NLRP3 inflammasome inhibitors and their use

Abstract

NLRP3 inflammasome inhibitors and pharmaceutical compositions comprising such inhibitors are described herein. These compounds and compositions are useful for treating diseases or disorders related to the NLRP3 inflammasome pathway.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This patent application claims the rights of international applications PCT / CN2023 / 082488 filed on 20 March 2023, PCT / CN2023 / 101049 filed on 19 June 2023, and PCT / CN2024 / 079655 filed on 1 March 2024, each of which is incorporated herein by reference in whole. [Background technology]

[0002] The NOD-like receptor (NLR) family, pyrin-domain-containing protein 3 (NLRP3), is an intracellular sensor that detects a wide range of microbial motifs, endogenous danger signals, and environmental irritants, leading to the formation and activation of the NLRP3 inflammasome. NLRP3 inflammasome assembly results in caspase-1-dependent release of pro-inflammatory cytokines IL-1β and IL-18, as well as gasdermin D-mediated pyroptotic cell death. Studies have revealed novel regulators of the NLRP3 inflammasome, including novel interacting or regulatory proteins, metabolic pathways, and regulatory mitochondrial hubs. Abnormal activation of the NLRP3 inflammasome has been associated with several inflammatory disorders, including cryopyrin-associated periodic syndromes, Alzheimer's disease, diabetes, and atherosclerosis.

[0003] Based on the above, it is necessary to identify inhibitors of the NLRP3 inflammasome. [Overview of the project]

[0004] In one embodiment, the present disclosure relates to novel compounds and compositions useful as inhibitors of the NLRP3 inflammasome pathway.

[0005] In one embodiment, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0006] In some embodiments, the present disclosure provides a compound represented by formula (Ia), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0007] In some embodiments of the compound of formula (Ia), the compound of formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0008] In another embodiment, what is provided herein is a compound represented by formula (III), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0009] In another embodiment, what is provided herein is a compound represented by formula (IV), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0010] Pharmaceutical compositions comprising compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutically acceptable excipients are also disclosed herein.

[0011] Furthermore, disclosed herein are methods for modulating the NLRP3 inflammasome in a subject, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject.

[0012] Furthermore, disclosed herein are methods for inhibiting NLRP3 in a subject, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the subject.

[0013] Furthermore, disclosed herein are methods for treating autoimmune or autoinflammatory diseases or conditions in subjects requiring treatment, comprising administering the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, to the subject.

[0014] In some embodiments, the disease or disorder is an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, e.g., autoinflammatory fever syndrome (e.g., cryopyrin-related periodic syndromes), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), an inflammatory arthritis-related disorder (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic), a kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type 1 / II diabetes and related complications (e.g., The following conditions are selected: nephropathy, retinopathy, hypertensive nephropathy, dialysis-related diseases, neuroinflammatory diseases (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., hidradenitis suppurativa, acne), wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).

[0015] Further aspects and advantages of the present disclosure will be readily apparent to those skilled in the art from the following detailed description, which shows and describes only exemplary embodiments of the present disclosure. As will be understood, other different embodiments of the present disclosure are possible, and some of their details can be modified in various obvious ways without departing from the present disclosure. Accordingly, the drawings and description should be considered illustrative in nature and not restrictive.

[0016] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. To the extent that any publications, patents, or patent applications incorporated by reference conflict with any disclosures contained herein, this Specified is intended to supersede and / or take precedence over any such conflicting material. [Modes for carrying out the invention]

[0017] While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Those skilled in the art will be able to conceive of numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternative forms to the embodiments of the present invention described herein may be used.

[0018] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the present invention pertains. All patents and publications referenced herein are incorporated by reference.

[0019] Unless the context requires otherwise, the word “comprise” and its variations, such as “comprises” and “comprising,” throughout the following specification and claims should be interpreted in an open and comprehensive sense, that is, “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute any interpretation of the scope or meaning of the claimed invention.

[0020] Throughout this specification, any reference to “some embodiments” or “an embodiment” means that any particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment of this disclosure. Therefore, even if the phrases “in one embodiment” or “in one embodiment” appear in various places throughout this specification, they do not necessarily all refer to the same embodiment. Furthermore, any particular feature, structure, or characteristic can be combined in any suitable manner in one or more embodiments. Also, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple references unless the context clearly indicates otherwise. It should be noted that as used herein, the term “or” is generally used in its ordinary sense, including “and / or,” unless the content clearly indicates otherwise.

[0021] As used herein, the following terms have the meanings set forth below, unless otherwise specified.

[0022] "Oxo" refers to O.

[0023] "Carboxyl" refers to the -COOH group.

[0024] "Cyano" refers to -CN.

[0025] "Alkyl" refers to a linear or branched saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whereever used herein, the terms "C1-C6 alkyl" or "C 1~6 Numerical ranges such as "alkyl" mean that an alkyl group can consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, but this definition also includes occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C 1~10 It is alkyl. In some embodiments, alkyl is C 1~6 It is alkyl. In some embodiments, alkyl is C 1~5 It is alkyl. In some embodiments, alkyl is C 1~4 It is alkyl. In some embodiments, alkyl is C 1~3It is alkyl. Unless otherwise specified herein, alkyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0026] "Alkenyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. It should be understood that this group can have either a cis or trans conformation with respect to the double bond(s), and that both isomers are included. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, and 1,3-butadienyl. Where used herein, always refer to "C2-C6 alkenyl" or "C 2~6Numerical ranges such as "alkenyl" mean that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also includes the appearance of the term "alkenyl" without a specified numerical range. Unless otherwise specified herein, the alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0027] "Alkynyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiinyl. Where used herein, it is always referred to as "C2-C6 alkynyl" or "C 2~6A numerical range such as "alkynyl" means that an alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise specified herein, an alkynyl group can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted by halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted by halogen.

[0028] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specified herein, an alkylene group can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted by halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted by halogen.

[0029] "Alkoxy" refers to a radical of the formula -OR a wherein R ais an alkyl radical as defined. In this specification, unless otherwise specified, the alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0030] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system may contain only hydrogen and carbon, as well as 5 to 18 carbon atoms, and at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. Ring systems from which the aryl group is derived include, but are not limited to, groups such as benzene, fluorene, indan, indene, tetralin, and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include a fused ring system (where the aryl is bonded via aromatic ring atoms when fused with a cycloalkyl or heterocycloalkyl ring) or a bridged ring system. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Examples of aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthreene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, aryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally replaced with a halogen.

[0031] A "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocyclic rings may include monocyclic rings with 3 to 10 members, bicyclic rings with 6 to 12 members, and bridging rings with 6 to 12 members. Each ring in a bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, such as phenyl, may be condensed with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, as long as the valence allows. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless otherwise specifically stated herein, carbocyclic rings may be optionally substituted.

[0032] "Cycloalkyl" refers to a partially or completely saturated monocyclic or polycyclic carbocyclic ring, which may include condensed (when condensed with an aryl or heteroaryl ring, the cycloalkyl is bonded via non-aromatic ring atoms), spiro, or bridging ring systems. In some embodiments, the cycloalkyl is completely saturated. Typical cycloalkyls include, but are not limited to, rings with 3 to 15 carbon atoms (e.g., C3-C3). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C3) 10 Fully saturated cycloalkyl or C3-C 10The cycloalkyl group includes cycloalkenyls, 3-8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyls), 3-6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyls), 3-5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyls), or 3-4 carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyls). In some embodiments, the cycloalkyl group is a 3-10 member fully saturated cycloalkyl group or a 3-10 member cycloalkenyl. In some embodiments, the cycloalkyl group is a 3-6 member fully saturated cycloalkyl group or a 3-6 member cycloalkenyl. In some embodiments, the cycloalkyl group is a 5-6 member fully saturated cycloalkyl group or a 5-6 member cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyls may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with halogen.

[0033] A "cycloalkenyl" refers to an unsaturated, non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, which preferably has 3 to 12 carbon atoms and includes a condensed or bridging ring system containing at least one double bond. In some embodiments, the cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, the cycloalkenyl contains 5 to 7 carbon atoms. The cycloalkenyl may be bonded to the rest of the molecule by single bonds. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0034] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0035] As used herein, the terms “haloalkyl” or “haloalkane” refer to alkyl radicals, as defined above, that are substituted with one or more halogen radicals, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When alkyl groups are substituted with halogen radicals with more than one alkyl group, each halogen can be independently selected from, for example, 1-chloro and 2-fluoroethane.

[0036] "Fluoroalkyl" refers to an alkyl radical as defined above, which is substituted with one or more fluoro radicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, and 1-fluoromethyl-2-fluoroethyl.

[0037] "Hydroxyalkyl" refers to an alkyl radical as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl group. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0038] "Aminoalkyl" refers to an alkyl radical as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0039] A "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, a heteroalkyl group is a C1-C6 heteroalkyl group composed of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, in which the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3-, CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified herein, heteroalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyls are optionally substituted with halogens.

[0040] "Heterocycloalkyl" refers to a 3-24 membered partially saturated or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1-3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include condensed (when condensed with an aryl or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom), spiro, or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized. The nitrogen atom may optionally be quaternized. Typical heterocycloalkyls include those with 2 to 15 carbon atoms (e.g., C2-C2). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2 to C2) 10 Fully saturated heterocycloalkyl or C2-C 10This includes heterocycloalkenyls, 2-8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyls or C2-C8 heterocycloalkenyls), 2-7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyls or C2-C7 heterocycloalkenyls), 2-6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyls or C2-C6 heterocycloalkenyls), 2-5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyls or C2-C5 heterocycloalkenyls), or 2-4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyls or C2-C4 heterocycloalkenyls). Examples of such heterocycloalkyl radicals include azilidinyl, azetidinyl, oxetanyl, dioxolanil, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, and pylori. Examples include, but are not limited to, dinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes, but is not limited to, all cyclic forms of carbohydrates, including, but is not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbon atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it should be understood that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl.In some embodiments, the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specified herein, heterocycloalkyls may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0041] A "heteroaryl" refers to a 5-14 membered ring radical comprising 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include a condensed (when condensed with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded via an aromatic ring atom) or bridging ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may optionally be oxidized. The nitrogen atoms may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl Examples include, but are not limited to, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthylidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with a halogen.

[0042] The term “substituted” refers to a moiety having a substituent that replaces one or more carbons or substituteable heteroatoms of a structure, for example, a hydrogen on an NH group. “Substituted” or “substituted with” will be understood to imply the implicit condition that such substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc., depending on the acceptable valence of the substituted atom and the substituent. In some embodiments, substituted refers to a moiety having a substituent that replaces two hydrogen atoms on the same carbon atom, for example, substituting two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term “substituted” is intended to include all acceptable substituents of an organic compound. In broad embodiments, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. There may be one or more acceptable substituents for a given organic compound, and they may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have any acceptable substituents of the organic compounds described herein that satisfy the hydrogen substituent and / or the valence of the heteroatom.

[0043] When referring to any substituent, the term "one or more" means that the group in question is optionally substituted with one, two, three, or four substituents. In some embodiments, the group in question is optionally substituted with one, two, or three substituents. In some embodiments, the group in question is optionally substituted with one or two substituents. In some embodiments, the group in question is optionally substituted with one substituent. In some embodiments, the group in question is optionally substituted with two substituents.

[0044] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of inorganic acids that can derive salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids that can derive salts include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Examples of inorganic bases that can derive salts include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of organic bases that can induce salt formation include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0045] As used herein, the terms “parenteral administration” and “administered parenterally” mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0046] The term "pharmaceutically acceptable" is used herein to mean, within the bounds of sound medical judgment, compounds, materials, compositions, and / or dosage forms suitable for use in contact with human and animal tissues, provided that the benefit-to-risk ratio is reasonable and without excessive toxicity, irritation, allergic reactions, or other problems or complications.

[0047] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be compatible with the other components of the formulation and “acceptable” in the sense that it is not harmful to the patient. Some examples of materials that can act as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (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, and corn oil. (10) Oils such as oat oil and soybean oil; (11) Glycols such as propylene glycol; (12) Polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (13) Esters such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers such as magnesium hydroxide and aluminum hydroxide; (16) Alginic acid; (17) Water free of pyrogens; (18) Isotonic saline solution; (19) Ringer's solution; (10) Ethyl alcohol; (11) Phosphate buffer; and (12) Other non-toxic, suitable substances used in pharmaceutical preparations.

[0048] An "effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective in producing the desired therapeutic effect.

[0049] As used herein, the terms “to treat,” “to treat,” or “to cure” include alleviating, reducing, or improving at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, for example, stopping the onset of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0050] As used herein, “NLRP3 inflammasome-related disease or disorder” or, alternatively, “NLRP3 inflammasome-mediated disease or disorder” means any disease or other adverse condition in which the NLRP3 inflammasome is known or suspected to play a role.

[0051] Compounds of the Disclosure This specification describes compounds or pharmaceutically acceptable salts thereof that are useful for treating diseases or disorders related to the NLRP3 inflammasome.

[0052] In one embodiment, the present disclosure provides compounds represented by formula (A) or formula (B), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] During the ceremony, Y is a C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 The aryl or 5-9 member heteroaryl is where C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, or C6-C 10 Aryl, or 5- to 9-membered heteroaryl, contains one or more R 6 It is arbitrarily replaced by; X is NR X , -O-, -S-, -S(O)-, or -S(O)2-; R XR is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents independently selected from; Each R 1A and R 1B These are independently hydrogen, halogen, -CN, -NO2, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or R 1A and R 1B They come together to form an oxo; or R 1A and R 1B These combine to form C3-C8 cycloalkyl or 4-8 member heterocycloalkyl groups; each of these groups comprises one or more R groups. 11 It is arbitrarily replaced by; Each R 11 These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; R 3 Phenyl, 5-12 member heteroaryl, C3-C 12 They are cycloalkyl, 4-12 member heterocycloalkyl, or C1-C6 alkyl; each of these is one or more R 8 It is arbitrarily replaced by; Each R 8 These are, independently, halogen, -OH, -CN, -NO2, and -OR a -OC(=O)R a, -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a ,SF5,-S(=O)R a -S(=O)2R a -S(=O)(=NR b )R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)R c R d ,-P(=O)R c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, C6-C 10 The aryl or 4-6 member heterocycloalkyl group is where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, aryl, or heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents selected more independently; R ZN is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; or R X and R ZN These, together with the atoms to which they are bonded, form a 5-8 member heterocycloalkyl group, and this heterocycloalkyl group has one or more R 13 It is arbitrarily replaced by; or R 3 and RZN together with the atoms to which they are attached form a 5- to 13-membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with one or more R 13 ; each R 13 is independently halogen, -OH, -CN, -NO2, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; each R 6 is independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, where each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;<​​​​It is arbitrarily replaced by; Each R 12 These are, independently, halogen, -OH, -CN, NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; Each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; or R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl, where the heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents independently selected from; Each R e These are independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl.

[0053] In some embodiments of formula (A), Y is a C3-C8 cycloalkyl or 3-8 member heterocycloalkyl, where the C3-C8 cycloalkyl or 3-8 member heterocycloalkyl is one or more R 6 It is arbitrarily substituted with. In some embodiments of formula (A), Y is C6~C 10 It is an aryl or 5-9 member heteroaryl, where C6-C 10 Aryl or 5- to 9-membered heteroaryls contain one or more R 6It is optionally substituted with. In some embodiments of formula (A), Y is a 5- to 9-membered heteroaryl. In some embodiments of formula (A), Y is C6-C 10 It is an aryl compound. In some embodiments of formula (A), Y is phenyl.

[0054] In another aspect, the disclosure provides compounds represented by formula (I) or formula (V), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] During the ceremony, X is NR X , -O-, -S-, -S(O)-, or -S(O)2-; R X R is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents independently selected from; Each R 1A and R 1B These are independently hydrogen, halogen, -CN, -NO2, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or R 1A and R 1B They come together to form an oxo; or R 1A and R 1B These combine to form a C3-C8 cycloalkyl or a 4-8 member heterocycloalkyl, each of which contains one or more R 11 It is arbitrarily replaced by; Each R 11These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; R 3 Phenyl, 5-12 member heteroaryl, C3-C 12 They are cycloalkyl, 4-12 member heterocycloalkyl, or C1-C6 alkyl; each of these is one or more R 8 It is arbitrarily replaced by; Each R 8 These are, independently, halogen, -OH, -CN, -NO2, and -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a ,SF5,-S(=O)R a -S(=O)2R a -S(=O)(=NR b )R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)R c R d ,-P(=O)R c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl, where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents selected more independently; R ZN is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; or R X and R ZN Together with the atoms to which they are bonded, one or more R 13 They form 4- to 8-membered rings, which are arbitrarily substituted; Each R 13 These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R 6A is -OH, -OCF2H, -CF2H, or -CF3; Each R 6 These are, independently, halogen, -CN, -NO2, -OH, and -OR a -SH, -SR a -SF5, -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, or cycloalkyl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; or two R 6 These, together with the atoms to which they are bonded, form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups, each of which consists of one or more R groups. 12 It is arbitrarily replaced by; Each R 12 These are, independently, halogen, -OH, -CN, NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; Each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; Each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; or R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl, where the heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents independently selected from; Each R e These are independently halogens, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; p is 1, 2, 3, or 4.

[0055] In some embodiments, compounds represented by formula (I), or pharmaceutically acceptable salts or stereoisomers thereof are provided herein. In some embodiments, compounds represented by formula (V), or pharmaceutically acceptable salts or stereoisomers thereof are provided herein.

[0056] In some embodiments of formula (I), the compound is not the following: [ka]

[0057] In some embodiments of formula (I) or (V), R 6A is -OH. In some embodiments, R 6A is -CF2H or CF3. In some embodiments, R 6A is -CF2H. In some embodiments, R 6A is -CF3. In some embodiments, R 6A It is -OCF2H.

[0058] In another aspect, the present disclosure provides compounds represented by formula (Ia) or formula (Va), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] In the formula, R 1A , R 1B , R 3 , R ZN , R 6 ,X and p have the same meanings as described herein. In some embodiments, R of formula (Ia) 1A , R 1B , R 3 , R ZN , R 6 ,X and p have the meanings described in formula (I). In some embodiments, R of formula (Va) 1A , R 1B , R3 , R ZN , R 6 X and p have the meanings described in formula (V).

[0059] In some embodiments, the Specified Material provides a compound represented by formula (Ia), or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the Specified Material provides a compound represented by formula (Va), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0060] In some embodiments of formula (Ia), the compound is not the following: [ka]

[0061] In another aspect, the present disclosure provides compounds represented by formula (Ia) or formula (Va), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] During the ceremony, X is -S-, -S(O)-, or -S(O)2-; R 1A , R 1B , R 3 , R ZN , R 6 and p have the same meanings as described herein. In some embodiments, R of formula (Ia) 1A , R 1B , R 3 , R ZN , R 6 and p have the meanings described in formula (I). In some embodiments, R in formula (Va) 1A , R 1B , R 3 , R ZN , R 6 And p have the meanings described in equation (V).

[0062] In some embodiments of formula (Ia), the compound is not the following: [ka]

[0063] In some embodiments of formulas (I), (Ia), (V), or (Va), p is 2 or 3. In some embodiments, p is 2.

[0064] In some embodiments of formula (Ia), the compound of formula (Ia) has the structure of formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0065] In another aspect, this disclosure relates to formula (III * The present invention provides compounds represented by ) or pharmaceutically acceptable salts or stereoisomers thereof. [ka] In the formula, p is 0, 1, 2, or 3. R 1A , R 1B , R 3 , R ZN , R 6 , R 6A And X have the same meanings as described herein. In some embodiments, formula (III * ) of R 1A , R 1B , R 3 , R ZN , R 6 , R 6A And X has the meaning described in formula (I). In some embodiments, formula (III * ) of R 1A , R 1B , R 3 , R ZN , R 6 , and X have the meanings described in formula (III).

[0066] Formula (III * In some embodiments of ), R 6A is -OH. In some embodiments, R 6A is -CF2H or CF3. In some embodiments, R 6A is -CF2H. In some embodiments, R 6A is -CF3. In some embodiments, R 6A It is -OCF2H.

[0067] In another embodiment, the present disclosure provides a compound represented by formula (III), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X is -NR X -, -O-, -S-, -S(O)-, or -S(O)2-; R X R is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents independently selected from; Each R 1A and R 1B These are independently hydrogen, halogen, -CN, -NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or R 1A and R 1B They come together to form an oxo; or R 1A and R 1BThese combine to form C3-C8 cycloalkyl or 4-8 member heterocycloalkyl groups; each of these groups comprises one or more R groups. 11 It is arbitrarily replaced by; Each R 11 These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; R 3 Phenyl, 5-12 member heteroaryl, C3-C 12 They are cycloalkyl, 4-12 member heterocycloalkyl, or C1-C6 alkyl; each of these is one or more R 8 It is arbitrarily replaced by; Each R 8 These are, independently, halogen, -OH, -CN, -NO2, and -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a ,SF5,-S(=O)R a -S(=O)2R a -S(=O)(=NR b )R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)R c R d ,-P(=O)R c R d -C(=O)R a, -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl, where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents selected more independently; R ZN is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; or R X and R ZN Together with the atoms to which they are bonded, one or more R 13 They form 4- to 8-membered rings, which are arbitrarily substituted; Each R 13 These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Each R 6 These are, independently, halogen, -CN, -NO2, -OH, and -OR a -SH, -SR a -SF5, -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, or cycloalkyl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; or two R 6 These, together with the atoms to which they are bonded, form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups, each of which consists of one or more R groups. 12 It is arbitrarily replaced by; Each R 12 These are, independently, halogen, -OH, -CN, NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; Each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; Each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R e 1 to 4 substituents are arbitrarily selected, chosen more independently; or R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl, where the heterocycloalkyl is R e Optionally substituted with 1 to 4 substituents independently selected from; Each R e These are independently halogens, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; p is 0, 1, 2, or 3.

[0068] In another aspect, the present disclosure provides compounds represented by formula (IIIa), formula (VIa), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] In the formula, each R 6B , R 6C , R 6D and R 6E Independently, hydrogen or R 6 and; R 1A , R 1B , R 3 , R ZN , R 6 And X have the same meanings as described herein. In some embodiments, R of formula (IIIa) or formula (VIa) 1A , R 1B , R 3 , R ZN , R 6 And X has the meaning described in formula (III). In some embodiments, R in formula (IIIa) or (VIa) 1A , R 1B , R 3 , R ZN , R 6 And X has the meanings described in formula (I). In some embodiments, R 6B is R 6 In some embodiments, R 6B is H. In some embodiments, R 6C is R 6 In some embodiments, R 6C is H. In some embodiments, R 6D is R 6 In some embodiments, R 6D is H. In some embodiments, R 6E is R 6 In some embodiments, R 6E is H. In some embodiments, R 6B , R 6D , R 6ER is independent of R 6 And R 6C is H. In some embodiments, R 6D and R 6E These, together with the atoms to which they are bonded, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which consists of one or more R 12 It is optionally replaced by R. In some embodiments, 6D and R 6E These, together with the atoms to which they are bonded, form a 5-6 member heterocycloalkyl group, each of which has one or more R 12 It is optionally replaced by R. In some embodiments, 6D and R 6E These, together with the atoms to which they are bonded, form a 4-6 membered cycloalkyl group, each of which has one or more R atoms. 12 It can be arbitrarily replaced with.

