Novel compounds as modulators of sodium channels and uses thereof

Abstract

Sodium channel inhibitors and pharmaceutical compositions comprising the inhibitors are described herein. The subject compounds and compositions are useful for the treatment of diseases or disorders, including pain.

Description

[0001] Invention Field

[0002] This disclosure relates to novel compounds or pharmaceutically acceptable salts thereof used as sodium channel modulators. This disclosure also relates to pharmaceutical compositions comprising one or more such compounds or pharmaceutically acceptable salts thereof as active ingredients, and further to the use of such compounds or pharmaceutically acceptable salts thereof in the treatment of diseases or disorders (e.g., pain).

[0003] background

[0004] Pain is a protective mechanism that enables healthy animals to avoid tissue damage and prevent further damage to already damaged tissue. However, in many cases, pain persists beyond its usefulness, or patients benefit from pain suppression. Neuropathic pain is a type of chronic pain caused by damage to sensory nerves (Dieleman, JP et al.). Pain, 2008. 137(3): p. 681-8).

[0005] Voltage-gated sodium channel (Na V s) participates in pain signal transduction. Na V s are biological mediators of electrical signals because they mediate the rapid rise in action potentials in many excitable cell types, such as neurons, skeletal muscle cells, and cardiomyocytes. Due to Na... V S plays a role in the initiation and propagation of neuronal signals, so reducing Na... V Current antagonists can block or reduce nerve signal transmission, and Na V The channel is considered a potential target for pain relief in cases of observed overexcitation. Several clinically useful analgesics have been identified as Na+ channels. V Inhibitors of the channel.

[0006] Therefore, there remains an unmet need for novel compounds that can function as sodium channel regulators. Invention Overview

[0008] In one aspect, this disclosure provides compounds of formula (A) as disclosed herein, or pharmaceutically acceptable salts thereof:

[0009] Formula (A).

[0010] In some embodiments of the compound of formula (A) or a pharmaceutically acceptable salt thereof, said compound has formula (I) as disclosed herein:

[0011] Formula (I).

[0012] In some embodiments of the compound of formula (A) or a pharmaceutically acceptable salt thereof, said compound has formula (B) as disclosed herein:

[0013] Formula (B).

[0014] This document also discloses pharmaceutical compositions comprising the compounds disclosed herein (e.g., compounds of formula (A), (I), or (B), or compounds listed in Tables 1, 2, 3, 4, or 5) or their pharmaceutically acceptable salts or stereoisomers, and pharmaceutically acceptable excipients.

[0015] This document also discloses a method for inhibiting voltage-gated sodium channels in an individual, the method comprising administering to the individual a compound disclosed herein (e.g., a compound of formula (A), (I), or (B), or a compound listed in Tables 1, 2, 3, 4, or 5) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0016] This document also discloses the use of the compounds disclosed herein (e.g., compounds of formula (A), (I) or (B), or compounds listed in Tables 1, 2, 3, 4 or 5) or pharmaceutically acceptable salts or stereoisomers thereof, or pharmaceutical compositions disclosed herein, in the preparation of a medicament for inhibiting voltage-gated sodium channels in an individual.

[0017] This document also discloses the use of the compounds disclosed herein (e.g., compounds of formula (A), (I) or (B), or compounds listed in Tables 1, 2, 3, 4 or 5) or pharmaceutically acceptable salts or stereoisomers thereof, or pharmaceutical compositions disclosed herein, in the preparation of a medicament for treating a disease or disorder in an individual in need.

[0018] In some implementations, the voltage-gated sodium channel is Na V 1.8. In some embodiments, the disease or disorder is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia.

[0019] By incorporating via reference

[0020] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically given by reference. Invention Details

[0022] definition

[0023] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures are not given or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout the specification and the following claims, the words “comprising,” “including,” and variations thereof should be interpreted in an open-ended, inclusive sense, i.e., “including but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0024] References to “some embodiments” or “implementation” in this specification mean that a particular feature, structure, or characteristic associated with that embodiment is included in at least one embodiment. Therefore, the phrases “in one embodiment” or “in an embodiment” appearing throughout this specification do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Additionally, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include the plural referent, unless the content clearly indicates otherwise. It should also be noted that the terms “or” or “or” are generally used to include the meaning of “and / or”, unless the content clearly indicates otherwise.

[0025] Unless otherwise stated, the following terms used herein have the following meanings.

[0026] Specific functional groups and chemical terms are defined in more detail below. For the purposes of this disclosure, chemical elements are determined according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally defined as they are defined herein. Furthermore, general principles of organic chemistry, as well as descriptions of specific functional groups and reactivity, are found in the following references: Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of these references are incorporated herein by reference.

[0027] Linking substituents are described in various locations within this disclosure. If the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl,” then “alkyl” should be understood to represent an alkylene linking group.

[0028] When the bond attached to a substituent is shown to intersect with the bonds of two atoms within the ring, then such a substituent can bond to any atom in the ring. When a substituent is listed without specifying which atom it bonds to the rest of the compound in the given structure, then such a substituent can bond to any atom in the structure. Combinations of multiple substituents and / or multiple variables are permitted, provided that such combinations produce a stable compound.

[0029] When any variable (e.g., R) i When a group appears more than once in any composition or structural formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Therefore, for example, if a group is shown as being surrounded by 0-2 R... iSubstitution allows the group to be optionally replaced by up to two R groups. i Replace, and R i Each time it appears, it is independently selected from R. i The definition of [the compound]. Similarly, combinations of multiple substituents and / or multiple variables are permitted, provided that such combinations produce stable compounds.

[0030] As used in this article, the term "C" i -C j "C" represents a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C1-C6 represents 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some implementations, the term "C" is used to indicate the number of carbon atoms. 1-12 "Indicates 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3, or especially 1 to 2 carbon atoms.

[0031] "Oxytochemical" refers to the compound oxygen (O).

[0032] "Cyano" refers to -CN.

[0033] Whether used as part of another term or alone, "amino" refers to -NR a R b , where R a and R b The group is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclic or other suitable organic groups, and each of them may optionally be substituted.

[0034] Whether used as part of another term or alone, "hydroxyl" refers to -OH.

[0035] Whether used as part of another term or alone, "alkyl" refers to a saturated monovalent hydrocarbon group having one to about ten, more preferably one to six, carbon atoms in a straight or branched chain. 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears herein, numerical ranges such as “C1-C6 alkyl” or “C1-6 alkyl” mean that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term “alkyl” without a specified numerical range. In some embodiments, alkyl is C1- 10 Alkyl group. In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C1-5 alkyl. In some embodiments, the alkyl group is C1-4 alkyl. In some embodiments, the alkyl group is C1-3 alkyl. Unless otherwise expressly stated in this specification, the alkyl group may optionally be substituted, for example, optionally substituted by one or more substituents, such as oxo, halogen, amino, cyano, nitro, hydroxy, haloalkyl, alkoxy, carboxylate, aryl, cycloalkyl, heterocyclic, heteroaryl, etc. In some embodiments, the alkyl group is optionally substituted by one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted by one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted by a halogen.

[0036] Whether used as part of another term or alone, "alkenyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group can be in the cis or trans configuration of the double bond or... E or ZConfiguration, and should be understood to include two isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this document, the numerical range is as in "C2-C6 alkenyl" or "C 2-6 "Alkenyl" means that an alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term "alkenyl" without a specified numerical range. Unless otherwise expressly stated in this specification, the alkenyl group may optionally be substituted, for example, by one or more substituents, such as oxo, halogen, amino, cyano, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxyl ester, aryl, cycloalkyl, heterocyclic, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted by one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with a halogen.

[0037] Whether used as part of another term or alone, "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having 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, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges are used such as "C2-C6 alkynyl" or "C 2-6 "Alynyl" means that an alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term "alkynyl" without a specified numerical range. Unless otherwise expressly stated in this specification, the alkynyl group may optionally be substituted, for example, by one or more substituents, such as oxo, halogen, amino, cyano, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxyl ester, aryl, cycloalkyl, heterocyclic, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted by one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0038] Whether used as part of another term or alone, "alkoxy" refers to the formula -ORa The group, wherein R a It is an alkyl group as defined. Whenever it appears herein, the numerical range is such as "C1-C6 alkoxy" or "C 1-6 "Alkoxy" means that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the use of the term "alkoxy" without a specified numerical range. In some embodiments, the alkoxy group is C1- 10 Alkoxy group. In some embodiments, the alkoxy group is C1-6 alkoxy. In some embodiments, the alkoxy group is C1-5 alkoxy. In some embodiments, the alkoxy group is C1-4 alkoxy. In some embodiments, the alkoxy group is C1-3 alkoxy. In some embodiments, the alkoxy group is C1-2 alkoxy. In some embodiments, the alkoxy group is methoxy. Unless otherwise expressly stated in this specification, the alkoxy group may optionally be substituted, for example, substituted with oxo, halogen, amino, cyano, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0039] Whether used as part of another term or alone, "aryl" refers to a group derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) ring systems. Polycyclic ring systems can include fused ring systems (e.g., aryl rings fused to cycloalkyl groups), bridged ring systems (e.g., aryl rings fused to bridged cycloalkyl rings), or spirocyclic ring systems (e.g., aryl rings fused to spirocycloalkyl rings). In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl) group. Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, azurite, benzene, arsenic, fluorene, as-indacene, s-indacene, indene, indene, naphthalene, phenalene, pleiadene, pyrene, and triphenylene[9,10]. Unless otherwise expressly stated in this specification, aryl groups may optionally be substituted, for example, by one or more substituents, such as halogens, amino groups, cyano groups, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid ester groups, aryl groups, cycloalkyl groups, heterocyclic groups, heteroaryl groups, etc. In some embodiments, aryl groups are optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the aryl group is optionally substituted with one or more substituents, such as halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen.

