Compounds as voltage-gated sodium channel inhibitors

Abstract

The present invention provides a compound as a voltage-gated sodium channel inhibitor, a method for preparing the same, a pharmaceutical composition thereof and use thereof. The compound has the structural feature of formula (I). TIFF2025529613000189.tif32128

Description

[Technical Field]

[0001] The present invention relates to a compound as a voltage-gated sodium channel inhibitor, its preparation method, pharmaceutical composition and use thereof. The compound has the structural feature of formula (I). [Background technology]

[0002] background There are nine main subtypes of human Navs, Nav1.1 to Nav1.9. Nav subtypes are classified as TTX-sensitive (TTX-S) or TTX-insensitive (TTX-R) depending on whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX). The tissue expression of different subtypes varies greatly.

[0003] Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7 are TTX-S type. 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 CNS.

[0004] Nav1.5, Nav1.8, and Nav1.9 are TTX-R type. Nav1.5 is mainly present in cardiac myocytes, while Nav1.8 and Nav1.9 are present in the dorsal root ganglia of the peripheral nervous system (PNS-DRG).

[0005] (Table 1) Nav subtype information TIFF2025529613000002.tif76138

[0006] Research has shown that ion channel changes are the molecular basis for peripheral sensitization, central sensitization, and disinhibition after inflammation or neuropathological injury, and are also an important molecular mechanism for pain generation. Currently, Nav inhibitors have proven effective. For example, the local anesthetic lidocaine relieves pain by inhibiting Nav, and nonselective Nav inhibitors such as lamotrigine, lacosamide, and mexiletine have been successfully used to treat chronic pain. However, due to a lack of subtype selectivity, currently clinically used Nav inhibitors can only inhibit sodium ion channels expressed in the heart and central nervous system. Their therapeutic window is narrow, limiting their scope of application.

[0007] Highly selective Nav1.8 inhibitors are an important direction for research and development of voltage-gated sodium ion channels. Nav1.8 is primarily distributed in the peripheral nervous system and localized in pain-sensing neurons, making it a highly selective target for pain treatment. Therefore, selective inhibition of Nav1.8 holds great promise for reducing potential toxic side effects.

[0008] Nav1.8 is a subtype of voltage-gated sodium ion channel (VGSC / Nav).

[0009] NaV1.8 is involved in the conduction and transmission of nociceptive action potentials. Due to its depolarizing voltage-dependence, NaV1.8 is a key mediator of the ascending phase of action potentials. NaV1.8 also contributes to repetitive high-frequency discharges due to its ability to rapidly recover from inactivation. Pain propagation can be blocked by inhibiting the activity of NaV1.8. Because NaV1.8 is primarily expressed in neurons that transmit pain signals in the dorsal root ganglion (DRG) of the peripheral nervous system, selective inhibition of NaV1.8 can also effectively reduce potential toxic side effects.

[0010] There is currently a need for drugs with superior activity as voltage-gated sodium channel inhibitors that specifically and selectively inhibit Nav1.8, thereby providing therapeutic benefit in the treatment of disease. Summary of the Invention

[0011] overview Based on the above, the present invention provides compounds as voltage-gated sodium channel inhibitors, which have the activity of selectively inhibiting Nav1.8, and are therefore useful for treating various diseases mediated by Nav1.8, particularly various types of pain.

[0012] The present invention relates to a compound of general formula (I): TIFF2025529613000003.tif32128 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof; wherein each substituent is as defined in the present invention.

[0013] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition further comprises another therapeutic agent.

[0014] In one embodiment, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament as a voltage-gated sodium channel inhibitor.

[0015] In one embodiment, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament as a sodium ion channel 1.8 (NaV1.8) inhibitor.

[0016] In one embodiment, the present invention provides the use of a compound defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same, as an inhibitor of a voltage-gated sodium channel.

[0017] In one embodiment, the present invention provides the use of a compound defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same, as an inhibitor of sodium ion channel 1.8 (NaV1.8).

[0018] In one embodiment, the present invention provides a method of inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject a compound defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same.

[0019] In one embodiment, the present invention provides a method of inhibiting sodium ion channel 1.8 (NaV1.8) in a subject, comprising administering to the subject a compound defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising any of them.

[0020] The voltage-gated sodium channel inhibitors according to the present invention are useful for the treatment of a disease selected from acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or status epilepticus, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, bipolar disorder, muscle rigidity, cardiac arrhythmias, 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 intractable pain, nociceptive pain, penetrating pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress or exercise-induced angina, palpitations, hypertension, migraine, or abnormal gastrointestinal activity.

[0021] In some embodiments, the disease associated with the methods of the present invention is selected from radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, post-surgical pain, back pain, tinnitus, or cancer pain. DETAILED DESCRIPTION OF THE INVENTION

[0022] definition The compounds of the present invention, their preparation methods, pharmaceutical compositions and uses thereof will be described in more 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 to provide a thorough and complete understanding of the present disclosure.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the present invention. As used herein, the term "and / or" means any and all combinations of one or more of the associated listed items.

[0024] Unless otherwise stated, terms used in the specification and claims have the following meanings.

[0025] The elements contained in the groups and compounds described in the present invention include carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen, and include their isotopes. Furthermore, the elements of carbon, hydrogen, oxygen, sulfur, or nitrogen contained in the groups and compounds of the present invention may be further replaced with one or more corresponding isotopes. The carbon isotopes include 12 C. 13 C and C 14 Isotopes of hydrogen include protium (H), deuterium (D, or heavy hydrogen), and tritium (T, or superheavy hydrogen), and isotopes of oxygen include 16 O. 17 O, and 18 O, sulfur isotopes 32 S, 33 S, 34 S, and 36 S, as an isotope of nitrogen 14 N and 15 N, fluorine isotopes 19 F, the isotope of chlorine is 35 Cl, 36 Cl, and 37 The isotopes of Cl and bromine are 79 Br and 81 Contains Br.

[0026] The term "alkyl" refers to a saturated straight-chain or branched-chain aliphatic hydrocarbon group, specifically a saturated hydrocarbon containing primary (normal), secondary, tertiary, or quaternary carbon atoms, or a combination thereof. For example, "C 1~6Phrases containing the term "alkyl" refer to alkyls containing 1 to 6 carbon atoms, each occurrence of which may independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. An embodiment may include alkyls containing 1 to 20 carbon atoms, preferably alkyls containing 1 to 10 carbon atoms, and more preferably lower alkyls containing 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non-limiting examples of alkyls 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, t-butyl, -C(C H3)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 (-CH2CH2CH2CH2CH2CH2CH3), hex-2-yl (-CH(CH3)CH2CH2CH2CH2CH3), 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(CH 3)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(CH3C(CH3)3), octyl (-(CH2)7CH3), and n-nonyl, as well as various branched isomers thereof.Alkyl can be substituted or unsubstituted. When alkyl is substituted, unless otherwise defined, preferably 1 to 5 substituents are present, and the substituents are independently selected from F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0027] "Alkenyl" refers to alkyl, as defined herein, containing at least one carbon-carbon double bond. In one example, alkenyl 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 groups, 2-propenyl groups, 3-butenyl groups, 2-butenyl groups, 4-pentenyl groups, 3-pentenyl groups, 2-hexenyl groups, 3-hexenyl groups, 2-heptenyl groups, 3-heptenyl groups, 4-heptenyl groups, 3-octenyl groups, 3-nonenyl groups, and 4-decenyl groups. When an alkenyl group is substituted, unless otherwise defined, preferably 1 to 5 substituents are present, and the substituents are independently selected from F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino groups.

[0028] "Alkynyl" refers to alkyl, as defined herein, containing at least one carbon-carbon triple bond. In one example, alkynyl 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 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. If an alkynyl is substituted, unless otherwise defined, there are preferably 1 to 5 substituents, the substituents being independently selected from F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0029] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic carbon-containing group. In one embodiment, cycloalkyl is a 3- to 6-membered (C 3~6 ) Monocyclic, 3-8 membered (C 3~8 ) Monocyclic, 3-10 membered (C 3~10 ) Monocyclic, 4-12 membered bicyclic (C 4~12 ), or 10 to 15 members (C 10~15 ) tricyclic systems. Carbocycles include bridged or spirocycles. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, and the like. Cycloalkyl groups may be substituted. When a cycloalkyl is substituted, preferably 1 to 5 substituents are present, unless otherwise defined, and the substituents are independently selected from F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0030] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted, saturated or partially unsaturated, monocyclic or polycyclic group containing a heteroatom selected from N, O, and S. In one embodiment, the heterocyclyl may be a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic system. The heterocyclyl is preferably a 3- to 10-membered monocyclic or bicyclic heterocyclyl, more preferably a 5- to 8-membered monocyclic or bicyclic heterocyclyl, containing at least one, preferably 1-4, 1-3, or 1-2 heteroatoms selected from N, O, or S. The heteroatom N or S in a heterocycle, if present, may be oxidized to various oxidation states, for example, to form an N-oxide. The heterocycle may be attached to the rest of the molecule via a heteroatom or a carbon atom. The heterocycle includes bridged or spiro rings. Non-limiting examples of monocyclic heterocycles include oxirane, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, dithiolanyl, oxacyclohexyl, thiacyclohexyl, azacyclohexyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dihydropyridyl, tetrahydrothienyl, thiothiolated tetrahydrothienyl, etc. Non-limiting examples of bicyclic heterocyclyls include benzodihydrofuran, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, octahydrocyclopentadienopyrrole, octahydropyrrolopyrrolyl, octahydrocyclopentadienyl, etc. If a heterocyclyl is substituted, unless otherwise defined, there are preferably 1 to 5 substituents, the substituents being independently selected from F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0031] "Aryl" refers to a substituted or unsubstituted all-carbon monocyclic or fused polycyclic unsaturated group having a conjugated π-electron system. In one embodiment, an aryl is a 6- to 14-membered aromatic ring, preferably a 6- to 10-membered aromatic ring. Non-limiting examples of an aryl include phenyl or naphthyl. An aryl may be fused to a heteroaryl, heterocyclyl, or cycloalkyl, and the point of attachment to the molecular moiety is on the aryl. Non-limiting examples of an aryl include benzene. When an aryl is substituted, unless otherwise defined, preferably 1 to 5 substituents are present, and the substituents are independently selected from F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0032] "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, heteroaryl is a 5- to 15-membered heteroaromatic ring, a 5- to 14-membered heteroaryl, or preferably a 5- to 10-membered heteroaromatic ring, or more preferably a 5- to 6-membered heteroaryl, each of which contains 1 to 4, preferably 1 to 3, and more preferably 1 to 2 heteroatoms. Non-limiting examples of heteroaryl include pyrrolyl, furanyl, thienyl, N-alkylpyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuran, benzimidazole, benzopyridine, or pyrrolopyridine. When heteroaryl is substituted, unless otherwise defined, preferably 1 to 5 substituents are present, and the substituents are independently selected from F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0033] "Halogen" means F, Cl, Br, or I. "Halogenation" refers to the replacement of one or more hydrogen atoms in a molecule or group with a halogen selected from F, Cl, Br, or I.

[0034] In various sections of this invention, linking substituents are described. When a structure explicitly requires a linking group, the Markush variable recited for that group should be understood as the linking group. For example, if a structure requires a linking group and the Markush group definition for this variable recites "alkyl" or "aryl," then "alkyl" or "aryl" should be understood to represent a linking alkylene group or arylene group, respectively. In some specific structures, when an alkyl group is explicitly represented as a linking group, the alkyl group represents a linking alkylene group, e.g., the alkyl in the group "-C1-C3 haloalkyl" should be understood as alkylene.

[0035] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts formed with inorganic acids or 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, secondary, or tertiary amines. Primary, secondary, or tertiary amines include naturally occurring substituted or unsubstituted amines, cyclic amines, and basic ion exchange resins (e.g., ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benethamine penicillin, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, trometamol, purine, piperidine, piperidine, N-ethylpiperidine, or polyamine resins). Salts derived from inorganic 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, methylparaben ... Examples of the carboxylic acids include citric 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, and trifluoromethanesulfonic acid.

[0036] The term "solvate," also known as a "solvate," refers to a compound containing solvent molecules, which can be bound to the compound molecule by methods including coordinate bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds, and the like. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, further including stoichiometric and non-stoichiometric solvates. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0037] The term "hydrate" refers to a compound bound to water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of compound molecules in the hydrate is deterministic. Thus, a hydrate of a compound can be represented by a general formula such as R x HO, where R is the compound and x is a number greater than 0. A given compound can form multiple types of hydrates, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrate (R 0.5 HO)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R 2 HO) and hexahydrate (R 6 HO)).

[0038] The term "prodrug" refers to any compound that, when administered to an organism, produces a drug substance, i.e., an active ingredient, as a result of spontaneous chemical reaction, enzyme-catalyzed chemical reaction, photolysis, and / or metabolic chemical reaction. Thus, a prodrug is a covalently modified analog or latent form of a therapeutically active compound. Suitable examples include, but are not limited to, compounds in the following forms: carboxylate esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfonate esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like.

[0039] The present invention also includes isotopically labeled compounds (isotopic variants), which are equivalent to the general formula compounds or specific compounds in this application, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, e.g., 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, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are all within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those that contain radioactive isotopes (e.g., 3 H and 14 Compounds incorporating C) are useful in drug and / or substrate tissue distribution assays. 3 H isotopes and carbon-14, i.e. 14C isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, deuterium (i.e., C) isotopes are preferred because the substituted compounds may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. 2 Substitution with heavier isotopes, such as H, may be preferred. Isotopically labeled compounds of the invention and prodrugs thereof may generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in carrying out the processes disclosed in the following procedures and / or examples and preparations.

[0040] The compounds of the present invention contain one or more asymmetric centers and therefore may have multiple stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds of the present invention may be in the form of separate enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including the following: chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis.

[0041] "Optional" or "may" means that the subsequently described event or circumstance may occur, but need not occur, and includes both the occurrence and non-occurrence of the event or circumstance. For example, "an aryl may be substituted with an alkyl" means that alkyl may be present, but is not necessarily present; the term includes both cases where the aryl is substituted with an alkyl and cases where the aryl is not substituted with an alkyl.

[0042] A "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or agent, 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 agents, and absorption delaying agents that are compatible with pharmaceutical administration. Each excipient must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not injurious 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, substituted or unsubstituted β-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, (10) oils such as corn oil and soybean oil, (11) diols such as propylene glycol, (12) polyols such as glycerin, sorbitol, mannitol, polyethylene glycol, (13) esters such as ethyl oleate and ethyl laurate, (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 drug formulations.

[0043] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) in a particular 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 shape, optical and electrical properties, stability, and / or solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0044] Unless otherwise specified, all technical and scientific terms used herein have standard meanings in the field to which the claimed subject matter belongs. In the event that there are multiple definitions for a term, those herein shall prevail. As used herein, singular forms such as "a," "an," and "one" should be understood to include plural referents unless otherwise specified.

[0045] Furthermore, the terms "comprise" and "include" are intended to be non-limiting, i.e., to include the subject matter specified in the present invention but not to exclude the subject matter of other aspects.

[0046] Unless otherwise indicated, the present invention uses conventional methods such as mass spectrometry, nuclear magnetic spectrometry, etc. to identify compounds, and the steps and conditions may refer to conventional operating steps and conditions in the art.

[0047] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques in analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and testing of the performance of light-emitting devices.

[0048] In addition, unless otherwise specified, it should be noted that the expression "independently of each other" used in the present invention should be understood in a broad sense and means that the described entities are independent of each other and can be independently the same specific group or different specific groups. More specifically, the expression "independently of each other" may mean that specific options represented by the same symbol in different groups do not affect each other, or that specific options represented by the same symbol in the same group do not affect each other.

[0049] The dosage form and administration route of the compound of the present invention or a composition thereof are not particularly limited.

[0050] Exemplary routes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intraperitoneal, intramuscular, or subcutaneous) injection, and / or topical administration.

[0051] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In these solid dosage forms, active compound is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binder, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) moisturizer, such as glycerin; (d) disintegrant, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, complex silicate. sodium carbonate; (e) solvents, such as paraffin; (f) absorption enhancers, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl 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.

[0052] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents (e.g., water or other solvents), solubilizers, and emulsifiers conventionally used in the art. Specific examples include ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. In addition to the inert diluent, the composition may further contain adjuvants such as wetting agents, suspending agents, sweeteners, flavorings, and perfumes. For example, suspensions may contain suspending agents. Specific examples include ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0053] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents, or excipients are selected from water, ethanol, and polyols, or suitable mixtures thereof.

[0054] Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalants, which are prepared under sterile conditions by mixing the active ingredient with a pharmaceutically acceptable carrier, along with preservatives, buffers, and / or propellants as required.

[0055] The present invention relates to the following embodiments.

[0056] In one embodiment, the present invention provides a compound of general formula (I'): TIFF2025529613000004.tif33128 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, During the ceremony, X is N or CR x and Y is N or CR y and Z is N or CR z and W is N or CR w and G is N or CR g and However, at most two of X, Y, and Z are simultaneously N, R x , R y and R z are each independently H, D, halogen, CN, or 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 is -L1-R1, and the group may be substituted with one or more deuterium atoms until fully deuterated; R w and R g are each independently H, D, halogen, CN, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, and -OR s1 and wherein these groups may be substituted with one or more deuterium atoms until fully deuterated; -L1- is -(CR a R b ) m -, and if valence is allowed, -(CR a R b ) m Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R a and R b together with the carbon atoms to which they are attached, form C 3~8forming a cycloalkyl or 3- to 10-membered heterocyclyl; R1 is -S(O) q -NR'R'', -S(O)(=NR')R4, or -N=S(O)R4R4'; A is C 3~8 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, and is optionally substituted with s R2 substituents; -L2- is a bond, -O-, -NR'-, -S-, -C(O)-, and -(CR c R d ) n -, and where valence allows, -(CR c R d ) n Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R c and R d together with the carbon atoms to which they are attached, form C 3~8 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R' is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R'' is -L3-B, B is C 3~8 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, and is optionally substituted with t R5 substituents; -L3- is -(CR e R f ) p -, and if valence is allowed, -(CR e R f ) p Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R eand R f together with the carbon atoms to which they are attached, form C 3~8 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R2, R 3a , R 3b , R 3c and R 3d H, D, halogen, CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, -OR s1 , -SR s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R4 and R4' are each independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; Each R5 is H, D, halogen, CN, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, -OR s1 , -SR s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R6 is H, C 1~6 Alkyl, and C1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R a , R b , R c , R d , R e , and R f are independently H, D, halogen, CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1 and R s2 are independently H, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; t is 1, 2, 3, 4, or 5; s is 1, 2, 3, 4, 5, 6, 7, or 8; q is 1 or 2.

