic phases, wash with saturated brine (2 mL × 2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under vacuum to obtain the crude product. The crude product is separated 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%, 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] (2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfonamido)ethyl)(methyl)carbamic acid tert-butyl ester (59 mg, 0.089 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added at 0 °C in an ice bath, followed by stirring at room temperature for 1 hour. The reaction was stopped, and the solvent was removed by rotary evaporation under vacuum to obtain a crude product; the crude product was purified by reverse-phase preparative chromatography (elution system: ammonia water, water, acetonitrile) to obtain the title compound (18.7 mg, yield: 37.5%, yellowish brown solid).

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

[0437] 1 1H NMR(400 MHz, DMSO-d6) δ 11.41(s, 1H), 8.62(d, J = 5.4 Hz, 1H), 8.26(d, J = 1.4 Hz, 1H), 8.12(s, 1H), 7.77(d, J = 5.3 Hz, 1H), 7.23–7.17(m, 1H), 7.10(dd, J = 7.1, 4.6 Hz, 3H), 2.96(t, J = 6.5 Hz, 2H), 2.47(t, J = 6.5 Hz, 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] First step: (R)-tert-butyl 3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfonamido)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 mixed solution of pyridine (2 mL) and dichloromethane (4 mL), and the reaction was carried out at 0 °C for 2 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, diluted with water (10 mL), adjusted to neutral with 1 N hydrochloric acid solution, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (222 mg, yield: 58%, 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] (R)-tert-Butyl 3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfamoyl)pyrrolidine-1-carboxylate (210 mg, 0.312 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (6 mL), and the reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (122.14 mg, yield: 68%, white solid).

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

[0449] 11H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.65 (d, J = 5.4 Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H), 8.12 (s, 1H), 7.80 (dd, J = 5.4, 1.9 Hz, 1H), 7.21 (dd, J = 9.2, 2.3 Hz, 1H), 7.15–7.06 (m, 3H), 4.05–3.96 (m, 1H), 3.22 (dd, J = 11.8, 6.6 Hz, 1H), 3.15 (dd, J = 15.2, 7.8 Hz, 1H), 3.10–3.05 (m, 1H), 2.96 (dd, J = 11.8, 5.4 Hz, 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: tert-Butyl (S)-3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfamoyl)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 tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (107 mg, 0.57 mmol) were dissolved in a mixed solution of pyridine (2 mL) and dichloromethane (4 mL), and the reaction was carried out at 0 °C for 2 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, diluted with water (10 mL), adjusted to neutral with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound was obtained by separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) (210 mg, yield: 56%, 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 tert-butyl (S)-3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfamoyl)pyrrolidine-1-carboxylate (210 mg, 0.312 mmol) in a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (6 mL), and react at room temperature for 2 h. Stop the reaction, rotary evaporate the solvent under vacuum, dilute with water (10 mL), extract with ethyl acetate (20 mL×3), and dry over anhydrous sodium sulfate. Purify by preparative high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (71.26 mg, yield: 40.0%, white solid).

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

[0461] 1 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 5.4 Hz, 1H), 8.33 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.13 (s, 1H), 7.81 (dd, J = 5.4, 2.0 Hz, 1H), 7.21 (dd, J = 9.2, 2.7 Hz, 1H), 7.14–7.05 (m, 3H), 3.96–3.86 (m, 1H), 3.07–2.97 (m, 2H), 2.92 (d, J = 6.6 Hz, 1H), 2.77 (dd, J = 11.6, 4.9 Hz, 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] First step: tert-butyl 4-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfamoyl)piperidine-1-carboxylate

[0466]

[0467] Under the condition of stirring at room temperature, dissolve tert-butyl 4-aminopiperidine-1-carbamate (76.55 mg, 0.38 mmol) in pyridine (2 mL). Cool the temperature to 0 °C. Dissolve 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (200 mg, 0.38 mmol) in dichloromethane (4 mL) and add it dropwise to the reaction solution. Stir the reaction at this temperature for 2 hours. Stop the reaction, pour the reaction solution into water (10 mL), and extract with ethyl acetate (10 mL × 3). Combine the extracts, wash with 1N HCl (5 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by column chromatography (silica gel, ethyl acetate:petroleum ether = 1:1) to obtain the title compound (120 mg, yield: 45.7%, 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)aminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 4)

[0470]

[0471] Under the condition of stirring at room temperature, place tert-butyl 4-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin)-2-sulfonamido)piperidine-1-carboxylate (120 mg, 0.17 mmol) into a 25 ml single-necked flask and dissolve it in dichloromethane (3 mL); add trifluoroacetic acid (1 mL), restore to room temperature, and continue to stir the reaction at room temperature for 1 hour. Stop the reaction, concentrate the reaction solution under reduced pressure to obtain the crude product, and the crude product is separated and purified by high performance liquid chromatography preparation (elution system: formic acid, water, acetonitrile) to obtain the title compound (87.96 mg, yield: 85.8%, 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)aminosulfonyl)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)pyridin-2-yl)sulfonamido)methyl)piperidine-1-carboxylate

[0477]

[0478] At 0 °C, 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 successively added to a mixed solution of pyridine (2 mL) and dichloromethane (4 mL), and the reaction was carried out for 2 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, diluted with water (10 mL), adjusted to neutral with 1 N hydrochloric acid solution, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (110 mg, yield: 41.2%, 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] tert-Butyl 4-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfonamido)methyl)piperidine-1-carboxylate (100 mg, 0.143 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (1 mL) and dichloromethane (3 mL), and the reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (40.99 mg, yield: 48%, white solid).

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

[0484] 11H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.63 (d, J = 5.4 Hz, 1H), 8.29 (d, J = 1.7 Hz, 1H), 8.12 (s, 1H), 7.77 (dd, J = 5.4, 1.9 Hz, 1H), 7.21 (dd, J = 9.2, 2.3 Hz, 1H), 7.14–7.06 (m, 3H), 3.19 (d, J = 12.0 Hz, 2H), 2.81 (d, J = 6.6 Hz, 2H), 2.74 (t, J = 11.8 Hz, 2H), 2.16 (s, 3H), 1.76 (d, J = 13.3 Hz, 2H), 1.63 (brs, 1H), 1.21 (dd, J = 23.0, 10.9 Hz, 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)pyridin-2-yl)sulfamoyl)methyl)pyrrolidine-1-carboxylate

[0489]

[0490] At 0 °C, 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-(aminomethyl)pyrrolidine-1-carboxylate (115 mg, 0.57 mmol) were dissolved in a mixed solution of pyridine (2 mL) and dichloromethane (4 mL), and the reaction was carried out for 2 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, diluted with water (10 mL), adjusted to neutral with 1 N hydrochloric acid solution, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound was obtained by separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) (256 mg, yield: 65.4%, 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] Dissolve tert-butyl (R)-3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfamoyl)methyl)pyrrolidine-1-carboxylate (240 mg, 0.35 mmol) in a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (6 mL), and stir the reaction at room temperature for 2 hours. Stop the reaction, rotary evaporate the solvent under vacuum, dilute with water (10 mL), extract with ethyl acetate (20 mL×3), and dry over anhydrous sodium sulfate. After filtration, rotary evaporate the filtrate under reduced pressure and purify by preparative high performance liquid chromatography (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 1H 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)pyridin-2-yl)sulfonylamino)methyl)pyrrolidine-1-carboxylate

[0501]

[0502] At 0 °C, 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 mixed solution of pyridine (2 mL) and dichloromethane (4 mL), and the reaction was carried out for 2 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, diluted with water (10 mL), adjusted to neutral with 1 N hydrochloric acid solution, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound was obtained by separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) (256 mg, yield: 65.4%, 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] (S)-tert-Butyl 3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)sulfonylamino)methyl)pyrrolidine-1-carboxylate (240 mg, 0.35 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (6 mL), and the reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The title compound was obtained by purification by preparative high performance liquid chromatography (elution system: formic acid, water, acetonitrile) (63.06 mg, yield: 30.7%, white solid).

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

[0508] 11H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 5.5 Hz, 1H), 8.36 (s, 1H), 8.29 (d, J = 1.7 Hz, 1H), 8.12 (s, 1H), 7.79 (dd, J = 5.4, 1.9 Hz, 1H), 7.21 (dd, J = 9.2, 2.6 Hz, 1H), 7.15–7.05 (m, 3H), 3.12 (dd, J = 11.3, 7.8 Hz, 1H), 3.09–3.03 (m, 1H), 2.99 (d, J = 7.8 Hz, 1H), 2.95 (d, J = 7.1 Hz, 2H), 2.74 (dd, J = 11.3, 7.3 Hz, 1H), 2.31 (dd, J = 14.7, 7.3 Hz, 1H), 2.16 (s, 3H), 1.88 (dt, J = 13.0, 6.5 Hz, 1H), 1.53 (dq, J = 15.4, 7.8 Hz, 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. After sealing, the reaction was carried out at 70 °C in an oil bath for 16 hours. The reaction was stopped, and the reaction solution was adjusted to slightly acidic with 1 N dilute hydrochloric acid, extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 10:1), and then purified by high performance liquid chromatography preparation (elution system: ammonia water, 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] 11H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.63 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.13 (s, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.78 (dd, J = 5.4, 1.9 Hz, 1H), 7.20 (dd, J = 9.1, 2.2 Hz, 1H), 7.14–7.05 (m, 3H), 3.77 (brs, 1H), 2.59 (dd, J = 9.3, 7.3 Hz, 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, 5.9 Hz, 1H), 0.93 (t, J = 7.2 Hz, 3H).