[0069] In some embodiments, the Specified Material provides a compound represented by formula (IIIa), or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the Specified Material provides a compound represented by formula (VIa), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0070] In some embodiments of formulas (A), (I), (Ia), (II), (III*), (III), or (IIIa), R X and R ZN Together with the atoms to which they are bonded, one or more R 13 This forms a 5- to 8-membered heteroalkyl group which can be optionally substituted. In some embodiments, R X and R ZN These, together with the atoms to which they are bonded, form a 6-membered heterocycloalkyl group. In some embodiments, R X and R ZN These, together with the atoms to which they are bonded, form a 7-membered heteroalkyl group. In some embodiments, R X and R ZNThese, together with the atoms to which they are bonded, form an 8-membered heteroalkyl group. In some embodiments, R 3 and R ZN Together with the atoms to which they are bonded, one or more R 13 They form 5- to 13-membered heterocycloalkyl groups, which are optionally substituted.

[0071] In another embodiment, the present disclosure provides a compound represented by formula (IV), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] In the formula, ring B is a 5- to 8-membered heterocycloalkyl; Each R 13 These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; q is 0, 1, 2, or 3; R 1A , R 1B , R 3 , R 6 and p have the same meanings as described herein. In some embodiments, R of formula (IV) 1A , R 1B , R 3 , R 6 and p have the meanings described in formula (I). In some embodiments, R of formula (IV) 1A , R 1B , R 3 , R 6 And p have the meanings described in formula (A).

[0072] In some embodiments of formula (IV), ring B is a 5-membered heterocycloalkyl group. In some embodiments, ring B is a 6-membered heterocycloalkyl group. In some embodiments, ring B is a 7-membered heterocycloalkyl group. In some embodiments, ring B is an 8-membered heterocycloalkyl group.

[0073] In some embodiments, the compound of formula (IV) has the structure of formula (IVa), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0074] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (V), (Va), or (VIa), X is -S-, -S(O)-, or -S(O)2-. In some embodiments, X is -S-. In some embodiments, X is -S(O)-. In some embodiments, X is -S(O)2-. In some embodiments, X is -O-. In some embodiments, X is -NR X That is the case.

[0075] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (V), (Va), or (VIa), R ZN R is hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, R ZN is hydrogen or a C1-C6 alkyl group. In some embodiments, R ZN is a C1-C6 alkyl group. In some embodiments, R ZN is methyl. In some embodiments, R ZN It is hydrogen.

[0076] Formulas (A), (B), (I), (Ia), (II), (III *In some embodiments of (III), (IIIa), (V), (Va), or (VIa), R X R is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl; where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R e It is optionally substituted with 1 to 4 substituents independently selected from. In some embodiments, R X is hydrogen or a C1-C6 alkyl group. In some embodiments, R X is a C1-C6 alkyl group. In some embodiments, R X is methyl or ethyl. In some embodiments, R X is methyl. In some embodiments, R X is ethyl. In some embodiments, R X It is hydrogen.

[0077] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 1A and R 1B These are, independently, hydrogen, halogen, -CN, -NO2, -OH, and -OR. a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments, R 1A and R 1B Each of these is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments, R 1A and R 1B Each is independently a halogen or a C1-C6 haloalkyl. In some embodiments, R 1A and R 1BThese are, independently, fluoro, chloro, bromo, and CF. 3 , or CHF 2 In some embodiments, R 1A and R 1B Each of these is CF3. In some embodiments, R 1A and R 1B Each of these is independently a C1-C6 alkyl group. In some embodiments, R 1A and R 1B Each of these is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, R 1A and R 1B Each is independently methyl. In some embodiments, R 1A and R 1B Each of them is independently hydrogen.

[0078] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 1A These are hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments, R 1A is a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments, R 1A is a halogen or a C1-C6 haloalkyl. In some embodiments, R 1A Fluoro, chloro, bromo, CF 3 , or CHF 2 In some embodiments, R 1A is CF3. In some embodiments, R 1A is a C1-C6 alkyl group. In some embodiments, R 1AR is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, R 1A is methyl. In some embodiments, R 1A It is hydrogen.

[0079] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 1B These are hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments, R 1B is a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments, R 1B is a halogen or a C1-C6 haloalkyl. In some embodiments, R 1B Fluoro, chloro, bromo, CF 3 , or CHF 2 In some embodiments, R 1B is CF3. In some embodiments, R 1B is a C1-C6 alkyl group. In some embodiments, R 1B R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, R 1B is methyl. In some embodiments, R 1B It is hydrogen.

[0080] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 1A and R 1BThese combine to form C3-C8 cycloalkyl or 4-8 member heterocycloalkyl groups; each of these groups comprises one or more R groups. 11 It is optionally replaced by R. In some embodiments, 1A and R 1B These combine to form a C3-C8 cycloalkyl group. In some embodiments, R 1A and R 1B These combine to form a 4- to 8-membered heterocycloalkyl group. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 It is cyclopropyl.

[0081] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 1A and R 1B They combine to form an oxo.

[0082] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), each R 6 These are, independently, halogen, -CN, -OH, OR a -SH, -SR a -SF5, -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b -C(=O)R a , -C(=O)OR b-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, or alkynyl is R e 1 to 4 substituents are arbitrarily selected, which are more independently selected. In some embodiments, each R 6 These are, independently, halogen, -CN, -NO2, -OH, and -OR a -SH, -SR a -SF5, -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments, each R 6 R is independently a halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments, each R 6 R is independently a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a C1-C6 hydroxyalkyl. In some embodiments, each R 6 These are halogens independently. In some embodiments, each R 6 R is independently fluoro or chloro. In some embodiments, each R 6 R is independently a C1-C6 alkyl group. In some embodiments, each R 6 R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, each R 6 is methyl or ethyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is -OH. In some embodiments, each R 6R is independently a halogen, -OH, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, where the C1-C6 alkoxyl is optionally substituted with 1-6 halogens. In some embodiments, each R 6 R is independently a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, or a C1-C6 alkoxyl, where the alkoxyl is optionally substituted with one or three halogens. In some embodiments, one or more R 6 R is independently a halogen, -OH, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, where the C1-C6 alkoxyl is optionally substituted with 1 to 6 halogens. In some embodiments, one or more R 6 These are independently a halogen, -OH, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, where the C1-C6 alkoxyl is optionally substituted with 1-6 halogens and 2 R 6 These, together with the atoms to which they are bonded, form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups, each of which consists of one or more R groups. 12 It can be arbitrarily replaced with.

[0083] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), each R 6 R is independently a C1-C6 haloalkyl. In some embodiments, each R 6 These are independently CF3, CF2H, or CFH2. In some embodiments, R 6 is CF3. In some embodiments, R 6 is CF2H. In some embodiments, R 6 is CFH2. In some embodiments, R 6 is -OCF3. In some embodiments, R6 is -OCHF2. In some embodiments, R 6 It is -OCH3.

[0084] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), two R 6 These, together with the atoms to which they are bonded, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which consists of one or more R 12 It is optionally replaced by. In some embodiments, two R 6 These, together with the atoms to which they are bonded, form a heteroaryl group. In some embodiments, two R 6 These, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group. In some embodiments, two R 6 These, together with the atoms to which they are bonded, form C4-C8 cycloalkyl groups. In some embodiments, two R groups 6 These, together with the atoms to which they are bonded, form C5-C6 cycloalkyl groups. In some embodiments, two R groups 6 These, together with the atoms to which they are bonded, form a 4- to 8-membered heterocycloalkyl group. In some embodiments, two R 6 These, together with the atoms to which they are bonded, form a 5-6 member heterocycloalkyl group. In some embodiments, two R 6 These, together with the atoms to which they are bonded, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which contains one or more R 12 It is optionally replaced by. In some embodiments, two R 6 These atoms, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, each of which contains one or more R atoms. 12 It is optionally replaced by. In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] That is the case.

[0085] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 C3~C 12 They are cycloalkyl or 4-12 member heterocycloalkyl; each of them has one or more R 8 It is optionally replaced by R. In some embodiments, 3 is one, two, or three R 8 It is a C3-C6 cycloalkyl group that is optionally substituted with R. In some embodiments, R 3 is one, two, or three R 8 It is a 4-6 member heterocycloalkyl group optionally substituted with R. In some embodiments, 3 teeth [ka] And each of these is one, two, or three R 8 It is optionally replaced by R. In some embodiments, 8 These are -OH and -OR, respectively, independently. a -SH, -SR a SF5, -NR c R d The following are selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, and C3-C6 cycloalkyl.

[0086] In some embodiments, R 3 R 3 Formulas (A), (B), (I), (Ia), (II), (III) are formed via the chiral carbon atom of the group. * It binds to compounds of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa). In some embodiments, R 3 The chiral carbon atom of the group has an S stereoconfiguration. In some embodiments, R 3 The chiral carbon atom of the group has an R stereoconfiguration.

[0087] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth [ka] That is the case.

[0088] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C 12 They are cycloalkyl or 4- to 12-membered heterocycloalkyl; each of these is optionally substituted. In some embodiments, R 3 is one or more R 8 It is optionally replaced by R. In some embodiments, 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R 3 is an optionally substituted C1-C6 haloalkyl. In some embodiments, R 3 is an optionally substituted C1-C6 hydroxyalkyl group. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth [ka] In some embodiments, R 3 teeth [ka] That is the case.

[0089] Formulas (A), (B), (I), (Ia), (II), (III *In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 is an optionally substituted C1-C6 aminoalkyl. In some embodiments, R 3 is an optionally substituted C1-C6 heteroalkyl group. In some embodiments, R 3 C3~C are arbitrarily substituted. 12 It is cycloalkyl. In some embodiments, R 3 These are optionally substituted 4- to 12-membered heterocycloalkyl groups.

[0090] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 is one or more R 8 C3-C arbitrarily replaced 12 It is cycloalkyl. In some embodiments, R 3 is one or more R 8 It is a C4-C6 cycloalkyl group that is optionally substituted with R. In some embodiments, 3 is one or more R 8 It is a cyclobutyl which is optionally substituted with R. In some embodiments, R 3 is one or more R 8 It is a cyclopentyl optionally substituted with R. In some embodiments, R 3 is one or more R 8 It is a cyclohexyl optionally substituted with R. In some embodiments, R 3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 3 It is a monoring. In some embodiments, R 3 It is a double ring.

[0091] Formulas (A), (B), (I), (Ia), (II), (III *In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 is one or more R 8 It is a 4- to 12-membered heterocycloalkyl group optionally substituted with R. In some embodiments, R 3 is a 4- to 8-membered heterocycloalkyl group. In some embodiments, R 3 is a 5-6 member heterocycloalkyl. In some embodiments, R 3 R is a 6-membered heterocycloalkyl. In some embodiments, R 3 R is a 5-membered heterocycloalkyl. In some embodiments, R 3 R is a 4-membered heterocycloalkyl. In some embodiments, R 3 It is a monoring. In some embodiments, R 3 It is a double ring.

[0092] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 teeth [ka] That is the case.

[0093] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 is cyclohexyl or piperidine. In some embodiments, R 3 is piperidine. In some embodiments, R 3 is morpholine. In some embodiments, R 3 is cyclohexyl. In some embodiments, R 3 R is cyclopentyl. In some embodiments, R 3 It is cyclobutyl.

[0094] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 These are phenyl or 5-12 member heteroaryl compounds, each containing one or more R 8 It is optionally replaced by R. In some embodiments, 3 R is phenyl. In some embodiments, R 3 is a 5-12 member heteroaryl. In some embodiments, R 3 is a 5-10 member heteroaryl. In some embodiments, R 3 is a 5-6 member heteroaryl. In some embodiments, R 3 R is a 5-membered heteroaryl. In some embodiments, R 3 It is a 6-membered heteroaryl compound.

[0095] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 This is 1 to 3 R 8 It is arbitrarily replaced.

[0096] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth [ka] In some embodiments, R 3 teeth [ka] In some embodiments, R 3 teeth [ka] That is the case.

[0097] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), each R 8 These are, independently, halogen, -OH, -CN, -NO2, and -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a ,SF5,-S(=O)R a -S(=O)2R a -S(=O)(=NR b )R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)R c R d ,-P(=O)R c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl, where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R e They are optionally substituted with 1 to 4 substituents that are selected more independently. In some embodiments, each R 8 R is independently a halogen, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl, where each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R e It is optionally substituted with 1 to 4 substituents independently selected from the given molecule.

[0098] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), each R 8 In some embodiments, each R is a halogen. 8 R is independently fluoro, bromo, or chloro. In some embodiments, each R 8 In some embodiments, each R is -OH. 8 R is independently a C1-C6 alkyl group. In some embodiments, each R 8 These are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0099] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), each R 8 These are independently C3-C6 cycloalkyl or 4-6 member heterocycloalkyl. In some embodiments, each R 8In some embodiments, each R is independently a C3-C6 cycloalkyl group. 8 R is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 8 In some embodiments, each R is independently a 4- to 6-membered heterocycloalkyl. 8 In some embodiments, each R is independently a 4-membered heterocycloalkyl. 8 R is independently a 5-membered heterocycloalkyl. In some embodiments, R 8 These are -OH and -OR, respectively, independently. a -SH, -SR a SF5, -NR c R d The following are selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, and C3-C6 cycloalkyl.

[0100] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), each R 11 These are, independently, halogen, -OH, and -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 11 R is independently a halogen, or -OH, -NH2. In some embodiments, each R 11 These are independently C1-C6 alkyl groups. In some embodiments, each R 11 These are independently C1-C6 haloalkyl groups.

[0101] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), each R 12 These are, independently, halogen, -OH, -CN, -NO2, and -OR a, -NR c R d These are C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl. In some embodiments, each R 12 These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl. In some embodiments, each R 12 These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, C1-C6 aminoalkyl.

[0102] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa), each R 13 These are, independently, halogen, -OH, -CN, -NO2, and -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments, each R 13 These are independently C1-C6 alkyl groups. In some embodiments, each R 13These are independently methyl, ethyl, n-propyl, isopropyl, sec-butyl, or tert-butyl.

[0103] In some embodiments of formula (IV) or (IVa), p is 5.

[0104] In some embodiments of formulas (I), (Ia), (IV), (V), or (Va), p is 4.

[0105] Formulas (A), (B), (I), (Ia), (II), (III * In some embodiments of (III), (IV), (IVa), (V), or (Va), p is 3. In some embodiments, p is at least 3. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 2. In some embodiments, p is 1.

[0106] In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl or heterocycloalkyl; where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R aR is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a These are independently C1-C6 alkyl groups.

[0107] In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R b R is hydrogen. In some embodiments of the compounds disclosed herein, each R b These are independently C1-C6 alkyl groups.

[0108] In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R dR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R c and R d is hydrogen. In some embodiments of the compounds disclosed herein, each R c and R d These are independently C1-C6 alkyl groups.

[0109] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms they bond to, one or more R e It forms a heterocycloalkyl group with arbitrary substitutions.

[0110] In some embodiments of the compounds disclosed herein, each R e R is independently a halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments of the compounds disclosed herein, each R e These are, independently, halogen, oxo, -CN, -OH, and -S(=O)C 1~6 Alkyl, -S(=O)2C 1~6 Alkyl, -S(=O)2NH2, -S(=O)2NHC 1~6 Alkyl, -S(=O)2N(C 1~6 Alkyl)2,-NH2,-NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, -C(=O)C 1~6 alkyl, -C(=O)OH, -C(=O)OC 1~6 Alkyl, -NHC(=O)C 1~6 These are alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments, R e -NHC(=O)CH3 and other -NHC(=O)C 1~3 It is alkyl. In some embodiments of the compounds disclosed herein, each R e R is independently a halogen, -CN, -OH, or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R e R is independently a halogen, -OH, or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R eR is independently a halogen or a C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R e These are, independently, halogens.

[0111] In some embodiments of the compounds disclosed herein, R 1A , R 1B , R 3 , R 6 , R 8 , R 11 , R 12 , R 13 , R ZN , R X , R a , R b , R c , and R d , and R e One or more of the groups contain deuterium at a higher proportion than the natural abundance of deuterium.

[0112] In some embodiments of the compounds disclosed herein, one or more 1 H is the following group, R 1A , R 1B , R 3 , R 6 , R 8 , R 11 , R 12 , R 13 , R ZN , R X , R a , R b , R c , and R d , and R e In one or more of these, one or more deuterium atoms are substituted.

[0113] In some embodiments of the compounds disclosed herein, R 1A , R 1B , R 3 , R 6 , R 8 , R 11 , R 12 , R 13 , R ZN , R X , R a , Rb , R c , and R d , and R e The amount of deuterium present in each of these is independently at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0114] Any combination of the groups described above for various variables is intended herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0115] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts or stereoisomers, are one of the compounds listed in Table 1 or Table 2. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 2-1] [Table 2-2]

[0116] C. Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and thusanmen (Z) isomers, as well as their corresponding mixtures. In some situations, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomer, enantiomer, and epimer forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form pairs of diastereoisomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography.

[0117] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, such as, respectively, 2 H(D), 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds described herein, and their pharmaceutically acceptable salts, solvates, or stereoisomers, containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example, those incorporating radioactive isotopes such as 3 H and 14 C are useful in drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly useful because of their ease of preparation and detectability.

[0118] In some embodiments, the amount of deuterium present in each of the substituents disclosed herein is, independently, at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%. In some embodiments, one or more substituents disclosed herein contain deuterium at a higher percentage than the natural abundance of deuterium. In some embodiments, one or more 1 H is replaced by one or more deuterium atoms in one or more of the substituents disclosed herein.

[0119] In some embodiments, the compounds described herein are labeled by means of other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0120] Medicinally acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0121] In some embodiments, the compounds described herein have an acidic or basic group and therefore react with certain inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting the purified compounds separately in their free form with suitable acids or bases and then isolating the salts thus formed.

[0122] Examples of pharmaceutically acceptable salts include salts prepared by the reaction of compounds described herein with minerals, organic acids, or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dioate, camphorates, camphor sulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dioate, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, hydrobroms, and hydroiodic acids. Examples include salts, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malons, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmoate, pectinate, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, pyrosulfates, pyrophosphates, propioates, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, suberinates, sebacinates, sulfonates, tartrates, thiocyanates, tosylateundeconate, and xylenesulfonates.

[0123] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the compounds in their free base form with pharmaceutically acceptable inorganic or organic acids, such acids include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphate metaphosphate, and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxyl acetate). Examples include cibenzoyl benzoic acid, cinnamic acid, mandelic acid, aryl sulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octo-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid, although not pharmaceutically acceptable in themselves, are used in the preparation of salts that are useful as intermediates in obtaining the compounds disclosed herein, their solvates or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0124] In some embodiments, the compounds described herein containing a free acid group react with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, or sulfate, with ammonia or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Typical salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1~4 Examples include alkyl(4) and others.

[0125] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing group they contain. In some embodiments, water-soluble, oil-soluble, or dispersible products are obtained by such quaternization.

[0126] solvate In some embodiments, the compounds described herein exist as solvates. In some embodiments, the disclosure provides a method for treating a disease by administering the compound in the form of such a solvate. In some embodiments, the disclosure provides a method for treating a disease by administering a composition comprising the compound in the form of such a solvate. The solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during a crystallization process using a pharmaceutically acceptable solvent.

[0127] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the range of formulas described herein. Tautomers are compounds that can be interconverted by the movement of hydrogen atoms involving the exchange of single bonds with adjacent double bonds, for example. [ka] In bond configurations that allow tautomerization, a chemical equilibrium of tautomers exists. All tautomer forms of the compounds disclosed herein are intended. The exact ratio of tautomers varies depending on several factors, such as temperature, solvent, and pH.

[0128] Treatment method This specification discloses methods for modulating the NLRP3 inflammasome in a subject, which include administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject. This specification also discloses methods for inhibiting the NLRP3 inflammasome in a subject, which include administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0129] This specification discloses a method for treating a disease at least partially modulated by the NLRP3 inflammasome in a subject requiring treatment, the method comprising administering a therapeutically effective amount of the compounds disclosed herein or a pharmaceutically acceptable salt thereof to the subject.

[0130] This specification discloses methods for treating autoimmune or autoinflammatory diseases or conditions in subjects requiring treatment, the methods comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to the subject.

[0131] In some embodiments, the disease or condition is an autoimmune disease.

[0132] In some embodiments, the disease or condition is an autoinflammatory disease.

[0133] In some embodiments, the disease or disorder is an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, e.g., autoinflammatory fever syndrome (e.g., cryopyrin-related periodic syndromes), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), an inflammatory arthritis-related disorder (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic), a kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type 1 / II diabetes and related complications (e.g., The following conditions are selected: nephropathy, retinopathy, hypertensive nephropathy, dialysis-related diseases, neuroinflammatory diseases (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., hidradenitis suppurativa, acne), wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).

[0134] In some embodiments, the disease or condition is obesity. In some embodiments, obesity is induced by a high-fat diet.

[0135] In one embodiment, this specification describes a method for reducing weight in a subject who requires weight loss, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the patient is overweight or obese. In some embodiments, the patient has a metabolic disorder. In some embodiments, the patient has diabetes or prediabetes.

[0136] Administration In some embodiments, compositions containing the compounds(s) described herein are administered for therapeutic purposes. In a particular therapeutic application, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially cessate at least one symptom of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective dose may optionally be determined by methods including, but not limited to, dose escalation and / or dose-ranging clinical trials.

[0137] Route of administration Appropriate routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, as just one example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0138] In some embodiments, the compounds described herein are administered topically rather than systemically, for example, by direct injection of the compound into an organ, often in depot or sustained-release formulations. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered by a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to an organ and selectively taken up by the organ. In yet another embodiment, compounds such as those described herein may be provided in the form of rapid-release formulations, sustained-release formulations, or intermediate-release formulations.

[0139] Pharmaceutical composition / formulation The compounds described herein are administered to subjects requiring them in pharmaceutical compositions, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0140] In another embodiment, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is provided herein. The pharmaceutical composition may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference with respect to such disclosures.

[0141] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizing agents, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, and any combination thereof.

Examples

[0142] The following examples are provided for illustrative purposes and are not intended to limit the claimed invention. The following examples further illustrate the present invention, but of course, should in no way be construed as limiting the scope of the present invention.