[0057] In one embodiment, the present invention provides a compound of general formula (I): TIFF2025529613000005.tif32128 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, During the ceremony, X is N or CR x and Y is N or CR y and Z is N or CR z and W is N or CR w and G is N or CR g and However, at most two of X, Y, and Z are simultaneously N, R x , R y and R z are each independently H, D, halogen, CN, or 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 is -L1-R1, and the group may be substituted with one or more deuterium atoms until fully deuterated; R w and R g are each independently H, D, halogen, CN, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, and -OR s1 and wherein these groups may be substituted with one or more deuterium atoms until fully deuterated; -L1- is -(CR a R b ) m -, and if valence is allowed, -(CR a R b ) m Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R a and R b together with the carbon atoms to which they are attached, form C 3~8 forming a cycloalkyl or 3- to 10-membered heterocyclyl; R1 is -S(O) q NR'R'' or -S(O)(=NR')R1, A is C 3~8 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10aryl, and 5- to 10-membered heteroaryl, optionally substituted with s R2 substituents; -L2- is a bond, -O-, -NR'-, -S-, -C(O)-, and -(CR c R d ) n -, and where valence allows, -(CR c R d ) n Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R c and R d together with the carbon atoms to which they are attached, form C 3~8 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R' is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R'' is -L3-B, B is C 3~8 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, optionally substituted with t R5 substituents; -L3- is -(CR e R f ) p -, and if valence is allowed, -(CR e R f ) p Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R e and R f together with the carbon atoms to which they are attached, form C 3~8 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R2, R 3a , R 3b , R 3c and R 3d H, D, halogen, CN, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, -OR s1 , -SR s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R4 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; Each R5 is H, D, halogen, CN, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, -OR s1 , -SR s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R6 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R a , R b , R c , R d , R e , and R f are independently H, D, halogen, CN, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1 and R s2 are independently H, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; t is 1, 2, 3, 4, or 5; s is 1, 2, 3, 4, 5, 6, 7, or 8; q is 1 or 2.

[0058] In one embodiment, the present invention relates to a compound represented by formula (I) or (I') above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, which is represented by formula (II): TIFF2025529613000006.tif34128.

[0059] In one embodiment, the present invention relates to a compound represented by formula (I) or (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein -L2- is -O-.

[0060] In one embodiment, the present invention relates to a compound represented by the above formula (I) or (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein -L2- is a bond.

[0061] In one embodiment, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer treatment ... 3~6 The present invention relates to the compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein the compound is selected from cycloalkyl, 5- to 6-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0062] In one embodiment, the present invention relates to the aforementioned 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, azepanyl, diazepanyl, octahydrocyclopentadienopyrrole, octahydropyrrolopyrrolyl, octahydrocyclopentadienyl, phenyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl.

[0063] In one embodiment, the present invention relates to the aforementioned compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein m is 0.

[0064] In one embodiment, the present invention relates to the compound described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein m is 1, 2, 3, 4, or 5; -(CR a R b ) m Any methylene unit in - may be independently replaced by -O-, -S-, and -C(O)-, and / or R a and R b together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl and a 3- to 5-membered heterocyclyl; R ais H, C 1~6 Alkyl, and C 1~6 haloalkyl; R b is H, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0065] In one embodiment, the present invention provides a compound represented by formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, having formula (III): This relates to the compound TIFF2025529613000007.tif41128.

[0066] In one embodiment, the present invention provides a compound represented by formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, having formula (IV): Regarding the compound TIFF2025529613000008.tif41128, During the ceremony, X is N or CR x and Y is N or CR y and R x and R y are each independently H, D, halogen, or C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R' is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R'' is -L3-B, B is a 5- to 7-membered heterocyclyl, optionally substituted with t R5 substituents; -L3- is -(CR e R f )p -, and if valence is allowed, -(CR e R f ) p any methylene unit in - may be independently replaced by -O-, -S-, and -C(O)-; R 2a , R 2b , R 2c , R 2d , R 2e , R 3a , R 3b , R 3c and R 3d H, D, halogen, CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, -OR s1 , -SR s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and wherein the group may be substituted with one or more deuterium atoms until fully deuterated; Each R5 is independently H, C 1~6 Alkyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R e and R f are independently H, D, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1 and R s2 are independently H, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; p is 0, 1, 2, or 3; t is 1, 2, or 3.

[0067] In one embodiment, the present invention relates to a compound represented by formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N, R x H, D, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R' is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R'' is -L3-B, B is a 5- to 6-membered heterocyclyl, optionally substituted with t R5 substituents; -L3- is -(CR e R f ) p - and R 2a , R 2b , R 2c , R 2d , R 2e , R 3a , R 3b , R 3c , and R 3d are independently H, D, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; Each R5 is independently H, D, C 1~6 Alkyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R e and R f are independently H, D, C1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; p is 0, 1, 2, or 3; t is 1, 2 or 3; Preferably, -L3-B is Selected from TIFF2025529613000009.tif23148.

[0068] In one embodiment, the present invention relates to a compound represented by formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N, R x is H or D, R' is H, R'' is -L3-B, B is a 5- to 6-membered heterocyclyl, preferably azacyclopentyl or azacyclohexyl; -L3- is -(CR e R f ) p - and p is 0 or 1; R 2a is C 1~6 alkyl, preferably methyl; R 2b is H or D, R 2c is a halogen, preferably F, R 2d is H or D, R 2e is H or D, R 3a is H or D, R 3b is C 1~6 haloalkyl, preferably -CF; R 3c is a halogen, preferably Cl, R 3d is H or D, R e H, D, and C 1~6 alkyl, R f H, D, and C 1~6 alkyl, Preferably, -L3-B is Selected from TIFF2025529613000010.tif17128.

[0069] In one embodiment, the present invention relates to a compound represented by the above general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, which is represented by formula (V): The file is TIFF2025529613000011.tif39128.

[0070] In one embodiment, the present invention relates to a compound represented by formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is N or CR x and Y is N or CR y and R x and R y are each independently H, D, halogen, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, and -OR s1 and wherein these groups may be substituted with one or more deuterium atoms until fully deuterated; -L2- is a bond, -O-, -S-, or -NH-; A is phenyl, C 3~8 selected from cycloalkyl, 5- to 6-membered heteroaryl, and 5- to 10-membered heterocyclyl, optionally substituted by s R2 substituents; If valence is allowed, -(CR a R b ) m any methylene unit in - may be independently replaced by -O-, -S-, and -C(O)-; R' is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R2, R 3a , R 3b , R 3c and R 3d H, D, halogen, CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, -OR s1 , -SR s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R4 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R a and R b H, D, halogen, C 1~6 Alkyl, or C 1~6 haloalkyl, which groups are substituted with one or more deuterium atoms until fully deuterated; or R a and R b together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl and a 3- to 5-membered heterocyclyl; R s1 and R s2 are independently H, C1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; m is 0, 1, 2, 3 or 4; s is 1, 2, 3, 4, 5, 6, 7, or 8.

[0071] In one embodiment, the present invention relates to a compound represented by formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N or CR y and R x and R y are each independently H, D, halogen, and C 1~6 alkyl, which groups may be substituted with one or more deuterium atoms until fully deuterated; A is, TIFF2025529613000012.tif18128 and 5- to 8-membered heterocyclyl, optionally substituted by s R2 substituents; If valence is allowed, -(CR a R b ) m any methylene unit in - is optionally independently replaced with -O-; -L2- is a bond or -O-; R' is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; Each R2 is independently H, D, halogen, or C 1~6 Alkyl, C 1~6 Haloalkyl, and -OR s1 wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R 2a H, D, halogen, C1~6 Alkyl, C 1~6 Haloalkyl, -OR s1a , and -SR s1a which group may be substituted with one or more deuterium atoms until fully deuterated; R 2b is H or D, R 2c H, D, halogen, -OR s1c , or -SR s1c and R 2d is H or D, R 2e is H or D, R 3a is H or D, R 3b is C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 3c is a halogen, R 3d is H or D, R4 is C 1~6 Alkyl and C 1~6 haloalkyl, which is substituted with one or more deuterium atoms until fully deuterated; R a and R b H, D, halogens, and C 1~6 alkyl, which groups may be substituted with one or more deuterium atoms until fully deuterated; or R a and R b together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, Each R s1 are independently H, C 1~6 Alkyl, or C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R s1a is H, C 1~6 Alkyl, or C 1~6haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1c is H, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; m is 1, 2 or 3; s is 1 or 2.

[0072] In one embodiment, the present invention relates to a compound represented by formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N or CR y and R x is H, R y is a halogen, A is, TIFF2025529613000013.tif18128 and azepanil, and substituted with s R2; -(CR a R b ) m - is -CH2-, -O-CH2-CH2-, Selected from TIFF2025529613000014.tif9128, -L2- is a bond or -O-; R' is H, each R2 is independently selected from H and halogen, preferably F, and the group is substituted with one or more deuterium atoms until fully deuterated; R 2a is H or C 1~6 alkyl, preferably methyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 2b is H, R 2cis halogen or -OR s1c and R 2d is H, R 2e is H, R 3a is H, R 3b is C 1~6 haloalkyl, preferably -CF; R 3c is a halogen, preferably Cl, R 3d is H, R4 is C 1~6 alkyl, preferably methyl; R s1c is H, C 1~6 Alkyl, or C 1~6 haloalkyl, preferably -CF; s is 1 or 2.

[0073] In one embodiment, the present invention provides a compound represented by formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, having formula (VI): TIFF2025529613000015.tif37128.

[0074] In one embodiment, the present invention relates to a compound represented by formula (VI) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is N or CR x and Y is N or CR y and R x and R y are each independently H, D, halogen, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, and -ORs1 and wherein these groups may be substituted with one or more deuterium atoms until fully deuterated; -L2- is a bond, -O-, -S-, or -NH-; A is phenyl, C 3~8 selected from cycloalkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, optionally substituted by s R2 substituents; R' is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R2, R 3a , R 3b , R 3c and R 3d H, D, halogen, CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, OR s1 , S.R. s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R4 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1 and R s2 are independently H, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; s is 1, 2, 3, 4, 5, 6, 7, or 8.

[0075] In one embodiment, the present invention relates to a compound represented by formula (VI) above, 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, azepanyl, diazepanyl, octahydrocyclopentadienopyrrole, octahydropyrrolopyrrolyl, octahydrocyclopentadienyl, phenyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, preferably A and its substituents are Selected from TIFF2025529613000016.tif34154, In the formula, R 2a , R 2b , R 2c and R 2d H, D, halogen, CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, -OR s1 , -SR s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and the group may be substituted with one or more deuterium atoms until fully deuterated.

[0076] In one embodiment, the present invention relates to a compound represented by formula (VI) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: -L2- is -O-, and A is selected from cyclopentyl and cyclohexyl, preferably cyclohexyl.

[0077] In one embodiment, the present invention relates to a compound represented by formula (VI) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: -L2- is a bond, A is selected from azepanyl, diazepanyl, octahydrocyclopentadienopyrrole, octahydropyrrolopyrrolyl and octahydrocyclopentadienyl, preferably when A is a nitrogen-containing heterocycle, A is linked to the phenyl via the nitrogen atom.

[0078] In one embodiment, the present invention relates to a compound represented by formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, which is represented by formula (VII): TIFF2025529613000017.tif37128, During the ceremony, X is N or CR x and Y is N or CR y and R x and R y are each independently H, D, halogen, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R' is H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein the group is substituted with one or more deuterium atoms until fully deuterated; R 2a , R 2b , R 2c , R 2d , R 2e , R 3a , R 3b , R 3c and R 3d H, D, halogen, CN, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, -OR s1 , -SR s1 , N.R. s1 R s2 , -C(O)R s1 , -C(O)OR s1 , -C(O)NR s1 R s2 , -SOR s1 and -SO2R s1 and wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R4 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1 and R s2 are independently H, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated.

[0079] In one embodiment, the present invention relates to a compound represented by formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is N or CR x and Y is N or CR y and R x and R y are each independently H, D, halogen, or C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R' is H, C 1~6 Alkyl, and C 1~6haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R 2a H, D, halogen, -OR s1a , -SR s1a , N.R. s1a R s2a , C 1~6 Alkyl, and C 1~6 haloalkyl, wherein the group is substituted with one or more deuterium atoms until fully deuterated; R 2b H, D, halogen, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 2c H, D, halogen, -OR s1c , -SR s1c , N.R. s1c R s2c , C 1~6 Alkyl, and C 1~6 haloalkyl, which groups may be optionally substituted with one or more deuterium atoms until fully deuterated; R 2d H, D, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl, which is substituted with one or more deuterium atoms until fully deuterated; R 2e H, D, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 3a H, D, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 3b H, D, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl, which is substituted with one or more deuterium atoms until fully deuterated; R 3c H, D, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 3d H, D, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl, which is substituted with one or more deuterium atoms until fully deuterated; R4 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1a , R s2a , R s1c , and R s2c are independently H, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated.

[0080] In one embodiment, the present invention relates to a compound represented by formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N or CR y and R x and R y are independently H, D, halogen, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R' is H, C 1~6 Alkyl, or C 1~6 haloalkyl, where the group may be optionally substituted with one or more deuterium atoms until fully deuterated; R 2a -ORs1a , -SR s1a , N.R. s1a R s2a , C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 2b is H, D, or halogen; R 2c H, D, halogen, -OR s1c , -SR s1c , or NR s1c R s2c which group may be substituted with one or more deuterium atoms until fully deuterated; R 2d is H, D, or halogen; R 2e is H, D, or halogen; R 3a is H, D, or halogen; R 3b H, D, halogen, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 3c is H, D, or halogen; R 3d is H, D, or halogen; R4 is H, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1a , R s2a , R s1c , and R s2c are independently H, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; However, if Y is N, then R 2a is C 1~6 Alkyl or C 1~6Not haloalkyl.

[0081] In one embodiment, the present invention relates to a compound represented by formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N or CR y and R x and R y are independently selected from H, D, or halogen; R' is H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 2a -OR s1a , -SR s1a , C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 2b is H, D, or halogen; R 2c H, D, halogen, -OR s1c , or -SR s1c wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R 2d is H or D, R 2e is H or D, R 3a is H or D, R 3b is C 1~6 is haloalkyl, R 3c is a halogen, R 3d is H or D, R4 is C 1~6 Alkyl or C 1~6 is haloalkyl, R s1a and R s1cindependently, C 1~6 Alkyl or C 1~6 haloalkyl; However, if Y is N, then R 2a is C 1~6 Alkyl or C 1~6 Not haloalkyl.

[0082] In one embodiment, the present invention relates to a compound represented by formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N or CR y and R x and R y are independently selected from H, D, or halogen; R' is H, R 2a -OR s1a , -SR s1a , or C 1~6 alkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 2b is H or D, R 2c is halogen, -OR s1c , or -SR s1c which group may be substituted with one or more deuterium atoms until fully deuterated; R 2d is H or D, R 2e is H or D, R 3a is H or D, R 3b is C 1~6 Alkyl or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 3c is a halogen, R 3dis H or D, R4 is C 1~6 Alkyl or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1a and R s1c are independently H, C 1~6 Alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated.

[0083] In one embodiment, the present invention relates to a compound represented by formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N or CR y and R x is H or D, R y is H, D, or halogen; R' is H, R 2a -OR s1a or -SR s1a wherein the group may be substituted with one or more deuterium atoms until fully deuterated; R 2b is H or D, R 2c is halogen, -OR s1c or -SR s1c and R 2d is H or D, R 2e is H or D, R 3a is H or D, R 3b is C 1~6 Alkyl or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R 3c is a halogen, R 3d is H or D, R4 is C 1~6 Alkyl or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated; R s1a and R s1c independently, C 1~6 Alkyl or C 1~6 haloalkyl, which may be substituted with one or more deuterium atoms until fully deuterated.

[0084] In one embodiment, the present invention relates to a compound represented by formula (VII) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein: X is CR x and Y is N or CR y and R x is H, R y is a halogen, preferably F, R' is H, R 2a -OR s1a which may be substituted with one or more deuterium atoms until fully deuterated, preferably -OCD3; R 2b is H, R 2c is halogen or -OR s1c is preferably F or -OCF3, R 2d is H, R 2e is H, R 3a is H, R 3b is C 1~6 haloalkyl, preferably -CF; R3c is a halogen, preferably Cl, R 3d is H, R4 is C 1~6 is alkyl, R s1a is C 1~6 is alkyl, R s1c is C 1~6 It is haloalkyl.

[0085] In one particular embodiment, the compound is selected from the following structures: TIFF2025529613000018.tif43128TIFF2025529613000019.tif247106TIFF2025529613000020.tif215104TIFF2025529613000021.tif174128.

[0086] In one particular embodiment, the present invention relates to a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition further comprises another therapeutic agent.

[0087] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition further comprises another therapeutic agent.

[0088] In one embodiment, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament as a voltage-gated sodium channel inhibitor.

[0089] In one embodiment, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament as a sodium ion channel 1.8 (NaV1.8) inhibitor.

[0090] In one embodiment, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same, as an inhibitor of a voltage-gated sodium channel.

[0091] In one embodiment, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same, as an inhibitor of sodium ion channel 1.8 (NaV1.8).

[0092] In one embodiment, the present invention provides a method of inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject a compound defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising same.

[0093] In one embodiment, the present invention provides a method of inhibiting sodium ion channel 1.8 (NaV1.8) in a subject, comprising administering to the subject a compound defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising any of them.

[0094] The voltage-gated sodium channel inhibitors according to the present invention are useful for the treatment of a disease selected from acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or status epilepticus, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, bipolar disorder, muscle rigidity, cardiac arrhythmias, 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 intractable pain, nociceptive pain, penetrating pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress or exercise-induced angina, palpitations, hypertension, migraine, or abnormal gastrointestinal activity.

[0095] In some embodiments, the disease associated with the methods of the present invention is selected from radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, post-surgical pain, back pain, tinnitus, or cancer pain. [Example]

[0096] Materials or reagents used herein were either commercially available or prepared by synthetic methods generally known in the art.

[0097] Example 1 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(2-(methylamino)ethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 1)

[0098] TIFF2025529613000022.tif52149

[0099] Step 1: tert-butyl (2-(benzylthio)pyridin-4-yl)carbamate

[0100] TIFF2025529613000023.tif15128

[0101] 2-(Benzylthio)-4-bromopyridine (3.7 g, 13.214 mmol) was dissolved in ultra-dry dioxane (37 mL) and tert-butylcarbamate (3.1 g, 26.429 mmol), cesium carbonate (12.9 g, 39.643 mmol), tris(dibenzylideneacetone)dipalladium (Pd2dba3) (1.2 g, 1.321 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (XantPhos) (1.5 g, 2.643 mmol) were added. The atmosphere was purged with nitrogen and the mixture was stirred in an oil bath at 100 °C for 16 h. The reaction was quenched and the reaction solution was rotary evaporated in vacuo. The residue was dissolved in dichloroethane (40 ml), and the resulting solution was suction filtered through a fritted funnel filled with diatomaceous earth. The filter cake was washed with dichloroethane (80 ml). The filtrate was collected, rotary dried, and adsorbed onto silica gel to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain the title compound (3.7 g, yield: 77.6%, colorless oil).