[0515] Example 9

[0516] (S)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(1-propylpyrrolidin-3-yl)sulfamoyl)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 continued to stir at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product; the crude product was separated and purified by preparative high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (27.16 mg, yield: 28.1%, 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), 1-fluoro-2-iodoethane (21.25 mg, 0.12 mmol) and potassium carbonate (33.7 mg, 0.24 mmol) were added, and the reaction was carried out in an oil bath at 50 °C for 16 hours. The reaction was stopped, water (10 mL) was added to the reaction solution to quench it, and it 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 concentrated under reduced pressure. It was purified by high performance liquid chromatography preparation (elution system: ammonia water, water, acetonitrile) to obtain the title compound (28.51 mg, yield: 37.7%, white solid).

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

[0525] 1 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.63 (d, J = 5.4 Hz, 1H), 8.27 (s, 1H), 8.15–8.07 (m, 2H), 7.78 (dd, J = 5.4, 1.7 Hz, 1H), 7.23–7.17 (m, 1H), 7.13–7.09 (m, 3H), 4.44 (dt, J = 44.0, 4.9 Hz, 2H), 3.79 (dd, J = 14.4, 6.6 Hz, 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. After sealing, the reaction was carried out in an oil bath at 70 °C for 16 hours. The reaction was stopped, and the reaction solution was adjusted to weakly acidic with 1 N dilute hydrochloric acid, extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. It was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 10:1), and then purified by high performance liquid chromatography preparation (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 continued to stir at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by high performance liquid chromatography preparation (elution system: formic acid, water, acetonitrile) to obtain the title compound (27.36 mg, yield: 25.5%, white solid).

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

[0536] 11H NMR (400 MHz, DMSO-d6) δ 11.35 (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, 3H), 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-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 13)

[0539]

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

[0541]

[0542] Dissolve 2-chloropyridin-4-amine (1 g, 7.8 mmol) in NMP (10 mL), add sodium methyl mercaptide (1.12 g, 15.6 mmol), and react at 200 °C under microwave for 0.5 h. Stop the reaction, quench the reaction solution with water (30 ml), extract the aqueous phase with chloroform / isopropanol (v:v = 3:1) (40 ml × 3), combine the organic phases, dry over anhydrous sodium sulfate, evaporate to dryness and mix the sample, and separate and purify by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain the title compound (900 mg, crude product), which is directly used in the next step of the 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] Dissolve 2-(methylthio)pyridin-4-amine (400 mg, 2.85 mmol) in pyridine (6 mL), add 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (691 mg, 2.85 mmol), and slowly add phosphorus oxychloride (1.31 g, 8.55 mmol) dropwise at 0 °C. Continue stirring the reaction for 2 hours. Stop the reaction, slowly add the reaction solution dropwise to ice water (30 mL), adjust the pH to 5 - 6 with 1N hydrochloric acid, extract the aqueous phase with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (5 mL × 2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under vacuum to obtain the crude product. The crude product is 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] Dissolve 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (200 mg, 0.55 mmol) in DMF (2 mL), add 4-fluoro-2-methylphenol (138 mg, 1.097 mmol), add cesium carbonate (357 mg, 1.097 mmol), and stir the reaction at 100 °C in an oil bath for 2 hours. Quench the reaction solution with water (10 mL), extract the aqueous phase with ethyl acetate (15 mL × 3), combine the organic phases, wash with saturated brine (5 mL × 2), dry over anhydrous sodium sulfate, rotary evaporate under vacuum to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 4:1) to obtain the title compound (273 mg, yield: 92.5%, white solid).

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

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

[0553]

[0554] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (250 mg, 0.53 mmol) was dissolved in methanol (3 mL), ammonium carbonate (153 mg, 1.59 mmol) and iodobenzene diacetate (683 mg, 2.12 mmol) were added, and the mixture was stirred at room temperature for 1 h. The reaction was stopped, the reaction solution was concentrated to dryness and triturated, and the crude product was separated by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1) to obtain the crude product. The crude product was dissolved in DMF and purified by preparative reverse-phase 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 1H 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-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 14)

[0559]

[0560] Step 1: 1-(Benzyloxy)-4-fluoro-2-(methoxy-d3)benzene

[0561]

[0562] 2-(Benzyloxy)-5-fluorophenol (400 mg, 1.83 mmol) was dissolved in DMF (4 mL), potassium carbonate (506 mg, 3.66 mmol) was added, and deuterated iodomethane (319 mg, 2.20 mmol) was added at 0 °C. The reaction tube was sealed and stirred at room temperature for 16 h. The reaction was stopped, the reaction solution was quenched with water (10 mL), the aqueous phase was extracted with ethyl acetate (15 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and triturated. The title compound was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) (340 mg, white solid, yield: 79.1%).

[0563] 1 1H NMR (400 MHz, CDCl3) δ 7.44–7.29 (m, 5H), 6.80 (dd, J = 8.8, 5.5 Hz, 1H), 6.65 (dd, J = 10.2, 2.9 Hz, 1H), 6.52 (td, J = 8.5, 2.9 Hz, 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, wash the filter cake with methanol (9 mL × 3), and rotary evaporate the filtrate to obtain the title compound (136 mg, yield: 73.5%, 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] Dissolve 4-fluoro-2-(methoxy-d3)phenol (50 mg, 0.34 mmol) in DMF (1 mL), add 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (62.8 mg, 0.17 mmol), add potassium carbonate (47.5 mg, 0.34 mmol), seal the tube, and stir at 100 °C for 2 h. Stop the reaction, quench the reaction mixture with water (10 ml), extract the aqueous phase with ethyl acetate (15 ml × 3), combine the organic phases, wash with saturated brine (5 ml × 2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under vacuum to obtain the crude product. The crude product is separated 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-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 14)

[0572]

[0573] Dissolve 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (85 mg, 0.17 mmol) in methanol (1 mL), add ammonium carbonate (50 mg, 0.52 mmol), add iodobenzene diacetate (224 mg, 0.70 mmol), and stir at room temperature for 0.5 h. The reaction solution was concentrated to dryness and stirred with a sample, 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 obtain 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methylsulfinimidoyl)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 1H NMR(400 MHz, DMSO-d6) δ 11.31(s, 1H), 8.63(d, J = 5.4 Hz, 1H), 8.40(s, 1H), 8.07(s, 1H), 7.82(d, J = 3.6 Hz, 1H), 7.29(dd, J = 8.8, 5.8 Hz, 1H), 7.14(dd, J = 10.6, 2.8 Hz, 1H), 7.00(s, 1H), 6.85(td, J = 8.6, 2.9 Hz, 1H), 4.37(s, 1H), 3.14(s, 3H).

[0576] Resolution of the chiral isomers of Compound 14:

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

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

[0579]

[0580] Compound 14 was separated by a chiral preparative separation column (chromatographic column: IC, 250*25mm, 10μm; Mobile phase: A - Supercritical CO2; B - MEOH(+0.1% 7.0mol / l Ammonia in MEOH), eluted at 50% B ratio, flow rate: 100mL / min, column temperature: room temperature) to obtain a 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 - methylsulfinimidoyl)pyridin - 4 - yl)-4-(trifluoromethyl)benzamide (Compound 15)

[0583]

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

[0585]

[0586] Dissolve 5 - chloro - 2 - fluoro - N-(2-(methylthio)pyridin - 4 - yl)-4-(trifluoromethyl)benzamide (78mg, 0.21mmol) in DMF (1mL), add 2-(methoxy - d3)-4-(trifluoromethoxy)phenol (90mg, 0.43mmol), add potassium carbonate (59mg, 0.43mmol), stir and react at 100℃ in an oil bath for 2 hours. Stop the reaction, quench the reaction solution with water (10ml), extract the aqueous phase with ethyl acetate (15ml×3), combine the organic phases, wash with saturated brine (5ml×2), dry over anhydrous sodium sulfate, and rotary evaporate under vacuum to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 3:1) to obtain the title compound (100mg, yield: 84.7%, white solid).

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

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

[0589]

[0590] 5-Chloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (88 mg, 0.16 mmol) was dissolved in methanol (1 mL), ammonium carbonate (45.6 mg, 0.48 mmol) was added, and iodobenzene diacetate (204 mg, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. The reaction was stopped, the reaction solution was evaporated to dryness and triturated, 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 obtain the title compound (57.30 mg, yield: 61.3%, white solid).

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

[0592] 1 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 7.80 (dd, J = 5.4, 1.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.23–7.12 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 3.14 (s, 3H).

[0593] Example 16

[0594] 5-Chloro-N-(2-(S-methylsulfinyl)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] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (70 mg, 0.192 mmol) and 4-(trifluoromethoxy)phenol (68.5 mg, 0.385 mmol) were dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (54 mg, 0.385 mmol) was added, and the reaction was carried out in an oil bath at 70 °C for 16 h. The reaction was stopped, and the reaction solution was quenched with saturated ammonium chloride solution (5 mL). It was extracted with ethyl acetate (20 mL × 3), and 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 (120 mg, yield: 93.02%, white solid).

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

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

[0601]

[0602] 5-Chloro-N-(2-(methylthio)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (100 mg, 0.192 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (55.3 mg, 0.575 mmol) and iodobenzene diacetate (247 mg, 0.767 mmol) were added, and the reaction was carried out at room temperature for 1 h. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and it was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:9), and then purified 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 1H 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-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 17)

[0607]

[0608] First step: 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0609]

[0610] Dissolve 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) in N,N-dimethylformamide (2 mL), add cesium carbonate (625.3 mg, 1.92 mmol), and react at 100 °C in an oil bath for 16 hours. Stop the reaction, quench the reaction solution with saturated ammonium chloride solution (5 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under reduced pressure. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (125 mg, yield: 92.6%, white solid).