[0143] The following synthetic schemes are provided for illustrative purposes only and not by way of limitation. The following examples illustrate various methods for making the compounds described herein. It will be understood by those skilled in the art that these compounds can be made by similar methods or by combining other methods known to those skilled in the art. It will also be understood by those skilled in the art that, using appropriate starting materials and optionally modifying the synthetic route, the compounds can be made in a manner similar to that described below. Generally, starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0144] Formulas (A), (B), (I), (Ia), (II), (III *Compounds and salts of (III), (IIIa), (IV), (IVa), (V), (Va), or (VIa) can be synthesized according to one or more exemplary schemes herein and / or art known in the art. The materials used herein are commercially available or prepared by synthetic methods commonly known in the art. These schemes are not limited to the compounds listed in the examples or to any specific substituents used for illustrative purposes. Various steps are described and shown in the following synthesis schemes, but in some cases the steps may be carried out in an order different from the order shown below. The numbering or R groups in each scheme do not necessarily correspond to those in the claims or other schemes or tables herein. [Table 3]

[0145] Example 1 [ka]

[0146] To a solution of compound 1-1 (3 g, 9.49 mmol) and tri(n-butyl)(1-ethoxyvinyl) stannane (3.4 g, 9.41 mmol) in 1,4-dioxane (30 mL), CuI (0.2 g, 1.05 mmol) and TEA (1.9 g, 18.78 mmol) were added. The mixture was purged three times with N2. Then, Pd(PPh3)2Cl2 (1.1 g, 1.57 mmol) was added. The mixture was purged three times with N2 and stirred at 100 °C for 2 hours. After cooling to room temperature, HCl (10 mL, 6 M) was added to the reaction mixture, and the resulting solution was stirred for 2 hours. The reaction mixture was then poured into H2O (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (40 mL), dried on anhydrous Na2SO4, filtered through Celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 0-20% ethyl acetate in petroleum ether to obtain intermediates 1-2 (1.2 g, 4.17 mmol, purity 80.6%, yield 43.9%) as yellow oil. LC-MS (ESI + ):m / z233.1(M+H) + .

[0147] To a solution of intermediates 1-2 (600 mg, 2.58 mmol) in DCM (5 mL), 4-methylbenzenesulfonic acid (667.4 mg, 3.88 mmol) and NBS (689.9 mg, 3.88 mmol) were added. The resulting solution was stirred under microwave conditions at 40°C for 30 minutes. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by flash column chromatography on silica gel eluted with 0-10% ethyl acetate in petroleum ether to obtain intermediate 1-3 (600 mg, 0.95 mmol, purity 49%, yield 36.8%) as yellow oil. LC-MS (ESI + ):m / z311.0(M+H) + .

[0148] To a solution of compound 1-4 (1.2 g, 10.51 mmol) in DCM (10 mL), di(1H-imidazole-1-yl)methanethion (2.1 g, 11.78 mmol) was gradually added at 0°C. The resulting solution was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to obtain intermediate 1-5 (1.5 g, 9.60 mmol, yield 91.3%) as a white solid, which was used directly in the next step without further purification.

[0149] To a solution of intermediates 1-5 (1.5 g, 9.60 mmol) in acetonitrile (10 mL), tert-butylhydrazine carboxylate (1.9 g, 14.38 mmol) and TEA (2.66 mL, 19.21 mmol) were added. The resulting solution was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to obtain intermediate 1-6 (2.5 g, 8.67 mmol, yield 90.3%) as a white solid. LC-MS (ESI) + ):m / z289.2(M+H) + .

[0150] To a solution of intermediate 1-6 (1 g, 3.47 mmol) in 1,4-dioxane (25 mL), HCl / 1,4-dioxane (25 mL, 4 M, 0.1 mol) was added. The resulting solution was stirred at 25°C for 4 hours. The mixture was then concentrated under vacuum to obtain intermediate 1-7 (1.1 g, crude) as a white solid, which was used in the next step without further purification.

[0151] To a solution of intermediates 1-7 (240 mg, 1.28 mmol) and 1-3 (396.5 mg, 1.27 mmol) in EtOH (12 mL), TEA (0.21 mL, 1.51 mmol) was added. The resulting solution was stirred at 25°C for 10 minutes and then at 80°C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions of 50%B to 80%). The mixture was then lyophilized to obtain intermediate 1-8 (140 mg, 0.35 mmol, yield 27.4%) as a white solid. LC-MS (ESI) + ):m / z401.2(M+H) + .

[0152] To a solution of intermediates 1-8 (160 mg, 0.40 mmol) in DCM (2 mL), BBr3 (0.80 mL) was added at 0°C. The resulting solution was then heated to 25°C and stirred for 2 hours. After cooling to 0°C, the reaction was quenched with MeOH (1 mL) and stirred at 30°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (3 mL) and then extracted with EA (3 mL × 2). The aqueous phase was adjusted to pH approximately 9 and then extracted with EA (5 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 25%B to 55%) to obtain compound 1.

[0153] LC-MS(ESI + ):m / z387.2(M+H) + .

[0154] 1H NMR(400MHz,DMSO-d6)10.46(br,1H),7.09(s,1H),7.07-6.73(m,2H),4.06-3.91(m,1H),3.41-3.38(m,2H),3.02-2.92(m,1 H),2.69-2.60(m,1H),2.29(s,3H),2.20(s,3H),1.94-1.77(m,3H),1.72-1.65(m,1H),1.57-1.47(m,1H),1.32-1.21(m,1H).

[0155] Example 2 [ka]

[0156] To a solution of compound 2-1 (6 g, 29.96 mmol) in DCM (80 mL), di(1H-imidazole-1-yl)methanethion (5871.8 mg, 32.95 mmol) was gradually added, and the resulting solution was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure and purified by flash column chromatography on silica gel eluted with 0-60% ethyl acetate in petroleum ether to obtain intermediate 2-2 (6.2 g, 25.58 mmol, yield 85.4%) as yellow oil.

[0157] 1 H NMR(400MHz,CDCl3)δ=3.77-3.24(m,5H),1.99-1.72(m,3H),1.60-1.45(m,10H)

[0158] To a solution of intermediate 2-2 (2 g, 8.25 mmol) in acetonitrile (20 mL), hydrazine (0.49 mL, 12.38 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 2-3 (2.2 g, 8.02 mmol, yield 97.2%) as a white solid. LC-MS (ESI+): m / z 275.2 (M+H) + .

[0159] The solutions of intermediates 2-3 (278 mg, 1.01 mmol), intermediates 1-3 (598.8 mg, 1.92 mmol), and TEA (0.17 mL, 1.22 mmol) in EtOH (3 mL) were stirred at 25 °C for 10 minutes, and then the resulting solutions were heated at 80 °C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by preparative HPLC (Welch Xtimate C18 150*25 mm*5 μm, mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions of 30%B to 60%) to obtain intermediate 2-4 (25 mg, 0.026 mmol, purity 50%, yield 2.5%) as a white solid. LC-MS (ESI + ):m / z487.1(M+H) + .

[0160] To a solution of intermediates 2-4 (25 mg, 0.051 mmol) in DCM (2 mL), BBr3 (0.10 mL, 1 M in THF, 0.1 mmol) was added at 0°C. The resulting solution was stirred at 25°C for 2 hours. The reaction was quenched with MeOH (1 mL) and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 μm, mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 40 mL / min, gradient conditions of 10% B to 40%) and lyophilized to obtain compound 2. LC-MS (ESI + ):m / z373.2(M+H) + . 1 H NMR(400MHz,CD3OD)δ=8.53(br,1H, HCOOH origin),7.07(s,1H),6.98(s,1H),4.30-4.16(m,1H),3.67-3.58(m,1H),3.54-3 .44(m,2H),3.30-3.25(m,1H),3.04-2.89(m,2H),2.37(s,3H),2.17-2.01(m,2H),1.89-1.77(m,1H),1.74-1.63(m,1H)

[0161] Example 3 [ka]

[0162] Compound 3 was synthesized by replacing intermediates 1-4 with (R)-1-ethylpiperidine-3-amine in the same manner as for compound 1. The crude product was purified by preparative HPLC [column: Welch Xtimate C18 150×25mm×5um, water (NH3H2O+NH4HCO3)-ACN]; B%: 40%~70%, 7 min] to obtain compound 3.

[0163] LCMS(ESI+):m / z401.2(M+H) + .

[0164] 1 HNMR:(400MHz,DMSO-d6)δ=10.98-9.83(m,1H),7.07(s,1H),7.01(s,1H),4.05-3.87(m,1H),3.43-3.35(m,2H),3.11-2.96(m,1H),2. 81-2.67(m,1H),2.41-2.27(m,5H),1.97-1.76(m,3H),1.73-1.62(m,1H),1.55-1.43(m,1H),1.34-1.21(m,1H),1.00(t,J=7.2Hz,3H).

[0165] Example 4 [ka]

[0166] Compound 4 was synthesized by replacing intermediates 1-4 with (1R,2R)-2-(benzyloxy)cyclohexane-1-amine in the same manner as for compound 1. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 40%B to 70%) and lyophilized to obtain compound 4.

[0167] LC-MS(ESI+):m / z388.2(M+H) + .

[0168] 1 ¹H NMR (400MHz, acetonitrile-d3): δ = 7.10 (s, 1H), 7.05 (s, 1H), 3.73-3.65 (m, 1H), 3.59-3.44 (m, 2H), 3.41-3.33 (m, 1H), 2.40 (s, 3H), 2.07-1.98 (m, 2H), 1.73-1.65 (m, 2H), 1.36-1.23 (m, 4H).

[0169] Example 5 [ka]

[0170] To a solution of compound 5-1 (1.2 g, 4.56 mmol) in THF (12 mL), ethyl magnesium bromide (1 M in THF, 4.56 mL, 4.56 mmol) was added dropwise at 0°C, and the mixture was stirred at 20°C for 12 hours. Volatile substances were removed under vacuum. The residue was adjusted to pH=5 with aqueous HCl (2 M) and extracted with ethyl acetate (200 mL x 2). The combined organic extracts were washed with brine (80 mL), dried on anhydrous Na2SO4, filtered through a Celite pad, and concentrated under reduced pressure to obtain intermediate 5-2 (828.0 mg, purity 69.6%, yield 54.4%) as a yellow oil. LC-MS (ESI+): m / z 233.1 (M+H) + .

[0171] A solution of intermediate 5-2 (800.0 mg, 3.45 mmol) in DCE (4 mL) was added to a mixture of CuBr2 (1539.0 mg, 6.89 mmol) in ethyl acetate (12 mL) at 80°C, and the reaction mixture was stirred at 80°C for 3 hours. After cooling to room temperature, volatiles were removed under vacuum. The residue was poured into water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic extract was washed with brine (50 mL), dried on anhydrous Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. This was then purified by flash column chromatography on silica gel eluted with 0-15% ethyl acetate in petroleum ether to obtain intermediate 5-3 (829 mg, purity 89.1%, yield 68.8%) as an orange oil. LC-MS (ESI+): m / z 311.0 (M+H) + .

[0172] Example 6 [ka]

[0173] Compound 5 was synthesized by replacing intermediates 1-3 with intermediates 5-3, following the same procedure as for compound 1. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions of 55%B to 85%) and lyophilized to obtain compound 5. LC-MS (ESI+): m / z 387.2 (M+H) + .

[0174] 1H NMR(400MHz,DMSO-d6)δ=14.99-14.88(m,1H),7.85(d,J=8.4Hz,1H),7.68-7.53(m,1H),7.25-7.19(m,2H),4.84-4.76(m,1H),4.17-3.97(m ,1H),3.06-2.76(m,1H),2.65-2.55(m,1H),2.19-2.16(m,3H),1.96- 1.75(m,3H),1.72-1.64(m,1H),1.58-1.46(m,1H),1.32-1.22(m,4H).

[0175] Example 7 [ka]

[0176] A solution of R-tert-butylpiperidine-3-ylcarbamate (2.00 g, 9.99 mmol) and ((2-bromoethoxy)methyl)benzene (2.14 g, 9.99 mmol) in MeCN (20 mL) was mixed with K2CO3 (2.76 g, 20.0 mmol). The resulting mixture was stirred at 60 °C for 1 hour. After cooling to room temperature, the mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to obtain intermediate 6-1 (2.16 g, yield 64.7%) as a white solid. LC-MS (ESI+): m / z 335.3 (M+H) + .

[0177] To a solution of intermediate 6-1 (500.0 mg, 1.49 mmol) in MeOH (2.0 mL), HCl / MeOH (2.0 mL, 4 M) was added, and the resulting mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 6-2 (570.0 mg, crude) as a white solid. LC-MS (ESI+): m / z 235.2 (M+H) + .

[0178] Example 8 [ka]

[0179] Compound 6 was synthesized by replacing intermediates 1-4 with intermediate 6-2, following the same procedure as for compound 1. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, water (NH3H2O+NH4HCO3)-ACN); B%: 30%~60%, 7 min) to obtain compound 6.

[0180] LC-MS(ESI+):m / z417.2(M+H) + .

[0181] 1 H NMR(400MHz,DMSO-d6)δ=7.05(s,1H),6.99(s,1H),4.54-4.26(m,1H),4.09-3.90(m,1H),3.49-3.46(m,4H),3.01-2.92(m,1H),2.71-2.62 (m,1H),2.39(t,J=6.0Hz,2H),2.29(s,3H),2.06-1.92(m,2H),1.86-1.75(m,1H),1.72-1.60(m,1H),1.56-1.42(m,1H),1.37-1.25(m,1H).

[0182] Example 9 [ka]

[0183] To a solution of di(1H-imidazole-1-yl)methanethion (1.00 g, 5.61 mmol) in dioxane (10 mL), tert-butylhydrazine carboxylate (700.0 mg, 5.50 mmol) was slowly added, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extract was washed with brine (10 mL), dried on anhydrous Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to obtain intermediate 7-1 (1.00 g, yield 73.3%) as a yellow solid.

[0184] LC-MS(ESI+): m / z 243.0(M+H) + .

[0185] 1 H NMR (400MHz, DMSO-d6) δ = 8.82 (s, 1H), 8.52 (s, 1H), 7.80 (s, 1H), 7.43 (s, 1H), 7.22 (s, 1H), 1.44 (s, 9H).

[0186] To a solution of intermediate 7-1 (552.1 mg, 2.28 mmol) and (1S,3R)-3-aminocyclohexane-1-ol hydrochloride (380.0 mg, 2.51 mmol) in dioxane (5.0 mL), TEA (0.95 mL, 6.84 mmol) was added. The resulting mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to obtain intermediate 7-2 (300.0 mg, purity 97.7%, yield 44.4%) as a white solid. LC-MS (ESI+): m / z 290.1 ​​(M+H) + .

[0187] Example 10 [ka]

[0188] Compound 7 was synthesized by replacing intermediates 1-6 with intermediates 7-2, following the same procedure as for compound 1. The crude product was separated and subjected to preparative HPLC (column: Welch Xtimate C). 18 The compound was purified using a 150*25mm*5um container (mobile phase A: water (NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 35%B to 65%), and then freeze-dried to obtain compound 7.

[0189] LC-MS(ESI+):m / z388.2(M+H) + .

[0190] 1 H NMR(400MHz,DMSO-d6)δ=10.47(br.s.,1H),7.08(s,1H),7.01(s,1H),4.69-4.60(m,1H),3.91-3.73(m,1H),3.50-3.3 7(m,3H),2.29(s,3H),2.19-2.10(m,1H),1.92-1.84(m,1H),1.83-1.75(m,1H),1.72-1.65(m,1H),1.31-1.01(m,4H).

[0191] Example 11 [ka]

[0192] To a solution of (3R,5R)-tert-butyl(5-fluoropiperidine-3-yl)carbamate (2.0 g, 9.16 mmol) and (CH2O)n (1.0 g) in MeOH (20 mL), HOAc (0.52 mL, 9.16 mmol) was added. The mixture was then stirred at 25°C for 0.5 hours. After adding NaBH3CN (2.65 g, 42.14 mmol), the resulting mixture was stirred at 25°C for 5 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm, water (NH3H2O ​​+ NH4HCO3)-ACN; B%: 25%~55%, 7 min) to obtain intermediate 8-1 (1.88 g, 88.3% yield) as a white solid.

[0193] LC-MS(ESI+): m / z 233.2(M+H) + .

[0194] To a solution of intermediate 8-1 (900.0 mg, 3.87 mmol) in MeOH (3.0 mL), 4 M HCl in MeOH (2.0 mL) was added, and the resulting solution was stirred at 20°C for 12 hours. Volatile substances were removed under vacuum to obtain intermediate 8-2 (688 mg, crude) as a white solid.

[0195] A mixture of intermediates 8-2 (588.0 mg, 3.49 mmol), 7-1 (929.0 mg, 3.83 mmol), and TEA (0.48 mL, 3.49 mmol) in dioxane (6.0 mL) was stirred at 80°C for 1 hour. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to obtain intermediate 8-3 (210.0 mg, yield 19.7%) as a yellow solid. LC-MS (ESI+): m / z 307.1 (M+H) + .

[0196] Example 12 [ka]

[0197] Compound 8 was synthesized by replacing intermediates 1-6 with intermediates 8-3, following the same procedure as for compound 1. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, water (NH3H2O+NH4HCO3)-ACN); B%: 42%~72%, 7 min), and lyophilized to obtain compound 8.

[0198] LC-MS(ESI+):m / z405.2(M+H) + .

[0199] 1 H NMR(400MHz,DMSO-d6)δ=10.36(br.s.,1H),7.07(s,1H),7.01(s,1H),5.11-4.74(m,1H),4.40-4.12(m,1H),3.44-3.37(m,2 H),2.98-2.88(m,1H),2.87-2.75(m,1H),2.29(s,3H),2.20(s,3H),2.17-2.00(m,2H),1.95-1.85(m,1H),1.71-1.46(m,1H).

[0200] Example 13 [ka]

[0201] Compound 9 was synthesized by replacing tert-butyl((3R,5R)-5-fluoropiperidine-3-yl)carbamate with tert-butyl((3R,5S)-5-fluoropiperidine-3-yl)carbamate, following the same procedure as for compound 8. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150×30mm×5um, water (FA)-ACN); B%: 10%~40%, 7 min), and lyophilized to obtain compound 9.

[0202] LC-MS(ESI+):m / z405.2(M+H) + .

[0203] 1 H NMR(400MHz,DMSO-d6)δ=11.27-9.92(m,1H),8.18(s,0.46H from HCOOH),7.08(s,1H),7.01(s,1H),4.78-4.56(m,1H),4.11-3.95(m, 1H),3.41-3.37(m,2H),3.08-2.91(m,2H),2.36-2.26(m,4H),2.25(s,3H),1.98-1.88(m,1H),1.84-1.69(m,1H),1.53-1.37(m,1H).

[0204] Example 14 [ka]

[0205] A mixture of tert-butyl((1s,3s)-3-hydroxy-3-methylcyclobutyl) carbamate (1.00 g, 4.97 mmol), benzoyl chloride (0.58 mL, 4.97 mmol), and TEA (0.69 mL, 4.97 mmol) in DCM (15.0 mL) was mixed with DMAP (607.2 mg, 4.97 mmol), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel eluted with 0-25% ethyl acetate in petroleum ether to obtain intermediate 10-1 (408.3 mg, purity 61.4%, yield 16.5%) as a white solid. LC-MS (ESI+): m / z: 328.1 (M+Na) + .

[0206] To a solution of intermediate 10-1 (440.0 mg, 1.44 mmol) in DCM (5.0 mL), TFA (1.0 mL, 13.06 mmol) was added, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH 8-9 with TEA and diluted with ethyl acetate (20 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 10-2 (300.0 mg, crude) as brown oil. LC-MS (ESI+): m / z: 206.2 (M+H)+ .

[0207] To a solution of intermediate 10-2 (300.0 mg, crude) in DCM (10.0 mL), di(1H-imidazole-1-yl)methanethion (286.4 mg, 1.61 mmol) was gradually added at 0°C, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 10-3 (350.0 mg, crude) as a brown oil, which was used in the next step without further purification.

[0208] To a solution of intermediate 10-3 (350.0 mg, crude) in MeCN (5.0 mL), tert-butylhydrazine carboxylate (374.2 mg, 2.83 mmol) and TEA (0.20 mL, 1.42 mmol) were added, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel eluted with 0-25% ethyl acetate in petroleum ether to obtain intermediate 10-4 (552.6 mg, purity 97.7%, yield 98.8% in 3 steps) as a white solid. LC-MS (ESI+): m / z: 380.2 (M+H) + .

[0209] To a solution of intermediate 10-4 (150.0 mg, 0.40 mmol) in dioxane (5.0 mL), HCl / dioxane (3.0 mL, 4 M) was added. The mixture was stirred at 20°C for 1.5 hours. Volatile substances were removed under vacuum to obtain intermediate 10-5 (110.0 mg, crude) as a white solid, which was used in the next step without further purification.

[0210] A solution of intermediate 10-5 (110.0 mg, crude), intermediate 1-3 (122.5 mg, 0.39 mmol), and TEA (50 μL, 0.36 mmol) in EtOH (3.0 mL) was stirred at 25°C for 10 minutes and then at 80°C for a further 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue. The residue was poured into water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic extracts were washed with brine (50 mL), dried on anhydrous Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain intermediate 10-6 (150.0 mg, crude) as a yellow oil. LC-MS (ESI+): m / z: 492.2 (M+H) + .

[0211] To a solution of intermediate 10-6 (110.0 mg, 0.22 mmol) in DCM (2.0 mL), BBr3 (0.22 mL, 1 M in DCM, 0.22 mmol) was added dropwise at 0°C, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by slowly adding MeOH (5.0 mL), and volatile matter was removed under vacuum to obtain the residue. The residue was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (15 mL), dried on anhydrous Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 80*45mm*3um, water (NH3H2O+NH4HCO3)-ACN; B%: 48%~78%, 9 min), and lyophilized to obtain intermediate 10⁻⁷ (30.0 mg, 88.2% purity, 27.6%) as a yellow solid. LC-MS (ESI+): m / z: 436.1 (M+H) + .

[0212] A mixture of intermediate 10-7 (15.0 mg, 0.034 mmol) and silver acetate (14.3 mg, 0.086 mmol) in acetic acid (2.0 mL) was stirred at 20°C for 12 hours. The mixture was filtered through a Celite pad, and the filtrate was freeze-dried to obtain intermediate 10-8 (15.0 mg, crude) as a brown solid. LC-MS (ESI+): m / z: 416.1 (M+H) + .

[0213] To a solution of intermediate 10-8 (20.0 mg, 0.048 mmol) in MeOH (2.0 mL), K2CO3 (6.7 mg, 0.048 mmol) was added. The mixture was stirred at 20°C for 0.5 hours. The mixture was then filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 23%B to 53%) to obtain compound 10.

[0214] LC-MS (ESI+): m / z: 374.1 (M+H) + .

[0215] 1 H NMR(400MHz,DMSO-d6)δ=10.93-10.08(m,1H),7.08(s,1H),7.02(s,1H),5.01(s,1H),4.01-3. 90(m,1H),3.47-3.40(m,2H),2.35-2.30(m,2H),2.28(s,3H),2.06-1.99(m,2H),1.25(s,3H).

[0216] Example 15 [ka]

[0217] Compound 11 was synthesized by replacing intermediates 1-4 with (R)-1-methylpyrrolidine-3-amine in the same manner as for compound 1. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 35%B to 65%) to obtain compound 11.

[0218] LC-MS (ESI+): m / z: 373.2 (M+H) + .

[0219] 1 H NMR(400MHz,DMSO-d6)δ=11.05-9.91(m,1H),7.07(s,1H),7.00(s,1H),4.45-4.31(m,1H),3.42-3.38(m,2H),2.76-2.68(m,1 H),2.62-2.54(m,1H),2.48-2.43(m,1H),2.42-2.35(m,1H),2.28(s,3H),2.25(s,3H),2.21-2.11(m,1H),1.75-1.65(m,1H).