[0102] MS(ESI):m / z 317.2[M+H] + .

[0103] Step 2: 2-(benzylthio)pyridin-4-amine

[0104] TIFF2025529613000024.tif15128

[0105] tert-Butyl (2-(benzylthio)pyridin-4-yl)carbamate (1 g, 3.16 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was added dropwise in an ice bath at 0°C, and the mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the reaction solution was quenched by adding saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated in vacuo to give the title compound (680 mg, colorless oil), which was used directly in the next reaction.

[0106] MS(ESI): m / z 217.1[M+H] + .

[0107] Step 3: N-(2-(benzylthio)pyridin-4-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)benzamide

[0108] TIFF2025529613000025.tif29128

[0109] 2-(Benzylthio)pyridin-4-amine (680 mg, 3.148 mmol) was dissolved in thionyl chloride (1 mL). After purging with nitrogen three times, the mixture was stirred at 80 °C for 2 hours and then rotary evaporated for further use. 5-Chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (763.6 mg, 3.148 mmol) was dissolved in methylene chloride (8 mL), and N,N-diisopropylethylamine (1.63 g, 12.592 mmol) was added dropwise at 0 °C in an ice bath to obtain a reaction solution. The reaction solution, which had been previously rotary evaporated, was dissolved in methylene chloride (1 mL) and added dropwise to the above reaction solution in an ice bath at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction was stopped. The reaction solution was rotary dried, and the residue was adsorbed onto silica gel. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain the title compound (370 mg, yield: 26.7%, colorless oil).

[0110] MS(ESI): m / z 441.1[M+H] + .

[0111] Step 4: N-(2-(benzylthio)pyridin-4-yl)-5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide

[0112] TIFF2025529613000026.tif28128

[0113] N-(2-(benzylthio)pyridin-4-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (330 mg, 0.749 mmol) was dissolved in N,N-dimethylformamide (3.3 mL), and 4-fluoro-2-methylphenol (94.3 mg, 0.749 mmol) and cesium carbonate (487.8 mg, 1.497 mmol) were added. The mixture was stirred in an oil bath at 100°C for 1 hour. The reaction was stopped, and water (5 mL) was added to quench the reaction solution. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried in vacuo to obtain a crude product, which was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain the title compound (343 mg, yield: 83.9%, colorless oil).

[0114] MS(ESI): m / z 547.0[M+H] + .

[0115] Step 5: 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride

[0116] TIFF2025529613000027.tif30128

[0117] N-(2-(benzylthio)pyridin-4-yl)-5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (100 mg, 0.183 mmol) was placed in a three-neck flask and purged with nitrogen. Glacial acetic acid:water:dichloromethane (7:1:2) (2 mL) was added to the flask, followed by 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (108 mg, 0.548 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was stopped, and water (3 mL) was added to quench the reaction solution. The aqueous phase was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated under vacuum to give the title compound (80 mg, crude product, pale yellow solid).

[0118] MS(ESI): m / z 523.1[M+H] + .

[0119] Step 6: tert-butyl (2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)ethyl)(methyl)carbamate

[0120] TIFF2025529613000028.tif28128

[0121] 4-(5-Chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (120 mg, 0.229 mmol) was dissolved in dichloromethane (1 mL), and a solution of tert-butyl(2-aminoethyl)(methyl)carbamate (39.9 mg, 0.229 mmol) in pyridine (1 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction was stopped, and the reaction solution was quenched by adding saturated sodium bicarbonate solution (3 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (2 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated in vacuo to give 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 (45 mg, yield: 29.8%, pale yellow solid).

[0122] MS(ESI): m / z 661.2[M+H] + .

[0123] Step 7: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(2-(methylamino))ethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 1)

[0124] TIFF2025529613000029.tif27128

[0125] tert-Butyl (2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)ethyl)(methyl)carbamate (59 mg, 0.089 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added in an ice bath at 0° C. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the reaction solution was spun in vacuo to remove the solvent, yielding a crude product. The crude product was purified by reverse-phase preparative chromatography (eluent: aqueous ammonia, water, acetonitrile) to yield the title compound (18.7 mg, yield: 37.5%, tan solid).

[0126] MS(ESI): m / z 561.1[M+H] + .

[0127] 1 H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.62(d,J=5.4Hz,1H),8.26(d,J=1.4Hz,1H),8.12(s,1H),7.77(d,J=5.3Hz,1H), 7.23-7.17(m,1H),7.10(dd,J=7.1,4.6Hz,3H),2.96(t,J=6.5Hz,2H),2.47(t,J=6.5Hz,2H),2.17(s,3H),2.16(s,3H).

[0128] Example 2 (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 2)

[0129] TIFF2025529613000030.tif39128

[0130] Step 1: tert-Butyl:(R)-3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)-benzamido)pyridine)-2-sulfonamido)pyrrolidine-1-carboxylic acid

[0131] TIFF2025529613000031.tif36128

[0132] 4-(5-Chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (300 mg, 0.57 mmol) and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (107 mg, 0.57 mmol) were dissolved in a mixture of pyridine (2 mL) and dichloromethane (4 mL) and reacted at 0°C for 2 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was diluted with water (10 mL), neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was spun under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (222 mg, yield: 58%, yellow solid).

[0133] MS(ESI): m / z 673.2[M+H] + .

[0134] 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)

[0135] TIFF2025529613000032.tif35128

[0136] tert-Butyl (R)-3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonylamino)pyrrolidine-1-carboxylate (210 mg, 0.312 mmol) was dissolved in a mixture of trifluoroacetic acid (2 mL) and dichloromethane (6 mL) and reacted at room temperature for 2 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was spun under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (eluent: formic acid, water, acetonitrile) to give the title compound (122.14 mg, yield: 68%, white solid).

[0137] MS(ESI): m / z 573.0[M+H] + .

[0138] 1 H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.65(d,J=5.4Hz,1H),8.34(d,J=1.7Hz,1H),8.1 2(s,1H),7.80(dd,J=5.4,1.9Hz,1H),7.21(dd,J=9.2,2.3Hz,1H),7.15-7.06(m,3H),4. 05-3.96(m,1H),3.22(dd,J=11.8,6.6Hz,1H),3.15(dd,J=15.2,7.8Hz,1H),3.10-3.05( m,1H),2.96(dd,J=11.8,5.4Hz,1H),2.17(s,3H),2.00-1.93(m,1H),1.81-1.74(m,1H).

[0139] Example 3 (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 3)

[0140] TIFF2025529613000033.tif39129

[0141] Step 1: tert-Butyl (S)-3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)pyrrolidine-1-carboxylic acid

[0142] TIFF2025529613000034.tif35128

[0143] 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 mixture of pyridine (2 mL) and dichloromethane (4 mL) and reacted at 0°C for 2 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was diluted with water (10 mL), neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was spun under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (210 mg, yield: 56%, yellow solid).

[0144] MS(ESI): m / z 673.3[M+H] + .

[0145] 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)

[0146] TIFF2025529613000035.tif36128

[0147] tert-Butyl (S)-3-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonylamino)pyrrolidine-1-carboxylate (210 mg, 0.312 mmol) was dissolved in a mixture of trifluoroacetic acid (2 mL) and dichloromethane (6 mL) and reacted at room temperature for 2 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The extract was dried over anhydrous sodium sulfate. After purification by high-performance liquid chromatography (eluent: formic acid, water, acetonitrile), the title compound was obtained (71.26 mg, yield: 40.0%, white solid).

[0148] MS(ESI): m / z 572.9[M+H] + .

[0149] 1 H NMR(400MHz,DMSO-d6)δ8.64(d,J=5.4Hz,1H),8.33(s,1H),8.31(d,J=1.8Hz, 1H),8.13(s,1H),7.81(dd,J=5.4,2.0Hz,1H),7.21(dd,J=9.2,2.7Hz,1H),7.1 4-7.05(m,3H),3.96-3.86(m,1H),3.07-2.97(m,2H),2.92(d,J=6.6Hz,1H),2. 77(dd,J=11.6,4.9Hz,1H),2.17(s,3H),1.92-1.87(m,1H),1.67-1.62(m,1H).

[0150] Example 4 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(piperidin-4-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 4)

[0151] TIFF2025529613000036.tif43128

[0152] Step 1: tert-Butyl 4-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)piperidine-1-carboxylic acid

[0153] TIFF2025529613000037.tif35128

[0154] tert-Butyl 4-aminopiperidine-1-carbamate (76.55 mg, 0.38 mmol) was dissolved in pyridine (2 mL) with stirring at room temperature. After the temperature was lowered to 0 °C, 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (200 mg, 0.38 mmol) was dissolved in dichloromethane (4 mL) and added dropwise to the reaction solution. The mixture was maintained at this temperature, stirred, and reacted for 2 hours. The reaction was stopped. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The extracts were combined, washed with 1N HCl (5 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was 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).

[0155] MS(ESI): m / z 687.2[M+H] + .

[0156] Step 2: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(piperidin-4-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 4)

[0157] TIFF2025529613000038.tif34128

[0158] While stirring at room temperature, tert-butyl 4-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonylamino)piperidine-1-carboxylate (120 mg, 0.17 mmol) was placed in a 25 mL one-neck flask and dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added. The mixture was returned to room temperature, stirred, and reacted at room temperature for 1 hour. The reaction was stopped, and 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 (eluent: formic acid, water, acetonitrile) to obtain the title compound (87.96 mg, yield: 85.8%, white solid).

[0159] MS(ESI): m / z 587.2[M+H] + .

[0160] Example 5 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(piperidin-4-ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 5)

[0161] TIFF2025529613000039.tif41128

[0162] Step 1: Tert-butyl 4-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)piperidine-1-carboxylate

[0163] TIFF2025529613000040.tif35128

[0164] 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (200 mg, 0.38 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (82 mg, 0.38 mmol) were added sequentially to a mixture of pyridine (2 mL) and dichloromethane (4 mL) at 0 °C and reacted for 2 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was diluted with water (10 mL), neutralized with 1N hydrochloric acid, and extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was spun under reduced pressure, and 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).

[0165] MS(ESI): m / z 701.1[M+H] + .

[0166] Step 2: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(piperidin-4-ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 5)

[0167] TIFF2025529613000041.tif37128

[0168] tert-Butyl 4-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonylamino)methyl)piperidine-1-carboxylate (100 mg, 0.143 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and dichloromethane (3 mL) and reacted at room temperature for 2 hours. The reaction was stopped, and the mixture was rotated under vacuum to remove the solvent. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was rotary evaporated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (eluent: formic acid, water, acetonitrile) to obtain the title compound (40.99 mg, yield: 48%, white solid).

[0169] MS(ESI): m / z 601.0[M+H] + .

[0170] 1 H NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.63(d,J=5.4Hz,1H),8.29(d,J=1.7Hz,1H ),8.12(s,1H),7.77(dd,J=5.4,1.9Hz,1H),7.21(dd,J=9.2,2.3Hz,1H),7.14-7.0 6(m,3H),3.19(d,J=12.0Hz,2H),2.81(d,J=6.6Hz,2H),2.74(t,J=11.8Hz,2H),2 .16(s,3H),1.76(d,J=13.3Hz,2H),1.63(brs,1H),1.21(dd,J=23.0,10.9Hz,2H).

[0171] Example 6 (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 6)

[0172] TIFF2025529613000042.tif35128

[0173] Step 1: tert-butyl (R)-3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)pyrrolidine-1-carboxylic acid

[0174] TIFF2025529613000043.tif30128

[0175] 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (300 mg, 0.57 mmol) and tert-butyl (S)-3-(aminomethyl)pyrrolidine-1-carboxylate (115 mg, 0.57 mmol) were dissolved in a mixture of pyridine (2 mL) and dichloromethane (4 mL) at 0°C and reacted for 2 hours. The reaction was stopped, and the mixture was rotated under vacuum to remove the solvent. The residue was diluted with water (10 mL), neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (256 mg, yield: 65.4%, yellow solid).

[0176] MS(ESI): m / z 687.3[M+H] + .

[0177] 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)

[0178] TIFF2025529613000044.tif33128

[0179] tert-Butyl (R)-3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)pyrrolidine-1-carboxylate (240 mg, 0.35 mmol) was dissolved in a mixture of trifluoroacetic acid (2 mL) and dichloromethane (6 mL) and stirred at room temperature for 2 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was spun under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (eluent: formic acid, water, acetonitrile) to give the title compound (112.26 mg, yield: 54.6%, white solid).

[0180] MS(ESI): m / z 587.0[M+H] + .

[0181] 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.64(d,J=5.5Hz,1H),8.31(d,J=1.7Hz,1H),8. 11(s,1H),7.77(dd,J=5.4,1.9Hz,1H),7.21(dd,J=9.2,2.4Hz,1H),7.14-7.06(m,3H) ,3.23-3.09(m,2H),3.08-3.02(m,1H),2.98(d,J=7.0Hz,2H),2.81(dd,J=11.6,7.7Hz ,1H),2.36(dt,J=15.3,7.6Hz,1H),2.16(s,3H),1.97-1.92(m,1H),1.61-1.56(m,1H).

[0182] Example 7 (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-ylmethyl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 7)

[0183] TIFF2025529613000045.tif34128

[0184] Step 1: tert-butyl (S)-3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)pyrrolidine-1-carboxylic acid

[0185] TIFF2025529613000046.tif29128

[0186] 4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine-2-sulfonyl chloride (300 mg, 0.57 mmol) and tert-butyl (R)-3-(aminomethyl)pyrrolidine-1-carboxylate (115 mg, 0.57 mmol) were dissolved in a mixture of pyridine (2 mL) and dichloromethane (4 mL) at 0°C and reacted for 2 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was diluted with water (10 mL), neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was spun under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (256 mg, yield: 65.4%, yellow solid).

[0187] MS(ESI): m / z 687.2[M+H] + .

[0188] 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)

[0189] TIFF2025529613000047.tif30128

[0190] tert-Butyl (S)-3-(((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridine)-2-sulfonamido)methyl)pyrrolidine-1-carboxylate (240 mg, 0.35 mmol) was dissolved in a mixture of trifluoroacetic acid (2 mL) and dichloromethane (6 mL) and reacted at room temperature for 2 hours. The reaction was stopped, and the mixture was rotated under vacuum to remove the solvent. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was rotary evaporated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (eluent: formic acid, water, acetonitrile) to obtain the title compound (63.06 mg, yield: 30.7%, white solid).

[0191] MS(ESI): m / z 586.9[M+H] + .

[0192] 1 H NMR(400MHz,DMSO-d6)δ8.63(d,J=5.5Hz,1H),8.36(s,1H),8.29(d,J=1.7Hz,1H),8.12(s,1H),7.7 9(dd,J=5.4,1.9Hz,1H),7.21(dd,J=9.2,2.6Hz,1H),7.15-7.05(m,3H),3.12(dd,J=11.3,7.8Hz,1H ),3.09-3.03(m,1H),2.99(d,J=7.8Hz,1H),2.95(d,J=7.1Hz,2H),2.74(dd,J=11.3,7.3Hz,1H),2. 31(dd,J=14.7,7.3Hz,1H),2.16(s,3H),1.88(dt,J=13.0,6.5Hz,1H),1.53(dq,J=15.4,7.8Hz,1H).

[0193] Example 8 (S)-5-chloro-N-(2-(N-(1-ethylpyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl))benzamide (Compound 8)

[0194] TIFF2025529613000048.tif41128

[0195] (S)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (102 mg, 0.178 mmol) was dissolved in tetrahydrofuran (1.5 mL), and triethylamine (54 mg, 0.535 mmol) and iodoethane (28 mg, 0.178 mmol) were added. The mixture was sealed and reacted in an oil bath at 70°C for 16 hours. The reaction was quenched. 1N diluted hydrochloric acid was added to the reaction solution to make it weakly acidic, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated under reduced pressure. The residue was separated and purified by column chromatography (silica gel, dichloromethane:methanol=10:1), and then purified by preparative high-performance liquid chromatography (eluent: aqueous ammonia, water, acetonitrile) to obtain the title compound (21.24 mg, yield: 19.9%, white solid).

[0196] MS(ESI): m / z 601.2[M+H] + .

[0197] 1 H NMR(400MHz,DMSO-d6)δ11.33(s,1H),8.63(d,J=5.4Hz,1H),8.27(d,J=1.8Hz,1H),8.1 3(s,1H),8.07(d,J=6.8Hz,1H),7.78(dd,J=5.4,1.9Hz,1H),7.20(dd,J=9.1,2.2Hz,1H ),7.14-7.05(m,3H),3.77(brs,1H),2.59(dd,J=9.3,7.3Hz,1H),2.42-2.25(m,4H),2. 22-2.14(m,4H),1.94-1.85(m,1H),1.52(dq,J=8.0,5.9Hz,1H),0.93(t,J=7.2Hz,3H).

[0198] Example 9 (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(1-propylpyrrolidin-3-yl)sulfonamido)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 9)

[0199] TIFF2025529613000049.tif42128

[0200] 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 propanal (24.33 mg, 0.42 mmol) were dissolved in dichloromethane (2 mL). Acetic acid (25.13 mg, 0.42 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 hours. Sodium triacetoxyborohydride (NaBH(OAc)3) (88.77 mg, 0.42 mmol) was then added, and the mixture was stirred and reacted at room temperature for another 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative high performance liquid chromatography (eluent: formic acid, water, acetonitrile) to obtain the title compound (27.16 mg, yield: 28.1%, white solid).

[0201] MS(ESI): m / z 615.2[M+H] + .

[0202] Example 10 (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)

[0203] TIFF2025529613000050.tif46128

[0204] (S)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (70 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 1-fluoro-2-iodoethane (21.25 mg, 0.12 mmol) and potassium carbonate (33.7 mg, 0.24 mmol) were added. The mixture was reacted in an oil bath at 50°C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (eluent: aqueous ammonia, water, acetonitrile) to give the title compound (28.51 mg, yield: 37.7%, white solid).

[0205] MS(ESI):m / z 618.9[M] + .

[0206] 1 H NMR(400MHz,DMSO-d6)δ11.33(s,1H),8.63(d,J=5.4Hz,1H),8.27(s,1H),8. 15-8.07(m,2H),7.78(dd,J=5.4,1.7Hz,1H),7.23-7.17(m,1H),7.13-7.09(m ,3H),4.44(dt,J=44.0,4.9Hz,2H),3.79(dd,J=14.4,6.6Hz,1H),2.72-2.58( m,5H),2.34-2.26(m,1H),2.16(s,3H),1.98-1.83(m,1H),1.58-1.51(m,1H).