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

[0612] Second step: 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methylsulfinimidoyl)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 the reaction was carried out at room temperature for 1 hour. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:10), and then purified by preparative high performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (35.02 mg, yield: 50.49%, white solid).

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

[0616] 1 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 8.41 (s, 1H), 7.84 (d, J = 4.7 Hz, 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] Resolution of chiral isomers of compound 17:

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

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

[0620]

[0621] Compound 17 was separated by a chiral preparative column (chromatographic column: OJ, 250*25 mm, 10 μm; mobile phase: A-Supercritical CO2; B-MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), eluted at 25% B ratio, flow rate: 70 mL / min, column temperature: room temperature) to obtain a 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-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 18)

[0624]

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

[0626]

[0627] Dissolve 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.27 mmol) in DMF (3 mL), add (3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole hydrochloride (98.8 mg, 0.54 mmol) and cesium carbonate (536 mg, 1.64 mmol), displace with nitrogen, and react at 100 °C for 12 hours. Stop the reaction, add water (15 mL) to the reaction solution, extract the aqueous phase with ethyl acetate (15 ml × 3), combine the organic phases, wash with saturated brine (10 ml × 2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under vacuum to obtain the crude product. The crude product is separated 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%, white solid).

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

[0629] Second step: 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(2-(S-methylsulfinyl)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), ammonium carbonate (58.6 mg, 0.60 mmol) and iodobenzene diacetate (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 concentrated in vacuo, quenched with saturated sodium bicarbonate solution (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, filtered, and the filtrate was concentrated in vacuo to obtain the crude product. The crude product was purified by reverse-phase preparative chromatography (elution system: ammonia water, water, acetonitrile) to obtain the title compound (10 mg, yield: 9.4%, white solid).

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

[0633] 1 1H NMR(400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.62 (d, J = 4.9 Hz, 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 = 9.6 Hz, 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-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 19)

[0636]

[0637] First step: 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 reaction was carried out at 100 °C in an oil bath for 16 h. The reaction was stopped, and the reaction solution was quenched with saturated ammonium chloride solution (5 mL). It was extracted with ethyl acetate (20 mL × 3), and 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%, white solid).

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

[0641] Step 2: 5-Chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(S-methylsulfinyl)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 the reaction was carried out at room temperature for 1 h. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and it was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10), and then purified by high performance liquid chromatography preparation (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (81.2 mg, yield: 39.8%, white solid).

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

[0645] 1 1H NMR(400 MHz, DMSO-d6) δ 11.14(s, 1H), 8.63(d, J = 5.4 Hz, 1H), 8.40(s, 1H), 7.92(s, 1H), 7.78(d, J = 5.2 Hz, 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-methylsulfinylsulfonyl)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 20)

[0648]

[0649] First step: 6-(Methylthio)pyridazin-4-amine

[0650]

[0651] Dissolve 6-chloropyridazin-4-amine (1 g, 7.7 mmol) in methanol (10 mL), add sodium methyl mercaptide (2.8 g, 38.6 mmol), seal the tube and stir the reaction at 100 °C for 16 hours. Stop the reaction, rotary evaporate the reaction solution and stir the sample, and separate and purify 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] Second step: 5-Chloro-2-fluoro-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide

[0654]

[0655] Dissolve 6-(methylthio)pyridazin-4-amine (75 mg, 0.53 mmol) in pyridine (2 mL), add 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (129 mg, 0.53 mmol), add phosphorus oxychloride (244 mg, 1.59 mmol) dropwise at 0 °C, and continue to stir the reaction for 2 hours. Stop the reaction, slowly drop the reaction solution into ice water (10 ml), adjust the pH to 5-6 with 1N hydrochloric acid, extract the aqueous phase with ethyl acetate (15 ml × 3), combine the organic phases, wash with saturated brine (5 ml × 2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under vacuum to obtain the crude product. The crude product is 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%, yellow solid).

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

[0657] Third step: 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide

[0658]

[0659] Dissolve 5-chloro-2-fluoro-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (80 mg, 0.22 mmol) in DMF (1 mL), add 4-fluoro-2-methylphenol (41.4 mg, 0.33 mmol), add cesium carbonate (142.7 mg, 0.44 mmol), and stir the reaction in an oil bath at 100 °C for 2 hours. Stop the reaction, quench the reaction solution with water (10 mL), extract the aqueous phase with ethyl acetate (15 mL × 3), combine the organic phases, wash with saturated brine (5 mL × 2), dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under vacuum to obtain the crude product. The crude product is separated 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%, white solid).

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

[0661] Step 4: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(S-methylsulfinimidoyl)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, rotary evaporate the reaction solution and mix with the sample, separate the crude product by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1), and purify the crude product by reverse-phase preparative chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (17.45 mg, yield: 27.3%, white solid).

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

[0665] 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.39 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.24–7.17 (m, 1H), 7.11 (d, J = 5.3 Hz, 3H), 4.86 (s, 1H), 3.31 (s, 3H), 2.16 (s, 3H).

[0666] Example 21

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

[0668]

[0669] First step: 5-Chloro-N-(6-(methylthio)pyridazin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

[0670]

[0671] Dissolve 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) in N,N-dimethylformamide (2 mL), add potassium carbonate (53 mg, 0.384 mmol), and react at 70 °C in an oil bath for 16 hours. Stop the reaction, quench the reaction solution with saturated ammonium chloride solution (5 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and rotary evaporate 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: 69.72%, white solid).

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

[0673] Second step: 5-Chloro-N-(6-(S-methylsulfinyl)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 the reaction was carried out at room temperature for 1 hour. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the product was separated and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:9), and then purified by preparative high performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (25.42 mg, yield: 36.7%, yellow solid).

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

[0677] 1 1H NMR(400 MHz, DMSO-d6) δ 11.65(s, 1H), 9.39(d, J = 2.4 Hz, 1H), 8.59(d, J = 2.4 Hz, 1H), 8.19(s, 1H), 7.55(s, 1H), 7.41(d, J = 8.8 Hz, 2H), 7.23(d, J = 9.1 Hz, 2H), 4.87(s, 1H), 3.29(s, 3H).

[0678] Example 22

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

[0680]

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

[0682]

[0683] 5-Chloro-2-fluoro-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (70 mg, 0.192 mmol) and 4,4-difluoroazepane hydrochloride (164 mg, 0.959 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cesium carbonate (437 mg, 1.342 mmol) was added, and the reaction was carried out at 100 °C in an oil bath for 16 hours. The reaction was stopped, and the reaction solution was quenched with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified 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] Step 2: 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(S-methylsulfinyl)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 22)

[0686]

[0687] 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (70 mg, 0.134 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (39 mg, 0.402 mmol) and iodobenzene diacetate (172 mg, 0.535 mmol) were added, and the reaction was carried out at room temperature for 1 hour. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10), and then purified by preparative high performance liquid chromatography (elution 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] 11H NMR (400 MHz, DMSO-d6) δ 11.51 (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-methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 23)

[0692]

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

[0694]

[0695] Dissolve 3-bromo-4-fluoroaniline (1 g, 5.26 mmol) in ultradry 1,4-dioxane (20 mL), add sodium methyl mercaptide (569 mg, 7.89 mmol), Pd2(dba)3 (485 mg, 0.53 mmol), XantPhos (609 mg, 1.05 mmol), DIEA (2.04 g, 15.78 mmol), displace with nitrogen, stir the reaction at 110 °C in an oil bath for 16 h. Stop the reaction, filter the reaction solution, wash the filter cake with DCM (30 ml × 3), concentrate the filtrate and mix the sample, and purify 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] Dissolve 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (980 mg, 4.04 mmol) in thionyl chloride (1.5 mL), displace with nitrogen, stir and react at 80 °C for 2 hours, and spin-dry for later use. Dissolve 4-fluoro-3-(methylthio)aniline (635 mg, 4.04 mmol) in ultradry DCM (10 mL), add pyridine (1.28 g, 16.16 mmol) at 0 °C, and then add the dichloromethane solution (2 mL) of the spin-dried product, and stir and react at room temperature for 2 hours. Stop the reaction, spin-dry the reaction solution and mix the sample, and separate and purify by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain the title compound (870 mg, yield: 56.4%, 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] Dissolve 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (300 mg, 0.785 mmol) in DMF (4 mL), add 4-fluoro-2-methylphenol (198 mg, 1.571 mmol), add cesium carbonate (512 mg, 1.571 mmol), and stir and react at 100 °C in an oil bath for 2 hours. Stop the reaction, quench the reaction solution with water (20 mL), extract the aqueous phase with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (5 mL×2), dry over anhydrous sodium sulfate, filter, and then spin-dry the filtrate under vacuum to obtain the crude product. The crude product is separated 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%, 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-methylsulfinimidoyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 23)

[0706]

[0707] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (290 mg, 0.59 mmol) was dissolved in methanol (3 mL), ammonium carbonate (171.3 mg, 1.78 mmol) and iodobenzene diacetate (766 mg, 2.36 mmol) were added, and the reaction was stirred at room temperature for 1 hour. The reaction was stopped, the reaction solution was evaporated to dryness and triturated, and the crude product was separated by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:10) to obtain the crude product of the title compound. The crude product was purified by reverse-phase preparative chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (197 mg, yield: 64.3%, white solid).