[0220] Example 16 [ka]

[0221] To a solution of (1R,2R)-2-aminocyclopentan-1-ol hydrochloride (400.0 mg, 2.91 mmol) and TEA (1.21 mL, 8.72 mmol) in dioxane (10.0 mL), tert-butyl 2-(1H-imidazole-1-carbonoyl)hydrazine-1-carboxylate (1000.0 mg, 4.13 mmol) was added at 20°C, and the mixture was stirred at 110°C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel eluted with 0-24% THF in DCM to obtain intermediate 12-1 (450.0 mg, purity 94.8%, yield 53.3%) as a white solid. LC-MS (ESI+): m / z: 297.9 (M+Na) + .

[0222] Example 17 [ka]

[0223] Compound 12 was synthesized by replacing intermediates 1-6 with intermediate 12-1 in the same manner as for compound 1. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40mm*3um, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 32%B to 62%) to obtain compound 12.

[0224] LC-MS (ESI+): m / z: 374.1 (M+H) + .

[0225] 1 H NMR(400MHz,DMSO-d6)δ=10.46(br.s.,1H),7.08(s,1H),7.01(s,1H),5.38-5.05(m,1H),3.98-3.89(m,2H), 3.43-3.38(m,2H),2.29(s,3H),2.09-1.98(m,1H),1.90-1.81(m,1H),1.70-1.59(m,2H),1.55-1.42(m,2H).

[0226] Example 18 [ka]

[0227] Compound 13 was synthesized by replacing (1R,2R)-2-aminocyclopentan-1-ol with (1S,3R)-3-aminocyclopentan-1-ol in the same manner as for compound 12. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150×30mm×5um, mobile phase: water (FA)-ACN) and lyophilized to obtain compound 13.

[0228] LC-MS(ESI+):m / z374.2(M+H) + .

[0229] 1H NMR(400MHz,DMSO-d6)δ=8.13(s,1H from HCOOH),7.08(s,1H),7.01(s,1H),5.01-4.45(m,1H),4.27-4.14(m,1H),4.13-4 .01(m,1H),3.43-3.40(m,2H),2.29(s,3H),2.25-2.15(m,1H),1.99-1.84(m,1H),1.78-1.54(m,3H),1.52-1.43(m,1H).

[0230] Example 19 [ka]

[0231] To a solution of compound 2 (150.0 mg, 0.23 mmol, 70% purity) and DIPEA (90 μL, 0.56 mmol) in THF (5.0 mL), 2-chloroacetonitrile (21.3 mg, 0.28 mmol) was added, and the reaction mixture was stirred at 67 °C for 2 hours. After cooling to room temperature, volatile matter was removed under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3um, mobile phase A: water (0.05% NH3H2O ​​+ 10mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 30% B to 60%), followed by preparative SFC (column: DAISEL CHIRALCEL OJ (250mm*30mm, 10um), conditions: CO2-EtOH (0.1% NH3H2O), starting B: 30%, flow rate: 70 ml / min), and then lyophilized to obtain compound 14.

[0232] LC-MS(ESI+):m / z412.2(M+H) + .

[0233] 1H NMR(400MHz,DMSO-d6)δ=10.50(br.s,1H),7.07(s,1H),7.00(s,1H),4.10-3.93(m,1H),3.77(s,2H),3.42-3.37(m,2H),3.06-2.96(m ,1H),2.71-2.64(m,1H),2.28(s,3H),2.18-2.02(m,2H),1.89-1.82(m,1H),1.78-1.70(m,1H),1.59-1.49(m,1H),1.31-1.22(m,1H).

[0234] Example 20 [ka]

[0235] tert-butyl5-hydroxypiperidine-3-yl)carbamate (900.0 mg, 4.16 mmol) and (CH2O) in MeOH (3.0 mL) n To a solution of (900.0 mg, 29.97 mmol), HOAc (0.24 mL, 4.16 mmol) was added, and the mixture was stirred at 25°C for 30 minutes. Then, NaBH3CN (653.3 mg, 10.40 mmol) was added, and the reaction mixture was stirred at 25°C for 12 hours. Volatile substances were removed under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions of 17%B to 47%), and lyophilized to obtain intermediate 15-cis (310.0 mg, yield 32.3%) as a white solid and intermediate 15-trans (320.0 mg, yield 33.4%) as a white solid. LC-MS(ESI+):m / z231.2(M+H) + .

[0236] To a solution of intermediate 15-cis (310.0 mg, 1.35 mmol) in MeOH (5.0 mL) was added HCl / dioxane (5.0 mL, 4 M), and the reaction mixture was stirred at 20 °C for 1 h. The volatiles were removed in vacuo to afford intermediate 15-1 (324.0 mg, crude) as a white solid, which was used in the next step without further purification.

[0237] Example 21

Chemical Structure

[0238] Compounds 15 and 16 were synthesized by replacing (1R,2R)-2-aminocyclopentan-1-ol with intermediate 15-1 in the same manner as the procedure for compound 12. The crude product was purified by preparative SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm), mobile phase: CO2 - EtOH (0.1% NH3H2O), flow rate: 80 mL / min, gradient condition of 35%B to 35%) to give the title compounds 15 and 16.

[0239] Compound 15 (first peak): LC-MS (ESI+): m / z 403.2 (M + H) + . 1 H NMR (400 MHz, DMSO-d6) δ = 10.47 (br.s, 1H), 7.37 - 7.06 (m, 2H), 7.00 (s, 1H), 4.87 - 4.80 (m, 1H), 4.08 - 3.85 (m, 1H), 3.61 - 3.50 (m, 1H), 3.43 - 3.37 (m, 2H), 3.03 - 2.91 (m, 1H), 2.85 - 2.75 (m, 1H), 2.28 (s, 3H), 2.19 (s, 3H), 2.11 - 2.03 (m, 1H), 1.68 - 1.56 (m, 2H), 1.19 - 1.08 (m, 1H).

[0240] Compound 16 (second peak): LC-MS (ESI+): m / z 403.2 (M + H) + . 1H NMR(400MHz,DMSO-d6)δ=10.47(br.s,1H),7.08(s,1H),7.05-6.74(m,2H),4.87-4.80(m,1H),4.08-3.85(m,1H),3.61-3.50(m,1H),3.4 4-3.37(m,2H),3.04-2.92(m,1H),2.85-2.75(m,1H),2.28(s,3H),2.19(s,3H),2.12-2.03(m,1H),1.69-1.54(m,2H),1.20-1.08(m,1H).

[0241] Example 22 [ka]

[0242] To a solution of compound 2 (150.0 mg, 0.25 mmol, 75% purity, HBr salt) in MeOH (1.5 mL), TEA (84 μL, 0.60 mmol) was added, and the reaction mixture was stirred at 25°C for 15 minutes. Then, oxetan-3-one (54.4 mg, 0.76 mmol) and HOAc (112.7 mg, 1.88 mmol) were added in sequence, and the mixture was stirred at 25°C for 30 minutes. Then, NaBH3CN (19.0 mg, 0.30 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was subjected to preparative TLC (DCM:MeOH=10:1), preparative SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um), conditions: CO2-EtOH (0.1%NH3H2O), starting B: 20%, flow rate: 150mL / min), and then preparative HPLC (column: Phenomenex C 18 Compound 17 was obtained by purification using a 80*40mm*3um container (mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 29%B to 59%).

[0243] LC-MS(ESI+):m / z429.1(M+H) + .

[0244] 1H NMR(400MHz,DMSO-d6)δ=10.47(br.s,1H),7.08(s,1H),7.04-6.82(m,2H),4.56-4.49(m,2H),4.47-4.40(m,2H),4.08-3.91(m,1H) ),3.44-3.41(m,2H),2.89-2.79(m,1H),2.60-2.52(m,2H),2.30(s,3H),1.93-1.67(m,4H),1.59-1.46(m,1H),1.37-1.28(m,1H).

[0245] Example 23 [ka]

[0246] Compounds 18 and 19 were synthesized by replacing (1R,2R)-2-aminocyclopentan-1-ol with (trans)-3-amino-1-methylpiperidine-4-ol hydrochloride, in the same manner as for compound 12. The crude products were separated by preparative SFC (column: DAIEL CHIRALPAK AD (250 mm*30 mm, 10 μm), mobile phase: CO2-EtOH (0.1% NH3H2O), flow rate: 70 mL / min, gradient condition: 25%), and then purified by preparative HPLC: Welch Xtimate C18 150*25 mm*5 μm, mobile phase: water (NH3H2O+NH4HCO3)-ACN, flow rate: 25 mL / min, gradient condition: 12%~42% to obtain the title compounds 18 and 19.

[0247] Compound 18 (1st peak): LC-MS (ESI+): m / z403.2 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ=10.49(br.s.,1H),7.08(s,1H),7.05-6.62(m,2H),5.11-4.66(m,1H),3.96-3.64(m,1H),3.44-3.40(m,2H),3.0 4-2.89(m,1H),2.72-2.58(m,1H),2.29(s,3H),2.16(s,3H),2.14-2.02(m,1H),1.98-1.88(m,1H),1.87-1.73(m,2H),1.56-1.41(m,1H).

[0248] Compound 19 (2nd peak): LC-MS (ESI+): m / z403.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ=10.49(br.s.,1H),7.08(s,1H),7.05-6.62(m,2H),5.11-4.66(m,1H),3.96-3.64(m,1H),3.44-3.40(m,2H),3.0 4-2.89(m,1H),2.72-2.58(m,1H),2.29(s,3H),2.16(s,3H),2.14-2.06(m,1H),1.98-1.88(m,1H),1.87-1.73(m,2H),1.56-1.41(m,1H).

[0249] Example 24 [ka]

[0250] Compound 20 was synthesized by replacing intermediates 1-4 with (R)-quinuclidine-3-amine in the same manner as for compound 1. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 30%B to 60%) to obtain compound 20.

[0251] LC-MS (ESI+): m / z: 399.1 (M+H) + .

[0252] 1 H NMR(400MHz,DMSO-d6)δ=7.07(s,1H),7.01(s,1H),4.02-3.91(m,1H),3.41-3.37(m,2H),3.19-3.10(m,1H),2.90-2.79(m,1H), 2.74-2.65(m,3H),2.62-2.54(m,1H),2.29(s,3H),2.03-1.97(m,1H),1.87-1.77(m,1H),1.65-1.54(m,2H),1.39-1.29(m,1H).

[0253] Example 25 [ka]

[0254] To a solution of 1-(2,4-dihydroxy-6-methylphenyl)ethane-1-one (2.40 g, 14.44 mmol) and K2CO3 (3.00 g, 21.71 mmol) in DMF (12.0 mL) and H2O (5.0 mL), a solution of 2-chloro-2,2-difluoroacetate sodium (2.20 g, 14.44 mmol) in DMF (8.0 mL) was added under N2 at 90°C. The resulting mixture was stirred at 90°C for 4 hours. After cooling to room temperature, the mixture was quenched with H2O (60 mL) and diluted with ethyl acetate (60 mL). The mixture was then acidified with citric acid aqueous solution (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic extract was dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel eluted with 0-20% ethyl acetate in petroleum ether to obtain intermediate 21-1 (370.0 mg, yield 11.9%) as a colorless oil.

[0255] To a solution of intermediate 21-1 (370.0 mg, 1.71 mmol) in DCM (6.0 mL), TBSCl (567.4 mg, 3.76 mmol), DMAP (33.5 mg, 0.27 mmol), and TEA (0.71 mL, 5.13 mmol) were added at 20°C, and the mixture was stirred at 20°C for 1.5 hours. H2O (30 mL) was added, and the mixture was extracted with DCM (30 mL x 3). The combined organic extract was dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel eluted with 0-20% ethyl acetate in petroleum ether to obtain intermediate 21-2 (520.0 mg, purity 98.68%, yield 90.7%) as a colorless oil. LC-MS (ESI+): m / z 331.2 (M+H) + .

[0256] To a solution of intermediate 21-2 (520.0 mg, 1.57 mmol) in DCE (3.0 mL), a mixture of CuBr2 (632.7 mg, 2.83 mmol) in ethyl acetate (6.0 mL) was added at 80°C, and the mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel eluted with 0-10% ethyl acetate in petroleum ether to obtain intermediate 21-3 (270.0 mg, purity 90.7%, yield 38.1%) as a colorless oil. LC-MS (ESI+): m / z 409.1 (M+H) + .

[0257] To a solution of intermediates 21-3 (170.0 mg, 0.42 mmol) and 1-7 (93.4 mg, 0.42 mmol) in EtOH (2.0 mL), concentrated HCl (51.9 μL, 0.62 mmol) was added at 30°C, and the mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the mixture was adjusted to pH=13 with NH3·H2O (0.3 mL), and volatile matter was removed under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm, mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 30%B to 60%), and lyophilized to obtain compound 21.

[0258] LC-MS(ESI+):m / z:385.2(M+H) + .

[0259] 1 H NMR(400MHz,DMSO-d6)δ=10.28(br.s.,1H),7.19(t,J=74.4Hz,1H),6.94-6.72(m,1H),6.55-6.50(m,2H),4.03-3.84(m,1H),3.39-3.37(m,2H) ),2.96-2.86(m,1H),2.64-2.56(m,1H),2.22(s,3H),2.16(s,3H),1.90 -1.71(m,3H),1.69-1.61(m,1H),1.53-1.45(m,1H),1.25-1.22(m,1H).

[0260] Example 26 [ka]

[0261] Compound 22 was synthesized by replacing (1R,2R)-2-aminocyclopentan-1-ol with 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-amine in the same manner as for compound 12. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um, mobile phase: water (FA)-ACN, flow rate: 25 mL / min, gradient conditions of 23%B to 53%) and preparative SFC (column: DAIEL CHIRALPAK AD (250mm*30mm, 10um), mobile phase: CO2-EtOH (0.1%NH3H2O), flow rate: 80 mL / min, gradient conditions of 45%B to 45%) to obtain compound 22.

[0262] LC-MS(ESI+): m / z 356.0(M+H) + .

[0263] 1 H NMR(400MHz,DMSO-d6)δ=12.32(br.s.,1H),11.21(br.s.,1H),7.62-7.53(m,1H ),7.03(s,1H),6.99(s,1H),6.12-5.71(m,1H),3.55-3.47(m,2H),2.30(s,3H).

[0264] Example 27 [ka]

[0265] To a solution of 1-(2-hydroxy-4-methoxy-6-methylphenyl)ethanone (1.00 g, 5.55 mmol) and DMAP (135.6 mg, 1.11 mmol) in DCM (30.0 mL), TEA (0.77 mL, 5.55 mmol) was added at 25°C. Then, benzoyl chloride (0.97 mL, 8.32 mmol) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried on anhydrous Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to obtain intermediate 23-1 (1.50 g, yield 95.1%) as a colorless oil.

[0266] To a solution of intermediate 23-1 (500.0 mg, 1.76 mmol) in DCE (5.0 mL) and EA (5.0 mL), CuBr2 (706.9 mg, 3.16 mmol) was added at 20°C, and the resulting mixture was stirred at 80°C for 3 hours. After cooling to room temperature, volatile matter was removed under vacuum to obtain the residue. The residue was purified by flash column chromatography on silica gel eluted with 0-50% dichloromethane in petroleum ether to obtain intermediate 23-2 (500.0 mg, yield 78.2%) as a colorless oil.

[0267] Intermediate 23-2 (250.0 mg, 0.69 mmol) was added at 20°C to a solution of intermediate 1-7 (154.7 mg, 0.69 mmol) and acetic acid (0.08 mL, 1.40 mmol) in EtOH (4.0 mL). The resulting mixture was then heated to 60°C and stirred for 2 hours. After cooling to room temperature, the mixture was adjusted to pH=13 with NH3·H2O (0.3 mL), concentrated under reduced pressure, and the residue was obtained. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions of 30%~60% B), and lyophilized to obtain intermediate 23-3 (50.0 mg, purity 94.9%, yield 15.2%) as a yellow solid. LC-MS(ESI+):m / z:453.4(M+H) + .

[0268] To a solution of intermediate 23-3 (45.0 mg, 0.10 mmol) in MeOH (2.0 mL), K2CO3 (41.2 mg, 0.30 mmol) was added at 20°C, and the mixture was heated to 50°C and stirred for 1 hour. After cooling to room temperature, volatile matter was removed under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions of 18%~48% B) to obtain compound 23.

[0269] LC-MS (ESI+): m / z: 349.1 (M+H) + .

[0270] 1H NMR(400MHz,DMSO-d6)δ=10.13(br.s.,1H),6.31-6.27(m,2H),3.98-3.87(m,1H),3.70(s,3H),3.40-3.36(m,2H),2.96-2.87(m ,1H),2.64-2.57(m,1H),2.21(s,3H),2.17(s,3H),1.92-1.73(m,3H),1.70-1.62(m,1H),1.55-1.43(m,1H),1.28-1.15(m,1H).

[0271] Example 28 [ka]

[0272] Compound 24 was synthesized by replacing (1R,2R)-2-aminocyclopentan-1-ol with (1s,3s)-3-aminocyclobutan-1-ol in the same manner as for compound 12. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um, mobile phase: water (NH3H2O+NH4HCO3)-ACN, flow rate: 25 mL / min, gradient conditions from 27%B to 57%) to obtain compound 24.

[0273] LC-MS(ESI+):m / z360.0(M+H) + .

[0274] 1 H NMR(400MHz,DMSO-d6)δ=10.38(br.s.,1H),7.07(s,1H),7.00(s,1H),5.14-5.04(m,1H), 3.94-3.76(m,2H),3.40-3.35(m,2H),2.63-2.53(m,2H),2.28(s,3H),1.89-1.76(m,2H).

[0275] Example 29 [ka]

[0276] To a solution of intermediates 21-3 (160.0 mg, 0.39 mmol) and 10-5 (218.4 mg, 0.78 mmol) in EtOH (4.0 mL), HOAc (0.14 mL, 2.42 mmol) was added at 30°C. The mixture was heated to 60°C and stirred for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH=8 with saturated NaHCO3 aqueous solution and then extracted with ethyl acetate (20 mL x 3). The combined organic extract was dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to obtain intermediate 25-1 (50.0 mg, purity 94.07%, yield 25.3%) as a yellow oil. LC-MS (ESI+): m / z 476.3 (M+H) + .

[0277] To a solution of intermediate 25-1 (35.0 mg, 0.074 mmol) in MeOH (2.0 mL), K2CO3 (30.5 mg, 0.22 mmol) was added at 20°C, and the mixture was stirred at 35°C for 7 hours. Volatile substances were removed under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm, mobile phase A: water (0.05% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 25%B to 55%), and lyophilized to obtain compound 25.

[0278] LC-MS(ESI+):m / z372.1(M+H) + .

[0279] 1 H NMR(400MHz,DMSO-d6)δ=10.33(br.s.,1H),7.19(t,J=74.0Hz,1H),6.55-6.53(m,1H),6.53-6.50(m,1H),4.97 (s,1H),3.99-3.86(m,1H),3.39-3.35(m,2H),2.35-2.27(m,2H),2.22(s,3H),2.05-1.96(m,2H),1.25(s,3H).

[0280] Example 30 [ka]

[0281] Compound 26 was synthesized by replacing (1R,2R)-2-aminocyclopentan-1-ol with (R)-2-((tert-butyldiphenylsilyl)oxy)propan-1-amine in the same manner as for compound 12. In the final step, the reaction mixture was stirred at -78°C for 8 hours. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase A: water (NH3·H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions 37%B~67%) and lyophilized to obtain compound 26.

[0282] LC-MS (ESI+): m / z: 347.9 (M+H) + .

[0283] 1 H NMR(400MHz,DMSO-d6)δ=10.46(br.s.,1H),7.10-7.04(m,1H),7.04-6.98(m,1H),4.92-4.81(m, 1H),3.90-3.78(m,1H),3.39-3.36(m,2H),3.28-3.25(m,2H),2.29(s,3H),1.08(d,J=5.6Hz,3H).

[0284] Example 31 [ka]

[0285] Compound 27 was synthesized by replacing (1R,2R)-2-aminocyclopentan-1-ol with 3-aminopyrrolidine-2-one, in the same manner as the procedure for compound 12. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 38%B to 68%) to obtain compound 27.

[0286] LC-MS (ESI+): m / z: 373.1 (M+H) + .

[0287] 1 H NMR(400MHz,DMSO-d6)δ=10.83-10.13(m,1H),7.86(s,1H),7.08(s,1H),7.02(s,1H),4.74-4.21 (m,1H),3.48-3.42(m,2H),3.25-3.19(m,2H),2.47-2.38(m,1H),2.30(s,3H),2.01-1.88(m,1H).

[0288] Example 32 [ka]

[0289] To a solution of 2-(2,6-dimethoxy-4-methylphenyl)ethane-1-ol (5.00 g, 25.48 mmol, prepared according to Reference: JACS, 2004, 126, 11966-11983) in DCM (100 mL), BBr3 (5.40 mL, 56.07 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched at 0°C by adding MeOH (15 mL), and volatile matter was removed under vacuum to obtain the residue. H2O (20 mL) was added, and the aqueous phase was extracted with DCM (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried on anhydrous Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain intermediate 28-1 (5.0 g, crude) as brown oil.

[0290] To a solution of intermediate 28-1 (5.0 g, crude) in acetone (400 mL), K2CO3 (15.00 g, 108.54 mmol) was added, and the mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel eluted with 20% ethyl acetate in petroleum ether to obtain intermediate 28-2 (2.74 g, purity 84%, yield 60.2% in 2 steps) as a white solid.

[0291] LC-MS (ESI+): m / z: 151.1 (M+H) + .

[0292] 1 H NMR(400MHz,DMSO-d6)δ=9.25(br.s,1H)6.10(s,1H)6.05(s,1H)4.44(t,J=8.80Hz,2H)2.96(t,J=8.80Hz,2H)2.13(s,3H).

[0293] To a solution of intermediate 28-2 (2.74 g, 18.24 mmol) in DCM (50.0 mL), solutions of acetic anhydride (5.64 mL, 60.20 mmol) and TiCl4 (13.00 mL, 118.58 mmol) in DCM (25.0 mL) were sequentially added at 0°C. The mixture was stirred at 0°C for 1 hour and then at 25°C for a further 5 hours. The mixture was quenched with H2O (20 mL) at 0°C, diluted with DCM (90 mL), washed with H2O (30 mL x 2) and brine (30 mL), dried on anhydrous Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel eluted with 20% ethyl acetate in petroleum ether to obtain intermediate 28-3 (2.22 g, yield 63.3%) as a white solid.

[0294] LC-MS (ESI+): m / z: 193.1 (M+H) + .

[0295] 1H NMR(400MHz,DMSO-d6)δ=10.77(br.s,1H)6.21(s,1H)4.54(t,J=8.80Hz,2H)3.06(t,J=8.80Hz,2H)2.47(s,3H)2.22(s,3H).

[0296] Example 33 [ka]

[0297] Compound 28 was synthesized by replacing 1-(2-hydroxy-4-methoxy-6-methylphenyl)ethane-1-one with intermediate 28-3, in the same manner as the procedure for compound 23. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 20 mL / min, gradient conditions from 40%B to 70%) and lyophilized to obtain compound 28.

[0298] LC-MS(ESI+):m / z361.2(M+H) + .

[0299] 1 H NMR(400MHz,CD3CN)δ=6.26(s,1H),4.58(t,J=8.80Hz,2H),4.14-4.03(m,1H),3.55(s,2H),3.10(t,J=8.80Hz,2H),2.85-2.71( m,1H),2.52-2.41(m,1H),2.34(s,3H),2.22(s,3H),2.12-2.08(m,2H),1.83-1.70(m,2H),1.62-1.53(m,1H),1.51-1.43(m,1H).