[0207] Example 11 (R)-5-chloro-N-(2-(N-(1-ethylpyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl))benzamide (Compound 11)

[0208] TIFF2025529613000051.tif44128

[0209] (R)-5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(pyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (80 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2.0 mL), and triethylamine (42.38 mg, 0.42 mmol) and iodoethane (21.78 mg, 0.14 mmol) were added. The mixture was sealed and reacted in an oil bath at 70°C for 16 hours. The reaction was quenched. 1N diluted hydrochloric acid was added to the reaction solution to make it weakly acidic, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3) and dried over anhydrous sodium sulfate. The residue was separated and purified by column chromatography (silica gel, dichloromethane:methanol=10:1), and then purified by high performance liquid chromatography (eluent: formic acid, water, acetonitrile) to obtain the title compound (44.72 mg, yield: 42.6%, white solid).

[0210] MS(ESI): m / z 601.1[M+H] + .

[0211] Example 12 (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(N-(1-propylpyrrolidin-3-yl)sulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 12)

[0212] TIFF2025529613000052.tif45128

[0213] (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 propanal (24.32 mg, 0.42 mmol) were dissolved in dichloromethane (2 mL) at room temperature. Acetic acid (25.13 mg, 0.42 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 hours. Sodium triacetoxyborohydride (88.77 mg, 0.42 mmol) was then added, and the mixture was stirred and reacted at room temperature for another 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative high-performance liquid chromatography (eluent: formic acid, water, acetonitrile) to obtain the title compound (27.36 mg, yield: 25.5%, white solid).

[0214] MS(ESI): m / z 615.2[M+H] + .

[0215] 1 H NMR(400MHz,DMSO-d6)δ11.35(s,1H),8.64-8.62(m,1H),8.28-8.27(m,1H ),8.15-8.08(m,2H),7.79-7.77(m,1H),7.21-7.19(m,1H),7.13-7.05(m,3 H),3.83-3.76(m,1H),2.69-2.64(m,1H),2.46-2.26(m,5H),2.16(s,3H),1 .95-1.86(m,1H),1.59-1.50(m,1H),1.40-1.31(m,2H),0.83-0.78(m,3H).

[0216] Example 13 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 13)

[0217] TIFF2025529613000053.tif65128

[0218] Step 1: 2-(methylthio)pyridin-4-amine

[0219] TIFF2025529613000054.tif14128

[0220] 2-Chloropyridin-4-amine (1 g, 7.8 mmol) was dissolved in NMP (10 mL) and sodium thiomethoxide (1.12 g, 15.6 mmol) was added. The mixture was reacted at 200°C for 0.5 hours under microwave irradiation. The reaction was stopped, and water (30 mL) was added to quench the reaction solution. The aqueous phase was extracted with chloroform / isopropanol (v:v = 3:1) (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and adsorbed onto silica gel. After separation and purification by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1), the title compound (900 mg, crude product) was obtained and used directly in the next reaction.

[0221] MS(ESI): m / z 141.2[M+H] + .

[0222] Step 2: 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0223] TIFF2025529613000055.tif27128

[0224] 2-(Methylthio)pyridin-4-amine (400 mg, 2.85 mmol) was dissolved in pyridine (6 mL), 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (691 mg, 2.85 mmol) was added, and phosphorus oxychloride (1.31 g, 8.55 mmol) was added dropwise at 0 °C. The mixture was then stirred and reacted for 2 hours. The reaction was stopped. The reaction solution was slowly added dropwise to ice water (30 mL), and the pH was adjusted to 5-6 with 1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated 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 = 4:1) to obtain the title compound (720 mg, yield: 69.2%, colorless oil).

[0225] MS(ESI):m / z 364.9[M+H] + .

[0226] Step 3: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0227] TIFF2025529613000056.tif24128

[0228] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (200 mg, 0.55 mmol) was dissolved in DMF (2 mL), 4-fluoro-2-methylphenol (138 mg, 1.097 mmol) was added, and cesium carbonate (357 mg, 1.097 mmol) was added. The mixture was stirred and reacted in an oil bath at 100 °C for 2 hours. The reaction solution was quenched by adding water (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 4:1) to obtain the title compound (273 mg, yield: 92.5%, white solid).

[0229] MS(ESI): m / z 471.1[M+H] + .

[0230] Step 4: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 13)

[0231] TIFF2025529613000057.tif27128

[0232] 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), and ammonium carbonate (153 mg, 1.59 mmol) and iodobenzene diacetate (683 mg, 2.12 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped. The reaction solution was rotary evaporated, and the residue was adsorbed onto silica gel. 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 reverse-phase preparative chromatography (eluent: formic acid, water, acetonitrile) to obtain the title compound (75.41 mg, yield: 28.2%, white solid).

[0233] MS(ESI): m / z 502.1[M+H] + .

[0234] 1 H NMR(400MHz,DMSO-d6)δ8.61(d,J=5.5Hz,1H),8.41(s,1H),8.38(s,1H),8.10(s,1H),7. 77(d,J=5.3Hz,1H),7.20(d,J=10.0Hz,1H),7.14-7.04(m,3H),3.12(s,3H),2.15(s,3H).

[0235] Example 14 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 14)

[0236] TIFF2025529613000058.tif60128

[0237] Step 1: 1-(benzyloxy)-4-fluoro-2-(methoxy-d3)benzene

[0238] TIFF2025529613000059.tif17128

[0239] 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 methyl iodide (319 mg, 2.20 mmol) was added at 0°C. The mixture was stirred and reacted in a sealed tube at room temperature for 16 hours. The reaction was stopped, and water (10 mL) was added to quench the reaction solution. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated, and the residue was adsorbed onto silica gel. The product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) to obtain the title compound (340 mg, white solid, yield: 79.1%).

[0240] 1 H NMR (400MHz, CDCl3) δ7.44-7.29(m,5H),6.80(dd,J=8.8,5.5Hz,1H),6.65(dd,J=10.2,2.9Hz,1H),6.52(td,J=8.5,2.9Hz,1H),5.10(s,2H).

[0241] Step 2: 4-Fluoro-2-(methoxy-d3)phenol

[0242] TIFF2025529613000060.tif17128

[0243] 1-(Benzyloxy)-4-fluoro-2-(methoxy-d3)benzene (300 mg, 1.275 mmol) was dissolved in methanol (9 mL), and Pd(OH)2 (60 mg) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with methanol (9 mL x 3). The filtrate was rotary evaporated to give the title compound (136 mg, yield: 73.5%, brown oil).

[0244] Step 3: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0245] TIFF2025529613000061.tif32128

[0246] 4-Fluoro-2-(methoxy-d3)phenol (50 mg, 0.34 mmol) was dissolved in DMF (1 mL), and 5-chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (62.8 mg, 0.17 mmol) and potassium carbonate (47.5 mg, 0.34 mmol) were added. The mixture was stirred and reacted in a sealed tube at 100°C for 2 hours. The reaction was stopped, and water (10 mL) was added to quench the reaction solution. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated 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 = 1:1) to obtain the title compound (100 mg, yield: 97.7%, white solid).

[0247] MS(ESI): m / z 490.1[M+H] + .

[0248] Step 4: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 14)

[0249] TIFF2025529613000062.tif30128

[0250] 5-Chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (85 mg, 0.17 mmol) was dissolved in methanol (1 mL), ammonium carbonate (50 mg, 0.52 mmol) was added, and iodobenzene diacetate (224 mg, 0.70 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was rotary evaporated, and the residue was adsorbed onto silica gel. The crude product was obtained by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1). The crude product was purified by reverse-phase preparative chromatography (eluent: formic acid, water, and acetonitrile) to give 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (FZ008-114) (47.93 mg, yield: 52.9%, white solid).

[0251] MS(ESI): m / z 521.1[M+H] + .

[0252] 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.63(d,J=5.4Hz,1H),8.40(s,1H),8.07(s,1H),7.82(d,J=3.6Hz,1H),7.29(dd ,J=8.8,5.8Hz,1H),7.14(dd,J=10.6,2.8Hz,1H),7.00(s,1H),6.85(td,J=8.6,2.9Hz,1H),4.37(s,1H),3.14(s,3H).

[0253] Resolution of chiral isomers of compound 14: (S)-5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (R)-5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0254] TIFF2025529613000063.tif31128

[0255] Compound 14 was separated by chiral preparative column (chromatographic column: DAICEL CHIRALPAK® IC, 250*25 mm, 10 μm; mobile phase: A - supercritical carbon dioxide; B - MEOH (+0.1% 7.0 mol / l ammonia in MEOH), 50% B proportional elution, flow rate: 100 mL / min, column temperature: room temperature), to give single-configuration compound 14E1 (shorter retention time) and compound 14E2 (longer retention time).

[0256] Example 15 5-chloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 15)

[0257] TIFF2025529613000064.tif32128

[0258] Step 1: 5-chloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0259] TIFF2025529613000065.tif25128

[0260] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (78 mg, 0.21 mmol) was dissolved in DMF (1 mL), 2-(methoxy-d3)-4-(trifluoromethoxy)phenol (90 mg, 0.43 mmol) was added, and potassium carbonate (59 mg, 0.43 mmol) was added. The mixture was stirred and reacted in an oil bath at 100 °C for 2 hours. The reaction was stopped, and water (10 mL) was added to quench the reaction solution. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum 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 (100 mg, yield: 84.7%, white solid).

[0261] MS(ESI): m / z 556.1[M+H] + .

[0262] Step 2: 5-chloro-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 15)

[0263] TIFF2025529613000066.tif26128

[0264] 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 mixture was stirred at room temperature for 0.5 hours. The reaction was stopped. The reaction solution was rotary evaporated, and the residue was adsorbed onto silica gel. 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 purified by reverse-phase preparative chromatography (eluent: formic acid, water, acetonitrile) to obtain the title compound (57.30 mg, yield: 61.3%, white solid).

[0265] MS(ESI): m / z 587.1[M+H] + .

[0266] 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.62(d,J=5.5Hz,1H),8.38(s,1H),8.09(s,1H),7.80(dd, J=5.4,1.8Hz,1H),7.30(d,J=8.8Hz,1H),7.23-7.12(m,2H),7.00(d,J=8.8Hz,1H),3.14(s,3H).

[0267] Example 16 5-chloro-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 16)

[0268] TIFF2025529613000067.tif34128

[0269] Step 1: 5-chloro-N-(2-(methylthio)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

[0270] TIFF2025529613000068.tif28128

[0271] 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), and potassium carbonate (54 mg, 0.385 mmol) was added. The mixture was reacted in an oil bath at 70 °C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), the title compound (120 mg, yield: 93.02%, white solid) was obtained.

[0272] MS(ESI): m / z 523.2[M+H] + .

[0273] Step 2: 5-chloro-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 16)

[0274] TIFF2025529613000069.tif27128

[0275] 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), and ammonium carbonate (55.3 mg, 0.575 mmol) and iodobenzene diacetate (247 mg, 0.767 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:9), the product was purified by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (68.69 mg, yield: 64.8%, white solid).

[0276] MS(ESI): m / z 554.0[M+H] + .

[0277] 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.60(d,J=5.5Hz,1H),8.34(d,J=1.9Hz,1H),8.15(s,1H),7.76( dd,J=5.4,2.0Hz,1H),7.52(s,1H),7.40(d,J=8.4Hz,2H),7.24-7.20(m,2H),4.36(s,1H),3.13(s,3H).

[0278] Example 17 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 17)

[0279] TIFF2025529613000070.tif32128

[0280] Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-trifluoromethyl)benzamide

[0281] TIFF2025529613000071.tif28128

[0282] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.274 mmol) and 4,4-difluoroazetidine hydrochloride (234 mg, 1.371 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (625.3 mg, 1.92 mmol) was added. The mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (125 mg, yield: 92.6%, white solid).

[0283] MS(ESI): m / z 480.1[M+H] + .

[0284] Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 17)

[0285] TIFF2025529613000072.tif30128

[0286] 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), and ammonium carbonate (40 mg, 0.41 mmol) and iodobenzene diacetate (175 mg, 0.543 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun in vacuo to remove the solvent. Separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10) was followed by preparation and purification by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (35.02 mg, yield: 50.49%, white solid).

[0287] MS(ESI): m / z 511.1[M+H] + .

[0288] 1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),8.63(d,J=5.3Hz,1H),8.41(s,1H),7.84(d,J=4.7Hz,1H),7.75(s,1H) ,7.35(s,1H),4.37(s,1H),3.39-3.32(m,4H),3.15(s,3H),2.24(brs,2H),2.07-2.04(m,2H),1.79(brs,2H).

[0289] Resolution of chiral isomers of compound 17: (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0290] TIFF2025529613000073.tif32128

[0291] Compound 17 was separated by chiral preparative column (chromatographic column: DAICEL CHIRALCEL® OJ, 250*25 mm, 10 μm; mobile phase: A - supercritical CO2; B - MEOH (+0.1% 7.0 mol / l ammonia in MEOH), 25% B proportional elution, flow rate: 70 mL / min, column temperature: room temperature), to give single-configuration compound 17E1 (shorter retention time) and compound 17E2 (longer retention time).

[0292] Example 18 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrol-2(1H)-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 18)

[0293] TIFF2025529613000074.tif34128

[0294] Step 1: 5-chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrol-2(1H)-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0295] TIFF2025529613000075.tif29128

[0296] 5-Chloro-2-fluoro-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.27 mmol) was dissolved in DMF (3 mL), and (3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrole hydrochloride (98.8 mg, 0.54 mmol) and cesium carbonate (536 mg, 1.64 mmol) were added. The atmosphere was purged with nitrogen, and the mixture was reacted at 100°C for 12 hours. The reaction was stopped, and water was added to the reaction solution (15 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated in vacuo to give the crude product. The crude product was 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).

[0297] MS(ESI): m / z 492.1[M+H] + .

[0298] Step 2: 5-chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrol-2(1H)-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 18)

[0299] TIFF2025529613000076.tif30128

[0300] 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrol-2(1H)-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.20 mmol) was dissolved in methanol (1.5 mL), and ammonium carbonate (58.6 mg, 0.60 mmol) and iodobenzene oxalate (261.9 mg, 0.81 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped. The reaction solution was spun down and quenched by adding saturated aqueous 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, and filtered. The filtrate was rotary evaporated in vacuo to give the crude product, which was purified by reverse-phase preparative chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (10 mg, yield: 9.4%, white solid).

[0301] MS(ESI):m / z 539.8[M+H] + .

[0302] 1 H NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.62(d,J=4.9Hz,1H),8.42(s,1H),7.82(s,1H),7.72(s,1H),7.16(s,1H) ,4.36(s,1H),3.39(brs,2H),3.19(d,J=9.6Hz,2H),3.14(s,3H),2.85(brs,2H),2.32(brs,2H),1.98(brs,2H).

[0303] Example 19 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 19)

[0304] TIFF2025529613000077.tif35128

[0305] Step 1: 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0306] TIFF2025529613000078.tif32128

[0307] 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), and cesium carbonate (268 mg, 0.823 mmol) was added. The mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), the title compound (200 mg, yield: 98.1%, white solid) was obtained.

[0308] MS(ESI): m / z 481.0[M+H] + .

[0309] Step 2: 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(S-methyliminosulfonyl)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 19)

[0310] TIFF2025529613000079.tif29128

[0311] 5-Chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(2-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (190 mg, 0.4 mmol) was dissolved in methanol (2 mL), and ammonium carbonate (114 mg, 1.19 mmol) and iodobenzene diacetate (510 mg, 1.58 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10), the product was purified by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (81.2 mg, yield: 39.8%, white solid).

[0312] MS(ESI): m / z 512.1[M+H] + .

[0313] 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.63(d,J=5.4Hz,1H),8.40(s,1H),7.92(s,1H),7.78 (d,J=5.2Hz,1H),7.66(s,1H),4.96(brs,1H),4.37(s,1H),3.14(s,3H),2.01-1.83(m,8H).

[0314] Example 20 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(S-methyliminosulfonyl)iridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 20)

[0315] TIFF2025529613000080.tif62128

[0316] Step 1: 6-(methylthio)iridazin-4-amine

[0317] TIFF2025529613000081.tif13128

[0318] 6-Chloropyridazin-4-amine (1 g, 7.7 mmol) was dissolved in methanol (10 mL) and sodium thiomethoxide (2.8 g, 38.6 mmol) was added. The mixture was stirred and reacted in a sealed tube at 100°C for 16 hours. The reaction was stopped. The reaction solution was rotary evaporated, and the residue was adsorbed onto silica gel. The residue was separated and purified 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%).

[0319] MS(ESI): m / z 142.0[M+H] + .

[0320] Step 2: 5-chloro-2-fluoro-N-(6-(methylthio)iridazin-4-yl)-4-(trifluoromethyl)benzamide

[0321] TIFF2025529613000082.tif27128

[0322] 6-(Methylthio)iridazin-4-amine (75 mg, 0.53 mmol) was dissolved in pyridine (2 mL), 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (129 mg, 0.53 mmol) was added, and phosphorus oxychloride (244 mg, 1.59 mmol) was added dropwise at 0 °C. The mixture was then stirred and reacted for 2 hours. The reaction was stopped. The reaction solution was slowly added dropwise to ice water (10 mL), and the pH was adjusted to 5-6 with 1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated 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 = 1:1) to obtain the title compound (90 mg, yield: 46.6%, yellow solid).

[0323] MS(ESI): m / z 365.0[M+H] + .

[0324] Step 3: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(methylthio)iridazin-4-yl)-4-(trifluoromethyl)benzamide

[0325] TIFF2025529613000083.tif25128

[0326] 5-Chloro-2-fluoro-N-(6-(methylthio)iridazin-4-yl)-4-(trifluoromethyl)benzamide (80 mg, 0.22 mmol) was dissolved in DMF (1 mL), 4-fluoro-2-methylphenol (41.4 mg, 0.33 mmol) was added, and cesium carbonate (142.7 mg, 0.44 mmol) was added. The mixture was stirred and reacted in an oil bath at 100 °C for 2 hours. The reaction was stopped, and water (10 mL) was added to quench the reaction solution. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated 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 = 1:1) to obtain the title compound (69 mg, yield: 67.0%, white solid).

[0327] MS(ESI): m / z 472.0[M+H] + .

[0328] Step 4: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(S-methyliminosulfonyl)iridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 20)

[0329] TIFF2025529613000084.tif28128

[0330] 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(6-(methylthio)iridazin-4-yl)-4-(trifluoromethyl)benzamide (60 mg, 0.13 mmol) was dissolved in methanol (1 mL), and ammonium carbonate (36.6 mg, 0.39 mmol) and iodobenzene diacetate (164 mg, 0.51 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped. The reaction solution was rotary evaporated, and the residue was adsorbed onto silica gel. 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 purified by reverse-phase preparative chromatography (eluent: formic acid, water, acetonitrile) to obtain the title compound (17.45 mg, yield: 27.3%, white solid).

[0331] MS(ESI): m / z 503.0[M+H] + .