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

[0709] 1 1H 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] Resolution of chiral isomers of Compound 23:

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

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

[0713]

[0714] Compound 23 was separated by a chiral preparative 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), eluted at 30% B ratio, flow rate: 70 mL / min, column temperature: room temperature) to obtain Compound 23E1 with a single configuration (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-methylsulfinimidoyl)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] Dissolve 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) in N,N-dimethylformamide (1 mL), add potassium carbonate (36.2 mg, 0.262 mmol), seal and react in an oil bath at 100 °C for 2 hours. Stop the reaction, quench the reaction solution with saturated ammonium chloride solution (5 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (80 mg, yield: 98.2%, 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-methylsulfinimidoyl)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 the reaction was carried out at room temperature for 1 hour. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the product was separated and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1), and then purified by high performance liquid chromatography preparation (elution system: formic acid, water, acetonitrile) to obtain the title compound (39.21 mg, yield: 52.7%, white solid).

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

[0726] 1 1H NMR(400 MHz, DMSO-d6) δ 10.88(s, 1H), 8.28(dd, J = 6.4, 2.6 Hz, 1H), 8.01(s, 1H), 7.96–7.90(m, 1H), 7.44(t, J = 9.3 Hz, 1H), 7.28(dd, J = 8.8, 5.9 Hz, 1H), 7.14(dd, J = 10.6, 2.8 Hz, 1H), 6.98(s, 1H), 6.85(td, J = 8.5, 2.9 Hz, 1H), 4.69(s, 1H), 3.18(s, 3H).

[0727] Example 25

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

[0729]

[0730] First step: 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 reaction was carried out in an oil bath at 100 °C for 2 hours. The reaction was stopped, and the reaction solution was quenched with saturated ammonium chloride solution (5 mL). It was extracted with ethyl acetate (20 mL × 3), and 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%, white solid).

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

[0734] Step 2: 5-Chloro-N-(4-fluoro-3-(S-methylsulfinimidoyl)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 the reaction was carried out at room temperature for 1 hour. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and it was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), and then purified by high performance liquid chromatography preparation (elution system: formic acid, water, acetonitrile) to obtain the title compound (16.02 mg, yield: 25.4%, white solid).

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

[0738] 11H 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-methylsulfinyl)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), and stir at 100 °C in an oil bath for 2 hours. Stop the reaction, quench the reaction mixture with water (10 mL), extract the aqueous phase with ethyl acetate (15 mL × 3), combine the organic phases, wash with saturated brine (5 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. The crude product is separated and purified 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-methylsulfinyl)phenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 26)

[0747]

[0748] 5-Chloro-N-(4-fluoro-3-(methylthio)phenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (87 mg, 0.16 mmol) was dissolved in methanol (1 mL), ammonium carbonate (46.4 mg, 0.48 mmol) and iodobenzene diacetate (206 mg, 0.64 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. The reaction was stopped, the reaction solution was evaporated to dryness and stirred with the sample, and the crude product was separated by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1), and the crude product was purified by reverse phase preparative chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (28.96 mg, yield: 31.5%, white solid).

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

[0750] 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.86 (s, 1H), 7.71 (d, J = 23.3 Hz, 2H), 7.48 (d, J = 8.0 Hz, 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-methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 27)

[0753]

[0754] First step: 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). 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 h. The reaction was stopped, and the reaction solution was 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, and concentrated in vacuo to obtain the crude product. The crude product was separated 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%, 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-methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide (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. The mixture was stirred at room temperature for 1 h. The reaction was stopped, and the reaction solution was concentrated in vacuo. It was quenched with water (2 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was purified by preparative reverse-phase chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (2.85 mg, yield: 0.59%, white solid).

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

[0762] 11H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.27 (dd, J = 6.4, 2.5 Hz, 1H), 8.01–7.90 (m, 1H), 7.69 (s, 1H), 7.46 (t, J = 9.3 Hz, 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] Resolution of chiral isomers of Compound 27:

[0764] (S)-5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide

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

[0766]

[0767] Compound 27 was separated by a chiral preparative column (column: AS, 250 * 25 mm, 10 μm; mobile phase: A - Supercritical CO2; B - MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), eluted at 45% B ratio, flow rate: 70 mL / min, column temperature: room temperature) to 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-methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 28)

[0770]

[0771] First step: 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). 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 reaction system was purged with nitrogen and stirred at 100 °C in an oil bath for 16 h. The reaction was stopped, and the reaction mixture was 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 concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 2:1) to obtain the title compound (100 mg, yield: 57.8%, 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-methylsulfinyl)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). Ammonium carbonate (56.6 mg, 0.589 mmol) and iodobenzene diacetate (253.1 mg, 0.785 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction was stopped, and the reaction mixture was concentrated in vacuo. The residue was quenched with saturated sodium bicarbonate solution (2 mL). The aqueous phase was extracted with ethyl acetate (5 mL×3). The combined organic phases were washed with saturated brine (3 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by reverse-phase preparative chromatography (elution system: ammonia, water, acetonitrile) to obtain the title compound (10 mg, yield: 9.4%, white solid).

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

[0779] 11H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.29 (d, J = 3.8 Hz, 1H), 8.01–7.85 (m, 1H), 7.65 (s, 1H), 7.45 (t, J = 9.3 Hz, 1H), 7.14 (s, 1H), 4.68 (s, 1H), 3.39 (d, J = 7.0 Hz, 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-methylsulfinyl)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] Dissolve 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) in N,N-dimethylformamide (2 mL), add cesium carbonate (205 mg, 0.63 mmol), and react at 100 °C in an oil bath for 1 hour. Stop the reaction, quench the reaction mixture with saturated ammonium chloride solution (5 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (120 mg, yield: 92.3%, 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-methylsulfinyl)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 the reaction was carried out at room temperature for 1 hour. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the product was separated and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1), and then purified by preparative high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (71.14 mg, yield: 64.1%, white solid).

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

[0791] 1 H NMR(400 MHz, DMSO-d6) δ 10.72(s, 1H), 8.27(s, 1H), 7.86(s, 2H), 7.64(s, 1H), 7.44(t, J = 9.1 Hz, 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-methylsulfinyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 30)

[0794]

[0795] The first step: (4-bromopyridin-2-yl)methanol

[0796]

[0797] Methyl 4-bromopyridine-2-carboxylate (2 g, 9.258 mmol) was dissolved in ethanol (50 mL), sodium borohydride (771 mg, 20.381 mmol) was added, and the reaction was carried out at room temperature for 16 hours after purging with nitrogen. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the product was separated and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain the title compound (1.23 g, yield: 70.7%, white solid).

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

[0799] Step 2: 4-Bromo-2-(chloromethyl)pyridine

[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 and react at room temperature for 3 hours. Stop the reaction, quench the reaction mixture with saturated sodium bicarbonate solution (100 mL), extract with dichloromethane (100 mL × 3), dry over anhydrous sodium sulfate, filter, and then rotary evaporate the solvent under vacuum. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 9:1) to obtain the title compound (10 g, yield: 85.1%, yellow oil).

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

[0803] Step 3: 4-Bromo-2-((methylthio)methyl)pyridine

[0804]

[0805] Dissolve 4-bromo-2-(chloromethyl)pyridine (10 g, 48.433 mmol) in N,N-dimethylformamide (80 mL). Slowly add sodium methylthiolate (4.07 mg, 58.076 mmol) at 0 °C and react at 0 °C for 2 hours. Stop the reaction, pour the reaction mixture into water (100 mL), extract with ethyl acetate (100 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter, and then rotary evaporate the solvent under vacuum. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain the title compound (9.3 g, yield: 88.1%, yellow oil).

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

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

[0808]

[0809] 4-Bromo-2-((methylthio)methyl)pyridine (4 g, 18.34 mmol) was dissolved in a mixed solvent of methanol (50 mL) and water (10 mL). Sodium periodate (3.93 g, 18.34 mmol) was slowly added at 0 °C, and the reaction was carried out at room temperature for 5 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the title compound (4.1 g, yield: 96.47%, white solid) was obtained by separation and purification through column chromatography (silica gel, dichloromethane:methanol = 9:1).

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

[0811] Step 5: N-(((4-Bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 -sulfanylidene)-2,2,2-trifluoroacetamide

[0812]

[0813] 4-Bromo-2-((methylsulfinyl)methyl)pyridine (2 g, 8.584 mmol) was dissolved in dichloromethane (20 mL). 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 diacetate (5.53 g, 17.17 mmol) were added. After purging with nitrogen, the reaction was carried out at room temperature for 16 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the title compound (1.18 g, yield: 40.2%, yellow oil) was obtained by separation and purification through column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1).

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

[0815] Step 6: ((4-Bromopyridin-2-yl)methyl)(imino)(methyl)-λ 6 -sulfoxide

[0816]

[0817] N-(((4-Bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 -sulfanylidene)-2,2,2-trifluoroacetamide (1.13 g, 3.285 mmol) was dissolved in methanol (10 mL). Potassium carbonate (2.27 g, 16.424 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the title compound (660 mg, yield: 81.08%, yellow oil) was obtained by separation and purification through column chromatography (silica gel, dichloromethane:methanol = 8:1).

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

[0819] Step 7: Benzyl (((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0820]

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

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

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

[0824]

[0825] Dissolve benzyl (((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (680 mg, 1.78 mmol) in tetrahydrofuran (12.8 mL), add tetrabutylammonium bromide (57.4 mg, 0.178 mmol) and 1,2-dibromoethane (1.34 g, 7.12 mmol), slowly add sodium hydroxide solution (50%, 3.2 mL), then heat to 60 °C and react for 16 hours. Stop the reaction, rotary evaporate the solvent under vacuum, dilute with water (10 mL), adjust to slightly acidic with 1N dilute hydrochloric acid, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and purify by column chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the title compound (400 mg, yield: 81.96%, yellow solid).