[0300] Example 34 [ka]

[0301] Compound 29 was synthesized by replacing (1R,2R)-2-aminocyclopentan-1-ol with (1s,3s)-3-amino-1-(trifluoromethyl)cyclobutan-1-ol in the same manner as for compound 12. The crude product was purified by preparative HPLC (column: C18 150×30 mm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions of 42%B to 72%) and lyophilized to obtain compound 29.

[0302] LC-MS(ESI+):m / z428.1(M+H) + .

[0303] 1 H NMR(400MHz,DMSO-d6)δ=10.45(br.s.,1H),7.52(br.s.,1H),7.08(s,1H),7.00(s,1H),6.63(s ,1H),4.21-4.00(m,1H),3.50-3.40(m,2H),2.85-2.73(m,2H),2.28(s,3H),2.27-2.21(m,2H).

[0304] Example 35 [ka]

[0305] Compound 30 was synthesized by replacing intermediate 21-1 with 1-(4-chloro-2-hydroxy-6-methylphenyl)ethane-1-one in the same manner as for compound 25. The crude product was purified by preparative HPLC (column: Xtimate C18 150*40mm*10um, mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions of 12%B to 42%) and lyophilized to obtain compound 30.

[0306] LC-MS(ESI+): m / z 340.1(M+H) + .

[0307] 1H NMR(400MHz,DMSO-d6)δ=10.67(br.s,1H),8.14(s,1H from HCOOH),6.79(d,J=1.6Hz,1H),6.76(d,J=1.6Hz,1H),4. 96(s,1H),4.01-3.86(m,1H),3.39-3.35(m,2H),2.34-2.26(m,2H),2.20(s,3H),2.04-1.96(m,2H),1.24(s,3H).

[0308] Example 36. Compound 37 was synthesized using intermediate 37-4. Similarly, the corresponding compounds were synthesized using other intermediates (Examples 37 to 54). [ka]

[0309] To a mixture of compound 37-1 (5.00 g, 19.16 mmol) in DMF (50.0 mL), NaOMe (40 mL, 30% in MeOH) was added at 25°C, and the mixture was stirred at 50°C for 1 hour. Cold H2O (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic extract was dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel eluted with 0-10% ethyl acetate in petroleum ether to obtain intermediate 37-2 (1.30 g, purity 90.0%, yield 22.4%) as a white solid.

[0310] LC-MS(ESI+):m / z:274.0(M+H) + .

[0311] 1 H NMR (400MHz, CDCl3) δ7.16 (d, J = 1.2 Hz, 1H), 6.83 (d, J = 1.2 Hz, 1H), 3.93 (s, 3H), 2.51 (s, 3H).

[0312] A mixture of intermediate 37-2 (200.0 mg, 0.73 mmol), CuI (14.0 mg, 0.074 mmol), and TEA (0.20 mL, 1.47 mmol) in dioxane (4.0 mL) was mixed with tributyl(1-ethoxyvinyl) stannane (100.0 mg, 0.28 mmol). Then, Pd(PPh3)2Cl2 (84.6 mg, 0.12 mmol) was added under N2 conditions, and the mixture was stirred under N2 conditions at 100°C for 12 hours. After cooling to room temperature, HCl (10 mL, 1 M) was added, and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated KF aqueous solution (40 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel eluted with 0-10% ethyl acetate in petroleum ether to obtain intermediate 37-3 (90.0 mg, purity 86.5%, yield 56.2%) as yellow oil.

[0313] LC-MS (ESI+): m / z: 190.1 (M+H) + A solution of CuBr2 (191.2 mg, 0.86 mmol) in HCl (1.0 mL) was added dropwise to a mixture of intermediate 37-3 (90.0 mg, 0.48 mmol) in DCE (1.0 mL) at 80°C. After addition, the mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography on silica gel eluted with 0-10% ethyl acetate in petroleum ether to obtain intermediate 37-4 (80.0 mg, purity 75.0%, yield 46.6%) as a white solid.

[0314] LC-MS (ESI+): m / z: 268.0 (M+H) + .

[0315] Example 37 [ka]

[0316] To a solution of compound 41-1 (5.00 g, 25.76 mmol) in THF (30 mL), n-BuLi (10.3 mL, 25.76 mmol, 2.5 M in hexane) was added under N2 at -78°C. After stirring at -78°C for 1 hour, a solution of I2 (7.19 g, 28.34 mmol) in THF (25 mL) was added, and the mixture was stirred at -78°C for a further 2 hours. Water (100 mL) was added to the reaction mixture, and it was extracted with siRNA (50 mL x 3). The combined organic layers were washed with brine (200 mL), dried on Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with petroleum ether to obtain intermediate 41-2 (4.00 g, yield 48.5%) as a yellow oil.

[0317] 1 H NMR (400MHz, CDCl3) δ=7.03-6.97(m,1H),6.82(s,1H),3.97(s,3H).

[0318] To a solution of intermediate 41-2 (3.50 g, 10.94 mmol) in toluene (25 mL), tributyl(1-ethoxyvinyl) stannan (5.53 g, 15.31 mmol) and Pd(PPh3)4 (253.0 mg, 0.22 mmol) were added. The reaction was stirred under N2 at 110°C for 16 hours. 6N HCl (15 mL) was added to the cooled reaction mixture and stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with HCl (40 mL × 2). The combined organic layers were washed with brine (40 mL × 3), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~8%) in petroleum ether to obtain intermediate 41-3 (2.50 g, yield 96.8%) as a yellow oil.

[0319] 1¹H NMR (400 MHz, CDCl3) δ = 7.05-6.96 (m, 1H), 6.96 (s, 1H), 3.91 (s, 3H), 2.55 (s, 3H). To a solution of intermediate 41-3 (2.50 g, 10.59 mmol) in THF (15 mL), pyrrolidone tribromide (4.13 g, 12.70 mmol) was added. The reaction was stirred at 40°C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with RINKAN (15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-7% ethyl acetate in petroleum ether to obtain intermediate 41-4 (2.40 g, yield 72.0%) as a yellow oil.

[0320] 1 H NMR (400MHz, CDCl3) δ=7.12-7.02(m,2H),4.34(s,2H),3.95(s,3H).

[0321] Example 38 [ka]

[0322] To a solution of compound 42-1 (1.60 g, 5.30 mmol) in DMF (10 mL), sodium chlorodifluoroacetate (2.00 g, 13.11 mmol) and Cs2CO3 (3.50 g, 10.74 mmol) were added. The reaction was stirred at 100°C for 2 hours. Water (20 mL) was added to the cooled reaction mixture, and the mixture was extracted with SiO2 (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with petroleum ether to obtain intermediate 42-2 (0.80 g, yield 42.9%) as a colorless oil.

[0323] 1H NMR (400MHz, CDCl3) δ = 7.37 (s, 1H), 7.19 (s, 1H), 6.57 (t, J = 72.8Hz, 1H), 2.57 (s, 3H).

[0324] Example 39 [ka]

[0325] To a solution of 4-amino-3-methoxy-5-methylbenzene-1-carbonitrile (3.50 g, 21.58 mmol) in ACN (50 mL), CuI (6.16 g, 32.37 mmol) and tert-butyl nitrite (4.45 g, 43.16 mmol) were added. The reaction was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with 0-8% ethyl acetate in petroleum ether to obtain intermediate 44-1 (4.10 g, yield 69.6%) as a white solid.

[0326] 1 H NMR (400MHz, CDCl3) δ=7.15(d,J=1.2Hz,1H),6.82(d,J=1.2Hz,1H),3.91(s,3H),2.50(s,3H).

[0327] To a solution of intermediate 44-1 (2.50 g, 9.15 mmol) in DCM (80 mL), tribromoborane (45.8 mL, 45.80 mmol, 1 M in DCM) was added at 0°C. The mixture was stirred at 50°C for 32 hours. The mixture was quenched by adding MeOH dropwise at 0°C, and then concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-8% ethyl acetate in petroleum ether to obtain intermediate 44-2 (1.10 g, yield 46.4%) as a white solid.

[0328] 1 H NMR (400MHz, CDCl3) δ = 7.08-7.06 (m, 2H), 5.83 (s, 1H), 2.49 (s, 3H).

[0329] To a solution of intermediate 44-2 (1.10 g, 4.25 mmol) and TEA (0.43 g, 4.25 mmol) in DCM (10 mL), 4-(dimethylamino)pyridine (0.095 g, 0.85 mmol) and benzoyl chloride (0.90 g, 6.37 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with 0-8% ethyl acetate in petroleum ether to obtain intermediate 44-3 (1.50 g, yield 97.2%) as a white solid.

[0330] 1 H NMR (400MHz, CDCl3)δ=8.28-8.26(m,2H),7.72-7.68(m,1H),7.66-7.56(m,2H),7.42(d,J=1.2Hz,1H),7.33(d,J=1.2Hz,1H),2.57(s,3H).

[0331] To a solution of intermediate 44-3 (1.50 g, 4.13 mmol) in toluene (15 mL), tributyl(1-ethoxyvinyl) stannan (2.09 g, 5.78 mmol) and Pd(PPh3)4 (0.1 g, 0.087 mmol) were added. The reaction was stirred under Ar at 120 °C for 16 hours. 1 M HCl (10 mL) was added to the cooled reaction mixture, and the reaction was stirred at room temperature for a further 4 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with SiO2 (40 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-8% ethyl acetate in petroleum ether to obtain intermediate 44-4 (897.0 mg, yield 77.7%) as a yellow oil.

[0332] 1 H NMR (400MHz, CDCl3) δ=8.06-8.04(m,2H),7.65-7.57(m,1H),7.48-7.37(m,4H),2.40(s,3H),2.29(s,3H).

[0333] Example 40 [ka]

[0334] To a solution of 5-fluoro-2-iodo-1-methoxy-3-methylbenzene (3.90 g, 14.66 mmol) in THF (30 mL), lithium diisopropylamide (8.8 mL, 17.59 mmol, 2 M in THF) was added dropwise under N2 at -78°C. After stirring at -78°C for 1 hour, dry DMF (1.6 mL, 20.52 mmol) was added dropwise to the mixture, and the reaction mixture was stirred at -78°C for 45 minutes. The reaction was quenched with HCl (30 mL, 1 M) at 20°C. The mixture was extracted with RINKAN (40 mL x 2). The combined organic layers were washed with brine (40 mL x 2), dried on Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-9% ethyl acetate in petroleum ether to obtain intermediate 46-1 (3.10 g, yield 71.9%) as a yellow solid.

[0335] 1 H NMR (400MHz, CDCl3) δ = 10.27 (s, 1H), 6.95 (d, J = 10.8Hz, 1H), 3.91 (s, 3H), 2.53 (s, 3H).

[0336] To a solution of intermediate 46-1 (3.36 g, 11.43 mmol) in DMF (20 mL), methyl 2-mercaptoacetate (1.82 g, 17.14 mmol) and K2CO3 (4.74 g, 34.27 mmol) were added. The mixture was stirred at 80°C for 1 hour. Water (20 mL) was added to the cooled reaction mixture, and the mixture was extracted with SiO2 (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried on Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-9% ethyl acetate in petroleum ether to obtain intermediate 46-2 (2.20 g, yield 53.1%) as a yellow solid.

[0337] 1 H NMR (400MHz, CDCl3) δ = 8.11 (s, 1H), 7.53 (s, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 2.60 (s, 3H).

[0338] To a solution of intermediate 46-2 (2.20 g, 6.07 mmol) in THF / H2O (15 mL / 5 mL), lithium hydroxide (0.73 g, 30.37 mmol) was added. The reaction was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 4 by adding 4N HCl (10 mL). The mixture was extracted with siRNA (40 mL x 2). The combined organic layers were washed with brine (40 mL x 2), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain intermediate 46-3 (2.00 g, yield 94.6%) as a yellow solid, which was used directly in the next step.

[0339] LC-MS(ESI-):m / z346.9(MH) - .

[0340] To a solution of intermediate 46-3 (1.00 g, 2.87 mmol) in DMF (10 mL), Cu2O (1.64 g, 11.49 mmol) was added. The reaction was stirred under N2 at 140°C for 16 hours. After cooling to room temperature, the mixture was filtered through a Celite pad, and the filtrate was added to water (15 mL). The mixture was extracted with SiO2 (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-5% ethyl acetate in petroleum ether to obtain intermediate 46-4 (0.60 g, yield 68.7%) as a yellow oil.

[0341] 1 H NMR (400MHz, DMSO-d6) δ = 7.77 (s, 1H), 7.72 (d, J = 5.2Hz, 1H), 7.48-7.46 (m, 1H), 3.89 (s, 3H), 2.52 (s, 3H).

[0342] To a solution of intermediate 46-4 (400.0 mg, 1.32 mmol) in toluene (10 mL), tributyl(1-ethoxyvinyl) stannan (665.0 mg, 1.84 mmol) and Pd(PPh3)4 (30.0 mg, 0.026 mmol) were added. The reaction was stirred under N2 at 120°C for 16 hours. After cooling to room temperature, 6N HCl (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with RINKAN (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-10% ethyl acetate in petroleum ether to obtain intermediate 46-5 (280.0 mg, yield 96.2%) as a yellow oil.

[0343] 1 H NMR (400MHz, CDCl3) δ = 7.46 (s, 1H), 7.42-7.37 (m, 2H), 3.95 (s, 3H), 2.58 (s, 3H), 2.36 (s, 3H).

[0344] To a solution of intermediate 46-5 (380.0 mg, 1.73 mmol) in THF (10 mL), pyrrolidone tribromide (1121.0 mg, 3.45 mmol) was added. The reaction was stirred at 40°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with 0-5% ethyl acetate in petroleum ether to obtain intermediate 46-6 (210.0 mg, yield 40.5%) as a yellow oil.

[0345] 1 H NMR (400MHz, DMSO-d6) δ = 7.78 (d, J = 5.6 Hz, 1H), 7.69 (s, 1H), 7.59-7.58 (m, 1H), 4.71 (s, 2H), 3.97 (s, 3H), 2.29 (s, 3H).

[0346] Example 41 [ka]

[0347] A solution of compound 48-1 (3.80 g, 19.68 mmol) in ACN (40 mL) was mixed with a solution of NBS (3.87 g, 21.76 mmol) in ACN (30 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Water (80 mL) was added to the mixture, and the mixture was extracted with SiO2 (80 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-5% ethyl acetate in petroleum ether to obtain intermediate 48-2 (4.30 g, yield 80.3%) as a yellow oil.

[0348] 1 H NMR (400MHz, CDCl3) δ=7.19(d,J=7.6Hz,1H),4.51(br.s,2H),2.20(s,3H).

[0349] To a solution of intermediate 48-2 (4.30 g, 15.81 mmol) in dioxane (80 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (8.03 g, 31.62 mmol), Pd(dppf)Cl2·CH2Cl2 (1.28 g, 1.58 mmol), and KOAc (3.88 g, 39.52 mmol) were added. The mixture was stirred under N2 at 100°C for 16 hours. Water (80 mL) was added to the cooled mixture, and the mixture was extracted with ELISA (80 mL x 2). The combined organic layers were washed with brine (80 mL), dried on Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-5% ethyl acetate in petroleum ether to obtain intermediate 48-3 (4.20 g, crude) as a yellow oil.

[0350] 1 H NMR (400MHz, CDCl3) δ = 7.26-7.15 (m, 1H), 4.60-4.47 (m, 2H), 2.09 (s, 3H), 1.37 (s, 12H).

[0351] To a solution of intermediate 48-3 (4.20 g, crude) in THF (50 mL), NaOH (1.58 g, 39.49 mmol, 2N) and H2O2 (8.95 g, 78.97 mmol, 30% of H2O) were slowly added at 0°C. The mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the mixture, and the mixture was extracted with SiO2 (60 mL x 2). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-5% ethyl acetate in petroleum ether to obtain intermediate 48-4 (0.85 g, 25.7% yield in 2 steps) as a yellow oil.

[0352] LC-MS(ESI+):m / z210.1(M+H) + .

[0353] 1 H NMR (400MHz, CDCl3) δ=6.85(d,J=7.6Hz,1H),5.18(br.s,1H),4.07(br.s,2H),2.15(s,3H).

[0354] A mixture of intermediate 48-4 (0.85 g, 4.06 mmol) and K2CO3 (843.0 mg, 6.10 mmol) in DMF (12 mL) was stirred at 0°C for 0.5 hours. CH3I (634.0 mg, 4.47 mmol) was slowly added to the mixture, and the mixture was stirred at 0°C for 1.5 hours. Water (50 mL) was added to the mixture, and it was extracted with HCl (60 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried on Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-5% ethyl acetate in petroleum ether to obtain intermediate 48-5 (0.50 g, yield 55.2%) as a yellow oil.

[0355] LC-MS(ESI+):m / z224.1(M+H) + .

[0356] 1 H NMR (400MHz, CDCl3) δ=6.96(d,J=7.2Hz,1H),4.16(br.s,2H),3.94(d,J=1.6Hz,3H),2.13(s,3H).

[0357] To a solution of intermediate 48-5 (400.0 mg, 1.79 mmol) in ACN (12 mL), tert-butyl nitrite (369.2 mg, 3.58 mmol) and CuI (512.0 mg, 2.69 mmol) were added. The reaction was stirred at 60°C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with petroleum ether to obtain intermediate 48-6 (400.0 mg, yield 67.0%) as a colorless oil.

[0358] 1 H NMR (400MHz, CDCl3) δ = 7.27-7.16 (m, 1H), 3.97 (d, J = 1.6Hz, 3H), 2.48 (s, 3H).

[0359] Example 42 [ka]

[0360] To a solution of 5-bromo-6-methyl-2,3-dihydrobenzofuran (130.0 mg, 0.61 mmol) in toluene (4 mL), tributyl(1-ethoxyvinyl)-stannan (308.0 mg, 0.85 mmol) and Pd(PPh3)4 (13.0 mg, 0.011 mmol) were added. The reaction was stirred under N2 at 120°C for 16 hours. After cooling to room temperature, 6N HCl (3 mL, 18.00 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with RINKAN (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-5% ethyl acetate in petroleum ether to obtain intermediate 49-1 (80.0 mg, yield 74.4%) as a white solid.

[0361] 1 H NMR (400MHz, CDCl3) δ=7.64(s,1H),6.64(s,1H),4.63(t,J=8.4Hz,2H),3.22(t,J=8.4Hz,2H),2.54(s,3H),2.53(s,3H).

[0362] To a solution of intermediate 49-1 (80.0 mg, 0.45 mmol) in THF (4 mL), pyrrolidone tribromide (146.7 mg, 0.45 mmol) was added. The reaction was stirred at 40°C for 4 hours. Water (10 mL) was added to the cooled reaction mixture, and the mixture was extracted with siRNA (10 mL x 3). The organic layers were washed together with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 49-2 (110.0 mg, 95.6%) as a yellow oil, which was used in the next step without further post-treatment.

[0363] 1 H NMR (400MHz, CDCl3) δ=7.63(s,1H),6.69(s,1H),4.66(t,J=8.8Hz,2H),4.37(s,2H),3.24(t,J=8.4Hz,2H),2.53(s,3H).

[0364] Example 43 [ka]

[0365] To a solution of 6-methyl-2,3-dihydro-1H-inden-4-ol (2.40 g, 16.19 mmol) in DCM (50 mL), acetic anhydride (5.46 g, 53.44 mmol) and TiCl4 (19.66 g, 103.64 mmol) in DCM (30 mL) were added at 0°C. The reaction was stirred at 0°C for 1 hour, then stirred at room temperature for 2 hours. The mixture was quenched with water (15 mL) at 0°C and extracted with DCM (60 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-3% ethyl acetate in petroleum ether to obtain intermediate 50-1 (2.3 g, crude) as a yellow oil, which was used directly in the next step.

[0366] LC-MS(ESI+): m / z 191.2(M+H) + .

[0367] A mixture of intermediate 50-1 (2.30 g, crude) and K2CO3 (2.51 g, 18.14 mmol) in DMF (30 mL) was mixed with CH3I (2.23 g, 15.72 mmol). The mixture was stirred at room temperature for 1.5 hours. Water (30 mL) was added to the mixture, and the mixture was extracted with SiO2 (30 mL x 2). The combined organic layer was washed with brine (40 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-3% ethyl acetate in petroleum ether to obtain intermediate 50-2 (1.00 g, 30.2% yield in 2 steps) as a yellow solid.

[0368] LC-MS(ESI+): m / z 205.2(M+H) + .

[0369] 1 H NMR (400MHz, CDCl3) δ=6.82(s,1H),3.79(s,3H),2.95(t,J=7.2Hz,2H),2.86(t,J=7.2Hz,2H),2.49(s,3H),2.22(s,3H),2.13-2.06(m,2H).

[0370] Example 44 [ka]

[0371] To a solution of 5-bromo-2-iodo-4-(trifluoromethyl)aniline (22.20 g, 60.67 mmol) in DMF (200 mL), methylboronic acid (3.83 g, 63.95 mmol), Pd(OAc)2 (0.34 g, 1.52 mmol), RuPhos (1.41 g, 3.03 mmol), and K2CO3 (50.3 g, 364.03 mmol) were added. The mixture was degassed with nitrogen for 2 minutes, heated to 110°C, and stirred for 16 hours. Water (200 mL) was added to the cooled reaction mixture, and the mixture was extracted with RINKAN (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-20% ethyl acetate in petroleum ether to obtain intermediate 53-1 (6.00 g, yield 52.3%) as a pale yellow oil.

[0372] LC-MS (ESI+): m / z 190.1 (M+H) + .

[0373] Example 45 [ka]

[0374] To a solution of tert-butyl-(R)-3-(methylamino)piperidine-1-carboxylate (2.00 g, 9.33 mmol) in EtOH (20 mL), methylhydrazine carbodithioate (0.57 g, 4.67 mmol) was added. The reaction was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with 0-5% MeOH in DCM to obtain intermediate 55-1 (650.0 mg, yield 24.1%) as a yellow oil.

[0375] LC-MS(ESI+):m / z289.2(M+H) + .

[0376] Example 46 [ka]

[0377] To a solution of 5-bromo-2-iodo-1-methoxy-3-methylbenzene (2.90 g, 8.87 mmol) in toluene (50 mL), tributyl(1-ethoxyvinyl) stannane (3.52 g, 9.76 mmol) and Pd(PPh3)4 (0.21 g, 0.18 mmol) were added under N2. The reaction was stirred under N2 at 120°C for 16 hours. HCl (68.0 mL, 6 mol / L) was added to the cooled reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with RINKAN (30 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-3% ethyl acetate in petroleum ether to obtain intermediate 56-1 (1.18 g, yield 54.7%) as a yellow solid.

[0378] 1 H NMR (400MHz, CDCl3) δ = 6.98 (s, 1H), 6.90 (s, 1H), 3.82 (s, 3H), 2.46 (s, 3H), 2.21 (s, 3H).