[0040] As used herein, for multicyclic (including but not limited to bicyclic, tricyclic, or tetracyclic) systems, the term "fusion" refers to two rings sharing two adjacent ring atoms. Examples include, but are not limited to, […]. , , , Etc. Whenever it appears herein, numerical ranges such as “5-6 fusion” refer to fused groups consisting of 5-membered and 6-membered rings fused together, although this definition also covers the occurrence of the term “fusion” without specifying a numerical range. For example It is a 5-5 fused group, and It consists of 5-6 fused groups.

[0041] As used herein, for multicyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) systems, the term "spiral" refers to two rings sharing a single ring atom. Examples include, but are not limited to, those mentioned above. , , Etc. Whenever it appears herein, numerical ranges such as “5-6 spiro” refer to spirocyclic groups consisting of 5-membered and 6-membered rings spirotropically interlocked, although this definition also covers the occurrence of the term “spiro” without a specified numerical range. For example It is a 3-6 spirocyclic group.

[0042] As used herein, for multi-ring (including, but not limited to, bicyclic, tricyclic, or tetracyclic) systems, the term "bridging" refers to two rings that share two non-adjacent ring atoms and one or more ring atoms between them. Examples include, but are not limited to, those shown below. , , wait.

[0043] In some embodiments, a polycyclic system having three or more rings (e.g., a tricyclic system) may comprise a first ring fused to a second ring and a third ring fused to the first ring, which refers to the “fused-fused” groups herein. Examples include, but are not limited to, those mentioned above. , , In other embodiments, a polycyclic system having three or more rings (e.g., a tricyclic system) may comprise a first ring fused to a second ring and a third ring spirofused to the first ring, which refers to the “fused-spiro” group herein. Examples include, but are not limited to, those mentioned above. , , In other embodiments, a polycyclic system having three or more rings (e.g., a tricyclic system) may comprise a first ring fused to a second ring and a third ring fused to the first ring, which refers to the “spiro-spiro” group herein. Examples include, but are not limited to, those mentioned above. , , wait.

[0044] Whether used as part of another term or alone, "cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbon ring, which may include fused ring systems (e.g., fused with another cycloalkyl ring), spirocyclic ring systems, or bridged ring systems. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having 3 to 15 carbon atoms (C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), cycloalkyl groups having 3 to 10 carbon atoms (C3-C4) 10 Fully saturated cycloalkyl or C3-C 10The cycloalkyl group comprises, for example, cycloalkyl (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkyl), cycloalkyl (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkyl), cycloalkyl (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkyl), or cycloalkyl (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkyl) having 3 to 5 carbon atoms. In some embodiments, the cycloalkyl group is a 3 to 10-membered fully saturated cycloalkyl or a 3 to 10-membered cycloalkyl. In some embodiments, the cycloalkyl group is a 3 to 6-membered fully saturated cycloalkyl or a 3 to 6-membered cycloalkyl. In some embodiments, the cycloalkyl group is a 5 to 6-membered fully saturated cycloalkyl or a 5 to 6-membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, 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]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in this specification, the cycloalkyl group is optionally substituted, for example, optionally substituted by one or more substituents, such as oxo, halogen, amino, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted by a halogen.

[0045] Whether used as part of another term or alone, "cycloalkoxy" refers to -O-cycloalkyl.

[0046] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0047] "Halogenated alkyl" refers to an alkyl group defined above that is substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0048] Whether used as part of another term or alone, "heteroaryl" refers to a 5- to 14-membered cyclic group comprising 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and containing at least one aromatic ring. In some embodiments, the heteroaryl group comprises 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group comprises 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 nitrogen atom. The heteroaryl group can be a monocyclic or polycyclic (including but not limited to bicyclic, tricyclic, or tetracyclic) cyclic system. Polycyclic ring systems can include fused ring systems (e.g., heteroaryl rings fused to cycloalkyl, heterocyclic, or aromatic rings, or aryl rings fused to heterocyclic rings), bridged ring systems (e.g., aryl or heteroaryl rings fused to bridged cycloalkyl or heterocyclic rings), or spirocyclic ring systems (e.g., aryl rings fused to spiroheterocyclic rings, or heteroaryl rings fused to spirocycloalkyl or spiroheterocyclic rings). The nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azatriyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxyl, benzonaphthofuranyl, benzooxazolyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cenylyl, and dibenzofuranyl. Dibenzothiophene, furanyl, furanone, isothiazolyl, imidazolyl, indazole, indole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indene, isoxazolyl, naphthidyl, oxadiazolyl, 2-oxoazapyridine, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide 1-Phenylacetyl-1H-pyrrole, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyrrole, pyrazolyl, pyridinyl, 1-pyridinyl oxide, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiopheneyl.Unless otherwise expressly stated in this specification, heteroaryl groups may optionally be substituted, for example, by one or more substituents, such as halogens, amino groups, cyano groups, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid ester groups, aryl groups, cycloalkyl groups, heterocyclic groups, heteroaryl groups, etc. In some embodiments, the heteroaryl group is optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heteroaryl group is optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the heteroaryl group is optionally substituted by a halogen.

[0049] Whether used as part of another term or alone, "heterocyclic group" refers to a 3- to 24-membered partially saturated or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic group is fully saturated. In some embodiments, the heterocyclic group is partially unsaturated. In some embodiments, the heterocyclic group comprises 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic group comprises 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic group comprises 1 to 3 nitrogen atoms. In some embodiments, the heterocyclic group comprises 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic group comprises 1 nitrogen atom. In some embodiments, the heterocyclic group comprises 1 nitrogen atom and 1 oxygen atom. Unless otherwise expressly stated in this specification, the heterocyclic group can be a monocyclic or polycyclic (including but not limited to bicyclic, tricyclic, or tetracyclic) cyclic system. Polycyclic ring systems can include fused ring systems (e.g., heterocyclic groups fused with a cycloalkyl group or another heterocyclic group), spirocyclic ring systems, or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic groups include, but are not limited to, heterocyclic groups having 2 to 15 carbon atoms (C2-C...). 15 Heterocyclic groups), heterocyclic groups having 2 to 10 carbon atoms (C2-C 10Heterocyclic groups, having 2 to 8 carbon atoms (C2-C8 heterocyclic groups), having 2 to 7 carbon atoms (C2-C7 heterocyclic groups), having 2 to 6 carbon atoms (C2-C6 heterocyclic groups), having 2 to 5 carbon atoms (C2-C5 heterocyclic groups), or having 2 to 4 carbon atoms (C2-C4 heterocyclic groups). Examples of such heterocyclic groups include, but are not limited to, azirropropyl, azirrobutyl, oxacyclobutyl, dioxacyclopentyl, dihydrofuranyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl The terms include trithiohexacyclohexyl, 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-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl. The term heterocyclic group also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic group has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic group, the number of carbon atoms in the heterocyclic group is different from the total number of atoms constituting the heterocyclic group (i.e., the skeletal atoms of the heterocyclic ring), which includes heteroatoms. In some embodiments, the heterocyclic group is a 3- to 8-membered fully saturated heterocyclic group. In some embodiments, the heterocyclic group is a 3- to 7-membered fully saturated heterocyclic group. In some embodiments, the heterocyclic group is a 3- to 6-membered fully saturated heterocyclic group. In some embodiments, the heterocyclic group is a 4- to 6-membered fully saturated heterocyclic group. In some embodiments, the heterocyclic group is a 5- to 6-membered fully saturated heterocyclic group. In some embodiments, the heterocyclic group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise expressly stated in this specification, heterocyclic groups may be optionally substituted as described below, for example, optionally substituted by one or more substituents, such as oxo, halogen, amino, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic, heteroaryl, etc.In some embodiments, the heterocyclic group is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic group is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic group is optionally substituted with a halogen.

[0050] The terms “partially saturated” or “fully saturated” refer to groups that include at least one double or triple bond and are intended to cover rings with multiple unsaturated sites, but not to include aromatic (i.e., fully unsaturated) groups.

[0051] The terms “optional” or “optionally” indicate that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of said event or condition. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any spatially impractical and / or synthetically infeasible substitution or substitution pattern. Therefore, any substituent described should generally be understood to have a molecular weight of at most about 1,000 Daltons, and more typically, at most about 500 Daltons.

[0052] When referring to optional substituents, the term "one or more" means that the host group is optionally substituted with 1, 2, 3, or 4 substituents or more. In some embodiments, the host group is optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, the host group is optionally substituted with 1, 2, or 3 substituents. In some embodiments, the host group is optionally substituted with 1 or 2 substituents. In some embodiments, the host group is optionally substituted with one substituent. In some embodiments, the host group is optionally substituted with two substituents.

[0053] "Effective dose" or "therapeutic effective dose" refers to the amount of compound that, when administered to an individual mammal as a single dose or as part of a series of doses, is effective in producing the desired therapeutic effect.

[0054] The term “treatment” as used in this article includes relieving, reducing or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing a disease or condition to subside, alleviating the condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0055] compound

[0056] This article describes compounds or pharmaceutically acceptable salts thereof that are used as sodium channel modulators and for the treatment of diseases or disorders such as pain, including neuropathic pain, musculoskeletal pain, acute pain, postoperative pain, visceral pain, etc.

[0057] In one respect, this paper provides compounds of formula (A):

[0058] Equation (A),

[0059] Or its pharmaceutically acceptable salt.