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

[0827] Step 9: Benzyl ((1-(4-bromopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0828]

[0829] Dissolve (1-(4-bromopyridin-2-yl)cyclopropyl)(imino)(methyl)-λ 6 -sulfoxide (400 mg, 1.46 mmol) in dichloromethane (6 mL), add pyridine (346 mg, 4.38 mmol), cool to 0 °C and slowly add benzyl chloroformate (623 g, 3.65 mmol), then react at room temperature for 3 hours. Stop the reaction, rotary evaporate the solvent under vacuum, dilute with water (10 mL), adjust to slightly acidic with 1N dilute hydrochloric acid, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (400 mg, yield: 67.11%, yellow oil).

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

[0831] Step 10: Benzyl ((1-(4-((diphenylmethylene)amino)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0832]

[0833] Dissolve ((1-(4-bromopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6Benzyl ((1-(4-aminopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ6-sulfanylidene)carbamate (330 mg, 0.81 mmol) and dibenzylideneamine (220 mg, 1.21 mmol) were dissolved in 1,4-dioxane (5 mL). Tris(dibenzylideneacetone)dipalladium(0) (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 purging with nitrogen, the reaction was carried out in an oil bath at 100 °C for 2 h. The reaction was stopped, and the reaction mixture was quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and 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 = 1:2) to obtain 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 6-sulfanylidene)benzyl carbamate

[0836]

[0837] Benzyl ((1-(4-((dibenzylidene)amino)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ6-sulfanylidene)carbamate (420 mg, 0.825 mmol) was dissolved in tetrahydrofuran (4 mL). 1N hydrochloric acid (4 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. The reaction was stopped, and the solvent was removed by rotary evaporation under vacuum. The residue was adjusted to slightly alkaline with 1N sodium hydroxide solution 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. After filtration, the solvent of the filtrate was removed by rotary evaporation under vacuum to obtain the title compound (270 mg, yield: 68.4%, white solid). 6

[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)-λ6-sulfanylidene)benzyl carbamate 6

[0840]

[0841] ​​Benzyl ((1-(4-aminopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (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 purging with nitrogen, the temperature was lowered to -10 °C using an ice-salt bath, and phosphorus oxychloride (274 mg, 1.783 mmol) was slowly added dropwise. The reaction was carried out 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 × 3), and the combined organic phases were washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:4) to obtain the title compound (300 mg, yield: 88.76%, yellow solid).

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

[0843] Step 13: Benzyl ((1-(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0844]

[0845] Benzyl ((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (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 carried out at 100 °C for 2 hours. The reaction was stopped, quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3) 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-methylsulfinimidoyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 30)

[0848]

[0849] Dissolve ((1-(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamic acid benzyl ester (70 mg, 0.103 mmol) in trifluoroacetic acid (1.5 mL), heat to 60 °C and react for 3 hours. Stop the reaction, rotary evaporate the solvent under vacuum, adjust to slightly alkaline with 1N sodium hydroxide solution, extract with ethyl acetate (2 mL × 3), combine the organic phases, wash with saturated brine (5 mL × 3), dry over anhydrous sodium sulfate, and rotary evaporate the solvent under vacuum. Purify by high performance liquid chromatography preparation (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (32 mg, yield: 57.14%, white solid).

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

[0851] 1 1H 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-methylsulfinimidoyl)cyclopropyl)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 31)

[0854]

[0855] Step 1: ((1-(4-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6-sulfylidene)carbamic acid benzyl ester

[0856]

[0857] ((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfylidene) benzyl carbamate (75 mg, 0.132 mmol) and 4-(trifluoromethoxy)phenol 2 (47 mg, 0.264 mmol) were dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (37 mg, 0.264 mmol) was added, and the temperature was raised to 70°C for 16 hours. The reaction was stopped, saturated ammonium chloride solution (10 mL) was added to the reaction solution to quench, and ethyl acetate (20 mL × 3) was used for extraction. The organic phases were combined and washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:3) to obtain the title compound (80 mg, yield: 83%, yellow oil).

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

[0859] Step 2: 5-Chloro-N-(2-(1-(S-methylimidosulfonyl)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 -sulfydene) benzyl carbamate (70 mg, 0.102 mmol) was dissolved in trifluoroacetic acid (1.5 mL), heated to 60 ° C for 3 hours. Stop the reaction, remove the solvent in vacuo, adjust to alkalinity with 1N sodium hydroxide solution, extract with ethyl acetate (2 mL × 3), wash the combined organic phases with saturated brine (5 mL × 3), dry over anhydrous sodium sulfate, and remove the solvent in vacuo. Purify by HPLC (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (39.27 mg, yield: 68.42%, white solid).

[0862] MS (ESI): m / z 594.0 [M+H] + ;

[0863] 11H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.12 (s, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.57 (dd, J = 5.5, 1.8 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J = 8.5 Hz, 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-methylsulfinyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 32)

[0866]

[0867] Step 1: Benzyl ((1-(4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0868]

[0869] Dissolve benzyl ((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (75 mg, 0.132 mmol) and 4,4-difluoroazepane hydrochloride (113 mg, 0.66 mmol) in N,N-dimethylformamide (2 mL), add cesium carbonate (300 mg, 0.923 mmol), and heat to 100 °C for reaction for 16 h. Stop the reaction, quench the reaction solution with saturated ammonium chloride solution (10 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 3), dry over anhydrous sodium sulfate, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3) to obtain the title compound (80 mg, yield: 88%, 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-methylsulfinimidoyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 32)

[0872]

[0873] Dissolve benzyl ((1-(4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (70 mg, 0.102 mmol) in trifluoroacetic acid (1.5 mL), heat to 60 °C and react for 3 hours. Stop the reaction, rotary evaporate the solvent under vacuum, adjust to slightly alkaline with 1N sodium hydroxide solution, extract with ethyl acetate (2 mL × 3), combine the organic phases, wash with saturated brine (5 mL × 3), dry over anhydrous sodium sulfate, rotary evaporate the solvent under vacuum; purify by high performance liquid chromatography preparation (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (19.21 mg, yield: 34.12%, white solid).

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

[0875] 1 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.47 (d, J = 5.5 Hz, 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-methylsulfinimidoyl)ethoxy)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 33)

[0878]

[0879] First step: 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 hydride (1.70 g, 42.60 mmol) was added at 0 °C, and the reaction was carried out for 0.5 h. 4-Bromo-2-fluoropyridine (5.00 g, 28.40 mmol) was added under nitrogen, and the reaction was continued at 0 °C for 2 h. The reaction was stopped, and the reaction was quenched by slowly adding water (250 mL). The aqueous phase was extracted with ethyl acetate (250 mL×3). The combined organic phases were washed with saturated brine (250 mL×2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was separated 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%, 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, and then iodobenzene diacetate (23.3 g, 72.53 mmol) was added under ice bath. The reaction system was purged with nitrogen, and the reaction was stirred at room temperature for 2 h. The reaction was stopped, and the reaction mixture was quenched by adding water (200 mL). The aqueous phase was extracted with ethyl acetate (200 mL×3). The combined organic phases were washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was separated and purified by reverse 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: Benzyl ((2-((4-bromopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfinyl)carbamate

[0888]

[0889] (2-((4-Bromopyridin-2-yl)oxy)ethyl)(imino)(methyl)-λ 6The sulfoxide (700 mg, 2.50 mmol) was dissolved in DCM (10 mL), pyridine (297 mg, 3.76 mmol) was added, the reaction system was purged with nitrogen, and CbzCl (513 mg, 3.00 mmol) was added under an ice bath. The reaction mixture was stirred at room temperature for 2 hours. The reaction was stopped, and the reaction solution was quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was 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: Benzyl ((2-((4-((diphenylmethylene)amino)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0892]

[0893] Benzyl ((2-((4-bromopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (700 mg, 1.69 mmol) was dissolved in dioxane (10 mL), diphenylamine (458 mg, 2.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (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 reaction system was purged with nitrogen, and the reaction mixture was stirred at 100 °C for 1.5 hours. The reaction was stopped, and the reaction solution was cooled and diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was purified by thin layer chromatography plate (developing agent system: ethyl acetate) to obtain the title compound (550 mg, yield: 63.2%, yellow solid).

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

[0895] Step 5: Benzyl ((2-((4-aminopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0896]

[0897] Benzyl ((2-((4-((diphenylmethylene)amino)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (500 mg, 0.97 mmol) was dissolved in tetrahydrofuran (2 mL), water (1 mL) and hydrochloric acid (1 mL) were added, the mixture was purged with nitrogen, and the reaction was carried out at room temperature for 1.5 hours. The solvent was removed under reduced pressure to obtain the crude title compound (400 mg, white solid), which was directly used in the next step of the reaction.

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

[0899] Step 6: Benzyl ((2-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0900]

[0901] Benzyl ((2-((4-aminopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (450 mg, 1.16 mmol) was dissolved in pyridine (15 mL), 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (283 mg, 1.16 mmol) was added, the mixture was purged with nitrogen, and phosphorus oxychloride (536 mg, 3.50 mmol) was added under ice bath. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, water (100 mL) was added to the reaction solution under ice bath, the aqueous phase was extracted with ethyl acetate (100 ml×3), the combined organic phases were washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the 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 (450 mg, yield: 67.0%, yellow solid).

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

[0903] Step 7: Benzyl ((2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate

[0904]

[0905] Benzyl ((2-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (80 mg, 0.13 mmol) was dissolved in DMF (2 mL), potassium carbonate (90 mg, 2.70 mmol) was added, 4-fluoro-2-methylphenol (35 mg, 0.27 mmol) was added, the reaction system was purged with nitrogen, and the reaction was carried out at 70 °C for 12 h. The reaction was stopped, 15 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (15 mL×3), the organic phases were combined, washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 2:1) to obtain the title compound (100 mg, yield: 86.4%, yellow solid).