[0379] To a solution of intermediate 56-1 (1.20 g, 4.94 mmol) and buto-2-ic acid (623.0 mg, 7.41 mmol) in DMSO (15 mL), DBU (1.50 g, 9.87 mmol), 1,4-bis(diphenylphosphin)butane (42.2 mg, 0.099 mmol), and PdCl2(PPh3)2 (35.8 mg, 0.049 mmol) were added under N2 conditions. The mixture was stirred at 100°C for 4 hours. Water (60 mL) was added to the cooled mixture, and the mixture was extracted with SiO2 (60 mL x 2). The combined organic layers were washed with brine (60 mL x 2), dried on Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-3% ethyl acetate in petroleum ether to obtain intermediate 56-2 (850.0 mg, yield 85.1%) as a yellow solid.

[0380] LC-MS(ESI+):m / z203.2(M+H) + .

[0381] 1 H NMR (400MHz, CDCl3) δ = 6.85 (s, 1H), 6.77 (s, 1H), 3.80 (s, 3H), 2.46 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H).

[0382] CuBr2 (1314.0 mg, 5.88 mmol) was added to a solution of intermediate 56-2 (850.0 mg, 4.20 mmol) in EA / DCE (5 mL / 5 mL). The reaction was stirred at 80°C for 16 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-3% ethyl acetate in petroleum ether to obtain intermediate 56-3 (550.0 mg, yield 46.7%) as a yellow solid.

[0383] LC-MS(ESI+):m / z281.0(M+H) + .

[0384] Example 47 [ka]

[0385] To a solution of 1,3-dimethoxy-2-(2-methoxyethyl)-5-methylbenzene (2.60 g, 12.36 mmol) in MeCN (60 mL), Selectfluor (3.94 g, 11.13 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours. Water (50 mL) was added to the mixture, and the mixture was extracted with siRNA (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with petroleum ether to obtain intermediate 57-1 (1.70 g, yield 60%) as a pale yellow oil.

[0386] LC-MS(ESI+): m / z 229.1(M+1) + .

[0387] Example 48 [ka]

[0388] Intermediate 57-2 was synthesized by replacing 2-(2,6-dimethoxy-4-methylphenyl)ethane-1-ol in intermediate 57-1, following the same procedure as for intermediate 28-3. To a solution of intermediate 57-2 (500.0 mg, 2.38 mmol) in DMF (10 mL), K2CO3 (657.8 mg, 4.76 mmol) and iodomethane (675.0 mg, 4.76 mmol) were added. The mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with siRNA (40 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-6% ethyl acetate in petroleum ether to obtain intermediate 57-3 (510.0 mg, 95.4%) as a white solid.

[0389] LC-MS(ESI+):m / z225.1(M+H) + .

[0390] 1 H NMR (400MHz, CDCl3) δ=4.69(t,J=8.8Hz,2H),3.80(s,3H),3.34(t,J=8.8Hz,2H),2.47(s,3H),2.13(d,J=2.4Hz,3H).

[0391] CuBr2 (583.0 mg, 2.61 mmol) was added to a solution of intermediate 57-3 (450.0 mg, 2.00 mmol) in DCE / EA (10 mL / 10 mL). The reaction was stirred at 80°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (PE / siRNA=5 / 1) to obtain intermediate 57-4 (430.0 mg, yield 71.0%) as a white solid.

[0392] LC-MS(ESI+):m / z303.0(M+H) + .

[0393] 1 H NMR (400MHz, CDCl3) δ=4.72(t,J=8.8Hz,2H),4.32(s,2H),3.84(s,3H),3.38(t,J=8.4Hz,2H),2.17(t,J=2.4Hz,3H).

[0394] Example 49 [ka]

[0395] Intermediate 58-1 was synthesized by replacing 1,3-dimethoxy-5-methylbenzene with 1,3-dimethoxy-5-(trifluoromethyl)benzene in the same manner as in the procedure for intermediate 28-3.

[0396] To a solution of intermediate 58-1 (2.80 g, 13.72 mmol) in toluene (30 mL), NIS (2.46 g, 10.97 mmol) was added at 0°C. The reaction was stirred at room temperature for 16 hours. Water (40 mL) was added to the reaction mixture and extracted with SiO (40 mL x 3). The combined organic layers were washed with saturated Na2S2O3 aqueous solution (40 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 58-2 (4.20 g, crude) as a yellow oil, which was used directly in the next step.

[0397] LC-MS(ESI-):m / z328.9(MH) -

[0398] To a solution of intermediate 58-2 (4.20 g, crude) in DMF (30 mL), iodomethane (2.17 g, 15.27 mmol) and potassium carbonate (2.64 g, 19.09 mmol) were added. The reaction was stirred at room temperature for 2 hours. Water (40 mL) was added to the reaction mixture and extracted with SiO2 (40 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~10%) in petroleum ether to obtain intermediate 58-3 (1.90 g, 40.2% yield in 2 steps) as a white solid.

[0399] 1 H NMR (400MHz, CDCl3) δ = 6.92 (s, 1H), 4.66 (t, J = 8.4Hz, 2H), 3.89 (s, 3H), 3.38 (t, J = 8.8Hz, 2H).

[0400] Example 50 [ka]

[0401] To a solution of compound 59-1 (990.0 mg, 4.65 mmol) in toluene (10 mL), tributyl(1-ethoxyvinyl) stannan (3356.0 mg, 9.29 mmol) and Pd(PPh3)4 (107.0 mg, 0.093 mmol) were added. The reaction was stirred under Ar at 120°C for 16 hours. HCl (10 mL) was added to the cooled reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with RINKAN (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~7%) in petroleum ether to obtain intermediate 59-2 (500.0 mg, yield 61.0%) as a yellow oil.

[0402] 1 H NMR (400MHz, CDCl3) δ=12.20(s,1H),6.53(s,1H),3.26-3.13(m,2H),3.12-3.02(m,2H),2.63(s,3H),2.57(s,3H).

[0403] To a solution of intermediate 59-2 (528.0 mg, 3.00 mmol) in DMF (8 mL), iodomethane (851 mg, 5.99 mmol) and K2CO3 (1.24 g, 8.99 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~7%) in petroleum ether to obtain intermediate 59-3 (340.0 mg, yield 59.7%) as a yellow solid.

[0404] 1 H NMR (400MHz, CDCl3) δ=6.52(s,1H),3.90(s,3H),3.39(t,J=4.0Hz,2H),3.14(t,J=4.4Hz,2H),2.45(s,3H),2.19(s,3H).

[0405] Example 51 [ka]

[0406] To a solution of compound 60-1 (10.50 g, 38.82 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (11.35 g, 58.20 mmol), and potassium fluoride (4.50 g, 77.45 mmol) in 1,4-dioxane / water (100 mL / 20 mL), Pd(dppf)Cl2 (2.84 g, 3.88 mmol) was added. The mixture was stirred under Ar at 110 °C for 16 hours. Water (300 mL) was added to the cooled reaction mixture and extracted with RINKAN (300 mL x 2). The combined organic layers were washed with brine (200 mL), dried on Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~65%) in petroleum ether to obtain intermediate 60-2 (1.10 g, yield 13.4%) as a yellow solid.

[0407] LC-MS(ESI+):m / z212.0(M+H) +

[0408] To a solution of intermediate 60-2 (1.10 g, 5.20 mmol) in EtOH / water (5 mL / 5 mL), KOH (1.50 g, 26.74 mmol) was added. The mixture was stirred under Ar at 110 °C for 16 hours. Water (20 mL) was added to the cooled reaction mixture. The mixture was adjusted to pH=2 with 1N HCl. The mixture was then extracted with ELISA (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by reverse-phase chromatography eluting with ACN (0%~20%) in H₂O to obtain intermediate 60-3 (400.0 mg, yield 38.0%) as a yellow solid.

[0409] LC-MS(ESI): m / z 201.0(MH) -

[0410] To a solution of intermediate 60-3 (400.0 mg, 1.97 mmol) in THF (5 mL), BH3 (5.92 mL, 5.92 mmol, 1 M in THF) was added at 0°C under Ar. The reaction was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture. The mixture was adjusted to pH=3 with 1N HCl. The mixture was then extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~60%) in petroleum ether to obtain intermediate 60-4 (370.0 mg, yield 99.6%) as a colorless oil.

[0411] 1 H NMR (400MHz, CDCl3) δ=6.86(s,2H),6.47(s,2H)3.95(t,J=4.8Hz,2H),2.93(t,J=4.8Hz,2H),2.58(s,1H).

[0412] To a solution of intermediate 60-4 (370.0 mg, 1.96 mmol) in THF (5 mL), triphenylphosphine (772.0 mg, 2.94 mmol) and DIAD (0.57 mL, 2.94 mmol) were added under Ar at 0°C. The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~15%) in petroleum ether to obtain intermediate 60-5 (200.0 mg, yield 59.8%) as a yellow solid.

[0413] 1 H NMR (400MHz, CDCl3) δ=6.42(s,1H),6.34(s,1H),4.99(s,1H),4.64-4.59(m,2H),3.13-3.09(m,2H).

[0414] To a solution of intermediate 60-5 (200.0 mg, 1.17 mmol) in DCM (5 mL), a solution of Ac2O (395.09 mg, 3.87 mmol) and TiCl4 (0.84 mL, 7.66 mmol) in DCM (5 mL) was added at 0°C. The reaction was stirred at 0°C for 1 hour. Then, the reaction was warmed to room temperature and stirred for 3 hours. Water (20 mL) was added to the reaction mixture and extracted with siRNA (20 mL × 2). The combined organic layer was washed with brine (20 mL), dried on Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~5%) in petroleum ether to obtain intermediate 60-6 (200.0 mg, yield 80.4%) as a white solid.

[0415] LC-MS(ESI+):m / z213.1(M+H) +

[0416] 1 H NMR (400MHz, CDCl3) δ=13.38(s,1H),6.50(s,1H),4.70(t,J=8.8Hz,2H),3.17(t,J=8.8Hz,2H),2.80(s,3H).

[0417] To a solution of intermediate 60-6 (100.0 mg, 0.47 mmol) in DMF (5 mL), iodomethane (79.5 mg, 0.56 mmol) and K2CO3 (97.0 mg, 0.70 mmol) were added. The reaction was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture and extracted with siRNA (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~10%) in petroleum ether to obtain intermediate 60-7 (100.0 mg, yield 93.6%) as a white solid.

[0418] 1H NMR (400MHz, CDCl3) δ=6.55(s,1H),4.61(t,J=8.8Hz,2H),3.86(s,3H),3.32(t,J=8.8Hz,2H),2.49(s,3H).

[0419] Example 52 [ka]

[0420] To a solution of compound 62-1 (6.10 g, 45.45 mmol) in THF (80 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (12.70 g, 50.00 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.24 g, 0.91 mmol), and [Ir(COD)OMe]2 (0.30 g, 0.46 mmol) were added. The reaction was stirred under N2 at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 62-2 (11.00 g, crude) as a brown oil, which was used in the next step without further purification.

[0421] LC-MS(ESI+):m / z261.1(M+H) + .

[0422] To a solution of intermediate 62-2 (11.00 g, crude) in THF (90 mL), NaOH (42.5 mL, 85.00 mmol, 2 mol / L in H2O) and H2O2 (28.80 g, 254.12 mmol, 30 wt% in H2O) were slowly added at 0°C. The mixture was stirred at room temperature for 2 hours. Water (90 mL) was added to the mixture and extracted with siRNA (90 mL x 3). The combined organic layers were washed with saturated sodium sulfite aqueous solution (60 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~20%) in petroleum ether to obtain intermediate 62-3 (1.40 g, 20.5% yield in 2 steps) as an off-white solid.

[0423] LC-MS(ESI+): m / z 151.2(M+H) + .

[0424] 1 H NMR (400MHz, CDCl3) δ=6.62(s,1H),6.47(s,1H),5.33(br.s,1H),5.11(s,2H),5.08(s,2H),2.31(s,3H).

[0425] To a solution of intermediate 62-3 (700.0 mg, 4.66 mmol) in HOAc (15 mL), NBS (830.0 mg, 4.66 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction mixture and extracted with siRNA (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~15%) in petroleum ether to obtain intermediate 62-4 (550.0 mg, yield 51.5%) as a yellow solid.

[0426] LC-MS (ESI): m / z 226.9 (MH) - .

[0427] 1 H NMR (400MHz, CDCl3) δ = 6.58 (s, 1H), 5.19 (s, 2H), 5.11-5.06 (m, 2H), 2.33 (s, 3H).

[0428] To a solution of intermediate 62-4 (550.0 mg, 2.40 mmol) in acetonitrile (12 mL), NIS (1.08 g, 4.80 mmol) was added. The reaction was stirred at room temperature for 1 hour. Saturated sodium sulfite aqueous solution (20 mL) was added to the reaction mixture and extracted with RINKAN (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~12%) in petroleum ether to obtain intermediate 62-5 (720.0 mg, yield 84.5%) as a yellow solid.

[0429] LC-MS(ESI): m / z 352.7(MH) - .

[0430] 1 H NMR (400MHz, CDCl3) δ=5.26-5.19(m,2H),5.08-5.02(m,2H),2.65(s,3H).

[0431] To a solution of intermediate 62-5 (700.0 mg, 1.97 mmol) in toluene (20 mL), tributyl(1-ethoxyvinyl) stannan (783.0 mg, 2.17 mmol) and Pd(PPh3)4 (46.0 mg, 0.039 mmol) were added. The reaction was stirred under N2 at 120°C for 16 hours. HCl (15.1 mL, 90.6 mmol, 6 mol / L in H2O) was added to the cooled reaction mixture, and the mixture was stirred at room temperature for a further 2 hours. Water (30 mL) was added to the reaction mixture, and it was extracted with RINKAN (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried on Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~12%) in petroleum ether to obtain intermediate 62-6 (300.0 mg, yield 56.2%) as a yellow solid.

[0432] LC-MS(ESI+): m / z 271.0(M+H) + .

[0433] 1 H NMR (400MHz, CDCl3) δ = 11.34 (s, 1H), 5.23 (s, 2H), 5.10-5.02 (m, 2H), 2.65 (s, 3H), 2.62 (s, 3H).

[0434] To a solution of intermediate 62-6 (2.60 g, 9.59 mmol) in DMF (30 mL), sodium formate (978.0 mg, 14.38 mmol) and Pd(PPh3)4 (665.0 mg, 0.58 mmol) were added. The mixture was stirred under H2 air at 95°C for 16 hours. Water (30 mL) was added to the cooled reaction mixture and extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~12%) in petroleum ether to obtain intermediate 62-7 (1.00 g, yield 54.2%) as a yellow solid.

[0435] LC-MS(ESI+): m / z 193.1(M+H) + .

[0436] 1 H NMR (400MHz, CDCl3) δ=12.66(s,1H),6.63(s,1H),5.11(s,2H),5.08-5.00(m,2H),2.67(s,3H),2.62(s,3H).

[0437] Example 53 [ka]

[0438] To a solution of compound 64-1 (4.54 g, 21.11 mmol) in 1,4-dioxane (50 mL), K3PO4 (8.96 g, 42.20 mmol), methylboronic acid (7.60 g, 127.00 mmol), Pd(OAc)2 (143.0 mg, 0.64 mmol), and S-Phos (521.4 mg, 1.27 mmol) were added. The mixture was stirred under Ar at 110°C for 16 hours. The mixture was concentrated to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~75%) in petroleum ether to obtain intermediate 64-2 (2.50 g, yield 78.9%) as a white solid.

[0439] LC-MS(ESI+): m / z 151.1(M+H) + .

[0440] 1 H NMR: (400MHz, CDCl3)δ=6.59(s,1H),6.55(s,1H),4.58(t,J=8.8Hz,2H),3.19(t,J=8.8Hz,2H),2.24(s,3H).

[0441] To a solution of intermediate 64-2 (1.10 g, 7.32 mmol) in DMF (10 mL), benzyl bromide (1.50 g, 8.79 mmol) and K2CO3 (3.0 g, 21.97 mmol) were added at room temperature. The reaction was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture and extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~15%) in petroleum ether to obtain intermediate 64-3 (1.70 g, yield 96.6%) as a white solid.

[0442] 1 H NMR: (400MHz, CDCl3)δ=7.45-7.29(m,5H),6.65(s,1H),6.59(s,1H),5.12(s,2H),4.60(t,J=8.8Hz,2H),3.18(t,J=8.8Hz,2H),2.24(s,3H).

[0443] To a solution of intermediate 64-3 (1.70 g, 7.07 mmol) in DCM (20 mL), NBS (1.66 g, 9.34 mmol) was added at 0°C. The reaction was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~7%) in petroleum ether to obtain intermediate 64-4 (2.20 g, yield 97.5%) as a white solid.

[0444] 1 H NMR: (400MHz, CDCl3)δ=7.50-7.30(m,5H),6.67(s,1H),5.11(s,2H),4.65(t,J=8.8Hz,2H),3.22(t,J=8.8Hz,2H),2.27(s,3H).

[0445] To a solution of intermediate 64-4 (2.20 g, 6.89 mmol) in DCM (25 mL), NIS (1.55 g, 6.89 mmol) was added at 0°C. The mixture was stirred at room temperature for 10 minutes. Silver trifluoromethanesulfonate (0.91 g, 3.54 mmol) was added to the mixture, and the reaction was stirred at room temperature for 3 hours. Water (50 mL) was added to the reaction mixture, and it was extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~6%) in petroleum ether to obtain intermediate 64-5 (2.40 g, yield 78.3%) as a white solid.

[0446] 1 H NMR: (400MHz, CDCl3)δ=7.56-7.32(m,5H),5.13(s,2H),4.65(t,J=8.8Hz,2H),3.22(t,J=8.8Hz,2H),2.62(s,3H).

[0447] To a solution of intermediate 64-5 (2.35 g, 5.28 mmol) in toluene (25 mL), tributyl(1-ethoxyvinyl) stannan (2.29 g, 6.34 mmol) and Pd(PPh3)4 (122.0 mg, 0.11 mmol) were added. The reaction was stirred under Ar at 120 °C for 16 hours. HCl (50 mL, 200 mmol) (4 M) was added to the cooled reaction mixture, and the mixture was stirred at room temperature for a further 2 hours. Water (50 mL) was added to the reaction mixture, and it was extracted with HCl (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~6%) in petroleum ether to obtain intermediate 64-6 (390.0 mg, yield 20.4%) as a colorless oil.

[0448] 1 H NMR: (400MHz, CDCl3)δ=7.35-7.25(m,5H),5.05(s,2H),4.59(t,J=8.8Hz,2H),3.17(t,J=8.8Hz,2H),2.31(s,3H),2.10(s,3H).

[0449] To a solution of intermediate 64-6 (160.0 mg, 0.44 mmol) in EtOH / dioxane (1 mL / 1 mL), TEA (0.06 mL, 0.44 mmol), 10% Pd / C (24 mg, 50% in water), and ammonium formate (17.0 mg, 0.27 mmol) were added. The reaction was stirred under an H2 balloon at 60°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~10%) in petroleum ether to obtain intermediate 64-7 (85.0 mg, 100% yield) as a yellow solid.

[0450] LC-MS(ESI+): m / z 193.1(M+H) + .

[0451] 1H NMR: (400MHz, CDCl3)δ=11.77(s,1H),6.62(s,1H),4.64(t,J=9.2Hz,2H),3.21(t,J=9.2Hz,2H),2.64(s,3H),2.52(s,3H).

[0452] Example 54 [ka]

[0453] To a solution of compound 68-1 (0.70 g, 1.65 mmol) in MeOH (10 mL), Pd(OH)2 (579 mg, 0.82 mmol) was added. The reaction was heated to 30°C and stirred under an H2 balloon for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 68-2 (0.40 g, yield 99.2%) as a colorless oil.

[0454] LC-MS(ESI+): m / z 245.1(M+H) + .

[0455] To a mixture of CaCO3 (184.0 mg, 1.84 mmol) in DCM (6 mL) and water (3 mL), intermediate 68-2 (150 mg, 0.61 mmol) and thiophosgene (105.8 mg, 0.92 mmol) were slowly added under N2 at 0°C. After addition, the reaction was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was extracted with DCM (30 mL x 3) and water (30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 68-3 (150.0 mg, yield 85.8%) as a yellow oil, which was used in the next step without further post-treatment. To a solution of intermediate 68-3 (150.0 mg, 0.52 mmol) in MeOH (5 mL), hydrazinium hydroxide solution (46 mg, 0.78 mmol, 85 wt%) was added under N2. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue, which was freeze-dried to obtain intermediate 68-4 (140.0 mg, yield 84.5%) as a white solid.

[0456] LC-MS(ESI+): m / z 319.1(M+H) + .

[0457] The following compounds were prepared using the same synthetic method as described for Compound 1 or Compound 2, by substituting appropriate starting materials, reagents, and reaction conditions. The reaction temperature varied from -78°C to 0°C for the final step under BBr3 conditions. [Table 4-1] [Table 4-2]

[0458] By substituting appropriate starting materials, reagents, and reaction conditions, the following compounds were prepared using a synthesis method similar to that described for compound 25. [Table 5]

[0459] Example 55 [ka]

[0460] Compound 66-15 (17.00 g, 123.54 mmol) and thiophosgene (28.4 g, 247.02 mmol) were added to a mixture of CaCO3 (37.10 g, 370.68 mmol) in DCM (150 mL) and H2O (75 mL) under N2 at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 66-16 (15.00 g, 104.75 mmol, yield 85%) as a yellow oil, which was used in the next reaction without further purification.

[0461] 1H NMR:(400MHz,DMSO-d6)δ=3.99-3.80(m,1H),2.46-2.32(m,2H),2.24-2.09(m,2H),1.00(s,3H).

[0462] To a solution of intermediate 66-16 (15.00 g, 104.75 mmol) in MeOH (100 mL), hydrazine hydrate (7.40 g, 125.65 mmol, 85 wt%) was added under N2. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain intermediate 66-14 (17.70 g, yield 96.4%) as a yellow solid.

[0463] 1 H NMR:(400MHz,DMSO-d6)δ=8.64(s,1H),7.73-7.62(m,1H),4.94(s,1H),4.48( s, 2H), 4.29-4.18 (m, 1H), 2.37-2.24 (m, 2H), 2.01-1.94 (m, 2H), 1.21 (s, 3H).

[0464] To a solution of compound 66-1 (10.00 g, 36.35 mmol) in dioxane / water (150 mL / 30 mL), potassium trifluoro(vinyl)borate (6.30 g, 47.03 mmol), Pd(dppf)Cl2 (2.70 g, 3.69 mmol), and K2CO3 (12.6 g, 91.17 mmol) were added. The mixture was stirred at 100 °C for 16 hours. Water (100 mL) was added to the cooled reaction mixture and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~12%) in petroleum ether to obtain intermediate 66-2 (7.70 g, yield 95.3%) as a white solid.

[0465] 1H NMR (400MHz, CDCl3)δ=7.25(s,2H),7.01-6.93(m,1H),6.18(dd,J=18.0,2.8Hz,1H),5.55(dd,J=12.4,2.8Hz,1H),3.92(s,3H),3.90(s,6H). To a solution of intermediate 66-2 (8.10 g, 36.45 mmol) in THF (100 mL), 9-BBN (146 mL, 0.5 M in THF, 73.00 mmol) was added. The mixture was stirred at room temperature for 16 hours, and the reaction was diluted with THF / water (50 mL / 50 mL). Sodium perborate tetrahydrate (33.60 g, 218.38 mmol) was added to the mixture, and the mixture was vigorously stirred for 1 hour. The suspension was diluted with saturated NaHCO3 aqueous solution (50 mL) and filtered. The aqueous phase was extracted with RINKAN (100 mL x 3). The combined organic phases were washed with brine (100 mL) and dried over Na2SO4. The solvent was evaporated, and the residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~20%) in petroleum ether to obtain intermediate 66-3 (8.60 g, yield 98.2%) as a white solid.