[0060] in:

[0061] X is -O-, -S-, or -N(R) a1 )-;

[0062] Ring A is aryl or heteroaryl;

[0063] Ring B is aryl, heteroaryl, or heterocyclic;

[0064] L 1 It is a key, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(R) b1 )2-、-N(R a2 )-、-C(=O)N(R a2 )-、-N(R a2 )C(=O)-、-N(R a2 )C(=O)N(R a2 )-、-S(=O)N(R a2 )-、-N(R a2 )S(=O)-、-S(=O)2N(R a2 )-、-N(R a2 )S(=O)2-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R a2 )-、-N(R a2 )C(=O)O-、-N(R a2 )C(=NCN)-、-C(=NCN)N(R a2-, -O-alkyl-, -alkyl-O-, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0065] L 2 It is -C(=O)N(R) a3 )-、-N(R a3 )C(=O)-、-C(=S)N(R a3 )-、-N(R a3 )C(=S)-、-S(=O)N(R a3 )-、-S(=O)2N(R a3 )-、-cycloalkyl-N(R a3 )-、-C(R b2 )2-N(R a3 )-、-C(=O)N(R a3 )-cycloalkyl-,-C(=O)N(R a3 )-heterocyclic-, heterocyclic or heteroaryl, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted with one or more R;

[0066] R 1 and R 2 Each is independently a halogen, -SF5, alkyl, alkynyl, or haloalkyl;

[0067] R 3 and R 4 Each can be independently hydrogen, -SF5, halogen, cyano, alkyl, alkynyl, or -N(R) a4 )2;

[0068] or R 1 and R 2 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted by one or more R groups;

[0069] or R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted by one or more R groups;

[0070] or R 1 and R 3 Together with the adjacent atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted with one or more R groups;

[0071] or R 2 and R 3 Together with the adjacent atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted with one or more R groups;

[0072] R 5 It is hydrogen, -SF5, halogen, or alkyl;

[0073] R 6 Each is independently a halogen, -SF5, alkyl, haloalkoxy or alkoxy, cycloalkyl-O- or halocycloalkyl-O-;

[0074] Or two Rs 6 Together with intercalary atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each optionally constituting one or more R groups. 8 replace;

[0075] R 7 Each of these can be independently halogenated, amino, oxo, -C(=O)-NH2, -C(=O)-NH-cycloalkyl, or -C(=NR)-NH2-cycloalkyl. a5 )-NR a6 R a7 -NHC(=NH)-NH2, -NHC(=O)-NH2, -C(=O)NHC(=NH)-NH2, -cycloalkyl-NH2, -CH(haloalkyl)-NH2, -cycloalkyl-C(=NR) a5 )-NR a6 R a7 -heterocyclic group-C(=NR) a5 )-NR a6 R a7 -S(=O)2R a9 -S(=O)2NR a6 R a7 -S(=O)(=NH)R a10 -N=S(=O)(R a6 R a7 -S(=O)(R) a9 (=NR) a5 -SF5, haloalkyl, alkyl, alkoxy, cycloalkyl or heterocyclic, wherein the cycloalkyl portion of -C(=O)-NH-cycloalkyl and -cycloalkyl-NH2 is optionally substituted by one or more groups independently selected from halogen, hydroxyl, amino, cyano or alkyl, wherein the haloalkyl, alkyl, alkoxy, cycloalkyl and heterocyclic are optionally substituted by one or more R;

[0076] R 8 Each is independently selected from halogen, -SF5, hydroxyl, cyano, alkyl, alkoxy, or haloalkyl;

[0077] Or two Rs 8Together with the intervening atom, a cycloalkyl or heterocyclic group is formed, each of which is optionally substituted by one or more groups, the groups being independently selected from halogens, -SF5, hydroxyl, cyano, alkyl, alkoxy, or haloalkyl;

[0078] R a1 R a2 R a3 R a4 R a8 R b1 and R b2 Each is independently hydrogen, -SF5, alkyl, cycloalkyl, heterocyclic, or haloalkyl;

[0079] R a5 R a6 R a7 and R a10 Each of these groups independently represents hydrogen, hydroxyl, -SF5, cyano, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, -C(=O)R a8 or -C(=O)OR a9 The alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, the groups being independently selected from halogen, hydroxy, amino or cyano;

[0080] R is independently a halogen, -SF5, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC( =O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; or

[0081] Two R atoms on the same atom together form an oxo group;

[0082] R a9 It is an alkyl, cycloalkyl, or haloalkyl group;

[0083] n is any integer from 0 to 5; and

[0084] m is any integer from 0 to 5.

[0085] In some embodiments of the compound of formula (A), ring A is aryl. In some embodiments, ring A is C. 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl, C 6-8 Aryl or C 6-7 Aryl. In some embodiments, ring A is C. 12 Aryl, C 11 Aryl, C 10 Aryl, C9 aryl, C8 aryl, C7 aryl, or C6 aryl. In some embodiments, ring A is phenyl.

[0086] In some embodiments of the compounds of formula (A), ring A is a heteroaryl group. In some embodiments, ring A is a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, a 5- to 8-membered heteroaryl group, a 5- to 7-membered heteroaryl group, or a 5- to 6-membered heteroaryl group. In some embodiments, ring A is a 10-membered heteroaryl group, a 9-membered heteroaryl group, an 8-membered heteroaryl group, a 7-membered heteroaryl group, a 6-membered heteroaryl group, or a 5-membered heteroaryl group. In some embodiments, ring A is a pyridyl group.

[0087] In some embodiments of the compound of formula (A), ring B is aryl. In some embodiments, ring B is C. 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl, C 6-8 Aryl or C 6-7 Aryl. In some embodiments, ring B is C. 12 Aryl, C 11 Aryl, C 10 Aryl, C9 aryl, C8 aryl, C7 aryl, or C6 aryl. In some embodiments, ring B is phenyl.

[0088] In some embodiments of the compound of formula (A), ring B is a heteroaryl group. In some embodiments, ring B is a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, a 5- to 8-membered heteroaryl group, a 5- to 7-membered heteroaryl group, or a 5- to 6-membered heteroaryl group. In some embodiments, ring B is a 10-membered heteroaryl group, a 9-membered heteroaryl group, an 8-membered heteroaryl group, a 7-membered heteroaryl group, a 6-membered heteroaryl group, or a 5-membered heteroaryl group. In some embodiments, ring B is pyridyl, 1-pyridyloxy, 1-pyridazinyloxy, pyrazolyl, indazole, benzisoxazolyl, dihydrobenzisothiazolyl, 1,1-dihydrobenzisothiazolyl, imidazopyridazinyl, or naphridyl.

[0089] In some embodiments of the compound of formula (A), ring B is a heterocyclic group. In some embodiments, ring B is a 5- to 10-membered heterocyclic group, a 5- to 9-membered heteroaryl group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group. In some embodiments, ring B is a 10-membered heterocyclic group, a 9-membered heterocyclic group, an 8-membered heterocyclic group, a 7-membered heterocyclic group, a 6-membered heteroaryl group, or a 5-membered heterocyclic group. In some embodiments, ring B is an imidazoalkyl, oxazolidinyl, pyrrolidine, or piperazine. In some embodiments, ring B is an imidazolidin-2-one, an oxazolidin-2-one, a pyrrolidine-2-one, or a piperazine-2-one.

[0090] In some embodiments of the compound of formula (A), ring B is , , , , , , , , , , , , or .

[0091] In some embodiments of the compound of formula (A), X is -S- or -N(R) a1 )-.

[0092] In some embodiments of the compound of formula (A), X is -S-.

[0093] In some embodiments of the compound of formula (A), X is -N(R) a1 )-, and R a1 It is hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups.

[0094] In some embodiments of the compound of formula (A), X is -N(R) a1 )-, and R a1 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R a1 It is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl.

[0095] In some embodiments of the compound of formula (A), X is -N(R) a1 )-, and Ra1 It is C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 Cycloalkyl. In some embodiments, R a1 It is a C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl.

[0096] In some embodiments of the compound of formula (A), X is -N(R) a1 )-, and R a1 It is C 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2 Halogenated alkyl groups. In some embodiments, R a1 It is a C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl, or C1 haloalkyl.

[0097] In some embodiments of the compound of formula (A), X is -N(R) a1 )-, and R a1 It is hydrogen, -CH3 or -CH2CF3.

[0098] In some embodiments, this document discloses compounds of formula (A) or pharmaceutically acceptable salts thereof:

[0099] Equation (A),

[0100] Where: X is -S- or -N(R) a1 )-, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R a1 L 1 L 2 Ring A, ring B, m, and n have the meanings defined in this paper.

[0101] In some embodiments of the compounds of formula (A), compounds of formula (A-1) are provided herein:

[0102] Equation (A-1),

[0103] Or a pharmaceutically acceptable salt thereof, wherein X is -S- or -N(R a1 )-, and R a1 R 6 And n has the meaning as defined in this article.

[0104] In some embodiments of compounds of formula (A) or (A-1), X is -S- or -N(R) a1 )-.

[0105] In some embodiments of compounds of formula (A) or (A-1), X is -S-.

[0106] In some embodiments of compounds of formula (A) or (A-1), X is -N(R a1 )-, and R a1 It is hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups.

[0107] In some embodiments of compounds of formula (A) or (A-1), X is -N(R a1 )-, and R a1 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R a1 It is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl.

[0108] In some embodiments of compounds of formula (A) or (A-1), X is -N(R a1 )-, and R a1 It is C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 Cycloalkyl. In some embodiments, R a1 It is a C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl.