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

[0907] Step 8: 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(2-(S-methylsulfinyl)ethoxy)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 33)

[0908]

[0909] Benzyl ((2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanylidene)carbamate (80 mg, 0.118 mmol) was dissolved in trifluoroacetic acid (1.5 mL), and the reaction was carried out at 60 °C for 3 h. The reaction was stopped, the solvent was removed in vacuo, the solution was adjusted to slightly alkaline with 1 N sodium hydroxide solution, and extracted with ethyl acetate (2 mL×3). The combined organic phases were washed with saturated brine (5 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The product was purified by preparative high performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (34.87 mg, yield: 54.22%, white solid).

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

[0911] 11H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.06 (s, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 5.8 Hz, 3H), 6.82 (d, J = 1.9 Hz, 1H), 6.42 (dd, J = 7.5, 2.2 Hz, 1H), 4.21 (t, J = 6.8 Hz, 2H), 3.88 (s, 1H), 3.43 (td, J = 6.8, 2.7 Hz, 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-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 34)

[0914]

[0915] First step: 2-(4-Acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0916]

[0917] Dissolve 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (120 mg, 0.33 mmol) in N,N-dimethylformamide (2 mL), add 1-(1,4-diazepan-1-yl)ethan-1-one (140.8 mg, 0.99 mmol) and cesium carbonate (322.7 mg, 0.99 mmol), displace with nitrogen, and react at 100 °C for 16 hours. Stop the reaction, add water to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 3), dry over anhydrous sodium sulfate, filter, and rotary evaporate the solvent under vacuum. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3) to obtain the title compound (90 mg, yield: 56.3%, white solid).

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

[0919] Second step: 2-(4-Acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 34)

[0920]

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

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

[0923] 1 1H NMR(400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.62 (d, J = 5.4 Hz, 1H), 8.40 (d, J = 3.2 Hz, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.73 (d, J = 17.0 Hz, 1H), 7.37 (d, J = 10.9 Hz, 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-methylsulfinimidoyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 35)

[0926]

[0927] First step: 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-(trifluoromethyl)benzamide (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 reaction was carried out in an oil bath at 100 °C for 16 h. The reaction was stopped, and the reaction solution was quenched by adding saturated ammonium chloride solution (10 mL). It was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (116 mg, yield: 88%, 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-methylsulfinimidoyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 35)

[0932]

[0933] 2-(4-Acetyl-1,4-diazepan-1-yl)-5-chloro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (96 mg, 0.19 mmol) was dissolved in methanol (2 mL). Ammonium carbonate (54.78 mg, 0.57 mmol) and iodobenzene diacetate (244.8 mg, 0.76 mmol) were added, and the reaction was carried out at room temperature for 1 h. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, separated and purified by column chromatography (silica gel, ethyl acetate), and then purified by preparative high performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (15.76 mg, yield: 14.85%, white solid).

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

[0935] 11H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.28 (d, J = 4.3 Hz, 1H), 8.03–7.91 (m, 1H), 7.67 (d, J = 16.7 Hz, 1H), 7.45 (t, J = 9.3 Hz, 1H), 7.35 (d, J = 9.6 Hz, 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-methylsulfinyl)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] Dissolve 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (200 mg, 0.55 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (220.2 mg, 1.1 mmol) in N,N-dimethylformamide (3 mL), add cesium carbonate (358.4 mg, 1.1 mmol), and react at 100 °C in an oil bath for 16 h. Stop the reaction, quench the reaction solution with saturated ammonium chloride solution (10 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and purify the filtrate by column chromatography (silica gel, petroleum ether:ethyl acetate = 7:3) to obtain the title compound (215 mg, yield: 72%, 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] 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) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction was stopped, and the solvent was removed by rotary evaporation under vacuum to obtain the title compound (337 mg, yield: 98%, 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] 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) were dissolved in tetrahydrofuran (1.5 mL), triethylamine (91.5 μl) was added, and the reaction was carried out in an oil bath at 50 °C for 16 hours. The reaction was stopped, and the solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 6.5:3.5) to obtain the title compound (148 mg, yield: 44.85%, 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-methylsulfinyl)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), then ammonium carbonate (11.31 mg, 0.118 mmol) and iodobenzene diacetate (50.25 mg, 0.156 mmol) were added, and the reaction was carried out at room temperature for 1 hour. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 6.5:3.5), and then further purified by preparative high performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (91 mg, yield: 67.4%, yellow oil).

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

[0955] Example 37

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

[0957]

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

[0959]

[0960] 5-Chloro-2-(1,4-diazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.23 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (208.89 mg, 0.9 mmol) were dissolved in tetrahydrofuran (2.5 mL), triethylamine (186.19 mg, 1.84 mmol) was added, and the reaction was carried out in an oil bath at 50 °C for 16 hours. The reaction was stopped, the solvent was removed by rotary evaporation under vacuum, and the residue was purified 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-methylsulfinylsulfonyl)pyridin-4-yl)-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-4-(trifluoromethyl)benzamide 2,2,2 (Compound 37)

[0963]

[0964] Dissolve 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) in methanol (1 mL), then add ammonium carbonate (24.7 mg, 0.257 mmol) and iodobenzene diacetate (110.8 mg, 0.344 mmol), and react at room temperature for 1 hour. Stop the reaction, remove the solvent by rotary evaporation under vacuum, separate and purify by column chromatography (silica gel, pure ethyl acetate), and then purify by high performance liquid chromatography preparation (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (57 mg, yield: 92.3%, yellow oil).

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

[0966] Example 38

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

[0968]

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

[0970]

[0971] Dissolve 2-chloro-4-nitropyridine (1000 mg, 6.31 mmol) in anhydrous 1,4-dioxane (20 mL), add dimethylsulfoximidamide (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 protection and stir the reaction overnight. Stop the reaction, rotary evaporate the reaction solution to dryness, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (1.2 g, yield: 88%, yellow solid).

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

[0973] Step 2: ((4-Aminopyridin-2-yl)imino)dimethyl-λ 6 -thioxane

[0974]

[0975] Dissolve dimethyl(4-nitropyridin-2-yl)imino)-λ 6 -6-thioxane (600 mg, 2.79 mmol) in anhydrous methanol (10 mL), add palladium on carbon (180 mg), replace with hydrogen and react at room temperature for 16 hours. Stop the reaction, filter the reaction solution, rotary evaporate the solvent of the filtrate under vacuum, and separate and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (460 mg, yield: 89%, white solid).

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

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

[0978]

[0979] Dissolve ((4-aminopyridin-2-yl)imino)dimethyl-λ 6-Thioketone (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 purging with nitrogen, the temperature was lowered to -10 °C, and phosphorus oxychloride (248.64 mg, 1.62 mmol) was added. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, and ice water (5 mL) was added to the reaction solution to quench it. The solution was adjusted to acidic 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, filtered, and the solvent was removed by rotary evaporation under vacuum. The crude product was purified by column chromatography (silica gel, dichloromethane:anhydrous methanol = 9:1) to obtain the title compound (263.7 mg, yield: 98%, yellow oil).

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

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

[0982]

[0983] 5-Chloro-N-(2-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)pyridin-4-yl)-2-fluoro-4-(trifluoromethyl)benzamide (132 mg, 0.324 mmol) and 4-fluoro-2-methylphenol (81.64 mg, 0.65 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cesium carbonate (316.7 mg, 0.972 mmol) was added, and the reaction was carried out at 100 °C in an oil bath for 2 hours. The reaction was stopped, and the reaction solution was filtered. Then it was purified by preparative high performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (38.25 mg, yield: 22.9%, white solid).

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

[0985] 11H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.03 (s, 1H), 7.99 (d, J = 5.7 Hz, 1H), 7.21 (d, J = 9.0 Hz, 1H), 7.10–7.08 (m, 4H), 7.03 (d, J = 5.7 Hz, 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 -sulfanylidene)amino)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 39)

[0988]

[0989] 5-Chloro-N-(2-((dimethyl(oxo)-λ 6 -sulfanylidene)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) were dissolved in N,N-dimethylformamide (2 mL), cesium carbonate (1.056 g, 3.24 mmol) was added, and the reaction was carried out at 100 °C in an oil bath for 16 hours. The reaction was stopped, the reaction solution was filtered, and the filtrate was then purified by preparative high performance liquid chromatography (elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (39.52 mg, yield: 23.3%, yellow solid).

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

[0991] 1 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.99 (d, J = 5.5 Hz, 1H), 7.64 (s, 1H), 7.33 (s, 1H), 7.03 (d, J = 8.8 Hz, 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 against Sodium Channel 1.8 (NaV1.8)

[0994] Purpose of the experiment: To determine the inhibitory rate of the compound on the human Nav1.8 ion channel stably expressed in CHO cells

[0995] Experimental method:

[0996] The compound was dissolved in DMSO to prepare a stock solution and diluted to a specific concentration with extracellular fluid (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)) for manual patch clamp testing.

[0997] A capillary glass tube was pulled into a recording electrode using a microelectrode puller. Under an inverted microscope, the recording electrode was manipulated by a microelectrode manipulator to contact the cell, and negative pressure was applied for aspiration to form a GΩ seal. After forming the GΩ seal, rapid capacitance compensation was performed, and then negative pressure was continuously applied to rupture the cell membrane to form a whole-cell recording mode. Then, slow capacitance compensation was performed and the membrane capacitance and series resistance were recorded. Leakage compensation was not applied. When the Nav1.8 current in the whole-cell recording was stable, the drug was administered. After each drug concentration acted for 5 min (or until the current was stable), the next concentration was tested. Two concentrations were tested for each test compound.