[0332] 1 H NMR(400MHz,DMSO-d6)δ11.66(s,1H),9.39(s,1H),8.63(d,J=2.0Hz,1H),8.21(s,1H),8.1 4(s,1H),7.24-7.17(m,1H),7.11(d,J=5.3Hz,3H),4.86(s,1H),3.31(s,3H),2.16(s,3H).

[0333] Example 21 5-chloro-N-(6-(S-methyliminosulfonyl)iridazin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 21)

[0334] TIFF2025529613000085.tif34128

[0335] Step 1: 5-chloro-N-(6-(methylthio)iridazin-4-yl)-2-(4-(trifluoromethoxy)phenyl)-4-(trifluoromethyl)benzamide

[0336] TIFF2025529613000086.tif28128

[0337] 5-Chloro-2-fluoro-N-(6-(methylthio)iridazin-4-yl)-4-(trifluoromethyl)benzamide (70 mg, 0.192 mmol) and 4-(trifluoromethoxy)phenol (68.3 mg, 0.384 mmol) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (53 mg, 0.384 mmol) was added. The mixture was reacted in an oil bath at 70 °C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (70 mg, yield: 69.72%, white solid).

[0338] MS(ESI): m / z 524.0[M+H] + .

[0339] Step 2: 5-chloro-N-(6-(S-methyliminosulfonyl)pyridazin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 21)

[0340] TIFF2025529613000087.tif27128

[0341] 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), and ammonium carbonate (36.04 mg, 0.375 mmol) and iodobenzene diacetate (161 mg, 0.5 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was rotated in vacuo to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:9), the product was purified by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (25.42 mg, yield: 36.7%, yellow solid).

[0342] MS(ESI): m / z 555.0[M+H] + .

[0343] 1 H NMR(400MHz,DMSO-d6)δ11.65(s,1H),9.39(d,J=2.4Hz,1H),8.59(d,J=2.4Hz,1H),8.19(s ,1H),7.55(s,1H),7.41(d,J=8.8Hz,2H),7.23(d,J=9.1Hz,2H),4.87(s,1H),3.29(s,3H).

[0344] Example 22 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(S-methyliminosulfonyl)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 22)

[0345] TIFF2025529613000088.tif35128

[0346] Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(methylthio)pyridazin-4-yl)-4-(trifluoromethyl)benzamide

[0347] TIFF2025529613000089.tif29128

[0348] 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), and cesium carbonate (437 mg, 1.342 mmol) was added. The mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (70 mg, yield: 75.95%, white solid).

[0349] MS(ESI): m / z 481.1[M+H] + .

[0350] Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(S-methyliminosulfonyl)pyridazin-4-yl)-4-(trifluoromethyl)benzamide (Compound 22)

[0351] TIFF2025529613000090.tif30128

[0352] 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), and ammonium carbonate (39 mg, 0.402 mmol) and iodobenzene diacetate (172 mg, 0.535 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun in vacuo to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10), the product was purified by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (15.88 mg, yield: 23.2%, white solid).

[0353] MS(ESI): m / z 512.0[M+H] + .

[0354] 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),9.44(s,1H),8.66(s,1H),7.80(s,1H),7.35(s,1H),4.89(s,1H) ,3.42-3.40(m,2H),3.38-3.34(m,2H),3.32(s,3H),2.27(brs,2H),2.08-2.00(m,2H),1.80(brs,2H).

[0355] Example 23 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 23)

[0356] TIFF2025529613000091.tif75128

[0357] Step 1: 4-Fluoro-3-(methylthio)aniline

[0358] TIFF2025529613000092.tif17128

[0359] 3-Bromo-4-fluoroaniline (1 g, 5.26 mmol) was dissolved in ultra-dry 1,4-dioxane (20 mL) and sodium thiomethoxide (569 mg, 7.89 mmol), Pd2(dba)3 (485 mg, 0.53 mmol), XantPhos (609 mg, 1.05 mmol), and DIEA (2.04 g, 15.78 mmol) were added. After purging with nitrogen, the mixture was stirred in an oil bath at 110 °C for 16 h. The reaction was then stopped. The reaction solution was filtered and the filter cake was rinsed with DCM (30 mL x 3). The filtrate was rotary evaporated, and the residue was adsorbed onto silica gel. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:2) to give the title compound (600 mg, colorless oil, yield: 72.6%).

[0360] MS(ESI): m / z 158.0[M+H] + .

[0361] Step 2: 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0362] TIFF2025529613000093.tif32128

[0363] 5-Chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (980 mg, 4.04 mmol) was dissolved in thionyl chloride (1.5 mL). After purging with nitrogen, the mixture was stirred and reacted at 80 °C for 2 hours and then rotary evaporated for further use. 4-Fluoro-3-(methylthio)aniline (635 mg, 4.04 mmol) was dissolved in ultra-dry DCM (10 mL), and pyridine (1.28 g, 16.16 mmol) was added at 0 °C. A solution of the above rotary evaporated product in dichloromethane (2 mL) for further use was then added. The mixture was stirred and reacted at room temperature for 2 hours. The reaction was stopped. The reaction solution was rotary evaporated, and the residue was adsorbed onto silica gel. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain the title compound (870 mg, yield: 56.4%, white solid).

[0364] MS(ESI):m / z 382.0[M+H] + .

[0365] Step 3: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0366] TIFF2025529613000094.tif30128

[0367] 5-Chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (300 mg, 0.785 mmol) was dissolved in DMF (4 mL), 4-fluoro-2-methylphenol (198 mg, 1.571 mmol) was added, and cesium carbonate (512 mg, 1.571 mmol) was added. The mixture was stirred and reacted in an oil bath at 100 °C for 2 hours. The reaction was stopped. The reaction solution was quenched by adding water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated 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 = 5:1) to obtain the title compound (290 mg, yield: 75.7%, yellow solid).

[0368] MS(ESI): m / z 488.1[M+H] + .

[0369] Step 4: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 23)

[0370] TIFF2025529613000095.tif29128

[0371] 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), and ammonium carbonate (171.3 mg, 1.78 mmol) and iodobenzene diacetate (766 mg, 2.36 mmol) were added. The mixture was stirred and reacted at room temperature for 1 hour. The reaction was stopped. The reaction solution was rotary evaporated, and the residue was adsorbed onto silica gel. The crude product was separated by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:10) to obtain the crude product. The crude product was purified by reverse-phase preparative chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (197 mg, yield: 64.3%, white solid).

[0372] MS(ESI): m / z 519.1[M+H] + .

[0373] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.25(dd,J=6.5,2.7Hz,1H),8.06(s,1H),7.92-7.85(m,1H), 7.43(t,J=9.3Hz,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).

[0374] Resolution of chiral isomers of compound 23: (S)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (R)-5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0375] TIFF2025529613000096.tif30128

[0376] Compound 23 was separated by chiral preparative column (chromatographic column: DAICEL CHIRALCEL® AS, 250*25 mm, 10 μm; mobile phase: A - supercritical carbon dioxide; B - MEOH (+0.1% 7.0 mol / l ammonia in MEOH), 30% B proportional elution, flow rate: 70 mL / min, column temperature: room temperature), to give single-configuration compound 23E1 (shorter retention time) and compound 23E2 (longer retention time).

[0377] Example 24 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 24)

[0378] TIFF2025529613000097.tif34128

[0379] Step 1: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0380] TIFF2025529613000098.tif29128

[0381] 4-Fluoro-2-(methoxy-d3)phenol (95 mg, 0.654 mmol) and 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (50 mg, 0.131 mmol) were dissolved in N,N-dimethylformamide (1 mL), and potassium carbonate (36.2 mg, 0.262 mmol) was added. The mixture was sealed and then reacted in an oil bath at 100 °C for 2 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10), the title compound (80 mg, yield: 98.2%, white solid) was obtained.

[0382] MS(ESI): m / z 507.1[M+H] + .

[0383] Step 2: 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 24)

[0384] TIFF2025529613000099.tif31128

[0385] 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), and ammonium carbonate (40 mg, 0.415 mmol) and iodobenzene diacetate (178 mg, 0.553 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun in vacuo to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), the product was purified by high-performance liquid chromatography (eluent: formic acid, water, acetonitrile) to give the title compound (39.21 mg, yield: 52.7%, white solid).

[0386] MS(ESI):m / z 538.0[M+H] + .

[0387] 1 H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),8.28(dd,J=6.4,2.6Hz,1H),8.01(s,1H),7.96-7.90(m,1H),7.44(t,J=9.3Hz,1H),7.28(dd,J=8. 8,5.9Hz,1H),7.14(dd,J=10.6,2.8Hz,1H),6.98(s,1H),6.85(td,J=8.5,2.9Hz,1H),4.69(s,1H),3.18(s,3H).

[0388] Example 25 5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 25)

[0389] TIFF2025529613000100.tif33128

[0390] Step 1: 5-chloro-N-(4-fluoro-3-(methylthio)phenyl)-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

[0391] TIFF2025529613000101.tif27128

[0392] 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), and potassium carbonate (43.4 mg, 0.314 mmol) was added. The mixture was reacted in an oil bath at 100 °C for 2 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:10), the title compound (80 mg, yield: 89.79%, white solid) was obtained.

[0393] MS(ESI):m / z 572.8[M+H] + .

[0394] Step 2: 5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-2-(2-(methoxy-d3)-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 25)

[0395] TIFF2025529613000102.tif29128

[0396] 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), and ammonium carbonate (30.3 mg, 0.315 mmol) and iodobenzene diacetate (135.15 mg, 0.42 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), the product was purified by high-performance liquid chromatography (eluent: formic acid, water, acetonitrile) to give the title compound (16.02 mg, yield: 25.4%, white solid).

[0397] MS(ESI): m / z 604.1[M+H] + .

[0398] 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.25(dd,J=6.4,2.6Hz,1H),8.03(s,1H),7.91(dd,J=8.3,3.6Hz,1H),7.43(t,J= 9.3Hz,1H),7.28(d,J=8.8Hz,1H),7.20(d,J=2.4Hz,1H),7.13(s,1H),7.00(d,J=8.7Hz,1H),4.68(s,1H),3.18(s,3H).

[0399] Example 26 5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 26)

[0400] TIFF2025529613000103.tif29128

[0401] Step 1: 5-chloro-N-(4-fluoro-3-(methylthio)phenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

[0402] TIFF2025529613000104.tif28128

[0403] 5-Chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (100 mg, 0.26 mmol) was dissolved in DMF (2 mL), 4-(trifluoromethoxy)phenol (93.3 mg, 0.52 mmol) was added, and cesium carbonate (170 mg, 0.52 mmol) was added. The mixture was stirred in an oil bath at 100°C for 2 hours. The reaction was stopped, and water (10 mL) was added to quench the reaction solution. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain the title compound (100 mg, yield: 71.4%, white solid).

[0404] MS(ESI): m / z 540.0[M+H] + .

[0405] Step 2: 5-chloro-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 26)

[0406] TIFF2025529613000105.tif30128

[0407] 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), and ammonium carbonate (46.4 mg, 0.48 mmol) and iodobenzene diacetate (206 mg, 0.64 mmol) were added. The mixture was stirred at room temperature for 0.5 hours. The reaction was stopped. The reaction solution was rotary evaporated, and the residue was adsorbed onto silica gel. 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 purified by reverse-phase preparative chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (28.96 mg, yield: 31.5%, white solid).

[0408] MS(ESI): m / z 571.0[M+H] + .

[0409] 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),7.86(s,1H),7.71(d,J=23.3Hz,2H), 7.48(d,J=8.0Hz,3H),7.34(s,2H),7.02(s,1H),4.75(s,1H),3.13(s,3H).

[0410] Example 27 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 27)

[0411] TIFF2025529613000106.tif33128

[0412] Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0413] TIFF2025529613000107.tif29128

[0414] 4,4-Difluoroazepane hydrochloride (80 mg, 0.58 mmol) was dissolved in DMF (2 mL), and 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (80 mg, 0.20 mmol) and cesium carbonate (210 mg, 0.64 mmol) were added. The mixture was stirred in an oil bath at 100 °C for 12 hours. The reaction was stopped, and water (5 mL) was added to quench the reaction solution. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum 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).

[0415] MS(ESI): m / z 497.1[M+H] + .

[0416] Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfamoyl)phenyl)-4-trifluoromethylbenzamide (Compound 27)

[0417] TIFF2025529613000108.tif30128

[0418] 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), and ammonium bicarbonate (27 mg, 0.28 mmol) and iodobenzene diacetate (118 mg, 0.36 mmol) were added. The mixture was stirred and reacted at room temperature for 1 hour. The reaction was stopped. The reaction solution was rotary evaporated and quenched by adding water (2 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum to obtain the crude product. The crude product was purified by reverse-phase preparative chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (2.85 mg, yield: 0.59%, white solid).

[0419] MS(ESI): m / z 539.0[M+H] + .

[0420] 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.27(dd,J=6.4,2.5Hz,1H),8.01-7.90(m,1H),7.69(s,1H),7.46(t,J=9 .3Hz,1H),7.34(s,1H),4.70(s,1H),3.40(brs,4H),3.20(s,3H),2.25(brs,2H),2.07(brs,2H),1.81(brs,2H).

[0421] Resolution of chiral isomers of compound 27: (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfamoyl)phenyl)-4-trifluoromethylbenzamide (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfamoyl)phenyl)-4-trifluoromethylbenzamide

[0422] TIFF2025529613000109.tif34128

[0423] Compound 27 was separated by chiral preparative column (chromatographic column: DAICEL CHIRALCEL® AS, 250*25 mm, 10 μm; mobile phase: A - supercritical carbon dioxide; B - MEOH (+0.1% 7.0 mol / l ammonia in MEOH), 45% B proportional elution, flow rate: 70 mL / min, column temperature: room temperature) to give compound 27E1 (shorter retention time) and compound 27E2 (longer retention time) in a single configuration.

[0424] Example 28 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrol-2(1H)-yl)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 28)

[0425] TIFF2025529613000110.tif37128

[0426] Step 1: 5-chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrol-2(1H)-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0427] TIFF2025529613000111.tif31128

[0428] (3aR,6aS)-5,5-Difluorohexahydrocyclopentadieno[c]pyrrole hydrochloride (100 mg, 0.681 mmol) was dissolved in DMF (1 mL), and 5-chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (130 mg, 0.340 mmol) and cesium carbonate (322 mg, 1.021 mmol) were added. The atmosphere was purged with nitrogen, and the mixture was stirred in an oil bath at 100 °C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried in vacuo to obtain a crude product, which 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: 57.8%, yellow solid).

[0429] MS(ESI): m / z 510.1[M+H] + .

[0430] Step 2: 5-chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrol-2(1H)-yl)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 28)

[0431] TIFF2025529613000112.tif29128

[0432] 5-Chloro-2-((3aR,6aS)-5,5-difluorohexahydrocyclopentadieno[c]pyrrol-2(1H)-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (100 mg, 0.196 mmol) was dissolved in methanol (1.5 mL), and ammonium carbonate (56.6 mg, 0.589 mmol) and iodobenzene oxalate (253.1 mg, 0.785 mmol) were added. The mixture was stirred and reacted at room temperature for 1 hour. The reaction was stopped. The reaction solution was spun down and quenched by adding saturated aqueous 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, and filtered. The filtrate was rotary evaporated in vacuo to give the crude product, which was purified by reverse-phase preparative chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (10 mg, yield: 9.4%, white solid).

[0433] MS(ESI):m / z 539.8[M+H] + .

[0434] 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.29(d,J=3.8Hz,1H),8.01-7.85(m,1H),7.65(s,1H),7.45(t,J=9.3Hz,1H),7 .14(s,1H),4.68(s,1H),3.39(d,J=7.0Hz,2H),3.23-3.19(m,5H),2.84(brs,2H),2.39-2.25(m,2H),1.96(brs,2H).

[0435] Example 29 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 29)

[0436] TIFF2025529613000113.tif35128

[0437] Step 1: 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide

[0438] TIFF2025529613000114.tif29128

[0439] 5-Chloro-2-fluoro-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (80 mg, 0.21 mmol) and 4,4-difluorocyclohexan-1-ol (114 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (205 mg, 0.63 mmol) was added. The mixture was reacted in an oil bath at 100 °C for 1 hour. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (120 mg, yield: 92.3%, white solid).

[0440] MS(ESI): m / z 498.1[M+H] + .

[0441] Step 2: 5-chloro-2-((4,4-difluorocyclohexyl)oxy)-N-(4-fluoro-3-(S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Compound 29)

[0442] TIFF2025529613000115.tif30128

[0443] 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), and ammonium carbonate (61 mg, 0.634 mmol) and iodobenzene diacetate (272.2 mg, 0.845 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1), the product was purified by high-performance liquid chromatography (eluent: formic acid, water, acetonitrile) to give the title compound (71.14 mg, yield: 64.1%, white solid).

[0444] MS(ESI): m / z 529.1[M+H] + .

[0445] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.27(s,1H),7.86(s,2H),7.64(s,1H),7 .44(t,J=9.1Hz,1H),4.94(brs,1H),4.68(s,1H),3.18(s,3H),1.88(brs,8H).

[0446] Example 30 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 30)

[0447] TIFF2025529613000116.tif65145

[0448] Step 1: (4-Bromopyridin-2-yl)methanol

[0449] TIFF2025529613000117.tif14128

[0450] Methyl 4-bromopyridine-2-carboxylate (2 g, 9.258 mmol) was dissolved in ethanol (50 mL), and sodium borohydride (771 mg, 20.381 mmol) was added. After purging with nitrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped. The mixture was spun under vacuum to remove the solvent, and the residue was 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).

[0451] MS(ESI): m / z 188.0[M+H] + .

[0452] Step 2: 4-Bromo-2-(chloromethyl)pyridine

[0453] TIFF2025529613000118.tif14128

[0454] (4-Bromopyridin-2-yl)methanol (9.7 g, 51.59 mmol) was dissolved in dichloromethane (60 mL), and thionyl chloride (9.21 mg, 77.414 mmol) was slowly added dropwise at 0°C. The mixture was allowed to react at room temperature for 3 hours. The reaction was stopped. The reaction solution was quenched by adding saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (100 mL x 3). The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was spun under vacuum to remove the solvent, and the residue was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 9:1) to obtain the title compound (10 g, yield: 85.1%, yellow oil).

[0455] MS(ESI):m / z 206.0[M+H] + .

[0456] Step 3: 4-Bromo-2-((methylthio)methyl)pyridine

[0457] TIFF2025529613000119.tif14128

[0458] 4-Bromo-2-(chloromethyl)pyridine (10 g, 48.433 mmol) was dissolved in N,N-dimethylformamide (80 mL), and sodium thiomethoxide (4.07 mg, 58.076 mmol) was slowly added at 0°C. The mixture was reacted at 0°C for 2 hours. The reaction was then stopped. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was spun under vacuum to remove the solvent, and the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain the title compound (9.3 g, yield: 88.1%, yellow oil).

[0459] MS(ESI): m / z 218.1[M+H] + .