[0109] In some embodiments of compounds of formula (A) or (A-1), X is -N(R a1 )-, and R a1 It is C 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2 Halogenated alkyl groups. In some embodiments, R a1 It is a C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl, or C1 haloalkyl.

[0110] In some embodiments of compounds of formula (A) or (A-1), X is -N(Ra1 )-, and R a1 It is hydrogen, -CH3 or -CH2CF3.

[0111] In some embodiments, this document discloses compounds of formula (A) or pharmaceutically acceptable salts thereof:

[0112] Equation (A),

[0113] in:

[0114] (a) R 1 and R 2 One of them is -CF3, and the other is a halogen or alkynyl group; or

[0115] (b) R 1 and R 2 One of them is -CH3, and the other is an alkynyl group;

[0116] X, R 3 R 4 R 5 R 6 R 7 L 1 L 2 Ring A, ring B, m, and n have the meanings defined in this paper.

[0117] In some embodiments, compounds of formula (A-2) are provided herein:

[0118] Equation (A-2),

[0119] Or its pharmaceutically acceptable salt, wherein:

[0120] (a) R 1 and R 2 One of them is -CF3, and the other is a halogen or alkynyl group; or

[0121] (b) R 1 and R 2 One of them is -CH3, and the other is an alkynyl group; and

[0122] X, R 6 , n and ring B have the meanings defined in this paper.

[0123] In some embodiments of compounds of formula (A) or (A-2), R 1 and R 2 One of them is -CF3, and the other is a halogen. In some implementations, R 1 and R 2One of them is -CF3, and the other is -F, -Cl, -Br, or -I. In some implementations, R 1 and R 2 One of them is -CF3, and the other is -F.

[0124] In some embodiments of compounds of formula (A) or (A-2), R 1 and R 2 One of them is -CF3, and the other is an alkynyl group. In some embodiments, R 1 and R 2 One of them is -CF3, and the other is C. 2-6 alkynyl group, C 2-5 alkynyl group, C 2-4 alkynyl or C 2-3 Alkyne group. In some embodiments, R 1 and R 2 One of them is -CF3, and the other is C6 ynyl, C5 ynyl, C4 ynyl, C3 ynyl, or C2 ynyl. In some embodiments, R 1 and R 2 One of them is -CF3, and the other is acetylene.

[0125] In some implementation schemes, R 1 and R 2 One of them is -CH3, and the other is an alkynyl group. In some embodiments, R 1 and R 2 One of them is -CH3, and the other is C. 2-6 alkynyl group, C 2-5 alkynyl group, C 2-4 alkynyl or C 2-3 Alkyne group. In some embodiments, R 1 and R 2 One of them is -CH3, and the other is C6 ynyl, C5 ynyl, C4 ynyl, C3 ynyl, or C2 ynyl. In some embodiments, R 1 and R 2 One of them is -CH3, and the other is ethynyl.

[0126] In some embodiments of the compounds of formula (A) or (A-2),

[0127] (a) R 1 and R 2 One of them is -CF3, and the other is -F or ethynyl; or

[0128] (b) R 1 and R 2One of them is -CH3, and the other is ethynyl.

[0129] In some embodiments, this document discloses compounds of formula (A) or pharmaceutically acceptable salts thereof:

[0130] Equation (A),

[0131] Where: R 5 It is an alkyl or halogen, X, R 1 R 2 R 3 R 4 R 6 R 7 L 1 L 2 Ring A, ring B, m, and n have the meanings defined in this paper.

[0132] In some embodiments, compounds of formula (A-3) are provided herein:

[0133] Equation (A-3),

[0134] Or a pharmaceutically acceptable salt thereof, wherein R 5 It is an alkyl or halogen, and X, R 6 And n has the meaning as defined in this article.

[0135] In some embodiments of compounds of formula (A) or (A-3), R 5 It is an alkyl or halogen.

[0136] In some embodiments of compounds of formula (A) or (A-3), R 5 It is an alkyl group. In some embodiments of compounds of formula (A) or (A-3), R 5 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments of compounds of formula (A) or (A-3), R 5 It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments of compounds of formula (A) or (A-3), R 5 It is a methyl group.

[0137] In some embodiments of compounds of formula (A) or (A-3), R 5 It is a halogen. In some embodiments of the compound of formula (A), R 5It is -F, -Cl, -Br, or -I. In some embodiments of the compound of formula (A), R 5 Yes -F.

[0138] In some embodiments of compounds of formula (A) or (A-3), R 5 It is -CH3 or -F.

[0139] In some embodiments, this document discloses compounds of formula (A) or pharmaceutically acceptable salts thereof:

[0140] Equation (A),

[0141] Where: R 3 and R 4 One of them is hydrogen, and the other is an alkynyl group, halogen, cyano group, or -N(R) group. a4 )2, X, R 1 R 2 R 5 R 6 R 7 R a4 L 1 L 2 Ring A, ring B, m, and n have the meanings defined in this paper.

[0142] In some embodiments, compounds of formula (A-4) are provided herein:

[0143] Equation (A-4),

[0144] Or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 One of them is hydrogen, and the other is an alkynyl group, halogen, cyano group, or -N(R) group. a4 )2, and X, R 6 R a4 And n has the meaning as defined in this article.

[0145] In some embodiments of compounds of formula (A) or (A-4), R 3 and R 4 One of them is hydrogen, and the other is an alkynyl group, halogen, cyano group, or -N(R) group. a4 )2.

[0146] In some embodiments of compounds of formula (A) or (A-4), R 3 and R 4 One of them is hydrogen, and the other is an alkynyl group. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is C.2-6 alkynyl group, C 2-5 alkynyl group, C 2-4 alkynyl or C 2-3 Alkyne group. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is a C6 ynyl, C5 ynyl, C4 ynyl, C3 ynyl, or C2 ynyl. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is acetylene.

[0147] In some embodiments of compounds of formula (A) or (A-4), R 3 and R 4 One of them is hydrogen, and the other is a halogen or cyano group. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is -F, -Cl, -Br, -I, or a cyano group. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is -F or cyano.

[0148] In some embodiments of compounds of formula (A) or (A-4), R 3 and R 4 One of them is hydrogen, and the other is -N(R) a4 )2. In some implementation schemes, R 3 and R 4 One of them is hydrogen, and the other is -N(R) a4 )2, and R a4 Each is either hydrogen or alkyl.

[0149] In some embodiments of compounds of formula (A) or (A-4), R 3 and R 4 One of them is hydrogen, and the other is -N(R) a4 )2, and one or more R a4 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is -N(R) a4 )2, and one or more R a4 It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments, R 3 and R4 One of them is hydrogen, and the other is -N(R) a4 )2, one of which is R a4 It is hydrogen, and another R a4 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is -N(R) a4 )2, one of which is R a4 It is hydrogen, and another R a4 It is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl.

[0150] In some embodiments of compounds of formula (A) or (A-4), R 3 and R 4 One of them is hydrogen, and the other is selected from acetylene, -F, cyano, -NH2 or -NHCH3.

[0151] In some embodiments, this document discloses compounds of formula (A) or pharmaceutically acceptable salts thereof:

[0152] Equation (A),

[0153] Where: L 1 It is -O-, -C(R) b1 )2-、-N(R a2 )-、-C(=O)N(R a2 - or -N(R) a2 C(=O)-,X、R 1 R 2 R 3 R 4 R 5 R 6 R 7 R a2 R b1 L 2 Ring A, ring B, m, and n have the meanings defined in this paper.

[0154] In some embodiments of the compound of formula (A), L 1 It is -O-, -C(R) b1 )2-、-N(R a2 )-、-C(=O)N(R a2 - or -N(R) a2)C(=O)-. In some implementations, R b1 It is hydrogen. In some implementations, R a2 Is it hydrogen or C? 1-6 Alkyl group. In some embodiments, L 1 It is -O-, -CH2-, -NH-, -N(CH3)-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)- or -N(CH3)C(=O)-.

[0155] In some embodiments, compounds of formula (A-5) are provided herein:

[0156] Equation (A-5),

[0157] Or its pharmaceutically acceptable salt, wherein L 1 It is -O-, -C(R) b1 )2-、-N(R a2 )-、-C(=O)N(R a2 - or -N(R) a2 C(=O)-, and X, R 6 R a2 R b1 And n has the meaning as defined in this article.

[0158] In some embodiments of compounds of formula (A) or (A-5), L 1 It is -O-, -C(R) b1 )2-、-N(R a2 )-、-C(=O)N(R a2 - or -N(R) a2 )C(=O)-.

[0159] In some embodiments of compounds of formula (A) or (A-5), L 1 Yes -O-.

[0160] In some embodiments of compounds of formula (A) or (A-5), L 1 It is -C(R) b1 )2-, and R b1 Each is hydrogen.

[0161] In some embodiments of compounds of formula (A) or (A-5), L 1 It is -N(R) a2 )-、-C(=O)N(R a2 - or -N(R) a2 C(=O)-, and R a2 It is hydrogen or alkyl. In some embodiments, R a2It is hydrogen. In some implementations, R a2 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R a2 It is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl.

[0162] In some embodiments of compounds of formula (A) or (A-5), L 1 It is -O-, -CH2-, -NH-, -N(CH3)-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)- or -N(CH3)C(=O)-.

[0163] In some embodiments of compounds of formula (A) or (A-5), L 1 It is -O-, -CH2-, -NH-, -N(CH3)-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)- or -N(CH3)C(=O)-.