[0998] The voltage stimulation protocol for recording Nav1.8 sodium current by whole-cell patch clamp was as follows: When the whole-cell seal was formed, the cell voltage was clamped at -120 mV for 30 ms. The clamped voltage was depolarized to 0 mV for 50 ms, and then the voltage was restored to -50 mV (the specific voltage refers to the half-inactivation voltage of the IV test) and maintained for 8 s. Then, the cell membrane potential was restored to -120 mV and maintained for 20 ms, and then depolarized to 0 mV again and maintained for 50 ms. Finally, it was restored to the clamped voltage of -120 mV and maintained for 30 ms. Data was collected every 20 s. The effect of the drug on the peak sodium current was observed. The experimental data was 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 gavage in rats

[1003] Purpose of the experiment: The purpose of this test example is to evaluate the pharmacokinetic properties of the compound of the present invention

[1004] The inventors evaluated the pharmacokinetics of the compounds of the present invention in rats. The animal information is shown in Table 2 for details.

[1005] Table 2: Information Table of Test Animals of the Present Invention

[1006] Germline Grade Gender Body weight Age Source SD rats SPF Male 180-220g 6 - 8 weeks Shanghai SIPPR - BK Laboratory Animal Co., Ltd.

[1007] Experimental method:

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

[1009] Sample preparation for LC-MS / MS determination: 20 μL of plasma samples were precipitated with 400 μL of methanol containing 100 ng / mL IS (IS is tolbutamide). The mixture was vortexed for 1 minute and then centrifuged at 18000 g for 7 minutes. 400 μL of the supernatant was transferred to a 96-well plate. 2 μL of the supernatant was analyzed by LC-MS / MS. The analysis results showed that the compounds of the present invention all had good pharmacokinetic properties in rats.

[1010]

[1011] Test Example C: Pharmacokinetic Evaluation of Intravenous Injection or Gavage of Quantified Compounds of the Present Invention 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 evaluated the pharmacokinetics of the compounds of the present invention in mice. The animal information is shown in Table 3 for details.

[1014] Table 3: Information Table of Test Animals of the Present Invention

[1015] Germline Grade Gender Body weight Age Source ICR mice SPF Male 26-32g 6 - 8 weeks Shanghai SIPPR - BK Laboratory Animal Co., Ltd.

[1016] Experimental method:

[1017] The compound of the present invention was administered to the test animals in the form of 5% DMSO + 5% tween80 + 90% saline solvent. 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, the animals were venously blooded at the following time points (blood volume was about 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 determination: 15 μL plasma sample was protein precipitated with 300 μL methanol containing 100 ng / mL IS (IS is tolbutamide). The mixture was vortexed for 1 minute and then centrifuged at 18000g for 10 minutes. 300 μL supernatant was transferred to a 96-well plate. 2 μL supernatant was subjected to LC-MS / MS analysis. The analysis results showed that the compounds of the present invention had good pharmacokinetic properties in mice.

[1019]

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

[1021] 1. A compound of the general 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 which is -L1-R1, and the group is optionally substituted with one or more deuteriums until fully deuterated;

[1031] R w and R g 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 and -OR s1 , and the group is optionally substituted with one or more deuteriums until fully deuterated;

[1032] -L1- is -(CR a R b ) m -, and when the valence allows, any methylene unit in -(CR a R b ) m - 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 form C 3-8 cycloalkyl or a 3- to 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- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, which is optionally substituted with s R2 substituents;

[1035] -L2- is selected from a bond, -O-,-NR'-,-S-,-C(O)- and -(CR c R d ) n -, and when the valence allows, -(CR c R d ) nAny one of the methylene units 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 form a C 3-8 cycloalkyl or a 3- to 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 groups being optionally substituted by one or more deuteriums up to complete deuteration;

[1037] R” is -L3-B;

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

[1039] -L3- is -(CR e R f ) p -, and when the valence allows, -(CR e R f ) p - Any one of the methylene units 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 form a C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group;

[1040] 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 by one or more deuteriums up to complete 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, where the groups are optionally substituted with one or more deuteriums up to complete 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 where the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1043] R6 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, where the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1044] R a R b R c R d R e and R f are each independently selected from H, D, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, where the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1045] R s1 and R s2 are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, where the groups are optionally substituted with one or more deuteriums up to complete 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 is 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 fully deuterated;

[1062] R w and R g Each is 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 until fully deuterated;

[1063] -L1- is -(CR a R b ) m -, and when valence allows, any methylene unit in -(CR a R b ) m - 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 form C 3-8 cycloalkyl or a 3- to 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- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with s R2 substituents;

[1066] -L2- is selected from a bond, -O-,-NR'-,-S-,-C(O)- and -(CR c R d ) n -, and when valence allows, any methylene unit in -(CR c R d ) n - 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 form C 3-8 cycloalkyl or a 3- to 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 is optionally substituted with one or more deuteriums until fully deuterated;

[1068] R” is -L3-B;

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

[1070] -L3- is -(CRe R f ) p -, optionally and independently, each methylene unit in -(CR e R f ) p - is 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 form C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group;

[1071] 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 , and the groups are optionally substituted by one or more deuteriums until fully deuterated;

[1072] R4 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl, and the groups are optionally substituted by one or more deuteriums until fully deuterated;

[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, the group is optionally substituted with one or more deuteriums until complete deuteration;

[1074] R6 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, the group is optionally substituted with one or more deuteriums until complete deuteration;

[1075] R a 、R b 、R c 、R d 、R e and R f are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl, the group is optionally substituted with one or more deuteriums until complete deuteration;

[1076] R s1 and R s2 are independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl, the group is optionally substituted with one or more deuteriums until complete 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 heterocyclic group;

[1088] Preferably, A is selected from cyclopentyl, cyclohexyl, azacyclohexyl, oxacyclohexyl, thiacyclohexyl, azacycloheptyl, diazacycloheptyl, octahydrocyclopentadienopyrrolyl, octahydropyrrolopyrrolyl, octahydrobicyclopentadienyl, phenyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl;

[1089] Preferably, m is 0;

[1090] Preferably, where:

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

[1092] -(CR a R b ) m - any one of the methylene units 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 form C 3-6 cycloalkyl and 3- to 5-membered heterocyclic groups;

[1093] R a is selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[1094] R b is selected from H, C 1-6 alkyl and C 1-6 haloalkyl.

[1095] The compound of 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] where:

[1100] X is N or CR x ;

[1101] Y is N or CR y ;

[1102] R x and R y are each independently selected from H, D, halogen, C 1-6 alkyl or C 1-6A haloalkyl group, optionally substituted with one or more deuteriums up to complete deuteration;

[1103] R’ is selected from H, C 1-6 alkyl and C 1-6 haloalkyl group, optionally substituted with one or more deuteriums up to complete deuteration;

[1104] R” is -L3-B;

[1105] B is a 5- to 7-membered heterocyclic group, optionally substituted with t R5 substituents;

[1106] -L3- is -(CR e R f ) p -, and when valence allows, any methylene unit in -(CR e R f ) p - 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 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 , and the groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1108] Each R5 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl group, optionally substituted with one or more deuteriums up to complete deuteration;

[1109] R e and R f are independently selected from H, D, C 1-6 alkyl and C1-6 A haloalkyl group, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[1110] R s1 and R s2 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl group, said group being optionally substituted with one or more deuteriums up to complete 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 is selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl group, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[1117] R’ is selected from H, C 1-6 alkyl and C 1-6 haloalkyl group, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[1118] R” is -L3-B;

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

[1120] -L3- is -(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 are independently selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl group, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[1122] R5 are each independently selected from H, D, C 1-6 alkyl and C 1-6A haloalkyl group, optionally substituted by one or more deuteriums up to full deuteration;

[1123] R e and R f are independently selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl, the group optionally substituted by one or more deuteriums 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 is H or D;

[1131] R’ is H;

[1132] R” is -L3-B;

[1133] B is a 5- or 6-membered heterocyclic group, preferably azetidinyl or cyclohexyl;

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

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

[1136] R 2b is H or D;

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

[1138] R 2d is H or D;

[1139] R 2e is H or D;

[1140] R 3a is H or D;

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

[1142] R 3c is a halogen, preferably Cl;

[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] a compound of 4.2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, which 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 , and the said groups are optionally substituted with one or more deuteriums until fully deuterated;

[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 heterocyclic, which are optionally substituted with s R2 substituents;

[1155] Where valence allows, any methylene unit in -(CR a R b ) m - is optionally and independently replaced by -O-, -S-, and -C(O)-;

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

[1157] 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 , the groups being 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, the groups being optionally substituted with one or more deuteriums up to full deuteration;

[1159] R a and R b are selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, the groups being optionally substituted with one or more deuteriums up to full deuteration;

[1160] Or R a and R b together with the carbon atom to which they are attached form C 3-6 cycloalkyl and 3- to 5-membered heterocyclic groups;

[1161] R s1 and R s2 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, the groups being optionally substituted with one or more deuteriums 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, and the groups are optionally substituted with one or more deuteriums up to full deuteration;

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

[1169] When valence permits, any one methylene unit in -(CR a R b ) m - 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, and the groups are optionally substituted with one or more deuteriums up to full deuteration;

[1172] Each R2 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR s1 , and the groups are optionally substituted with one or more deuteriums up to full deuteration;

[1173] R 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR s1a and -SR s1a , and the groups are optionally substituted with one or more deuteriums up to full deuteration;

[1174] R 2b is H or D;

[1175] R 2c is H, D, halogen, -OR s1c or -SR s1c ;

[1176] R 2d is H or D;

[1177] R 2e is H or D;