[0460] Step 4: 4-Bromo-2-((methylsulfinyl)methyl)pyridine

[0461] TIFF2025529613000120.tif13128

[0462] 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), and sodium periodate (3.93 g, 18.34 mmol) was slowly added at 0°C. The mixture was reacted at room temperature for 5 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 9:1) to obtain the title compound (4.1 g, yield: 96.47%, white solid).

[0463] MS(ESI):m / z 234.0[M+H] + .

[0464] Step 5: N-(((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6-sulfanylidene)-2,2,2-trifluoroacetamide

[0465] TIFF2025529613000121.tif15128

[0466] 4-Bromo-2-((methylsulfinyl)methyl)pyridine (2 g, 8.584 mmol) was dissolved in dichloromethane (20 mL), and 2,2,2-trifluoroacetamide (1.94 g, 17.17 mmol), magnesium oxide (1.34 g, 34.33 mmol), rhodium acetate (190 g, 0.43 mmol), and iodobenzene acetate (5.53 g, 17.17 mmol) were added. After purging with nitrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to give the title compound (1.18 g, yield: 40.2%, yellow oil).

[0467] MS(ESI): m / z 345.0[M+H] + .

[0468] Step 6: ((4-bromopyridin-2-yl)methyl)(imino)(methyl)-λ 6 -sulfoxide

[0469] TIFF2025529613000122.tif14128

[0470] 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) and potassium carbonate (2.27 g, 16.424 mmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 8:1) to give the title compound (660 mg, yield: 81.08%, yellow oil).

[0471] MS(ESI):m / z 249.0[M+H] + .

[0472] Step 7: Benzyl(((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0473] TIFF2025529613000123.tif15128

[0474] ((4-bromopyridin-2-yl)methyl)(imino)(methyl)-λ 6 The 2-sulfoxide (660 mg, 2.66 mmol) was dissolved in dichloromethane (10 mL), pyridine (632 mg, 8 mmol) was added, and the mixture was cooled to 0 °C. Then, benzyl chloroformate (1.09 g, 6.4 mmol) was slowly added dropwise. The mixture was then allowed to react at room temperature for 3 hours. The reaction was then stopped. The mixture was spun under vacuum to remove the solvent, and the residue was diluted with water (10 mL). The resulting solution was adjusted to a weak acidic state with 1N dilute hydrochloric acid and extracted with ethyl acetate (30 mL × 3). The combined organic phase was 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 (900 mg, yield: 88.58%, yellow oil).

[0475] MS(ESI): m / z 383.1[M+H] + .

[0476] Step 8: (1-(4-bromopyridin-2-yl)cyclopropyl)(imino)(methyl)-λ 6 -sulfoxide

[0477] TIFF2025529613000124.tif16128

[0478] Benzyl(((4-bromopyridin-2-yl)methyl)(methyl)(oxo)-λ6 (-sulfanylidene)carbamate (680 mg, 1.78 mmol) was dissolved in tetrahydrofuran (12.8 mL), tetrabutylammonium bromide (57.4 mg, 0.178 mmol) and 1,2-dibromoethane 9 (1.34 g, 7.12 mmol) were added, and sodium hydroxide solution (50%, 3.2 mL) was slowly added dropwise. The mixture was then heated to 60 °C and reacted for 16 h. The reaction was stopped. The mixture was spun under vacuum to remove the solvent, and the residue was diluted with water (10 mL). The resulting solution was adjusted to a weak acidity with 1N dilute hydrochloric acid and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the title compound (400 mg, yield: 81.96%, yellow solid).

[0479] MS(ESI): m / z 275.0[M+H] + .

[0480] Step 9: Benzyl((1-(4-bromopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0481] TIFF2025529613000125.tif17128

[0482] (1-(4-bromopyridin-2-yl)cyclopropyl)(imino)(methyl)-λ 6The 2-sulfoxide (400 mg, 1.46 mmol) was dissolved in dichloromethane (6 mL), pyridine (346 mg, 4.38 mmol) was added, and the mixture was cooled to 0 °C. Then, benzyl chloroformate (623 g, 3.65 mmol) was slowly added dropwise. The mixture was then allowed to react at room temperature for 3 hours. The reaction was then stopped. The mixture was spun under vacuum to remove the solvent, and the residue was diluted with water (10 mL). The resulting solution was adjusted to a weak acidity with 1N dilute hydrochloric acid and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (400 mg, yield: 67.11%, yellow oil).

[0483] MS(ESI): m / z 409.0[M+H] + .

[0484] Step 10: Benzyl((1-(4-((diphenylmethylene)amino)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0485] TIFF2025529613000126.tif21128

[0486] Benzyl((1-(4-bromopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6(-sulfanylidene)carbamate (330 mg, 0.81 mmol) and dibenzylimine (220 mg, 1.21 mmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (18.2 mg, 0.08 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (94 mg, 0.162 mmol), and cesium carbonate (790 mg, 2.43 mmol) were added. After purging with nitrogen, the mixture was reacted in an oil bath at 100 °C for 2 hours. The reaction was stopped. The reaction solution was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate=1:2), the title compound (400 mg, yield: 97.08%, yellow oil) was obtained.

[0487] MS(ESI): m / z 510.5[M+H] + .

[0488] Step 11: Benzyl((1-(4-aminopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0489] TIFF2025529613000127.tif17128

[0490] Benzyl((1-(4-((diphenylmethylene)amino)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6(-sulfanylidene)carbamate (420 mg, 0.825 mmol) was dissolved in tetrahydrofuran (4 mL), and 1N dilute hydrochloric acid (4 mL) was slowly added dropwise. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was rotated under vacuum to remove the solvent. The residue was adjusted to a weak alkalinity with 1N sodium hydroxide solution and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was rotated under vacuum to remove the solvent, and the title compound (270 mg, yield: 68.4%, white solid) was obtained.

[0491] MS(ESI):m / z 346.1[M+H] + .

[0492] Step 12: Benzyl((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0493] TIFF2025529613000128.tif28128

[0494] Benzyl((1-(4-aminopyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 5-Chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (144.1 mg, 0.594 mmol) was 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 mixture was reacted at room temperature for 2 hours. The reaction solution was poured into ice water (30 mL), adjusted to a weak acidity with 1N dilute hydrochloric acid, and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:4) to obtain the title compound (300 mg, yield: 88.76%, yellow solid).

[0495] MS(ESI): m / z 570.0[M+H] + .

[0496] Step 13: Benzyl((1-(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0497] TIFF2025529613000129.tif29128

[0498] Benzyl((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 N,N-dimethylformamide (2 mL) was used to dissolve 4-fluoro-2-methylphenol (20 mg, 0.158 mmol), and cesium carbonate (86 mg, 0.264 mmol) was added. The mixture was heated to 100°C and reacted for 2 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3). The organic phase was collected and dried over sodium sulfate. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3), the title compound (110 mg, yield: 93.2%, yellow oil) was obtained.

[0499] MS(ESI): m / z 676.1[M+H] + .

[0500] Step 14: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 30)

[0501] TIFF2025529613000130.tif27128

[0502] Benzyl((1-(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 (-sulfanylidene)carbamate (70 mg, 0.103 mmol) was dissolved in the solution, and the mixture was heated to 60 °C and reacted for 3 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was adjusted to a weak alkaline state with 1 N sodium hydroxide solution and extracted with ethyl acetate (2 mL × 3). The combined organic phase was washed with saturated brine (5 mL × 3) and dried over anhydrous sodium sulfate. The mixture was spun under vacuum to remove the solvent. After preparation and purification by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile), the title compound (32 mg, yield: 57.14%, white solid) was obtained.

[0503] MS(ESI): m / z 542.0[M+H] + .

[0504] 1 H NMR(400MHz,DMSO-d6)δ 11.06(s,1H),8.46(d,J=5.6Hz,1H),8.08(s,1H),7.87(d,J=1.4Hz,1H),7.60(dd,J=5.5,1.9Hz,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).

[0505] Example 31 5-Chloro-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 31)

[0506] TIFF2025529613000131.tif31128

[0507] Step 1: Benzyl((1-(4-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0508] TIFF2025529613000132.tif29128

[0509] Benzyl((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 4-(trifluoromethoxy)phenol 2 (47 mg, 0.264 mmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (37 mg, 0.264 mmol) was added. The mixture was heated to 70 °C and reacted for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3), the title compound (80 mg, 83% yield, yellow oil) was obtained.

[0510] MS(ESI):m / z 728.0[M+H] + .

[0511] Step 2: 5-chloro-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (Compound 31)

[0512] TIFF2025529613000133.tif29128

[0513] Trifluoroacetic acid (1.5 mL) was used to prepare the compound benzyl((1-(4-(5-chloro-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 (-sulfanylidene)carbamate (70 mg, 0.102 mmol) was dissolved in the solution, and the mixture was heated to 60 °C and reacted for 3 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was adjusted to a weak alkaline state with 1N sodium hydroxide solution and extracted with ethyl acetate (2 mL × 3). The combined organic phase was washed with saturated brine (5 mL × 3) and dried over anhydrous sodium sulfate. The mixture was spun under vacuum to remove the solvent. After preparation and purification by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile), the title compound (39.27 mg, yield: 68.42%, white solid) was obtained.

[0514] MS(ESI): m / z 594.0[M+H] + .

[0515] 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.44(d,J=5.6Hz,1H),8.12(s,1H),7.83(d,J=1.5Hz,1H),7.57(dd,J=5.5,1.8Hz,1H),7. 50(s,1H),7.40(d,J=8.5Hz,2H),7.24-7.19(m,2H),3.71(s,1H),2.90(s,3H),1.76(brs,1H),1.44(brs,1H),1.30-1.19(m,2H).

[0516] Example 32 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 32)

[0517] TIFF2025529613000134.tif32128

[0518] Step 1: Benzyl((1-(4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0519] TIFF2025529613000135.tif31128

[0520] Benzyl((1-(4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)cyclopropyl)(methyl)(oxo)-λ 6 (4,4-Difluoroazepane hydrochloride) (75 mg, 0.132 mmol) and 4,4-difluoroazepane hydrochloride (113 mg, 0.66 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (300 mg, 0.923 mmol) was added. The mixture was heated to 100 °C and reacted for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3), the title compound (80 mg, 88% yield, yellow oil) was obtained.

[0521] MS(ESI): m / z 685.1[M+H] + .

[0522] Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(1-(S-methyliminosulfonyl)cyclopropyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 32)

[0523] TIFF2025529613000136.tif30128

[0524] 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) was dissolved in the solution, and the mixture was heated to 60 °C and reacted for 3 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was adjusted to a weak alkaline state with 1 N sodium hydroxide solution and extracted with ethyl acetate (2 mL × 3). The combined organic phase was washed with saturated brine (5 mL × 3) and dried over anhydrous sodium sulfate. The mixture was spun under vacuum to remove the solvent. After preparation and purification by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile), the title compound (19.21 mg, yield: 34.12%, white solid) was obtained.

[0525] MS(ESI): m / z 551.1[M+H] + .

[0526] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.47(d,J=5.5Hz,1H),7.85(s,1H),7.73-7.67(m,2H),7.36(s,1H),3.69(s,1H), 3.42-3.33(m,4H),2.92(s,3H),2.24(brs,2H),2.11-2.00(m,2H),1.79(brs,3H),1.49-1.43(m,1H),1.31-1.21(m,2H).

[0527] Example 33 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(2-(S-methyliminosulfonyl)ethoxy)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 33)

[0528] TIFF2025529613000137.tif85144

[0529] Step 1: 4-Bromo-2-(2-(methylthio)ethoxy)pyridine

[0530] TIFF2025529613000138.tif12128

[0531] 2-(Methylthio)ethan-1-ol (3.14 g, 34.10 mmol) was dissolved in N,N-dimethylformamide (60 mL) and sodium hydride (1.70 g, 42.60 mmol) was added at 0 °C. The reaction was continued for 0.5 hours. 4-Bromo-2-fluoropyridine (5.00 g, 28.40 mmol) was added under nitrogen and the reaction was continued for 2 hours at 0 °C. The reaction was stopped and quenched by slowly adding water (250 mL). The aqueous phase was extracted with ethyl acetate (250 mL x 3). The combined organic phase was washed with saturated brine (250 mL x 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum 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).

[0532] MS(ESI): m / z 247.9[M+H] + .

[0533] Step 2: (2-((4-bromopyridin-2-yl)oxy)ethyl)(imino)(methyl)-λ 6 -sulfoxide

[0534] TIFF2025529613000139.tif14128

[0535] 4-Bromo-2-(2-(methylthio)ethoxy)pyridine (4.5 g, 18.13 mmol) was dissolved in methanol (50 mL), and ammonium carbonate (5.2 g, 54.40 mmol) was added. Then, iodobenzene diacetate (23.3 g, 72.53 mmol) was added in an ice bath. After purging with nitrogen, the mixture was stirred and reacted at room temperature for 2 hours. The reaction was stopped, and water (200 mL) was added to quench the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum to obtain the crude product. The crude product was separated and purified using a reverse-phase column (mobile phase: water:methanol = 85:15) to obtain the title compound (900 mg, yield: 17.7%, yellow oil).

[0536] MS(ESI):m / z 279.0[M+H] + .

[0537] Step 3: Benzyl((2-((4-bromopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0538] TIFF2025529613000140.tif13128

[0539] (2-((4-bromopyridin-2-yl)oxy)ethyl)(imino)(methyl)-λ 6HCl sulfoxide (700 mg, 2.50 mmol) was dissolved in DCM (10 mL) and pyridine (297 mg, 3.76 mmol) was added. After replacing the atmosphere with nitrogen, CbzCl (513 mg, 3.00 mmol) was added in an ice bath and stirred at room temperature for 2 hours. The reaction was stopped. The reaction solution was quenched by adding water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum 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 (800 mg, yield: 77.2%, colorless oil).

[0540] MS(ESI): m / z 415.0[M+H] + .

[0541] Step 4: Benzyl((2-((4-((diphenylmethylene)amino)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0542] TIFF2025529613000141.tif19128

[0543] Benzyl((2-((4-bromopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (700 mg, 1.69 mmol) was dissolved in dioxane (10 mL), and diphenylimine (458 mg, 2.54 mmol), tris(dibenzylideneacetone)dipalladium (154 mg, 0.16 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (195 mg, 0.33 mmol), and cesium carbonate (1654 mg, 5.08 mmol) were added. The atmosphere was purged with nitrogen, and the mixture was stirred at 100 °C for 1.5 hours. The reaction was stopped, the reaction solution was cooled, and water (100 mL) was added. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum to obtain the crude product. The crude product was separated and purified on a thin layer chromatography plate (developing agent: ethyl acetate) to obtain the title compound (550 mg, yield: 63.2%, yellow solid).

[0544] MS(ESI): m / z 514.2[M+H] + .

[0545] Step 5: Benzyl((2-((4-aminopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0546] TIFF2025529613000142.tif15128

[0547] 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), and water (1 mL) and hydrochloric acid (1 mL) were added. After purging with nitrogen, the mixture was reacted at room temperature for 1.5 hours. The reaction solution was rotary evaporated in vacuo to give the crude title compound (400 mg, white solid), which was used directly in the next reaction.

[0548] MS(ESI): m / z 350.1[M+H]+ .

[0549] Step 6: Benzyl((2-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0550] TIFF2025529613000143.tif28128

[0551] Benzyl((2-((4-aminopyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 5-Chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (283 mg, 1.16 mmol) was dissolved in pyridine (15 mL) and added. After purging with nitrogen, phosphorus oxychloride (536 mg, 3.50 mmol) was added in an ice bath and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was stopped, and water was added to the reaction solution (100 mL) in an ice bath. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum 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).

[0552] MS(ESI): m / z 574.1[M+H] + .

[0553] Step 7: Benzyl((2-((4-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)oxy)ethyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate

[0554] TIFF2025529613000144.tif30128

[0555] 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) and 4-fluoro-2-methylphenol (35 mg, 0.27 mmol) were added. The mixture was purged with nitrogen and reacted at 70°C for 12 hours. The reaction was stopped, and water was added to the reaction solution (15 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum 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).

[0556] MS(ESI): m / z 680.1[M+H] + .

[0557] Step 8: 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-(2-(S-methyliminosulfonyl)ethoxy)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 33)

[0558] TIFF2025529613000145.tif28128

[0559] Trifluoroacetic acid (1.5 mL) was used to prepare the compound 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 the solution, and the mixture was heated to 60 °C and reacted for 3 hours. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The residue was adjusted to a weak alkaline state with 1N sodium hydroxide solution and extracted with ethyl acetate (2 mL × 3). The combined organic phase was washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was spun under vacuum to remove the solvent. After preparation and purification by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile), the title compound (34.87 mg, yield: 54.22%, white solid) was obtained.

[0560] MS(ESI): m / z 546.0[M+H] + .

[0561] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.06(s,1H),7.67(d,J=7.5Hz,1H),7.22(d,J=9.0Hz,1H),7.09(d,J=5.8Hz,3H),6.82(d,J= 1.9Hz,1H), 6.42(dd,J=7.5,2.2Hz,1H),4.21(t,J=6.8Hz,2H),3.88(s,1H),3.43(td,J=6.8,2.7Hz,2H),2.91(s,3H),2.16(s,3H).

[0562] Example 34 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-(S-methylsulfonimido)pyridin-4-yl)-4-trifluoromethylbenzamide (Compound 34)

[0563] TIFF2025529613000146.tif35128

[0564] Step 1: 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide

[0565] TIFF2025529613000147.tif28128

[0566] 5-Chloro-2-fluoro-N-(2-methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-(1,4-diazepan-1-yl)ethan-1-one (140.8 mg, 0.99 mmol) and cesium carbonate (322.7 mg, 0.99 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was reacted at 100°C for 16 hours. The reaction was stopped. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was spun under vacuum to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:3), the title compound (90 mg, yield: 56.3%, white solid) was obtained.

[0567] MS(ESI): m / z 487.0[M+H] + .

[0568] Step 2: 2-(4-acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-(S-methylsulfonimido)pyridin-4-yl)-4-trifluoromethylbenzamide (Compound 34)

[0569] TIFF2025529613000148.tif33128

[0570] 2-(4-Acetyl-1,4-diazepan-1-yl)-5-chloro-N-(2-methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide (90 mg, 0.18 mmol) was dissolved in methanol (1 mL), and ammonium carbonate (18 mg, 0.54 mmol) and iodobenzene acetate (60.3 mg, 0.72 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the reaction solution was spun under vacuum to remove the solvent. The product was separated and purified by column chromatography (silica gel, dichloromethane:methane = 20:1), followed by purification by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (2 mg, yield: 2.1%, white solid).

[0571] MS(ESI): m / z 518.1[M+H] + .