[0164] In some embodiments, this document discloses compounds of formula (A) or pharmaceutically acceptable salts thereof:

[0165] Equation (A),

[0166] Wherein: ring A is a 5-membered heteroaryl or 5-membered heterocyclic group, and rings B, X, and R are... 1 R 2 R 3 R 4 R 5 R 6 R 7 L 1 L 2 m and n have the meanings defined in this article.

[0167] In some embodiments, compounds of formula (A-6) are provided herein:

[0168] Equation (A-6),

[0169] Or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl or 5-membered heterocyclic group, and X, R 6 And n has the meaning as defined in this article.

[0170] In some embodiments of compounds of formula (A) or (A-6), ring A is a 5-membered heteroaryl or a 5-membered heterocyclic group.

[0171] In some embodiments of compounds of formula (A) or (A-6), ring A is pyrrole, pyrazolyl, furanyl, or oxazolyl.

[0172] In some embodiments of compounds of formula (A) or (A-6), ring A is , , or .

[0173] In some embodiments, compounds having formula (I) are provided herein:

[0174] Formula (I),

[0175] in:

[0176] The ring C is a cycloalkyl, heterocyclic, aryl, or heteroaryl group;

[0177] p is any integer from 0 to 3;

[0178] q is any integer between 0 and 4.

[0179] X, R 1 To R 8 Ring B, L 1 L 2 and m have the meanings defined in this article.

[0180] In some embodiments of the compounds of formula (I), the ring C is a cycloalkyl group. In some embodiments, the ring C is a C14 group. 3-10 cycloalkyl, C 4-10 cycloalkyl, C 5-10 cycloalkyl, C 5-9 cycloalkyl, C 5-8 cycloalkyl, C 5-7 cycloalkyl or C 5-6 Cycloalkyl. In some embodiments, the cyclic C is C10. 10 Cycloalkyl, C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl.

[0181] In some embodiments of the compounds of formula (I), ring C is a heterocyclic group. In some embodiments, ring C is a 3- to 10-membered heterocyclic group, a 4- to 10-membered heterocyclic group, a 5- to 10-membered heterocyclic group, a 5- to 9-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group. In some embodiments, ring C is a 10-membered heterocyclic group, a 9-membered heterocyclic group, an 8-membered heterocyclic group, a 7-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered heterocyclic group, a 4-membered heterocyclic group, or a 3-membered heterocyclic group.

[0182] In some embodiments of the compounds of formula (I), the ring C is aryl. In some embodiments, the ring C is C 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl, C 6-8 Aryl or C 6-7 Aryl. In some embodiments, the ring C is C 12 Aryl, C 11 Aryl, C 10 Aryl, C9 aryl, C8 aryl, C7 aryl or C6 aryl.

[0183] In some embodiments of the compounds of formula (I), the ring C is a heteroaryl group. In some embodiments, the ring C is a 4- to 10-membered heteroaryl, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl. In some embodiments, the ring C is a 10-membered heteroaryl, a 9-membered heteroaryl, an 8-membered heteroaryl, a 7-membered heteroaryl, a 6-membered heteroaryl, a 5-membered heteroaryl, or a 4-membered heteroaryl.

[0184] In some embodiments of the compound of formula (I), the ring C is phenyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, or dioxacyclopentyl.

[0185] In some embodiments of the compound of formula (I), yes , , or .

[0186] In some embodiments of the compound of formula (I), yes , , , , , , or .

[0187] In some embodiments of the compound of formula (I), R 8 Each is a halogen. In some implementations, R 8 Each is -F, -Cl, -Br, or -I. In some implementations, R 8 Each is -F.

[0188] In some embodiments of the compound of formula (I), R 6 It is an alkoxy group. In some embodiments, R 6 It is C 1-6 Alkoxy, C 1-5Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy or C 1-2 Alkyl group. In some embodiments, R 6 It is C6 alkoxy, C5 alkoxy, C4 alkoxy, C3 alkoxy, C2 alkoxy, or C1 alkoxy.

[0189] In some embodiments of the compound of formula (I), p is 1, and R 6 It is -OCH3.

[0190] In some embodiments, compounds having formula (A-7) are provided herein:

[0191] Equation (A-7),

[0192] in:

[0193] The ring carbon is a cycloalkyl, heterocyclic, aryl, or heteroaryl group; and

[0194] R 6 R 8 Rings B, p, q, and X have the meanings defined in this paper.

[0195] In some embodiments of the compound of formula (A-7), yes , , or .

[0196] In some embodiments of the compound of formula (A-7), yes , , , , , , or .

[0197] In some embodiments, compounds having formula (II) are provided herein:

[0198] Equation (II),

[0199] in:

[0200] Ring D is a cycloalkyl, heterocyclic, aryl, or heteroaryl group;

[0201] p is any integer from 0 to 3;

[0202] q is any integer between 0 and 4.

[0203] X, R 1 To R 8 L 1 L 2 Ring B and m have the meanings defined in this paper.

[0204] In some embodiments of the compound of formula (II), R 1 and R 2 One of them is -CF3, and the other is an alkyl group (e.g., C10). 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, such as C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments, R 1 and R 2 One of them is -CF3, and the other is -CH3.

[0205] In some embodiments of the compound of formula (II), R 5 It is hydrogen.

[0206] In some embodiments of the compound of formula (II), R 3 and R 4 One of them is hydrogen, and the other is an alkyl group (e.g., C10). 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, such as C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is -CH3.

[0207] In some embodiments of the compound of formula (II), L 1 It is a key.

[0208] In some embodiments of the compound of formula (II), L 2 It is -C(=O)N(R) a3 )-, and R a3 It is hydrogen or alkyl.

[0209] In some embodiments, compounds having formula (A-10) are provided herein:

[0210] Equation (A-10),

[0211] in:

[0212] Ring D is a cycloalkyl, heterocyclic, aryl, or heteroaryl group; and p, q, X, and R 6 To R 8 It has the meaning as defined in this article.

[0213] In some embodiments of formula (II) or (A-10), X is O.

[0214] In some embodiments of compounds of formula (II) or (A-10), ring D is cycloalkyl. In some embodiments, ring D is C. 3-10 cycloalkyl, C 4-10 cycloalkyl, C 5-10 cycloalkyl, C 5-9 cycloalkyl, C 5-8 cycloalkyl, C 5-7 cycloalkyl or C 5-6 Cycloalkyl. In some embodiments, ring D is C. 10 Cycloalkyl, C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl.

[0215] In some embodiments of compounds of formula (II) or (A-10), ring D is a heterocyclic group. In some embodiments, ring D is a 3- to 10-membered heterocyclic group, a 4- to 10-membered heterocyclic group, a 5- to 10-membered heterocyclic group, a 5- to 9-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group. In some embodiments, ring D is a 10-membered heterocyclic group, a 9-membered heterocyclic group, an 8-membered heterocyclic group, a 7-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered heterocyclic group, a 4-membered heterocyclic group, or a 3-membered heterocyclic group.

[0216] In some embodiments of compounds of formula (II) or (A-10), ring D is aryl. In some embodiments, ring D is C. 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl, C 6-8 Aryl or C 6-7 Aryl. In some embodiments, ring D is C. 12 Aryl, C 11 Aryl, C 10 Aryl, C9 aryl, C8 aryl, C7 aryl or C6 aryl.

[0217] In some embodiments of compounds of formula (II) or (A-10), ring D is a heteroaryl group. In some embodiments, ring D is a 4- to 10-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl. In some embodiments, ring D is a 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl, or 4-membered heteroaryl.

[0218] In some embodiments of compounds of formula (II) or (A-10), ring D is dihydrofuranyl, tetrahydrofuranyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, dihydropyranyl, tetrahydropyranyl, spiroheptyl, spiroheptenyl, oxaspiroheptyl, or oxaspiroheptenyl.

[0219] In some embodiments of the compounds of formula (II) or (A-10). yes , , , , , , , , or .

[0220] In some embodiments of compounds of formula (II) or (A-10), R 6 Each is an independent halogen. In some implementations, R 6 Each can be independently -F, -Cl, -Br, or -I. In some implementations, R 6 Each is -F.

[0221] In some embodiments of compounds of formula (II) or (A-10), R 8 Each is an alkyl group independently. In some embodiments, R 8 Each is C independently 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R 8 Each is independently a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments, R 8 Each is -CH3. In some implementations, R 8 Each is an independent halogen. In some implementations, R 8 Each can be independently -F, -Cl, -Br, or -I. In some implementations, R 8Each is -F.

[0222] In some embodiments of compounds of formula (II) or (A-10), p is 1, and R 6 Yes -F. In some implementations, q is 1, and R 8 It is -CH3. In some implementations, q is 2, and both R... 8 Both are -CH3. In some implementations, q is 2, and both R... 8 Both are -F. In some implementations, p is 1, R 6 It is -F, q is 2, and both R's are true. 8 All are -F.

[0223] In some embodiments of compounds of formula (II) or (A-10), yes , , , , , , , , , or .

[0224] In some embodiments of compounds of formula (II) or (A-10), yes or In some implementation schemes, yes In some implementation schemes, yes .

[0225] In some embodiments of formula (II) or (A-10), ring B is aryl. In some embodiments, ring B is phenyl.

[0226] In some embodiments of formula (II) or (A-10), ring B is a heteroaryl group. In some embodiments, ring B is pyrazolyl, pyridinyl, 1-pyridinyl oxide, 1-pyridazinyl oxide, indazole, benzisoxazolyl, dihydrobenzisothiazolyl, 1,1-dihydrobenzisothiazolyl, imidazopyridazinyl, or naphridinyl.