[1178] R 3a is H or D;

[1179] R 3b is C 1-6 a haloalkyl group, said group optionally being substituted by one or more deuteriums up to complete deuteration;

[1180] R 3c is a halogen;

[1181] R 3d is H or D;

[1182] R4 is selected from C 1-6 alkyl and C 1-6 a haloalkyl group, said group optionally being substituted by one or more deuteriums up to complete deuteration;

[1183] R a and R b are each independently selected from H, D, a halogen and C 1-6 alkyl, said group optionally being substituted by one or more deuteriums up to complete deuteration;

[1184] or R a and R b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;

[1185] R s1 are each independently selected from H, C 1-6 alkyl or C 1-6 a haloalkyl group, said group optionally being substituted by one or more deuteriums up to complete deuteration;

[1186] R s1a is selected from H, C 1-6 alkyl or C 1-6 a haloalkyl group, said group optionally being substituted by one or more deuteriums up to complete deuteration;

[1187] R s1c is selected from H, C 1-6 alkyl or C 1-6 a haloalkyl group, said group optionally being substituted by one or more deuteriums up to complete 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 xis H;

[1194] R y is a 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] -L2- is a bond or -O-;

[1198] R’ is H;

[1199] Each R2 is independently selected from H and halogen, preferably F, and the group is optionally substituted with one or more deuteriums until fully deuterated;

[1200] R 2a is H or C 1-6 alkyl, preferably methyl, and the group is optionally substituted with one or more deuteriums until fully deuterated;

[1201] R 2b is H;

[1202] R 2c is a 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 a halogen, preferably Cl;

[1208] R 3d is H;

[1209] R4 is 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] A compound of 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 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 , and the groups are optionally substituted with one or more deuteriums until fully deuterated;

[1218] -L2- is a bond, -O-, -S- or -NH-;

[1219] A is selected from phenyl, C 3-8 cycloalkyl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group, which is optionally substituted with s R2 substituents;

[1220] R' is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, and the groups are optionally substituted with one or more deuteriums until fully deuterated;

[1221] 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 group is optionally substituted with one or more deuteriums until fully deuterated;

[1222] R4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, said group is optionally substituted with one or more deuteriums until fully deuterated;

[1223] R s1 and R s2 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, said group is optionally substituted with one or more deuteriums until fully deuterated;

[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, azacycloheptyl, diazacycloheptyl, octahydrocyclopentadienopyrrolyl, octahydropyrrolopyrrolyl, octahydrobicyclopentadienyl, phenyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl. Preferably, A and its substituents are selected from the following:

[1227]

[1228] Wherein, R 2a , R 2b , R 2c and R 2d 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 group is optionally substituted with one or more deuteriums until fully deuterated;

[1229] Preferably, wherein:

[1230] -L2- is -O-;

[1231] A is selected from cyclopentyl and cyclohexyl, preferably cyclohexyl;

[1232] Preferably, wherein:

[1233] -L2- is a key;

[1234] A is selected from azepanyl, diazepanyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[1,2 - a]pyrrolyl, and octahydro - spiro[4.5]dec - 1 - en - 8 - yl. Preferably, when A is a nitrogen - containing heterocycle, it is linked to the phenyl group through a nitrogen atom.

[1235] A compound of 6.2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, which 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, and the said groups are optionally substituted with one or more deuteriums until fully deuterated;

[1241] R’ is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, and the said groups are optionally substituted with one or more deuteriums until fully deuterated;

[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 ,wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[1243] R4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[1244] R s1 and R s2 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[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, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[1249] R’ is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[1250] R 2a is selected from H, D, halogen, -OR s1a 、 -SR s1a 、 NR s1a R s2a 、 C 1-6 alkyl and C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[1251] R 2b is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the group is optionally substituted with one or more deuteriums until fully deuterated;

[1252] R 2c is selected from H, D, halogen, -ORs1c 、 -SR s1c 、 NR s1c R s2c 、 C 1-6 alkyl and C 1-6 haloalkyl, and said groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1253] R 2d is H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, and said groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1254] R 2e is H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, and said groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1255] R 3a is H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, and said groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1256] R 3b is selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, and said groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1257] R 3c is selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, and said groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1258] R 3d is H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, and said groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1259] R4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl, and said groups are optionally substituted with one or more deuteriums up to complete deuteration;

[1260] R s1a 、 R s2a 、 R s1c and R s2c are each independently selected from H, C 1-6 alkyl or C 1-6A haloalkyl group, optionally substituted with one or more deuteriums up to complete deuteration;

[1261] Preferably, wherein:

[1262] X is CR x ;

[1263] Y is N or CR y ;

[1264] R x and R y are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, the group optionally substituted with one or more deuteriums up to complete deuteration;

[1265] R’ is H, C 1-6 alkyl or C 1-6 haloalkyl, the group optionally substituted with one or more deuteriums up to complete deuteration;

[1266] R 2a is -OR s1a , -SR s1a , NR s1a R s2a , C 1-6 alkyl or C 1-6 haloalkyl, the group optionally substituted with one or more deuteriums,

[1267] up to complete deuteration;

[1268] R 2b is H, D or halogen;

[1269] R 2c is H, D, halogen, -OR s1c , -SR s1c or NR s1c R s2c , the group optionally substituted with one or more deuteriums up to complete 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 is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, the group optionally substituted with one or more deuteriums up to complete deuteration;

[1274] R 3c is H, D or a halogen;

[1275] R 3d is H, D or a halogen;

[1276] R4 is H, C 1-6 alkyl or C 1-6 haloalkyl, the group optionally being substituted by one or more deuteriums up to complete deuteration;

[1277] R s1a 、R s2a 、R s1c and R s2c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, the group optionally being substituted by one or more deuteriums up to complete deuteration;

[1278] provided that when Y is N, R 2a is not C 1-6 alkyl or C 1-6 haloalkyl;

[1279] Preferably, wherein:

[1280] X is CR x ;

[1281] Y is N or CR y ;

[1282] R x and R y are independently selected from H, D or a halogen;

[1283] R’ is H, C 1-6 alkyl or C 1-6 haloalkyl;

[1284] R 2a is -OR s1a 、-SR s1a 、C 1-6 alkyl or C 1-6 haloalkyl, the group optionally being substituted by one or more deuteriums up to complete deuteration;

[1285] R 2b is H, D or a halogen;

[1286] R 2c is H, D, a halogen, -OR s1c or -SR s1c ,the group optionally being substituted by one or more deuteriums up to complete deuteration;

[1287] R2d is H or D;

[1288] R 2e is H or D;

[1289] R 3a is H or D;

[1290] R 3b is C 1-6 haloalkyl;

[1291] R 3c is halogen;

[1292] R 3d is H or D;

[1293] R4 is C 1-6 alkyl or C 1-6 haloalkyl;

[1294] R s1a and R s1c are independently selected from C 1-6 alkyl or C 1-6 haloalkyl;

[1295] provided that when Y is N, R 2a is not C 1-6 alkyl or C 1-6 haloalkyl;

[1296] Preferably, wherein:

[1297] X is CR x ;

[1298] Y is N or CR y ;

[1299] R x and R y are independently selected from H, D or halogen;

[1300] R’ is H;

[1301] R 2a is -OR s1a 、-SR s1a or C 1-6 alkyl, and the groups are optionally substituted with one or more deuteriums until fully deuterated;

[1302] R 2b is H or D;

[1303] R 2c is halogen, -OR s1c or -SR s1c and the groups are optionally substituted with one or more deuteriums until fully deuterated;

[1304] R 2d is H or D;

[1305] R 2e is H or D;

[1306] R 3a is H or D;

[1307] R 3b is C 1-6 alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuteriums up to complete deuteration;

[1308] R 3c is 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 deuteriums up to complete deuteration;

[1311] R s1a and R s1c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, said group being optionally substituted with one or more deuteriums up to complete 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 is -OR s1a or -SR s1a , said group being optionally substituted with one or more deuteriums up to complete deuteration;

[1319] R 2b is H or D;

[1320] R 2c is 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, and the group is optionally substituted with one or more deuteriums until fully deuterated;

[1325] R 3c is halogen;

[1326] R 3d is H or D;

[1327] R4 is C 1-6 alkyl or C 1-6 haloalkyl, and the group is optionally substituted with one or more deuteriums until fully deuterated;

[1328] R s1a and R s1c are independently selected from C 1-6 alkyl or C 1-6 haloalkyl, and the group is optionally substituted with one or more deuteriums until fully deuterated;

[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 , and the group is optionally substituted with one or more deuteriums until fully deuterated, 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 is C 1-6 The haloalkyl 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 is C 1-6 alkyl;

[1346] R s1c is C 1-6 haloalkyl.

[1347] A compound of 7.1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, said compound being selected from:

[1348]

[1349]

[1350]

[1351]

[1352] 8. A pharmaceutical composition comprising a compound according to any one of 1 - 7 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.

[1353] 9. Use of a compound according to any one of 1 - 7 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, in the manufacture of a drug for use as a voltage - gated sodium channel inhibitor;

[1354] Preferably, the voltage-gated sodium channel inhibitor is a sodium channel 1.8 (NaV1.8) inhibitor;

[1355] Preferably, the voltage-gated sodium channel inhibitor is used for treating diseases selected from the following: acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy or epileptic disorders, neurodegenerative diseases, mental disorders such as anxiety and depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe or refractory 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 activity;

[1356] Preferably, the diseases are selected from radicular pain, sciatica, back pain, headache, neck pain, refractory pain, acute pain, postoperative pain, back pain, tinnitus or cancer pain.

Claims

1. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

2. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

3. A compound having the following 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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