[0572] 1 H NMR(400MHz,DMSO-d6)δ 11.30(s,1H),8.62(d,J=5.4Hz,1H),8.40(d,J=3.2Hz,1H),7.84(d,J=5.5Hz,1H),7.73(d,J=17.0Hz,1H),7.37 (d,J=10.9Hz,1H),4.38(s,1H),3.62-3.54(m,2H),3.49-3.34(m,6H),3.15(s,3H),1.89(s,3H),1.74(brs,2H).

[0573] Example 35 4-Acetyl-1,4-diazacyclopenta-5-chloro-N-(4-fluoro-3-S-methanesulfonyliminophenyl)-4-trifluoromethylbenzamide (Compound 35)

[0574] TIFF2025529613000149.tif40131

[0575] Step 1: 4-acetyl-1,4-diazacyclopenta-5-chloro-4-fluoro-3-methylthiobenzamide

[0576] TIFF2025529613000150.tif32128

[0577] 5-Chloro-2-fluoro-N-4-fluoro-3-methylthiobenzamide (100 mg, 0.262 mmol) and 1-(1,4-diazacyclopentenyl)ethanone (75 mg, 0.525 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (171 mg, 0.525 mmol) was added. The mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (116 mg, 88% yield, yellow oil).

[0578] MS(ESI): m / z 504.1[M+H] + .

[0579] Step 2: 4-Acetyl-1,4-diazacyclopenta-5-chloro-N-(4-fluoro-3-S-methanesulfonyliminophenyl)-4-trifluoromethylbenzamide (Compound 35)

[0580] TIFF2025529613000151.tif32128

[0581] 4-Acetyl-1,4-diazacyclopenta-5-chloro-4-fluoro-3-methylthiobenzamide (96 mg, 0.19 mmol) was dissolved in methanol (2 mL), and ammonium carbonate (54.78 mg, 0.57 mmol) and iodobenzene diacetate (244.8 mg, 0.76 mmol) were added. The mixture was allowed to react at room temperature for 1 hour. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. The product was separated and purified by column chromatography (silica gel, ethyl acetate), followed by purification by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (15.76 mg, yield: 14.85%, white solid).

[0582] MS(ESI): m / z 535.1[M+H] + .

[0583] 1 H NMR(400MHz,DMSO-d6)δ 10.92(s,1H),8.28(d,J=4.3Hz,1H),8.03-7.91(m,1H),7.67(d,J=16.7Hz,1H),7.45(t,J=9.3Hz,1 H),7.35(d,J=9.6Hz,1H),4.70(s,1H),3.62-3.35(m,8H),3.20(s,3H),1.90(s,3H),1.76(brs,2H).

[0584] Example 36 5-chloro-2-(4-(2,2-difluoroethyl)-1,4-diaz-1-yl)-N-(2-(S-methylsulfonimido)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0585] TIFF2025529613000152.tif24146

[0586] Step 1: tert-Butyl: 4-(4-chloro-2-((2-(methylthio)pyridin-4-yl)carbamoyl)-5-(trifluoromethyl)phenyl)-1,4-diaza-1-carboxylic acid

[0587] TIFF2025529613000153.tif30128

[0588] 5-Chloro-2-fluoro-N-2-methylthiopyridin-4-yl-4-trifluoromethylbenzamide (200 mg, 0.55 mmol) and tert-butyl 1,4-diaza-1-carboxylate (220.2 mg, 1.1 mmol) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (358.4 mg, 1.1 mmol) was added. The mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped. The reaction solution was quenched by adding saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 7:3) to obtain the title compound (215 mg, yield: 72%, yellow oil).

[0589] MS(ESI): m / z 545.1[M+H] + .

[0590] Step 2: 5-chloro-2-(1,4-diaz-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0591] TIFF2025529613000154.tif36128

[0592] Tert-butyl 4-(4-chloro-2-((2-(methylthio)pyridin-4-yl)carbamoyl)-5-(trifluoromethyl)phenyl)-1,4-diaza-1-carboxylate (205 mg, 0.377 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent, yielding the title compound (337 mg, yield: 98%, yellow oil).

[0593] MS(ESI): m / z 445.1[M+H] + .

[0594] Step 3: 5-chloro-2-(4-(2,2-difluoroethyl)-1,4-diaz-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0595] TIFF2025529613000155.tif32128

[0596] 5-Chloro-2-(1,4-diaza-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), and triethylamine (91.5 μL) was added. The mixture was reacted in an oil bath at 50° C. for 16 hours. The reaction was stopped, and the mixture was spun in vacuo to remove the solvent. The residue was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate=6.5:3.5) to give the title compound (148 mg, yield: 44.85%, yellow oil).

[0597] MS(ESI): m / z 509.1[M+H] + .

[0598] Step 4: 5-chloro-2-(4-(2,2-difluoroethyl)-1,4-diaz-1-yl)-N-(2-(S-methylsulfonimido)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0599] TIFF2025529613000156.tif31128

[0600] 5-Chloro-2-(4-(2,2-difluoroethyl)-1,4-diaz-1-yl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)benzamide (114 mg, 0.212 mmol) was dissolved in methanol (1 mL), and ammonium carbonate (11.31 mg, 0.118 mmol) and iodobenzene acetate (50.25 mg, 0.156 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was spun under vacuum to remove the solvent. After separation and purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 6.5:3.5), the product was purified by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (91 mg, yield: 67.4%, yellow oil).

[0601] MS(ESI): m / z 540.1[M+H] + .

[0602] Example 37 5-chloro-N-(2-methanesulfonylimino)pyridin-4-yl)-2-(4-(2,2,2-trifluoroethyl)-1,4-diazacyclopent-1-yl)-4-trifluoromethylbenzamide (Compound 37)

[0603] TIFF2025529613000157.tif35128

[0604] Step 1: 5-chloro-N-2-methylthiopyridin-4-yl-2-(2,2,2-trifluoroethyl)-1,4-diazacyclopent-1-yl)-4-trifluoromethylbenzamide

[0605] TIFF2025529613000158.tif30128

[0606] 5-Chloro-2-(1,4-diazacyclopent-1-yl)-N-(2-methylthio)pyridin-4-yl)-4-trifluoromethylbenzamide (100 mg, 0.23 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (208.89 mg, 0.9 mmol) were dissolved in tetrahydrofuran (2.5 mL), and triethylamine (186.19 mg, 1.84 mmol) was added. The mixture was reacted in an oil bath at 50 °C for 16 hours. The reaction was stopped, and the mixture was spun in vacuo to remove the solvent. The residue was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 7:3) to give the title compound (68 mg, yield: 56.7%, yellow oil).

[0607] MS(ESI): m / z 527.1[M+H] + .

[0608] Step 2: 5-chloro-N-(2-methanesulfonylimino)pyridin-4-yl)-2-(4-(2,2,2-trifluoroethyl)-1,4-diazacyclopent-1-yl)-4-trifluoromethylbenzamide (Compound 37)

[0609] TIFF2025529613000159.tif33128

[0610] 5-Chloro-N-2-methylthiopyridin-4-yl-2-(2,2,2-trifluoroethyl)-1,4-diazacyclopent-1-yl)-4-trifluoromethylbenzamide (45 mg, 0.086 mmol) was dissolved in methanol (1 mL), and ammonium carbonate (24.7 mg, 0.257 mmol) and iodobenzene acetate (110.8 mg, 0.344 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the mixture was rotated in vacuo to remove the solvent. The product was separated and purified by column chromatography (silica gel, pure ethyl acetate), followed by purification by high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (57 mg, yield: 92.3%, yellow oil).

[0611] MS(ESI): m / z 558.1[M+H] + .

[0612] Example 38 5-chloro-N-(2-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (Compound 38)

[0613] TIFF2025529613000160.tif29162

[0614] Step 1: (4-aminopyridin-2-yl)imino)dimethyl-6-sulfone

[0615] TIFF2025529613000161.tif17128

[0616] 2-Chloro-4-nitropyridine (1000 mg, 6.31 mmol) was dissolved in anhydrous 1,4-dioxane (20 mL), and dimethylsulfinyl imine (881 mg, 9.46 mmol), cesium carbonate (6.2 g, 18.93 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (730 mg, 1.26 mmol), and tris[dibenzylideneacetone]dipalladium(O) (577 mg, 0.63 mmol) were added. The mixture was stirred and reacted overnight at 100 °C under nitrogen protection. The reaction was stopped. The reaction solution was rotary evaporated, and the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to give the title compound (1.2 g, yield: 88%, yellow solid).

[0617] MS(ESI): m / z 216.1[M+H] + .

[0618] Step 2: (4-aminopyridin-2-yl)imino)dimethyl-λ 6 -sulfonamide

[0619] TIFF2025529613000162.tif18128

[0620] Dimethyl(4-nitropyridin-2-yl)imino)-λ 6 1-Sulfonamide (600 mg, 2.79 mmol) was dissolved in anhydrous methanol (10 mL), and palladium on carbon (180 mg) was added. After replacing the atmosphere with hydrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, and the reaction solution was filtered. The filtrate was spun under vacuum to remove the solvent, and the residue was separated and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain the title compound (460 mg, yield: 89%, white solid).

[0621] MS(ESI): m / z 186.2[M+H] + .

[0622] Step 3: 5-chloro-N-(2-(dimethyl(oxo)-λ 6 -sulfanylidene)amino)pyridin-4-yl)-2-fluoro-4-(trifluoromethyl)benzamide

[0623] TIFF2025529613000163.tif33128

[0624] (4-aminopyridin-2-yl)imino)dimethyl-λ using pyridine (2 mL) 65-Sulfonamidene (120 mg, 0.648 mmol) and 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (157.17 mg, 0.648 mmol) were dissolved in the solution. After purging with nitrogen, the temperature was lowered to -10 °C, and phosphorus oxychloride (248.64 mg, 1.62 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped. The reaction solution was quenched by adding ice water (5 mL), adjusted to acidity with 1N hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was spun under vacuum to remove the solvent, and the residue was separated and purified by column chromatography (silica gel, dichloromethane:anhydrous methanol = 9:1) to obtain the title compound (263.7 mg, yield: 98%, yellow oil).

[0625] MS(ESI): m / z 410.0[M+H] + .

[0626] 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)

[0627] TIFF2025529613000164.tif32128

[0628] 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), and cesium carbonate (316.7 mg, 0.972 mmol) was added. The mixture was reacted in an oil bath at 100°C for 2 hours. The reaction was stopped. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to obtain the title compound (38.25 mg, yield: 22.9%, white solid).

[0629] MS(ESI): m / z 516.1[M+H] + .

[0630] 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.03(s,1H),7.99(d,J=5.7Hz,1H),7.21(d,J=9.0Hz,1H) ,7.10-7.08(m,4H),7.03(d,J=5.7Hz,1H),6.93(s,1H),3.34(s,3H),3.32(s,3H),2.16(s,3H).

[0631] Example 39 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)pyridin-4-yl)-4-(trifluoromethyl)benzamide (Compound 39)

[0632] TIFF2025529613000165.tif31128

[0633] 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-difluoroazetidine hydrochloride (322.4 mg, 1.944 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (1.056 g, 3.24 mmol) was added. The mixture was reacted in an oil bath at 100°C for 16 hours. The reaction was stopped. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound (39.52 mg, yield: 23.3%, yellow solid).

[0634] MS(ESI): m / z 525.1[M+H] + .

[0635] 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),7.99(d,J=5.5Hz,1H),7.64(s,1H),7.33(s,1H),7.03 (d,J=8.8Hz,2H),3.41-3.34(m,10H),2.23(brs,2H),2.10-2.01(m,2H),1.80-1.78(m,2H).

[0636] Biological Test Evaluation Test Example A: Blocking activity of the compounds of the present invention against sodium ion channel 1.8 (NaV1.8).

[0637] Experimental objective: To determine the inhibitory rate of compounds against human Nav1.8 ion channel stably expressed by CHO cells.

[0638] Experimental Method: Compounds were dissolved in DMSO to prepare stock solutions, which were then diluted with extracellular solution (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl, 2 mM CaCl, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaHPO 2H O, pH 7.4 (NaOH)) to the specific concentrations used in manual patch clamp experiments.

[0639] A microelectrode puller was used to stretch a glass capillary tube to form a recording electrode. Using a microelectrode manipulator under an inverted microscope, the recording electrode was brought into contact with the cell and negative suction pressure was applied to form a GΩ seal. Once a GΩ seal was formed, rapid capacitance compensation was performed, followed by continued negative pressure to rupture the cell membrane and form a whole-cell recording mode. Slow capacitance compensation was performed, and film capacitance and series resistance were recorded. No leakage compensation was applied. Once the whole-cell recorded Nav1.8 currents stabilized, compound administration began. Compounds were applied at the first concentration for 5 minutes (or until the current stabilized), and then a second concentration was tested. Two concentrations of each test compound were tested.

[0640] The voltage stimulation protocol for whole-cell patch-clamp recording of Nav1.8 sodium currents was as follows: once a whole-cell seal was formed, the cell voltage was clamped at -120 mV for 30 ms. The clamp voltage was depolarized to 0 mV for 50 ms, and then the voltage was returned to -50 mV for 8 s (the specific voltage referred to half the inactivation voltage in the IV test). Subsequently, the cell membrane potential was restored to -120 mV for 20 ms, then further depolarized to 0 mV for 50 ms, and finally returned to the clamp voltage of -120 mV for 30 ms. Data acquisition was repeated every 20 s. The effect of the compound on the peak value of the sodium current was observed. Experimental data were collected using an EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0641] Experimental results TIFF2025529613000166.tif208143

[0642] Test Example B: Quantitative pharmacokinetic evaluation of compounds of the present invention administered intravenously or orally by gavage to rats.

[0643] Experimental Objective: The objective of this study was to evaluate the pharmacokinetic properties of compounds of the present invention.

[0644] The present inventors have performed a pharmacokinetic evaluation of the compounds of the present invention in rats. The animal information is shown in Table 2.

[0645] Table 2: Information on test animals in the present invention TIFF2025529613000167.tif13163

[0646] Experimental Method: The compounds of the present invention were administered to test animals as a solution of 5% DMSO, 5% Tween 80, and 90% saline. The animals were fasted for 12 hours before administration, but had free access to water. For the intravenous administration group, the dose was 1 mg / kg. For gavage administration, the dose was 10 mg / kg. After administration, blood was collected intravenously from the animals (approximately 0.3 mL of blood) at the following time points: 0.083 hours, 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, and 24 hours. EDTA-K2 had been added to the collection tubes as an anticoagulant. Each blood sample was centrifuged at 6800 g for 6 minutes at low temperature, and the plasma was collected and stored at -80°C.

[0647] Sample preparation for LC-MS / MS assay: 20 μL of plasma sample was subjected to protein precipitation using 400 μL of methanol containing 100 ng / mL of IS (tolbutamide). The mixture was vortexed for 1 minute and then centrifuged at 18,000 g for 7 minutes. 400 μL of the supernatant was transferred to a 96-well plate. 2 μL of the supernatant was subjected to LC-MS / MS analysis. The analytical results showed that the compounds of the present invention have good pharmacokinetic properties in rats.

[0648] TIFF2025529613000168.tif109164

[0649] Test Example C: Quantitative Pharmacokinetic Evaluation of Compounds of the Present Invention Administered Intravenously or Orally by Gavage to Mice

[0650] Experimental Objective: The objective of this study was to evaluate the pharmacokinetic properties of compounds of the present invention.

[0651] The present inventors have performed a pharmacokinetic evaluation of the compounds of the present invention in mice. The animal information is shown in Table 3.

[0652] Table 3: Information on test animals in the present invention TIFF2025529613000169.tif13163

[0653] Experimental Method: The compounds of the present invention were administered to test animals as a solution of 5% DMSO, 5% Tween 80, and 90% saline. The animals were fasted for 12 hours before administration, but had free access to water. For the intravenous administration group, the dose was 1 mg / kg. For gavage administration, the dose was 10 mg / kg. After administration, blood was collected intravenously from the animals (approximately 0.3 mL of blood) at the following time points: 0.083 hours, 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, and 24 hours. EDTA-K2 had been added to the collection tubes as an anticoagulant. Each blood sample was centrifuged at 6800 g for 6 minutes in a cold place, and the plasma was collected and stored at -80°C.

[0654] Sample preparation for LC-MS / MS assay: 15 μL of plasma sample was subjected to protein precipitation using 300 μL of methanol containing 100 ng / mL of IS (tolbutamide). The mixture was vortexed for 1 minute and then centrifuged at 18,000 g for 10 minutes. 300 μL of the supernatant was transferred to a 96-well plate. 2 μL of the supernatant was subjected to LC-MS / MS analysis. The analytical results showed that the compounds of the present invention have good pharmacokinetic properties in mice.

[0655] TIFF2025529613000170.tif40164

Claims

1. General formula (I'): A compound represented by, or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant, During the ceremony X is N or CR ｘ And, Y is N or CR ｙ And, Z is N or CR ｚ And, W is N or CR ｗ And, G is N or CR ｇ And, However, at most two of X, Y, and Z are simultaneously N. R ｘ 、R ｙ and R ｚ are each independently H, D, halogen, CN, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, -OR ｓ１ and -L １ -R １ is selected from, where at least one of R ｘ , R ｙ and R ｚ is -L １ -R １ and the group may be substituted with one or more deuterium until it is fully deuterated. R ｗ and R ｇ However, each is independent of H, D, halogen, CN, and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl and -OR ｓ１ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. -L １ - but - (CR ａ R ｂ ) ｍ - and if valence is acceptable, -(CR ａ R ｂ ) ｍ Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R ａ and R ｂ However, together with the carbon atoms to which they are bonded, C ３～８ They form cycloalkyl or 3-10 membered heterocyclines, R １ However, -S(O) ｑ NR'R'', -S(O)(=NR')R ４ , or -N=S(O)R ４ R ４ 'and, A is C ３～８ Cycloalkyl, 3-10 membered heterocyclyl, C ６～１０ Selected from aryls and 5-10 member heteroaryls, s R ２ They may be substituted with substituents, -L ２ - is bonded to -O-, -NR'-, -S-, -C(O)-, and -(CR ｃ R ｄ ) ｎ - is selected from, and if valence is acceptable, - (CR ｃ R ｄ ) ｎ Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R ｃ and R ｄ However, together with the carbon atoms to which they are bonded, C ３～８ Forming a cycloalkyl or 3-10 membered heterocycline, R' is H, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R'' is -L ３ -B, B is C ３～８ Cycloalkyl, 3-10 membered heterocyclyl, C ６～１０ Selected from aryls and 5- to 10-membered heteroaryls, t R ５ They may be substituted with substituents, -L ３ - but - (CR ｅ R ｆ ) ｐ - and if valence is acceptable, -(CR ｅ R ｆ ) ｐ Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R ｅ and R ｆ However, together with the carbon atoms to which they are bonded, C ３～８ Forming a cycloalkyl or 3-10 membered heterocycline, R ２ 、 R ３ａ 、 R ３ｂ 、 R ３ｃ and R ３ｄ 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 -SO ２ R ｓ１ and may be substituted with one or more deuteriums until fully deuterated, R ４ and R ４ ’ are each independently H, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, and C １～６ haloalkyl, and said groups may be substituted with one or more deuteriums until they are fully deuterated. Each R ５ However, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 -SO ２ R ｓ１ The group is independently selected from the above, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ６ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ａ , R ｂ , R ｃ , R ｄ , R ｅ , and R ｆ However, independently, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ and R ｓ２ However, independently, H and C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. m is 0, 1, 2, 3, 4, 5, or 6. n is 0, 1, 2, 3, 4, 5, or 6. p is 0, 1, 2, 3, 4, 5, or 6, t is 1, 2, 3, 4, or 5, s is 1, 2, 3, 4, 5, 6, 7, or 8, q is 1 or 2. Compounds represented by general formula (I'), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof.