[0227] In some embodiments of formula (II) or (A-10), ring B is a heterocyclic group. In some embodiments, ring B is imidazoalkyl, oxazolidinyl, pyrrolidinyl, or piperazineyl.

[0228] In some embodiments of compounds of formula (II) or (A-10), ring B is pyrazolyl, pyridyl, 1-pyridyloxy, 1-pyridazinyl, or benzisoxazolyl. In some embodiments, ring B is pyridyl. In some embodiments, ring B is 1-pyridyloxy. In some embodiments, ring B is 1-pyridazinyl. In some embodiments, ring B is benzisoxazolyl.

[0229] In some embodiments of compounds of formula (II) or (A-10), ring B is , , , , , , , , , , , , or .

[0230] In some embodiments of compounds of formula (II) or (A-10), m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0, 1, or 2.

[0231] In some embodiments of compounds of formula (II) or (A-10), m is 1.

[0232] In some embodiments of compounds of formula (II) or (A-10), R 7 It is -C(=NR) a5 )-NR a6 R a7 In some implementations, R 7 It is an alkoxy group, which is optionally substituted with one or more R groups. In some embodiments, m is 1, and R is... 7 It is -C(=NR) a5 )-NR a6 R a7 In some implementations, m is 1, and R 7 It is C 1-6 Alkoxy group, wherein the alkoxy group is optionally substituted with one or more R groups.

[0233] In some embodiments of compounds of formula (II) or (A-10), R 7 yes , , , , , or In some implementations, m is 1, and R 7 yes In some implementations, m is 1, and R 7 yes In some implementations, m is 1, and R 7 yes .

[0234] In some embodiments of the compound of formula (A-10), Selected from , , , or .

[0235] In some embodiments of the compound of formula (II), yes , , , , , , (For example or ), (For example or ), (For example or ),or (For example or ).

[0236] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is -C(=O)N(R) a3 )-, and R a3 It is an alkyl group.

[0237] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is -C(=O)N(R) a3 )-, and R a3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, L 2 It is -C(=O)N(R) a3 )-, and R a3It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments, L 2 It is -C(=O)N(R) a3 )-, and R a3 It is -CH3. In some implementations, R a3 It is -CH3.

[0238] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is -N(R) a3 )C(=O)-、-C(=S)N(R a3 )-、-S(=O)N(R a3 )-、-S(=O)2N(R a3 )-、-cycloalkyl-N(R a3 - or -C(R) b2 )2-N(R a3 )-.

[0239] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is -N(R) a3 )C(=O)-、-C(=S)N(R a3 )-、-S(=O)N(R a3 )-、-S(=O)2N(R a3 )-、-cycloalkyl-N(R a3 - or -C(R) b2 )2-N(R a3 )-, R a3 It is hydrogen or alkyl, and R b2 It is hydrogen or a haloalkyl group. In some embodiments, R a3 It is hydrogen. In some implementations, R a3 It is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R a3 It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments, R b2 One of them is hydrogen, and R b2 Another is a haloalkyl group. In some embodiments, R b2 One of them is C 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2Halogenated alkyl groups. In some embodiments, R b2 One of them is a C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl, or C1 haloalkyl.

[0240] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is -NHC(=O)- -C(=S)NH- -S(=O)2NH- or L 2 of The end indicates the connection point with ring B.

[0241] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is -C(=O)NH-. In some implementations, L 2 It is -C(=O)NH- L 2 of The end indicates the connection point with ring B.

[0242] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is a heterocyclic group or a heteroaryl group.

[0243] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is a heterocyclic group. In some implementations, L 2 It is a 3- to 10-membered heterocyclic group, a 4- to 10-membered heterocyclic group, a 5- to 10-membered heterocyclic group, a 5- to 9-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group. In some embodiments, L 2 It can be a 10-membered heterocyclic group, a 9-membered heterocyclic group, an 8-membered heterocyclic group, a 7-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered heterocyclic group, a 4-membered heterocyclic group, or a 3-membered heterocyclic group.

[0244] In some embodiments of compounds of formula (A), (I), or (II), L 2 It is a heteroaryl group. In some implementations, L 2 It is a 4- to 10-membered heteroaryl, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl. In some embodiments, L 2 It is a 10-membered heteroaryl, a 9-membered heteroaryl, an 8-membered heteroaryl, a 7-membered heteroaryl, a 6-membered heteroaryl, a 5-membered heteroaryl, or a 4-membered heteroaryl.

[0245] In some embodiments of compounds of formula (A), (I), or (II), L2 It is imidazole, triazole, or tetraazole.

[0246] In some embodiments of compounds of formula (A), (I), or (II), L 2 yes , , , , , or L 2 of The end indicates the connection point with ring B.

[0247] In some embodiments, compounds of formula (A-8) are provided herein:

[0248] Equation (A-8),

[0249] Or its pharmaceutically acceptable salt, wherein L 2 It is -C(=O)N(R) a3 )-、-N(R a3 )C(=O)-、-C(=S)N(R a3 )-、-S(=O)N(R a3 )-、-S(=O)2N(R a3 )-、-cycloalkyl-N(R a3 - or -C(R) b2 )2-N(R a3 )-, and X, ring B, R 6 R 7 R a3 , n, and m have the meanings defined in this article.

[0250] In some embodiments of the compound of formula (A) or (A-8), L 2 Not -C(=O)NH- L 2 of The end indicates the connection point with ring B.

[0251] In some embodiments of the compound of formula (A) or (A-8), L 2 It is -C(=O)N(R) a3 )-, and R a3 It is an alkyl, cycloalkyl, or haloalkyl group.

[0252] In some embodiments of the compound of formula (A) or (A-8), L 2 It is -C(=O)N(R) a3 )-, and R a3 It is an alkyl group.

[0253] In some embodiments of the compound of formula (A) or (A-8), L 2 It is -NHC(=O)- -C(=O)N(CH3)- -C(=S)NH- -S(=O)2NH- , Imidazole, triazole or tetraazole, wherein L 2 of The end indicates the connection point with ring B.

[0254] In some embodiments, compounds of formula (A-9) are provided herein:

[0255] Equation (A-9),

[0256] Or a pharmaceutically acceptable salt thereof, wherein X, cyclic B, R 6 And n has the meaning as defined in this article, and

[0257] (a) R 7 It is -C(=NR) a5 )-NR a6 R a7 -cycloalkyl-NH2 or -CH (haloalkyl)-NH2;

[0258] (b) R 7 It is -C(=O)-NH-cycloalkyl, wherein the cycloalkyl moiety is optionally substituted with one or more hydroxyl groups;

[0259] (c) R 7 It is -NHC(=NH)-NH2, -NHC(=O)-NH2 or -C(=O)NHC(=NH)-NH2;

[0260] (d) R 7 It is a cycloalkyl-C (=NR) a5 )-NR a6 R a7 -heterocyclic group-C(=NR) a5 )-NR a6 R a7 The cycloalkyl and heterocyclic groups are optionally substituted with one or more R groups;

[0261] (e) R 7 It is -N=S(=O)(R a6 R a7 );or

[0262] (f) R 7 It is -S(=O)(R)a9 (=NR) a5 ).

[0263] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -C(=NR) a5 )-NR a6 R a7 -cycloalkyl-NH2 or -CH (haloalkyl)-NH2. In some embodiments, R 7 It is -C(=NR) a5 )-NR a6 R a7 In some implementations, R 7 It is -cycloalkyl-NH2 or -CH (haloalkyl)-NH2.

[0264] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is a cycloalkyl-NH2. In some embodiments, R 7 Yes - (C 3-8 cycloalkyl)-NH2, -(C 3-7 cycloalkyl)-NH2, -(C 3-6 cycloalkyl)-NH2, -(C 3-5 cycloalkyl)-NH2 or -(C 3-4 (cycloalkyl)-NH2. In some embodiments, R 7 It is -(C8 cycloalkyl)-NH2, -(C7 cycloalkyl)-NH2, -(C6 cycloalkyl)-NH2, -(C5 cycloalkyl)-NH2, -(C4 cycloalkyl)-NH2 or -(C3 cycloalkyl)-NH2.

[0265] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -CH (haloalkyl)-NH2. In some embodiments, R 7 It is -CH(C) 1-6 (halogenated alkyl)-NH2,-CH(C 1-5 (halogenated alkyl)-NH2,-CH(C 1-4 (halogenated alkyl)-NH2,-CH(C 1-3 (Halogenated alkyl)-NH2 or -CH(C 1-2 (Haloalkyl)-NH2. In some embodiments, R 7It is -CH(C6 haloalkyl)-NH2, -CH(C5 haloalkyl)-NH2, -CH(C4 haloalkyl)-NH2, -CH(C3 haloalkyl)-NH2, -CH(C2 haloalkyl)-NH2 or -CH(C1 haloalkyl)-NH2.

[0266] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -C(=NR) a5 )-NR a6 R a7 And R a5 R a6 and R a7 Each of these groups independently represents hydrogen, hydroxyl, cyano, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, -C(=O)R a8 or -C(=O)OR a9 The alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, the groups being independently selected from halogen, hydroxy, amino or cyano.

[0267] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is C 3-8 cycloalkyl-C(=NR) a5 )-NR a6 R a7 And R a5 R a6 and R a7 Each of these groups independently represents hydrogen, hydroxyl, cyano, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, -C(=O)R a8 or -C(=O)OR a9 The alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, the groups being independently selected from halogen, hydroxy, amino or cyano.