[0466] 1 H NMR (400MHz, CDCl3) δ = 7.25 (s, 2H), 3.92 (s, 3H), 3.88 (s, 6H), 3.78-3.72 (m, 2H), 3.01 (t, J = 6.8Hz, 2H).

[0467] A solution of intermediate 66-3 (6.60 g, 27.47 mmol) in HOAc (35 mL) and HBr (48 wt% in water, 35 mL) was stirred at 120°C for 16 hours. Water (50 mL) was added to the cooled reaction mixture, and the mixture was extracted with siRNA (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with MeOH (0%~5%) in DCM to obtain intermediate 66-4 (3.20 g, yield 64.7%) as a yellow solid.

[0468] LC-MS(ESI+):m / z181.1(M+H)+

[0469] To a solution of intermediate 66-4 (1.00 g, 5.55 mmol) in MeOH (10 mL), sulfurous dichloride (2 mL) was added at 0°C. The reaction was stirred at 65°C for 6 hours. The solvent was evaporated to obtain the residue. The residue was dissolved in saturated NaHCO3 aqueous solution (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~50%) in petroleum ether to obtain intermediate 66-5 (0.37 g, yield 34.3%) as a yellow solid.

[0470] 1 H NMR (400MHz, DMSO-d6) δ=9.92(s,1H),6.98(s,1H),6.76(s,1H),4.56(t,J=8.8Hz,2H),3.79(s,3H),3.09(t,J=8.8Hz,2H).

[0471] To a solution of intermediate 66-5 (680.0 mg, 3.50 mmol) in THF (10 mL), LiAlH4 (292.0 mg, 7.69 mmol) was added at 0°C under N2. The reaction was stirred at room temperature for 1 hour. The mixture was diluted with DCM (10 mL), and water (0.5 mL), 15% NaOH (0.5 mL), and water (1 mL) were added sequentially at 0°C. Na2SO4 was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~50%) in petroleum ether to obtain intermediate 66-6 (494.0 mg, yield 84.9%) as a white solid.

[0472] 1H NMR(400MHz,DMSO-d6)δ=9.33(s,1H),6.28(s,1H),6.18(s,1H),5.03(t,J=5. 6Hz,1H), 4.47(t,J=8.8Hz,2H),4.32(d,J=5.6Hz,2H),2.99(t,J=8.8Hz,2H).

[0473] To a solution of intermediate 66-6 (0.60 g, 3.61 mmol) in DCM (10 mL), PDC (2.70 g, 7.18 mmol) was gradually added while maintaining the internal temperature at 0°C. After the addition, the reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~30%) in petroleum ether to obtain intermediate 66-7 (0.21 g, yield 35.4%) as a yellow solid.

[0474] 1 H NMR (400MHz, CDCl3) δ=9.83(s,1H),6.90-6.87(m,2H),5.12(s,1H),4.68(t,J=8.8Hz,2H),3.23(t,J=8.8Hz,2H).

[0475] To a solution of intermediate 66-7 (0.26 g, 1.58 mmol) in DCM (5 mL), BAST (0.80 mL, 4.34 mmol) was added under N2 at 0°C. The reaction was stirred at room temperature for 16 hours. Water (20 mL) and saturated NaHCO3 aqueous solution (5 mL) were added to the reaction mixture, and the mixture was extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~22%) in petroleum ether to obtain intermediate 66-8 (0.23 g, yield 78.2%) as a yellow solid.

[0476] 1 H NMR(400MHz, CDCl3)δ=6.64-6.36(m,3H),4.94(br.s,1H),4.65(t,J=8.4Hz,2H),3.18(t,J=8.8Hz,2H).19 F NMR (376MHz, CDCl3)δ=-110.16.

[0477] To a solution of intermediate 66-8 (230 mg, 1.23 mmol) in DCM (5 mL), NBS (0.22 g, 1.24 mmol) was added at -40°C. The reaction was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was adjusted to pH=4 with HCl (2N), then extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with DCM (0%~50%) in petroleum ether to obtain intermediate 66-9 (0.28 g, yield 85.2%) as a white solid.

[0478] LC-MS (ESI): m / z 263.0 (MH) - .

[0479] To a solution of intermediate 66-9 (0.28 g, 1.06 mmol) in toluene (5 mL), tributyl(1-ethoxyvinyl) stannane (459.0 mg, 1.27 mmol) and Pd(PPh3)4 (23.0 mg, 0.020 mmol) were added under Ar. After addition, the reaction was stirred at 120 °C for 16 hours. 4 M HCl (5 mL) was added to the cooled reaction mixture, and the mixture was stirred at room temperature for a further 2 hours. Water (20 mL) was added to the reaction mixture, and it was extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~15%) in petroleum ether to obtain intermediate 66-10 (0.16 g, yield 66.1%) as a yellow solid.

[0480] 1 H NMR(400MHz, CDCl3)δ=12.87(s,1H),7.06(t,J=54.8Hz,1H),6.76(s,1H),4.74(t,J=8.8Hz,2H),3.22(t,J=8.8Hz,2H),2.66(s,3H).

[0481] To a solution of intermediate 66-10 (155.0 mg, 0.68 mmol) and TEA (69.0 mg, 0.68 mmol) in DCM (5 mL), DMAP (17.0 mg, 0.14 mmol) and benzoyl chloride (124.0 mg, 0.88 mmol) were added. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~12%) in petroleum ether to obtain intermediate 66-11 (220.0 mg, yield 97.4%) as a yellow solid.

[0482] 1 H NMR(400MHz,CDCl3)δ=8.25-8.12(m,2H),7.71-7.65(m,1H),7.57-7.50(m,2H) ,7.05-6.75(m,2H),4.70(t,J=8.6Hz,2H),3.16(t,J=8.6Hz,2H),2.46(s,3H).

[0483] To a solution of intermediate 66-11 (40.0 mg, 0.12 mmol) in siRNA / DCE (1 mL / 1 mL), copper(II) bromide (36.0 mg, 0.16 mmol) was added. The reaction was stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by preparative TLC (PE / EA = 5 / 1) to obtain crude intermediate 66-12 (49.0 mg) as a white solid, which was used directly in the next step without further purification. To a solution of intermediates 66-12 (156.0 mg, 0.38 mmol) and 66-14 (67.0 mg, 0.38 mmol) in EtOH (5 mL), HBr (48 wt% in water, 96 mg) was added. After stirring at room temperature for 1 hour, the reaction was stirred at 60 °C for 16 hours. The solvent was removed under vacuum, and the residue was diluted with EA. NH4OH was added to the mixture to pH=10 at 0 °C. H2O (10 mL) was added to the mixture, and the mixture was extracted with siRNA (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by column chromatography on silica gel eluted with MeOH (0%~4.9%) in DCM to obtain intermediate 66-13 (105.0 mg, yield 56.7%) as a yellow solid.

[0484] LC-MS(ESI+):m / z488.1(M+H) + .

[0485] To a solution of intermediate 66-13 (95.0 mg, 0.19 mmol) in MeOH (3 mL), K2CO3 (131.0 mg, 0.95 mmol) was added at room temperature. The mixture was stirred at 50°C for 1 hour. The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by preparative HPLC (Waters 3767 / QDA) column (SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 15-25%; retention time: 6.7-7.8 mins of 17 minutes) to obtain compound 66.

[0486] LC-MS(ESI+):m / z384.0(M+H) + .

[0487] 1 H NMR(400MHz,CD3CN)δ=6.83(t,J=55.2Hz,1H),6.67(s,1H),4.65(t,J=8.8Hz,2H),4.07-3.9 8(m,1H),3.47(s,2H),3.25-3.18(m,2H),2.49-2.42(m,2H),2.08-1.95(m,2H),1.31(s,3H).

[0488] Example 56 [ka]

[0489] To a solution of intermediate 28-3 (1200 mg, 6.24 mmol) and TEA (632 mg, 6.24 mmol) in DCM (5 mL), 4-(dimethylamino)pyridine (153 mg, 1.25 mmol) and benzoyl chloride (1141 mg, 8.12 mmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with 0-4% ethyl acetate in petroleum ether to obtain intermediate 31-1 (1561 mg, yield 84.4%) as a white solid.

[0490] 1 H NMR:(400MHz,CDCl3)δ=8.21-8.12(m,2H),7.72-7.64(m,1H),7.58-7.48(m,2H),6 .59(s,1H),4.62(t,J=8.8Hz,2H),3.08(t,J=8.8Hz,2H),2.41(s,3H),2.31(s,3H).

[0491] CuBr2 (490 mg, 2.19 mmol) was added to a solution of intermediate 31-1 (500 mg, 1.69 mmol) in siRNA (3 mL) and DCE (3 mL). The reaction was stirred at 80°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-6% ethyl acetate in petroleum ether to obtain intermediate 31-2 (500 mg, yield 79.0%) as a yellow solid.

[0492] 1H NMR:(400MHz,CDCl3)δ=8.20-8.08(m,2H),7.71-7.61(m,1H),7.61-7.47(m,2H),6 .63(s,1H),4.64(t,J=8.4Hz,2H),4.23(s,2H),3.09(t,J=8.8Hz,2H),2.33(s,3H).

[0493] To a solution of intermediate 66-14 (300 mg, 1.71 mmol) in EtOH (10 mL), intermediate 31-2 (705 mg, 1.88 mmol) and concentrated HCl (85 mg, 0.86 mmol, 37 wt%) were added at room temperature. After stirring at room temperature for 10 minutes, the mixture was stirred at 80°C for 1 hour. NH4OH was added to the mixture to pH=10 at 0°C. The mixture was then extracted with siRNA (30 mL × 3) and water (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-10% MeOH in DCM to obtain intermediate 31-3 (230 mg, yield 29.8%) as a red oil.

[0494] LC-MS(ESI+):m / z452.2(M+H) + .

[0495] To a solution of intermediate 31-3 (200 mg, 0.44 mmol) in MeOH (10 mL), K2CO3 (304 mg, 2.20 mmol) was added at room temperature. The mixture was stirred at 50°C for 1 hour. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by HPLC (column: Waters Sun FirePrep C18 OBD 10 μm 19*250 mm; mobile phase: [0.1% FA-ACN in water]; B% 5%~95% ACN, 6.97 min) to obtain compound 31.

[0496] LC-MS(ESI+):m / z348.0(M+H) + .

[0497] 1H NMR(400MHz,CD3CN)δ=8.11(s,0.7H,HCOOH origin),6.26(s,1H),4.57(t,J=8.8Hz,2H),4.07-3.98(m,1H) ,3.55(s,2H),3.10(t,J=8.8Hz,2H),2.49-2.43(m,2H),2.32(s,3H),2.11-2.00(m,2H),1.31(s,3H).

[0498] By substituting appropriate starting materials, reagents, and reaction conditions, the following compounds were prepared using a synthesis method similar to that described for compound 66. [Table 6]

[0499] Example 57 [ka]

[0500] To a MeNH2 solution (6.9 mL, 13.80 mmol, 2 M in THF), a solution of intermediate 1-3 (1.0 g, 3.21 mmol) in THF (6.0 mL) was added at 0°C, and the mixture was stirred at 0°C for 20 minutes to obtain intermediate 36-1. TEA (0.45 mL, 3.22 mmol) and intermediate 2-2 (1.45 g, 5.99 mmol) were added to the mixture at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Volatile substances were removed under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Xtimate C18 150*40mm*10μm, mobile phase A: water (0.05% NH3H2O ​​+ 10mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 55 mL / min, gradient conditions from 60%B to 90%) to obtain intermediate 36-2 (660.0 mg, purity 97.86%, yield 39.9%) as a yellow solid.

[0501] LC-MS(ESI+):m / z504.3(M+H) + .

[0502] A mixture of intermediate 36-2 (300.0 mg, 0.60 mmol) and K2CO3 (247.0 mg, 1.79 mmol) in acetone (4.0 mL) was mixed with CH3I (0.11 mL, 1.79 mmol) at 25°C, and the mixture was stirred at 25°C for 1 hour. H2O (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic extract was dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain intermediate 36-3 (310.0 mg, crude).

[0503] To a solution of intermediate 36-3 (310.0 mg, crude) in EtOH (3.0 mL), hydrazine hydrate (0.47 mL, purity 85%, 8.14 mmol) was added at 25°C, and the mixture was stirred at 50°C for 6 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*30 mm*5 μm, mobile phase A: water (0.225% FA), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions of 23%B to 53%) to obtain intermediate 36-4 (130.0 mg, purity 86.26%, yield 38.9% in 2 steps) as a white solid.

[0504] LC-MS(ESI+):m / z484.0(M+H) +

[0505] To a solution of intermediate 36-4 (90.0 mg, 0.19 mmol) in DCM (2.0 mL), BBr3 (89.7 μL, 0.93 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour and then at 30°C for 2 hours. An additional BBr3 (89.7 μL, 0.91 mmol) was added at 30°C, and the mixture was stirred for a further 1 hour at 30°C. The mixture was quenched with MeOH (20.0 mL) at 0°C, and volatile matter was removed under vacuum to obtain the crude product. The crude product was sequentially purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm, mobile phase A: water (0.225% FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions 1%B to 31%), SFC (column: DAIEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: CO2-EtOH (0.1% NH3H2O), flow rate: 80 mL / min, gradient conditions 40% to 40%) and preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm, mobile phase A: water (0.225% FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions 2%B to 32%) to obtain intermediate 36-5 (3.0 mg, yield 4.3%) as brown oil.

[0506] LC-MS(ESI+): m / z 370.2(M+H) + .

[0507] 1 H NMR(400MHz,DMSO-d6)δ=7.06(s,1H),7.02(s,1H),4.00(s,2H),3.83-3.80(m,1H),3.17-3.10(m,1H),2.96(s,3 H),2.95-2.91(m,1H),2.65-2.56(m,2H),2.30(s,3H),1.94-1.85(m,1H),1.79-1.70(m,1H),1.58-1.46(m,2H). To a solution of intermediate 36-5 (60.0 mg, 0.13 mmol) in MeOH (1.0 mL), TEA (36.9 μL, 0.27 mmol) was added at 20°C. Then, HOAc (24.0 mg, 0.40 mmol) and (CH2O) were added. n(12.0 mg, 0.40 mmol) was added to the mixture at 30°C. NaBH(OAc)3 (112.4 mg, 0.53 mmol) was added at 30°C, and the mixture was stirred at 40°C for 8 hours. Additional NaBH(OAc)3 (112.4 mg, 0.53 mmol) was added at 40°C, and the mixture was stirred for a further 3 hours. H2O (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic extract was dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was sequentially purified by SFC (column: DAIEL CHIRALCEL OD (250mm*30mm, 10μm), mobile phase: CO2-EtOH (0.1%NH3H2O), flow rate: 150mL / min, gradient conditions of 20%~20%) and preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm, mobile phase A: water (0.225%FA), mobile phase B: acetonitrile, flow rate: 25mL / min, gradient conditions of 2%B~32%) to obtain compound 36.

[0508] LC-MS(ESI+):m / z384.2(M+H) + .

[0509] 1 H NMR(400MHz,DMSO-d6)δ=7.11(s,1H),7.01(s,1H),4.13(s,2H),3.87-3.78(m,1H),3.07(s,3H),2.89-2.79(m,1H),2. 70-2.61(m,1H),2.30(s,3H),2.21(s,3H),2.09-1.99(m,1H),1.96-1.81(m,2H),1.73-1.50(m,2H),1.41-1.28(m,1H).

[0510] Example 58 [ka]

[0511] To a solution of intermediate 1-3 (2.00 g, 6.43 mmol) in EtOH (12 mL), a solution of NaOAc (580.0 mg, 7.07 mmol) in H2O / HOAc (6 mL / 0.6 mL) was added. The reaction was stirred at 100 °C for 16 hours. Water (20 mL) was added to the cooled reaction mixture, and the mixture was extracted with siRNA (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-3.3% ethyl acetate in petroleum ether to obtain intermediate 52-1 (1.10 g, yield 58.9%) as a white solid.

[0512] 1 H NMR: (400MHz, CDCl3)δ=7.11(s,1H),6.98(s,1H),4.99(s,2H),3.88(s,3H),2.33(s,3H),2.16(s,3H).

[0513] To a solution of intermediate 52-1 (1.10 g, 3.79 mmol) in HCl (10 mL), HCl (5 mL, 1 N) was added. The reaction was stirred at 85°C for 2 hours. Water (20 mL) was added to the cooled reaction mixture, and the mixture was extracted with HCl (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with 0-20% ethyl acetate in petroleum ether to obtain intermediate 52-2 (700.0 mg, 2.82 mmol, yield 74.4%) as a white solid.

[0514] 1 H NMR: (400MHz, CDCl3)δ=7.12(s,1H),6.99(s,1H),4.63-4.52(m,2H),3.87(s,3H),3.23-3.12(m,1H),2.29(s,3H).

[0515] Example 59 [ka]

[0516] Compound 52 was synthesized by replacing intermediate 36-1 with intermediate 52-2, following the same procedure as for compound 36. In the final step, NaBH3CN was used instead, and the crude product was purified by preparative HPLC (column: Waters Xbridge C18 10 μm OBD 19*250 mm; mobile phase: 0.1% NH4HCO3 in water, 9.088 min) to obtain compound 52.

[0517] LC-MS(ESI+):m / z371.2(M+H) + .

[0518] 1 H NMR:(400MHz,DMSO-d6)δ=9.76(br.s,1H),7.25-7.16(m,2H),6.70-6.62(m,1H),5.16(s,2H),3.85-3.72(m,1H),2.58(s,3H), 2.44-2.40(m,1H),2.33-2.27(m,1H),2.25-2.19(m,2H),2.17(s,3H),1.65-1.61(m,1H),1.58-1.51(m,2H),1.49-1.47(m,1H).

[0519] Example 60 [ka]

[0520] To a solution of intermediate 28-3 (164 mg, 0.85 mmol) in toluene (4 mL), DDQ (386 mg, 1.70 mmol) was added at room temperature. The reaction was stirred at 110 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~22%) in petroleum ether to obtain intermediate 72-1 (64 mg, yield 40%) as a yellow solid.

[0521] 1H NMR (400MHz, DMSO-d6) δ = 10.51 (s, 1H), 7.81 (d, J = 2.0Hz, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 2.26 (s, 3H), 1.24 (s, 3H).

[0522] To a solution of intermediate 72-1 (85 mg, 0.45 mmol) and TEA (46 mg, 0.45 mmol) in DCM (2 mL), DMAP (11 mg, 0.09 mmol) and benzoyl chloride (83 mg, 0.59 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~10%) in petroleum ether to obtain intermediate 72-2 (75 mg, yield 56%) as a white solid. LC-MS(ESI+): m / z 295.2(M+H) + .

[0523] 1 H NMR (400MHz, CDCl3)δ=8.26-8.21(m,2H),7.73-7.65(m,1H),7.58-7.50(m,3H),7.31(s,1H),6.60(d,J=2.0Hz,1H),2.50(s,3H),2.44(s,3H).

[0524] To a solution of intermediate 72-2 (75 mg, 0.25 mmol) in DCM (3 mL), DIEA (39 mg, 0.30 mmol) and trimethylsilyl trifluoromethanesulfonate (67 mg, 0.30 mmol) were added at 0°C. After stirring at room temperature for 0.5 hours, NBS (53 mg, 0.30 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~7%) in petroleum ether to obtain crude intermediate 72-3 (65 mg) as a yellow oil, which was used directly in the next step.

[0525] To a solution of crude intermediate 72-3 (65 mg) and intermediate 66-14 (39 mg, 0.22 mmol) in EtOH (3 mL), HBr (38 mg, 0.23 mmol, 48 wt% in water) was added. After stirring at room temperature for 1 hour, the mixture was heated to 60°C and stirred for a further 16 hours. The solvent was removed under vacuum, and the mixture was diluted with siRNA. NH4OH was added to the mixture to pH=10 at 0°C. Then, H2O (10 mL) was added to the mixture and extracted with siRNA (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain intermediate 72-4 (18 mg, 16% yield in 2 steps) as a yellow solid. LC-MS(ESI+):m / z450.1(M+H) + .

[0526] To a solution of intermediate 72-4 (18 mg, 0.04 mmol) in MeOH (1 mL), K2CO3 (28 mg, 0.20 mmol) was added. The reaction was stirred at 50°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was purified by preparative HPLC (Waters 3767 / QDA) column (SunFire C18, 19*250 mm; 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 12-22%; retention time: 8.4-9.2 mins of 17 minutes) to obtain compound 72. LC-MS (ESI+): m / z 345.9 (M+H) + . 1 H NMR(400MHz,CD3CN)δ=7.64-7.58(m,1H),6.99(s,1H),6.92-6.86(m,1H),4.11 -4.04(m,1H),3.60(s,2H),2.55-2.45(m,5H),2.08-2.03(m,2H),1.32(s,3H).

[0527] Example 61 [ka]

[0528] A solution of compound 201-1 (1.00 g, 3.16 mmol), Pd(OAc)2 (142.0 mg, 0.63 mmol), tert-butylcarbazate (627.0 mg, 4.74 mmol), and K2CO3 (874.0 mg, 6.32 mmol) in dry DMF (10 mL) was stirred at 90°C for 16 hours under CO atmosphere. Water (30 mL) was added to the cooled reaction mixture, and the mixture was extracted with siRNA (30 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried on Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~8%) in petroleum ether to obtain intermediate 201-2 (0.88 g, yield 79.9%) as a white solid.

[0529] 1 H NMR (400MHz, CDCl3) δ=7.62(s,1H),7.11(s,1H),6.97(s,1H),6.70(s,1H),3.87(s,3H),2.46(s,3H),1.46(s,9H). A solution of intermediate 201-2 (0.83 g, 2.38 mmol) and Lawson's reagent (964.0 mg, 2.38 mmol) in dioxane (5 mL) was stirred at 85°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0%~20%) in petroleum ether to obtain intermediate 201-3 (0.50 g, yield 57.7%) as a yellow oil.

[0530] LC-MS(ESI+): m / z 309.0 (M+H-56) + .

[0531] To a solution of intermediate 201-3 (0.50 g, 1.37 mmol) in DMF (5 mL), methyl bromoacetate (0.14 mL, 1.51 mmol) and TEA (0.23 mL, 1.64 mmol) were added. The mixture was stirred at 65°C for 3 hours. Water (20 mL) was added to the cooled reaction mixture, and the mixture was extracted with RINKAN (20 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried on Na₂SO₄, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel eluted with ethyl acetate (0%~25%) in petroleum ether to obtain intermediate 201-4 (200.8 mg, yield 33.6%) as a yellow oil.

[0532] LC-MS(ESI+):m / z381.0(M+H-56) + .

[0533] To a solution of intermediate 201-4 (0.20 g, 0.46 mmol) in DCM (5 mL), TFA (1 mL) was added. The reaction was stirred at room temperature for 30 minutes. The mixture was evaporated to obtain the crude product, which was diluted with water (10 mL), and the pH of the mixture was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain intermediate 201-5 (139.0 mg, yield 99.3%) as a yellow solid, which was used in the next step without further workup.