2. General formula (I): A compound represented by, or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant, During the ceremony, X is N or CR ｘ And, Y is N or CR ｙ And, Z is N or CR ｚ And, W is N or CR ｗ And, G is N or CR ｇ And, However, at most two of X, Y, and Z are simultaneously N. R ｘ , R ｙ and R ｚ Each of these is independent of H, D, halogen, CN, and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, -OR ｓ１ and -L １ -R １ Selected from, here, R ｘ , R ｙ and R ｚ At least one of them is -L １ -R １ The group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｗ and R ｇ However, each is independent of H, D, halogen, CN, and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl and -OR ｓ１ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. -L １ - but - (CR ａ R ｂ ) ｍ - and if valence is acceptable, -(CR ａ R ｂ ) ｍ Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R ａ and R ｂ However, together with the carbon atoms to which they are bonded, C ３～８ They form cycloalkyl or 3-10 membered heterocyclines, R １ However, -S(O) ｑ NR'R'' or -S(O)(=NR')R ４ And, A is C ３～８ Cycloalkyl, 3-10 membered heterocyclyl, C ６～１０ Selected from aryls and 5-10 member heteroaryls, s R ２ They may be substituted with substituents, -L ２ - is bonded to -O-, -NR'-, -S-, -C(O)-, and -(CR ｃ R ｄ ) ｎ - is selected from, and if valence is acceptable, - (CR ｃ R ｄ ) ｎ Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R ｃ and R ｄ However, together with the carbon atoms to which they are bonded, C ３～８ Forming a cycloalkyl or 3-10 membered heterocycline, R' is H, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R'' is -L ３ -B, B is C ３～８ Cycloalkyl, 3-10 membered heterocyclyl, C ６～１０ Selected from aryls and 5- to 10-membered heteroaryls, t R ５ They may be substituted with substituents, -L ３ - but - (CR ｅ R ｆ ) ｐ - and if valence is acceptable, -(CR ｅ R ｆ ) ｐ Any methylene unit in - may be independently replaced by -NR'-, -O-, -S-, and -C(O)-, and / or R ｅ and R ｆ However, together with the carbon atoms to which they are bonded, C ３～８ Forming a cycloalkyl or 3-10 membered heterocycline, R ２ , R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ However, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 -SO ２ R ｓ１ The group is independently selected from the above, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ４ However, H, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. Each R ５ However, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 -SO ２ R ｓ１ The group is independently selected from the above, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ６ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ａ , R ｂ , R ｃ , R ｄ , R ｅ , and R ｆ However, independently, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ and R ｓ２ However, independently, H and C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. m is 0, 1, 2, 3, 4, 5, or 6. n is 0, 1, 2, 3, 4, 5, or 6. p is 0, 1, 2, 3, 4, 5, or 6, t is 1, 2, 3, 4, or 5, s is 1, 2, 3, 4, 5, 6, 7, or 8, q is 1 or 2. Compounds represented by general formula (I'), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof.

3. Formula (II): The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

4. -L ２ The compound according to claim 1, wherein - is -O-, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

5. -L ２ The compound according to claim 1, wherein the - is a bond, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

6. A is phenyl, C ３～６ A compound according to claim 1, selected from cycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclil, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant.

7. A is selected from cyclopentyl, cyclohexyl, azacyclohexyl, oxacyclohexyl, thiacyclohexyl, azepanyl, diazepanyl, octahydrocyclopentadienopyrrole, octahydropyrrolopyrrol, octahydrocyclopentadienyl, phenyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein m is 0.

9. m is 1, 2, 3, 4, or 5. - (CR ａ R ｂ ) ｍ Any methylene unit in - may be independently replaced by -O-, -S-, and -C(O)-, and / or R ａ and R ｂ However, together with the carbon atoms to which they are bonded, C ３～６ Forming cycloalkyl and 3-5 membered heterocyclines, R ａ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyls, R ｂ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

10. Formula (III): The compound described in claim 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

11. Formula (IV): (In the formula, X is N or CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, each is independent of H, D, halogen, and C. １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R' is H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R'' is -L ３ -B, B is a 5-7 member heterocycline, and t R ５ They may be substituted with substituents, -L ３ - but - (CR ｅ R ｆ ) ｐ - and if valence is acceptable, -(CR ｅ R ｆ ) ｐ Any methylene unit in the - can be independently replaced by -O-, -S-, and -C(O)-, R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ２ｅ , R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ However, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 -SO ２ R ｓ１ The group is independently selected from the above, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. Each R ５ However, independently, H and C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｅ and R ｆ However, independently, H, D, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ and R ｓ２ However, independently, H and C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. p is 0, 1, 2, or 3, (t is 1, 2, or 3) The compound described in claim 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

12. X is CR ｘ And, Y is N, R ｘ However, H, D, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R' is H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R'' is -L ３ -B, B is a 5-6 member heterocycline, and t R ５ They may be substituted with substituents, -L ３ - but - (CR ｅ R ｆ ) ｐ - and R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ２ｅ , R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ However, independently, H, D, halogen, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. Each R ５ However, independently, H, D, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｅ and R ｆ However, independently, H, D, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. p is 0, 1, 2, or 3, t is 1, 2, or 3, Preferably, -L ３ -B, Selected from, The compound described in claim 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

13. X is CR ｘ And, Y is N, R ｘ However, it is H or D, R' is H, R'' is -L ３ -B, B is a 5-6 member heterocyclyl, preferably azacyclopentyl or azacyclohexyl. -L ３ - but - (CR ｅ R ｆ ) ｐ - and p is 0 or 1, R ２ａ However, C １～６ Alkyl, preferably methyl, R ２ｂ However, it is H or D, R ２ｃ However, the halogen is preferably F, R ２ｄ However, it is H or D, R ２ｅ However, it is H or D, R ３ａ However, it is H or D, R ３ｂ However, C １～６ Haloalkyl, preferably -CF ３ And, R ３ｃ However, the halogen is preferably Cl, R ３ｄ However, it is H or D, R ｅ However, H, D, and C １～６ Selected from alkyl groups, R ｆ However, H, D, and C １～６ Selected from alkyl groups, Preferably, -L ３ -B, Selected from, The compound described in claim 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

14. Formula (V): The compound described in claim 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

15. X is N or CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, each is independent of H, D, halogen, and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl and -OR ｓ１ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. -L ２ - is a bond, -O-, -S-, or -NH-, A is phenyl, C ３～８ Selected from cycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl, and s R ２ They may be substituted with substituents, If valence is acceptable, -(CR ａ R ｂ ) ｍ Any methylene unit in the - can be independently replaced by -O-, -S-, and -C(O)-, R' is H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ , R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ However, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 -SO ２ R ｓ１ The group is independently selected from the above, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ４ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ａ and R ｂ However, H, D, halogen, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. or R ａ and R ｂ However, together with the carbon atoms to which they are bonded, C ３～６ Forming cycloalkyl and 3-5 membered heterocyclines, R ｓ１ and R ｓ２ However, independently, H and C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. m is 0, 1, 2, 3 or 4, s is 1, 2, 3, 4, 5, 6, 7, or 8. The compound described in claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

16. X is CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, each is independent of H, D, halogen, and C. １～６ Selected from alkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. A, and selected from 5-8 member heterocyclyls, and s R ２ They may be substituted with substituents, If the valence is acceptable, -(CR ａ R ｂ ) ｍ Any methylene unit within the - can be independently replaced by -O-. -L ２ - is a bond or -O-, R' is H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. Each R ２ However, independently, H, D, halogen, C １～６ Alkyl, C １～６ Haloalkyl and -OR ｓ１ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ａ However, H, D, halogen, C １～６ Alkyl, C １～６ Haloalkyl, -OR ｓ１ａ , and -SR ｓ１ａ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｂ However, it is H or D, R ２ｃ However, H, D, halogen, -OR ｓ１ｃ , or -SR ｓ１ｃ And, R ２ｄ However, it is H or D, R ２ｅ However, it is H or D, R ３ａ However, it is H or D, R ３ｂ However, C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ｃ However, it is a halogen, R ３ｄ However, it is H or D, R ４ However, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ａ and R ｂ However, H, D, halogen, and C １～６ Selected from alkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. or R ａ and R ｂ However, together with the carbon atoms to which they are bonded, C ３～６ Forming a cycloalkyl group, Each R ｓ１ However, independently, H and C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ａ However, H, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ｃ However, H, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. m is 1, 2, or 3. s is 1 or 2. The compound described in claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

17. X is CR ｘ And, Y is N or CR ｙ And, R ｘ However, it is H, R ｙ However, it is a halogen, A, and selected from azepanyl, s R ２ It has been replaced with, -(CR) ａ R ｂ ) ｍ が、-CH ２ -、-O-EH ２ -CH ２ -、 Selected from, -L ２ - is a bond or -O-, R' is H, Each R ２ However, independently selected from H and halogens, preferably F, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ａ However, H or C １～６ The group is alkyl, preferably methyl, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｂ However, it is H, R ２ｃ However, halogen or -OR ｓ１ｃ And, R ２ｄ However, it is H, R ２ｅ However, it is H, R ３ａ However, it is H, R ３ｂ However, C １～６ Haloalkyl, preferably -CF ３ And; R ３ｃ However, the halogen is preferably Cl, R ３ｄ However, it is H, R ４ However, C １～６ Alkyl, preferably methyl, R ｓ１ｃ However, H, C １～６ Alkyl, or C １～６ Haloalkyl, preferably -CF ３ And, s is 1 or 2. The compound described in claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

18. Equation (VI): The compound described in claim 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

19. X is N or CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, each is independent of H, D, halogen, and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl and -OR ｓ１ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. -L ２ - is a bond, -O-, -S-, or -NH-, A is phenyl, C ３～８ Selected from cycloalkyl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, and s R ２ They may be substituted with substituents, R' is H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ , R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ However, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 -SO ２ R ｓ１ The group is independently selected from the above, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ４ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ and R ｓ２ However, independently, H and C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. s is 1, 2, 3, 4, 5, 6, 7, or 8. The compound described in claim 18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

20. A is selected from cyclopentyl, cyclohexyl, azacyclohexyl, oxacyclohexyl, thiacyclohexyl, azepanyl, diazepanyl, octahydrocyclopentadienopyrrole, octahydropyrrolopyrrolyl, octahydrocyclopentadienyl, phenyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, preferably A and its substituents are (In the formula, R ２ａ , R ２ｂ , R ２ｃ and R ２ｄ However, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 -SO ２ R ｓ１ (Selected independently from the above, the group may be substituted with one or more deuterium atoms until it is completely deuterated.) Selected from, The compound described in claim 18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

21. -L ２ - is -O-, and A is selected from cyclopentyl and cyclohexyl, preferably cyclohexyl. The compound described in claim 18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

22. -L ２ - is a combination, A is selected from azepanyl, diazepanyl, octahydrocyclopentadienopyrrole, octahydropyrrolopyrrolyl, and octahydrocyclopentadienyl, and preferably, if A is a nitrogen-containing heterocycle, A is linked to phenyl via a nitrogen atom. The compound described in claim 18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

23. Formula (VII): (In the formula, X is N or CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, each is independent of H, D, halogen, and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R' is H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ２ｅ , R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ However, H, D, halogen, CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 -SO ２ R ｓ１ The group is independently selected from the above, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ４ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ and R ｓ２ However, independently, H and C １～６ Alkyl, or C １～６ (Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated.) The compound described in claim 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

24. X is N or CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, each is independent of H, D, halogen, and C. １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R' is H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ａ However, H, D, halogen, -OR ｓ１ａ , -SR ｓ１ａ , NR ｓ１ａ R ｓ２ａ , C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｂ However, H, D, halogen, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｃ However, H, D, halogen, -OR ｓ１ｃ , -SR ｓ１ｃ , NR ｓ１ｃ R ｓ２ｃ , C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｄ However, H, D, halogen, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｅ However, H, D, halogen, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ａ However, H, D, halogen, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ｂ However, H, D, halogen, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ｃ However, H, D, halogen, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ｄ However, H, D, halogen, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ４ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ａ , R ｓ２ａ , R ｓ１ｃ , and R ｓ２ｃ However, H and C are independent of each other. １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. The compound described in claim 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

25. X is CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, independently, H, D, halogen, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R' is H, C １～６ Alkyl, or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ａ However, -OR ｓ１ａ , -SR ｓ１ａ , NR ｓ１ａ R ｓ２ａ , C １～６ Alkyl, or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｂ However, it is H, D, or halogen, R ２ｃ However, H, D, halogen, -OR ｓ１ｃ , -SR ｓ１ｃ , or NR ｓ１ｃ R ｓ２ｃ The group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｄ However, it is H, D, or halogen, R ２ｅ However, it is H, D, or halogen, R ３ａ However, it is H, D, or halogen, R ３ｂ However, H, D, halogen, C １～６ Alkyl, or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ｃ However, it is H, D, or halogen, R ３ｄ However, it is H, D, or halogen, R ４ However, H, C １～６ Alkyl, or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ａ , R ｓ２ａ , R ｓ１ｃ , and R ｓ２ｃ However, H and C are independent of each other. １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. However, if Y is N, R ２ａ However, C １～６ Alkyl or C １～６ Not a haloalkyl The compound described in claim 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

26. X is CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, it is independently selected from H, D, or halogen. R' is H, C １～６ Alkyl, or C １～６ It is a haloalkyl, R ２ａ However, -OR ｓ１ａ , -SR ｓ１ａ , C １～６ Alkyl, or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｂ However, it is H, D, or halogen, R ２ｃ However, H, D, halogen, -OR ｓ１ｃ , or -SR ｓ１ｃ The group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｄ However, it is H or D, R ２ｅ However, it is H or D, R ３ａ However, it is H or D, R ３ｂ However, C １～６ It is a haloalkyl, R ３ｃ However, it is a halogen, R ３ｄ However, it is H or D, R ４ However, C １～６ Alkyl or C １～６ It is a haloalkyl, R ｓ１ａ and R ｓ１ｃ However, independently, C １～６ Alkyl or C １～６ Selected from haloalkyls, However, if Y is N, R ２ａ is C １～６ Alkyl or C １～６ Not a haloalkyl The compound described in claim 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

27. X is CR ｘ And, Y is N or CR ｙ And, R ｘ and R ｙ However, it is independently selected from H, D, or halogen. R' is H, R ２ａ However, -OR ｓ１ａ , -SR ｓ１ａ , or C １～６ It is alkyl, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｂ However, it is H or D, R ２ｃ However, halogen, -OR ｓ１ｃ , or -SR ｓ１ｃ The group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｄ However, it is H or D, R ２ｅ However, it is H or D, R ３ａ However, it is H or D, R ３ｂ However, C １～６ Alkyl or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ｃ However, it is a halogen, R ３ｄ However, it is H or D, R ４ However, C １～６ Alkyl or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ａ and R ｓ１ｃ However, H and C are independent of each other. １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the aforementioned group may be substituted with one or more deuterium atoms until it is completely deuterated. The compound described in claim 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

28. X is CR ｘ And, Y is N or CR ｙ And, R ｘ However, it is H or D, R ｙ However, it is H, D, or halogen, R' is H, R ２ａ However, -OR ｓ１ａ or -SR ｓ１ａ The group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ｂ However, it is H or D, R ２ｃ However, halogen, -OR ｓ１ｃ or -SR ｓ１ｃ And, R ２ｄ However, it is H or D, R ２ｅ However, it is H or D, R ３ａ However, it is H or D, R ３ｂ However, C １～６ Alkyl or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ｃ However, it is a halogen, R ３ｄ However, it is H or D, R ４ However, C １～６ Alkyl or C １～６ It is a haloalkyl group, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ｓ１ａ and R ｓ１ｃ However, independently, C １～６ Alkyl or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. The compound described in claim 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

29. X is CR ｘ And, Y is N or CR ｙ And, R ｘ However, it is H, R ｙ However, the halogen is preferably F, R' is H, R ２ａ However, -OR ｓ１ａ The group may be substituted with one or more deuterium atoms until it is completely deuterated, preferably -OCD. ３ And, R ２ｂ However, it is H, R ２ｃ However, halogen or -OR ｓ１ｃ And preferably F or -OCF ３ And, R ２ｄ However, it is H, R ２ｅ However, it is H, R ３ａ However, it is H, R ３ｂ However, C １～６ Haloalkyl, preferably -CF ３ And, R ３ｃ However, the halogen is preferably Cl, R ３ｄ However, it is H, R ４ However, C １～６ It is alkyl, R ｓ１ａ However, C １～６ It is alkyl, R ｓ１ｃ However, C １～６ It is a haloalkyl, The compound described in claim 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof.

30. A compound according to Claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, selected from Claim 30.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, and a pharmaceutically acceptable excipient, preferably further comprising another therapeutic agent.

32. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, or a pharmaceutical composition containing thereof, in the preparation of a pharmaceutical as a voltage-opening sodium channel inhibitor.

33. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, or a pharmaceutical composition containing thereof, in the preparation of a pharmaceutical as a sodium ion channel 1.8 (NaV 1.8) inhibitor.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, for use as a voltage-opening sodium channel inhibitor.

35. A pharmaceutical composition for use as a sodium ion channel 1.8 (NaV 1.8) inhibitor, comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof.

36. A pharmaceutical composition for inhibiting electropotentially open sodium channels in a target, comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof.

37. A pharmaceutical composition for inhibiting sodium ion channel 1.8 (NaV 1.8) in a target, comprising a compound described in any one of claims 1 to 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof.

38. The pharmaceutical composition according to claim 34 or 36, wherein a voltage-opening sodium channel inhibitor is used to treat a disease selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, systemic neuralgia, epilepsy or epileptic state, neurodegenerative disease, mental disorders such as anxiety or depression, bipolar disorder, muscle rigidity, arrhythmia, motor disorder, neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radiculopathy, sciatica, back pain, headache, neck pain, severe or intractable pain, nociceptive pain, penetration pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress or exercise-induced angina pectoris, palpitations, hypertension, migraine, or abnormal gastrointestinal activity.

39. A pharmaceutical composition for the treatment of a disease selected from radiculopathy, sciatica, back pain, headache, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain in a subject, comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof.

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