[0268] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is a 3 to 8 membered heterocyclic group -C(=NR) a5 )-NRa6 R a7 And R a5 R a6 and R a7 Each of these groups independently represents hydrogen, hydroxyl, cyano, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, -C(=O)R a8 or -C(=O)OR a9 The alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, the groups being independently selected from halogen, hydroxy, amino or cyano.

[0269] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -N=S(=O)(R a6 R a7 ), and R a6 and R a7 Each of these groups independently represents hydrogen, hydroxyl, cyano, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, -C(=O)R a8 or -C(=O)OR a9 The alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, the groups being independently selected from halogen, hydroxy, amino or cyano.

[0270] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -S(=O)(R) a9 (=NR) a5 ), and R a6 and R a7 Each of these groups independently represents hydrogen, hydroxyl, cyano, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, -C(=O)R a8 or -C(=O)OR a9 The alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, the groups being independently selected from halogen, hydroxy, amino or cyano.

[0271] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is F. , , , , , , , , , , , , , , , , , , , , , , , , or .

[0272] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -C(=NR) a5 )-NR a6 R a7 And R a5 It is hydrogen.

[0273] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -C(=NH)-NR a6 R a7 -(C 3-4 cycloalkyl)-NH2 or -CH(C 1-3 (Halogenated alkyl)-NH2.

[0274] In some implementation schemes, R a5 R a6 and R a7 Each of these groups is independently hydrogen, hydroxyl, cyano, alkoxy, or -C(=O)R. a8 or -C(=O)OR a9 In some implementations, R a8 It is hydrogen, alkyl, cycloalkyl, or haloalkyl. In some embodiments, R a9It is an alkyl, cycloalkyl, or haloalkyl group. In some embodiments, R a5 R a6 and R a7 Each is either hydrogen or hydroxyl.

[0275] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -C(=NH)-NH2, -C(=NH)-NHOH, -C(=NOH)-NH2, -cyclopropyl-NH2 or -CH(C1 haloalkyl)-NH2.

[0276] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 yes or .

[0277] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -C(=O)-NH-cycloalkyl, wherein the cycloalkyl portion is optionally substituted with one or more hydroxyl groups.

[0278] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -C(=O)-NH-(C 3-6 cycloalkyl), -C(=O)-NH-(C 3-5 cycloalkyl) or -C(=O)-NH-(C 3-4 (Cycloalkyl), wherein the cycloalkyl moiety is optionally substituted with one or more hydroxyl groups. In some embodiments, R 7 It is -C(=O)-NH-(C6 cycloalkyl), -C(=O)-NH-(C5 cycloalkyl), -C(=O)-NH-(C4 cycloalkyl) or -C(=O)-NH-(C3 cycloalkyl), wherein the cycloalkyl portion is optionally substituted with one or more hydroxyl groups.

[0279] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 yes , or .

[0280] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -NHC(=NH)-NH2, -NHC(=O)-NH2 or -C(=O)NHC(=NH)-NH2.

[0281] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-10) or (B), m is 2.

[0282] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 One of them is a halogen, and the other is -C (=NR) a5 )-NR a6 R a7 In some implementations, R 7 One of them is an alkyl group, and the other is -C (=NR). a5 )-NR a6 R a7 In some implementations, R 7 One of them is a halogen, and the other is a cycloalkyl-C (=NR) a5 )-NR a6 R a7 In some implementations, R 7 One of them is an alkyl group, and the other is a -cycloalkyl-C (=NR) a5 )-NR a6 R a7 In some implementations, R a5 R a6 and R a7 Each of these groups independently represents hydrogen, hydroxyl, cyano, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, -C(=O)R a8 or -C(=O)OR a9 The alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, the groups being independently selected from halogen, hydroxy, amino or cyano.

[0283] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-10) or (B), R 7 One of them is fluorine, and the other is... , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0284] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-10) or (B), R 7 One of them is -CH3, and the other is , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0285] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-10) or (B), R 7 It is -C(=NH)-NHOH.

[0286] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-10) or (B), R 7 It is -C(=O)-NH-cycloalkyl, wherein the cycloalkyl portion is optionally substituted with one or more hydroxyl groups.

[0287] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-10) or (B), R 7 It is -C(=O)-NH-(C 3-6 (cycloalkyl), wherein the cycloalkyl portion is optionally substituted with one or more hydroxyl groups.

[0288] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-10) or (B), R 7 It is -NHC(=NH)-NH2, -NHC(=O)-NH2 or -C(=O)NHC(=NH)-NH2.

[0289] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), partial or yes , , , , , , , , , , , , , , , , or .

[0290] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), partial or yes or .

[0291] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), partial or yes , or .

[0292] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), partial or yes , or .

[0293] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), partial or yes .

[0294] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), partial or yes , , , or .

[0295] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), partial or yes , , , , , , , , or .

[0296] In some embodiments of compounds of formula (A) or (A-2), (A-3), (A-4), (A-5), (A-8), (A-9), or (A-10), partial yes .

[0297] In some embodiments of the compound of formula (A), R 1 and R 2 Together with the atoms they are attached to, they form cycloalkyl or heterocyclic groups, each optionally substituted with one or more R atoms. In some embodiments, R atoms... 1 and R 2 Together with the atoms they are attached to, they form C 3-7Cycloalkyl (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl or C7 cycloalkyl, etc.) or 3 to 7-membered heterocyclic group (e.g. 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group or 7-membered heterocyclic group, etc.), wherein each cycloalkyl or heterocyclic group is optionally substituted by one or more (e.g. two or three) R.

[0298] In some embodiments of the compound of formula (A), R 3 and R 4 Together with the atoms they are attached to, they form cycloalkyl or heterocyclic groups, each optionally substituted with one or more R atoms. In some embodiments, R atoms... 3 and R 4 Together with the atoms they are attached to, they form C 3-7 Cycloalkyl (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl or C7 cycloalkyl, etc.) or 3 to 7-membered heterocyclic group (e.g. 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group or 7-membered heterocyclic group, etc.), wherein each cycloalkyl or heterocyclic group is optionally substituted by one or more (e.g. two or three) R.

[0299] In some embodiments of the compound of formula (A), R 1 and R 3 Together with their adjacent atoms, they form cycloalkyl or heterocyclic groups, each optionally substituted with one or more R atoms. In some embodiments, R atoms... 1 and R 3 Together with the adjacent atoms they are attached to, they form C 3-7 Cycloalkyl (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl or C7 cycloalkyl, etc.) or 3 to 7-membered heterocyclic group (e.g. 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group or 7-membered heterocyclic group, etc.), wherein each cycloalkyl or heterocyclic group is optionally substituted by one or more (e.g. two or three) R.

[0300] In some embodiments of the compound of formula (A), R 2 and R 3 Together with their adjacent atoms, they form cycloalkyl or heterocyclic groups, each optionally substituted with one or more R atoms. In some embodiments, R atoms... 2 and R 3 Together with the adjacent atoms they are attached to, they form C 3-7Cycloalkyl (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl or C7 cycloalkyl, etc.) or 3 to 7-membered heterocyclic group (e.g. 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group or 7-membered heterocyclic group, etc.), wherein each cycloalkyl or heterocyclic group is optionally substituted by one or more (e.g. two or three) R.

[0301] In some embodiments, compounds having formula (B) are provided herein:

[0302] Equation (B),

[0303] in:

[0304] Ring E is a cycloalkyl or heterocyclic group;

[0305] q1 is any integer from 0 to 4;

[0306] R 1 R 4 R 5 R 6 R 7 R, ring A, ring B, L 1 L 2 m and n have the meanings defined in this article.

[0307] In some embodiments of the compound of formula (B), ring E is C. 3-7 Cycloalkyl (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl or C7 cycloalkyl, etc.) or 3 to 7-membered heterocyclic groups (e.g. 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group or 7-membered heterocyclic group, etc.).

[0308] In some embodiments of the compound of formula (B), q1 is 0. In some embodiments, q1 is 1. In some embodiments, q1 is 2. In some embodiments, q1 is 3. In some embodiments, q1 is 4.

[0309] In some embodiments of the compound of formula (A) or formula (B), ring B is phenyl or heteroaryl (e.g., 5 to 12-membered heteroaryl, 5 to 6-membered heteroaryl, 5-membered heteroaryl or 6-membered heteroaryl, etc.).

[0310] In some embodiments of compounds of formula (A) or (B), ring B is phenyl or pyridyl.

[0311] In some embodiments of the compound of formula (A) or formula (B), m is 1, 2, 3, or 4, R 7 One of them is independently -C(=O)-NH-cycloalkyl, -C(=NR) a5 )-NR a6 Ra7 -NHC(=NH)-NH2, -NHC(=O)-NH2, -C(=O)NHC(=NH)-NH2, -cycloalkyl-NH2, -CH(haloalkyl)-NH2, -cycloalkyl-C(=NR) a5 )-NR a6 R a7 or -heterocyclic group-C(=NR) a5 )-NR a6 R a7 The cycloalkyl portion of -C(=O)-NH-cycloalkyl and -cycloalkyl-NH2 is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, cyano, or alkyl groups, and the cycloalkyl and heterocyclic groups are optionally substituted with one or more R groups. In some embodiments, m is 1.

[0312] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 yes , , , , , , , , , , , , , , , , , , , , , or .

[0313] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10), or (B), ring B is 1-oxypyridyl or a 5-membered heteroaryl (e.g., wait).