[0534] LC-MS(ESI+):m / z305.0(M+H) +

[0535] 1 H NMR (400MHz, CDCl3) δ = 8.80 (s, 1H), 7.13 (s, 1H), 6.99 (s, 1H), 3.89 (s, 3H), 3.58 (s, 2H), 2.37 (s, 3H).

[0536] To a solution of intermediate 201-5 (149.1 mg, 0.49 mmol) in dioxane (2 mL), Lawson's reagent (206.3 mg, 0.51 mmol) was added. The reaction was stirred at 65°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (PE / siRNA=5 / 1) to obtain intermediate 201-6 (85.0 mg, yield 54.2%) as a yellow solid.

[0537] LC-MS(ESI+):m / z321.0(M+H) + .

[0538] To a solution of intermediate 201-6 (85.0 mg, 0.27 mmol) in THF (5 mL) / water (2.5 mL), K2CO3 (92.0 mg, 0.67 mmol) and iodomethane (98.0 mg, 0.69 mmol) were added at 0°C. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture and extracted with siRNA (10 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by preparative TLC (PE / siRNA = 5 / 1) to obtain intermediate 201-7 (72.0 mg, 0.22 mmol, yield 79.8%) as a yellow solid.

[0539] LC-MS(ESI+): m / z 335.0(M+H) + .

[0540] To a solution of intermediate 201-7 (69.0 mg, 0.21 mmol) in EtOH (1 mL), (1s,3s)-3-amino-1-methylcyclobutan-1-ol hydrochloride (85.0 mg, 0.63 mmol) and TEA (0.09 mL, 0.63 mmol) were added. The mixture was stirred at room temperature for 30 minutes, then at 60°C for 16 hours. Water (15 mL) was added to the cooled reaction mixture, and the mixture was extracted with ELISA (15 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was recrystallized from diethyl ether (10 mL) to obtain intermediate 201-8 (50.0 mg, yield 61.5%) as a white solid.

[0541] LC-MS(ESI+):m / z388.1(M+H) + .

[0542] To a solution of intermediate 201-8 (45.0 mg, 0.12 mmol) in DCM (2 mL), tribromoborane (0.36 mL, 0.36 mmol, 1 M in DCM) was added at -78°C. The reaction was stirred at -78°C for 3 hours. The reaction was quenched with MeOH at -78°C, and the mixture was then concentrated under reduced pressure at room temperature to obtain the crude product. This was purified by preparative HPLC (column: C18 OBD 10 μm 19*250 mm; mobile phase: [0.1% FA-ACN in water]; B%: 5%~10% ACN, 8.7 min) to obtain compound 201.

[0543] LC-MS(ESI+):m / z374.1(M+H) +

[0544] 1 H NMR(400MHz,DMSO-d6)δ=7.32-7.10(m,1H),7.06(s,1H),6.99(s,1H),4.99(br.s,1H),4.02 -3.90(m,1H),3.15(s,2H),2.39-2.30(m,2H),2.27(s,3H),2.04-1.92(m,2H),1.26(s,3H).

[0545] By substituting appropriate starting materials, reagents, and reaction conditions, the following compounds were prepared using a synthesis method similar to that described for compound 201. [Table 7]

[0546] Example B-1: NLRP3 Inflammasome Assay

[0547] [Table 8]

[0548] Assay procedure

[0549] 1) IC 50 Compound dilution for the test: Starting at 100 μM, a 3-fold dilution was performed. Next, 11 doses were distributed at a 1% DMSO concentration. 9 μL of the compound (10 mM stock from the compound management team) was added to a 384 LDV plate. Echo was used for dilution, the compound was transferred, and the plate was assayed at 100 μM (the highest concentration in 1% DMSO, 1.25 μL).

[0550] 2) Radioactive ligand dilution: The working concentration was 25 nM [3H]-MCC950. 1 μL of [3H]-MCC950 (23 μM stock) was added to 919 μL of assay buffer.

[0551] 3) Prepare 100 μl of insect cell lysate and transfer it to a 96-well assay plate. Final concentration: 15 μg / well for IC50 test.

[0552] 4) Transfer 25 μL of diluted ligand to the assay plate.

[0553] 5) Cover the assay plate with foil tape and incubate at room temperature for 1.5 hours with gentle shaking.

[0554] 6) Filter the wells of the assay plate through the wells of the GF / B filter plate using a Packard Harvester. Wash eight times with cold wash buffer (4°C, 0.4 mL per well per wash).

[0555] 7) Place the filter plate in a 50°C oven for 0.5 hours.

[0556] 8) Seal the bottom of the dry filter plate with backing tape. Dispense 50 μL of Microscint-20 into each well of the filter plate, and cover the GF / B plate with TopSeal-A.

[0557] 9) Microbeta was used to count the signals.

[0558] 10) Microbeta settings: The counting time was 30 seconds per well.

[0559] Example B-2: NLRP3 inflammasome activation assay for human monocytes

[0560] Day 1: Human monocytes were isolated from PBMCs. Monocytes are isolated from PBMCs using a human panmonocyte isolation kit and an LS column. The monocytes are resuspended in RPMI 1640 medium, the cells are counted, and then seeded into a 96-well plate and incubated overnight at 37°C and 5% CO2. Day 2: Stimulate cells with LPS and ATP 1. Remove the culture medium and pre-treat the monocytes by adding different concentrations of the compound or DMSO as a control to the corresponding wells, then incubate at 37°C and 5% CO2. Dilute the compound and DMSO with serum-free RPMI 1640 medium. 2. Add serum-free RPMI 1640 medium containing LPS to all wells, then incubate the cells at 37°C and 5% CO2 for a period of time. 3. At the end of incubation, remove the cells from the negative control well and stimulate the cells with ATP for a short period. Transfer the supernatant to a new plate and store at -80°C. Day 3: Run ELISA. Run Elisa according to the BD Biosciences instructions.

[0561] Example B-3: IL-1β-releasing THP-1 assay

[0562] THP-1 cells were cultured in RPMI1640 medium, 10% FBS, 1% PS, and 55 μM β-Mer at 37°C in a 5% CO2 incubator.

[0563] IL-1β release detection

[0564] 1) Seed THP-1 in complete RPMI 1640 medium containing PMA into a 96-well plate coated with poly-L-lysine and incubate for 24 hours.

[0565] 2) Remove the culture medium, wash the differentiated THP-1 cells with PBS, and add RPMI 1640 medium without FBS.

[0566] 3) Add LPS and incubate for 3 hours in an incubator at 37°C and 5% CO2.

[0567] 4) Add the compound and incubate in an incubator at 37°C and 5% CO2 for 30 minutes.

[0568] 5) Add nigericin and incubate in a 37°C, 5% CO2 incubator for 1 hour.

[0569] 6) Collect the supernatant and test for IL-1β by ELISA.

[0570] Data Analysis

[0571] a) Assay robustness check using DMSO and low-control data:

[0572] H=average(DMSO)

[0573] L=average (low control)

[0574] SD(H) = STDEV(DMSO)

[0575] SD(L) = STDEV (low control)

[0576] CV%(H)=100*(SD_H / Average_H)

[0577] CV%(L)=100*SD_L / Average_L

[0578] Z'=1-3*(SD_H+SD_L) / (Average_H-Average_L)

[0579] Change % = Sample / Mean_L * 100

[0580] b) Fit the cpd IC50 to the nonlinear regression equation:

[0581] Y = Minimum + (Maximum - Minimum) / (1 + 10^((LogIC50 - X) * Hill Slope))

[0582] X:cpd concentration

[0583] Y: Change %

[0584] Highest and lowest: Plateaus in the same units as Y

[0585] logIC50: Same logarithmic units as X

[0586] Hill slope: Slope coefficient or hill slope

[0587] THP-1 IL-1βIC for selected compounds 50 The data is shown in Table 3.

[0588] Example B-4: NLRP3 Enzyme Activity ADP-Glo ​​Assay

[0589] An NLRP3 activity assay was performed using the ADP-Glo ​​assay to measure the hydrolysis of NLRP3 to the substrate ATP. First, an inhibitor containing 0.5% DMSO was added using Echo, followed by the addition of 5 μL of NLRP3 (ICE, YM2306T-H06MHS) enzyme solution to each well. The mixture was centrifuged at 1000 rpm for 1 minute at room temperature and allowed to react for 10 minutes. Next, 5 μL of ATP (Promega, V915A) substrate solution was added to each well at room temperature for 90 minutes. NLRP3 and ATP were prepared at final concentrations of 15 nM and 1 μM, respectively, in 50 mM HEPES, 10 mM MgCl2, 0.01% Brij-35, 1 mM EGTA, and 2 mM DTT buffer. Subsequently, 10 μL of ADP-Glo ​​reagent solution (Promega, V9102) was added to each assay well, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 45 minutes. Finally, 20 μL of ADP-Glo ​​detection solution (Promega, V9102) was added to each well, centrifuged at 1000 rpm for 1 minute, and allowed to react at room temperature for 45 minutes. The luminescence signal values ​​were read using a BMG instrument, and the IC50 values ​​were determined by fitting the data to an S-shaped dose-response curve using nonlinear regression. The enzyme ADP-Glo ​​assay data for the selected compounds are shown in Table 3.

[0590] Example B-5: hERG screening assay using electrophysiological manual patch clamp

[0591] Cell line: hERG-CHO cells

[0592] Methods: CHO cells stably expressing hERG transcripts were investigated using whole-cell manual patch-clamp technique. hERG-CHO cells were cultured in 35 mm dishes at 37°C in a 5% CO2 incubator until confluence reached a maximum of 70–80%. The culture medium (F12 medium (Invitrogen 11765062, ThermoFisher, USA) supplemented with 10% fetal bovine serum (Invitrogen 10099141, ThermoFisher, USA), 100 ug / mL G418 (Invitrogen 11811023, ThermoFisher, USA), and 100 ug / mL hygromycin B (Invitrogen 10687010, ThermoFisher, USA)) was removed, and the hERG-CHO cells were washed with an extracellular solution (in mM): 140 NaCl, 5 KCl, 1 CaCl2, 1.25 MgCl2, 10 HEPES, and 10 glucose, adjusted to pH 7.4 with NaOH. Next, the cells were dissociated with 0.25% trypsin-EDTA for 3–5 minutes, then the digestion solution was removed, and the cells were resuspended in extracellular solution by pipetting several times up and down with a pipette. The resuspended cells were transferred to a recording dish and perfused with extracellular solution. An electrode (3–5 megaohm tip resistance) was withdrawn from a borosilicate glass pipette (Sutter instrument BF150-86-10) and filled with intracellular solution (at mM): 140 KCl, 1 MgCl2, 1 CaCl2, 10 EGTA, and 10 HEPES, KOH, pH 7.2. Data was obtained using a patch-clamp amplifier, the signal was filtered at 2 kHz, and sampled at a frequency of 10 kHz using pClamp 10 software. The cells were held at -100mV, and the hERG potassium current was activated for 2 seconds with a depolarization potential of +20mV, followed by 1 second with a repolarization potential of -50mV, and then returned to the holding potential. The experiment was performed at room temperature.

[0593] Data Analysis: Data was searched and analyzed using pClamp 10, GraphPad Prism 8, and Excel software. The peak amplitude of the hERG current was measured using clamp fitting and exported to Excel and GraphPad Prism 8 for further analysis. The concentration of the compound that resulted in a 50% current cutoff (IC) was also measured. 50 This was obtained by applying the normalized concentration-inhibition relationship to the formula in the Prism 8 software, as follows: Y=lowest+(highest-lowest) / (1+10^(LogIC 50 -X)*Hill Slope)) In the formula, Y is the inhibition percentage corresponding to X, [X] is the logarithm of the concentration of the compound in the external solution, and Hill slope is the Hill coefficient. The inhibition rate was calculated using the following formula: Inhibition = (1 - I / Io) * 100%, where Io and I are the current amplitudes measured in the presence of the control and the compound, respectively. n is 2 or more cells for each concentration.

[0594] Results: hERG and compound IC on concentration-reaction curves 50

[0595] Table 4 shows the hERG inhibition data for the selected compounds. Table 3. Enzyme activity ADP-Glo ​​assay IC 50 (nM):0 <A≦10;10<B≦100;100<C≦1000;1000<D。 THP-1 IL-1βIC 50 (nM):0 <A≦10;10<B≦100;100<C≦1000;1000<D。 [Table 9] [Table 10]

[0596] The examples and embodiments described herein are for illustrative purposes only, and it will be understood that various modifications or changes in light thereof will be suggested to those skilled in the art and will be included in the spirit and scope of this application and the appended claims. All publications, patents and patent applications referenced herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. A compound having the structure of formula (A) or formula (B), or a pharmaceutically acceptable salt or stereoisomer thereof: 【Chemistry 1】 During the ceremony, Y is C ３ to C ８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６ to C １０ aryl, or 5- to 9-membered heteroaryl, and the C ３ to C ８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６ to C １０ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ６ and X is NR Ｘ -O-, -S-, -S(O)-, or -S(O) ２ - and R Ｘ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C ３ ~C ６ The alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R ｅ They are optionally substituted with 1 to 4 substituents independently selected from the above, Each R １Ａ and R １Ｂ These are independently hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, or C １ ~C ６ It is an aminoalkyl, or R １Ａ and R １Ｂ They come together to form an oxo, or R １Ａ and R １Ｂ Together, C ３ ~C ８ They form cycloalkyl or 4- to 8-membered heterocycloalkyl groups, each of which has one or more R １１ It is arbitrarily replaced with, Each R １１ These are, independently, halogen, -OH, -CN, and -NO ２ , -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ６ It is a cycloalkyl or a 4-6 member heterocycloalkyl, R ３ It is phenyl, 5-12 member heteroaryl, C ３ ~C １２ Cycloalkyl, 4-12 member heterocycloalkyl, or C １ ~C ６ They are alkyl groups, and each of them has one or more R ８ It is arbitrarily replaced with, Each R ８ is, independently, halogen, -OH, -CN, -NO ２ , -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , SF ５ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O)(=NR ｂ )R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ , -NR ｃ C(=O)NR ｄ R ｂ , -NR ａ C(=O)R ｂ , -NR ｂ C(=O)OR ｂ , -NR ２ S(=O) ａ R ｃ , -N=S(=O)R ｄ R ｃ , -P(=O)R ｄ R ａ , -C(=O)R ｂ , -C(=O)OR ｃ , -C(=O)NR ｄ R １ , C ６ ~C １ ~C ６ haloalkyl, C １ ~C ６ hydroxyalkyl, C １ ~C ６ heteroalkyl, C １ ~C ６ aminoalkyl, C ３ ~C ６ cycloalkyl, C ６ ~C １０ The alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, aryl, or heterocycloalkyl is R ｅ They are optionally substituted with 1 to 4 substituents that are selected more independently. R ＺＮ is hydrogen, C １ ~C ６ Alkyl or C １ ~C ６ It is a haloalkyl, or R Ｘ and R ＺＮ These, together with the atoms to which they are bonded, form a 5-8 member heterocycloalkyl group, and this heterocycloalkyl group contains one or more R １３ It is arbitrarily replaced with, or R ３ and R ＺＮ These, together with the atoms to which they are bonded, form a 5- to 13-membered heterocycloalkyl group, and this heterocycloalkyl group contains one or more R １３ It is arbitrarily replaced with, Each R １３ These are, independently, halogen, -OH, -CN, and -NO ２ , -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, or C １ ~C ６ It is an aminoalkyl, Each R ６ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -SH, -SR ａ , -SF ５ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, or C ３ ~C ８ It is a cycloalkyl, and each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, or cycloalkyl is R ｅ 1 to 4 substituents are arbitrarily selected, which are more independently selected. or two R ６ These, together with the atoms to which they are bonded, form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups, each of which consists of one or more R １２ It is arbitrarily replaced with, Each R １２ These are, independently, halogen, -OH, -CN, and -NO ２ , -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ６ It is a cycloalkyl or a 4-6 member heterocycloalkyl, Each R ａ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R ｅ 1 to 4 substituents are arbitrarily selected, which are more independently selected. Each R ｂ These are, independently, hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R ｅ 1 to 4 substituents are arbitrarily selected, which are more independently selected. R ｃ and R ｄ These are, independently, hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R ｅ One to four substituents are arbitrarily selected, which are more independently selected. or R ｃ and R ｄ These, together with the atoms to which they are bonded, form a heterocycloalkyl group, and the heterocycloalkyl group is R ｅ They are optionally substituted with 1 to 4 substituents independently selected from the above, Each R ｅ These are, independently, halogen, oxo, -CN, -OH, and -S(=O)CH ３ , -S (=O) ２ CH ３ , -S (=O) ２ NH ２ , -S (=O) ２ NHCH ３ , -S (=O) ２ N(CH ３ ) ２ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, or C ３ ~C ６ It is a cycloalkyl, A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A compound having the structure of formula (I) or formula (V), or a pharmaceutically acceptable salt or stereoisomer thereof: 【Chemistry 2】 During the ceremony, X is NR Ｘ -O-, -S-, -S(O)-, or -S(O) ２ - and R Ｘ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C ３ ~C ６ The alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R ｅ They are optionally substituted with 1 to 4 substituents independently selected from the above, Each R １Ａ and R １Ｂ These are independently hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, or C １ ~C ６ It is an aminoalkyl, or R １Ａ and R １Ｂ Together, C ３ ~C ８ They form cycloalkyl or 4- to 8-membered heterocycloalkyl groups, each of which has one or more R １１ It is arbitrarily replaced with, Each R １１ These are, independently, halogen, -OH, -CN, and -NO ２ , -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ６ It is a cycloalkyl or a 4-6 member heterocycloalkyl, or R １Ａ and R １Ｂ They come together to form an oxo, R ３ It is phenyl, 5-12 member heteroaryl, C ３ ~C １２ Cycloalkyl, 4-12 member heterocycloalkyl, or C １ ~C ６ Alkyl, and each of these has one or more R ８ It is arbitrarily replaced with, Each R ８ These are, independently, halogen, -OH, -CN, and -NO ２ , -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ -SH, -SR ａ SF ５ , -S(=O)R ａ , -S (=O) ２ R ａ , -S(=O)(=NR ｂ ) R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)R ｃ R ｄ , -P(=O)R ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Aminoalkyl, C ３ ~C ６ The alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is R ｅ They are optionally substituted with 1 to 4 substituents that are selected more independently. R ＺＮ is hydrogen, C １ ~C ６ Alkyl or C １ ~C ６ It is a haloalkyl, or R Ｘ and R ＺＮ These, together with the atoms to which they are bonded, form one or more R １３ They form a 4-8 member ring which is arbitrarily substituted, Each R １３ These are, independently, halogen, -OH, -CN, and -NO ２ , -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, or C １ ~C ６ It is an aminoalkyl, R ６Ａ is -OH, -OCF ２ H, -CF ２ H, or -CF ３ And, Each R ６ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -SH, -SR ａ , -SF ５ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, or C ３ ~C ８ It is a cycloalkyl, and each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, or cycloalkyl is R ｅ 1 to 4 substituents are arbitrarily selected, which are more independently selected. or two R ６ These, together with the atoms to which they are bonded, form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups, each of which consists of one or more R １２ It is arbitrarily replaced with, Each R １２ These are, independently, halogen, -OH, -CN, and -NO ２ , -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ６ It is a cycloalkyl or a 4-6 member heterocycloalkyl, Each R ａ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R ｅ 1 to 4 substituents are arbitrarily selected, which are more independently selected. Each R ｂ These are, independently, hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R ｅ 1 to 4 substituents are arbitrarily selected, which are more independently selected. R ｃ and R ｄ These are, independently, hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is R ｅ 1 to 4 substituents are arbitrarily selected, which are more independently selected. or R ｃ and R ｄ These, together with the atoms to which they are bonded, form a heterocycloalkyl group, and the heterocycloalkyl group is R ｅ They are optionally substituted with 1 to 4 substituents independently selected from the above, Each R ｅ These are, independently, halogen, oxo, -CN, -OH, and -S(=O)CH ３ , -S (=O) ２ CH ３ , -S (=O) ２ NH ２ , -S (=O) ２ NHCH ３ , -S (=O) ２ N(CH ３ ) ２ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, or C ３ ~C ６ It is a cycloalkyl, p is 1, 2, 3, or 4. However, the aforementioned compound is 【Transformation 3】 isn't it, A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. R ６Ａ A compound according to claim 1 or 2, wherein the hydroxyl group is -OH, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. R ６Ａ ga-CF ２ H or -CF ３ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. R ６Ａ ga-OCF ２ A compound according to claim 1 or 2, wherein H is present, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. R ３ However, it is a 4- to 12-membered heterocycloalkyl, and the heterocycloalkyl is one or more R ８ A compound according to any one of claims 1 to 5, optionally substituted with, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. R ３ but, 【Chemistry 4】 The compound according to claim 6, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. R ３ However, one or more R ８ C arbitrarily replaced by ３ ~C １２ A compound according to any one of claims 1 to 5, which is a cycloalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. R ３ but, 【Transformation 5】 The compound according to claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. Each R ６ However, independently, halogen, -CN, -NO ２ , -OH, -C(=O)R ａ , -OR ａ -SH, -SR ａ , -SF ５ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C ３ ~C ８ A compound according to any one of claims 1 to 9, which is a cycloalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

11. Each R ６ However, independently, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, or C １ ~C ６ A compound according to claim 10, which is a hydroxyalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

12. Each R ６ However, independently of methyl or CF ３ The compound according to claim 10 or 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

13. Two R's ６ These combine to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which contains one or more R １２ A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted by.

14. Two R's ６ These combine to form a cycloalkyl or heterocycloalkyl group, each of which has one or more R １２ The compound according to claim 13, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted by. 【Request Item 15】 【Chemistry 6】 but 【Transformation 7】 The compound according to claim 14, or a pharmaceutically acceptable salt or stereoisomer thereof.

16. R １Ａ However, hydrogen, halogen, or C １ ~C ６ A compound according to any one of claims 1 to 15, which is alkyl (e.g., methyl), or a pharmaceutically acceptable salt or stereoisomer thereof.

17. R １Ｂ The compound according to any one of claims 1 to 16, wherein the compound is hydrogen or methyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. R １Ａ and R １Ｂ Together, C ３ ~C ８ A compound according to any one of claims 1 to 17 that forms a cycloalkyl group, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. R １Ａ and R １Ｂ A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compounds combine to form an oxo.

20. R Ｘ and R ＺＮ However, together with the atoms to which they are bonded, one or more R １３ A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or stereoisomer thereof, which forms a 5- to 8-membered ring that is optionally substituted.

21. R ＺＮ A compound according to any one of claims 1 to 20, wherein the compound is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

22. X is -S-, -S(O)-, or -S(O) ２ - The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof.

23. The compound according to claim 22, wherein X is -S-, or a pharmaceutically acceptable salt or stereoisomer thereof.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound from Table 1 or Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

25. Compounds having the structure of formula (III), (IIIa), or (VIa) as described herein, or pharmaceutically acceptable salts or stereoisomers thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

27. A method for modulating or inhibiting NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome activity in a subject, comprising administering to the subject a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 26.

28. A method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 26.

29. The method according to claim 28, wherein the disease or disorder is an autoimmune or autoinflammatory disease, or the disease or disorder is obesity.

30. A method for reducing the weight of a subject who needs to lose weight, comprising administering to the subject a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 26.

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