[0314] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 Independently, it is halogen, amino, oxo, -C(=O)-NH2, -C(=O)-NH-cycloalkyl, -C(=NR)-NH2-cycloalkyl, -C(=NR)-NH2-cycloalkyl, -C(=O ... a5 )-NR a6 R a7-NHC(=NH)-NH2, -NHC(=O)-NH2, -C(=O)NHC(=NH)-NH2, -cycloalkyl-NH2, -CH(haloalkyl)-NH2, -cycloalkyl-C(=NR) a5 )-NR a6 R a7 -heterocyclic group-C(=NR) a5 )-NR a6 R a7 -S(=O)2R a9 -S(=O)2NR a6 R a7 -S(=O)(=NH)R a10 The alkyl, alkyl, cycloalkyl, or heterocyclic group, wherein the cycloalkyl portion of -C(=O)-NH-cycloalkyl and -cycloalkyl-NH2 is optionally substituted by one or more groups independently selected from halogen, hydroxyl, amino, cyano, or alkyl; wherein the alkyl, alkyl, cycloalkyl, and heterocyclic group is optionally substituted by one or more R groups.

[0315] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), R 7 It is -CH3, -CF3, -CHF2, -S(=O)2CH3, -C(=O)-NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0316] In some embodiments of compounds of formula (A), (I), (II), (A-7), (A-8), (A-9), (A-10), or (B), ring B is a fused heteroaryl or a fused aryl. In some embodiments, ring B is a 9- or 10-membered fused heteroaryl. In some embodiments, ring B is a fused C 10 Aryl.

[0317] In some embodiments of compounds of formula (A), (I), (II), (A-7), (A-8), (A-9), (A-10), or (B), ring B is Ring F is aryl or heteroaryl, ring G is aryl, heteroaryl, heterocyclic, or cycloalkyl, and R is... f and R g Each is R independently 7 q2 is any integer between 0 and 2, and q3 is any integer between 0 and 2.

[0318] In some embodiments of compounds of formula (A), (I), (II), (A-7), (A-8), (A-9), (A-10) or (B), ring F is a 5-membered heteroaryl, and ring G is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclic group or C 5-6 Cycloalkyl.

[0319] In some embodiments of compounds of formula (A), (I), (II), (A-7), (A-8), (A-9), (A-10), or (B), ring B is , , , , , or Each of them is optionally controlled by one or more R 7 replace.

[0320] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), L 2 It is -C(=O)N(R) a3 )-、-C(=O)N(R a3 )-cycloalkyl- or -C(=O)N(R a3 )-heterocyclic-, wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more R.

[0321] In some embodiments of compounds of formula (A), (I), (II), (A-8), (A-9), (A-10) or (B), L 2 It is -C(=O)NH- or .

[0322] In some embodiments of compounds of formula (A), (I), (II) or (B), L 1 It is a key.

[0323] In some embodiments of the compound of formula (A) or formula (B), ring A is aryl.

[0324] In some embodiments of the compound of formula (A) or formula (B), ring A is R 6A R 6B and R 6C Each is independently hydrogen or R 6 ,

[0325] Or R 6A and R 6B Together with their adjacent atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each optionally bound by one or more R groups. 8 replace,

[0326] Or R 6B and R 6C Together with their adjacent atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each optionally bound by one or more R groups. 8 replace.

[0327] In some embodiments of the compound of formula (A) or formula (B), ring A is , , , or In some implementation schemes, yes .

[0328] In some embodiments of the compound of formula (A) or formula (B), R 1 It's CF3.

[0329] In some embodiments of the compound of formula (A) or formula (B), R 4 It is CH3.

[0330] In some embodiments of compounds of formula (A), (I), (II), (A-8), or (B), yes , , , , , , , , , , , , , , , or R 7A R 7B R 7C R 7D and R 7E Each is independently hydrogen or R 7 .

[0331] In some embodiments of compounds of formula (A), (I), (II), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (A-9), (A-10), or (B), X is O. In some embodiments, X is -S-. In some embodiments, X is -N(R a1 )-, and R a1 It is hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl group. In some embodiments, X is -N(R) a1 )-, and R a1 It is hydrogen, -CH3 or -CH2CF3.

[0332] In some embodiments of compounds of formula (A), (I), (II) or (B), yes or In some implementation schemes, yes or In some implementation schemes, yes or In some implementation schemes, yes or .

[0333] Those skilled in the art will understand that and It is a tautomer. Therefore, the group disclosed herein... Compounds can be considered to have groups The corresponding compounds.

[0334] In some embodiments of the compounds disclosed herein, R 1 R 2 R 3 R 4 R5 R 6 R 7 R 8 L 1 L 2 R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 R b1 and R b2 One or more of the groups contain deuterium in a percentage higher than the natural abundance of deuterium.

[0335] In some embodiments of the compounds disclosed herein, the following groups R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 L 1 L 2 R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 R b1 and R b2 One or more of, one or more 1 H is replaced by one or more deuterium atoms.

[0336] In some embodiments of the compounds disclosed herein, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 L 1 L 2 R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 Ra9 R b1 and R b2 The abundance of deuterium in each of them is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0337] In some embodiments of the compounds disclosed herein, one or more of ring A, ring B, and ring C 1 H is replaced by one or more deuterium atoms.

[0338] This document focuses on any combination of the groups described above for various variables. Throughout the specification, those skilled in the art select their groups and substituents to provide stable moieties and compounds.

[0339] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are one of the compounds in Table 1 or Table 2.

[0340] Table 1 Exemplary Compounds

[0341]

[0342]

[0343]

[0344]

[0345] Table 2 Exemplary Compounds

[0346]

[0347]

[0348] Other forms of the compounds disclosed herein

[0349] Isomer / Stereoisomer

[0350] 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 provided herein include all cis (syn, zusammen (Z)), trans (anti, entgegen (E)) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimeric forms and their corresponding mixtures. In still other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers produced by a single preparation step, combination or interconversion can be used in the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereoisomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereoisomers have different physical properties (such as melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized to separate the diastereoisomers. In some embodiments, the diastereoisomers are separated by chiral chromatography or preferably by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are recovered together with the resolving agent by any practical method that does not cause racemization.

[0351] One of ordinary skill in the art will understand that a wedge bond ( ) or a slashed wedge bond ( ) represents the absolute configuration of a chiral center, while a bold bond ( ) or a slashed bond ( ) represents the relative configuration of a chiral center.

[0352] Isotope-Enriched Compound

[0353] Unless otherwise indicated, the compounds described herein can exhibit their natural isotopic abundances, or one or more atoms in the compound can be artificially enriched with specific isotopes having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, designated as 1 H (protium), 2 H (deuterium) and 3H (tritium). Tritium is the most abundant hydrogen isotope in nature. Enrichment of deuterium can provide several therapeutic advantages, such as increased in vivo half-life and / or exposure, or provide compounds for studying drug elimination and metabolic pathways in vivo.

[0354] For example, the compounds described herein can be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes selected from deuterium (… 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Isotopes. In some embodiments, the compounds described herein are artificially enriched with one or more isotopes selected from the following: 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br、 131 I and 125 I. In some embodiments, the abundance of enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0355] In some embodiments, the compound is deuterated at at least one position. In some embodiments, some or all of the compounds disclosed herein are... 1 H atoms are 2 H atom substitution.

[0356] Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997, as well as the synthetic methods described below. For example, deuterium-substituted compounds can be synthesized using various methods, such as those described in the following literature: Dean, Dennis C. (ed.), Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [in Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0357] Deuterated starting materials are readily available and used in the synthetic methods described herein to provide the synthesis of deuterated compounds. A wide range of deuterated reagents and building blocks are available from chemical suppliers such as Aldrich Chemical Co.

[0358] Pharmaceutically Acceptable Salt

[0359] In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0360] In some embodiments, the compounds described herein have acidic or basic groups, and thus can react with a variety of inorganic or organic bases and any of inorganic and 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 by reacting the purified free form of the compound alone with a suitable acid or base and isolating the resulting salt.

[0361] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with organic or inorganic acids, such salts including acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, disglucurons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-2-phosphates, glycerol phosphates, glycolates, hemisulfates, heptahydrates, hexyn-1,6-dicitates, hydroxybenzoates, γ-hydroxybenzoates. Butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0362] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts, which are formed by reacting the compounds in their free base form with pharmaceutically acceptable inorganic or organic acids, including but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; 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, trifluoroethane. Acids, including citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids, such as oxalic acid, although not pharmaceutically acceptable on their own, may be used to prepare intermediate salts that can be used to obtain the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0363] In some embodiments, the compounds described herein containing free acid groups react with a suitable base, such as, for example, a pharmaceutically acceptable hydroxide, carbonate, bicarbonate, or sulfate of a metal cation; ammonia; or a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali metal or alkaline earth metal salts, such as salts of lithium, sodium, potassium, calcium, and magnesium, as well as aluminum. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2O. + (C 1-4 Alkyl)4, etc.

[0364] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternary ammonium compounds containing any basic nitrogen-containing group. In some embodiments, such quaternization yields water-soluble, oil-soluble, or dispersible products.

[0365] Tautomer

[0366] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the structural formulas described herein. Tautomers are compounds that can interconvert through hydrogen atom migration, accompanied by the conversion of single bonds and adjacent double bonds. In bond arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomer forms of the compounds disclosed herein are considered. The exact proportions of tautomers depend on a variety of factors, including temperature, solvent, and pH.

[0367] Treatment

[0368] This document discloses a method for modulating sodium ion channels in an individual in need, the method comprising administering to the individual a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0369] This document discloses a method for inhibiting sodium ion channels in an individual in need, the method comprising administering to the individual a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0370] This document discloses a method for inhibiting voltage-gated sodium channels in an individual in need, the method comprising administering to the individual a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0371] In some implementations, the voltage-gated sodium channel is Na V 1.8.

[0372] This document discloses methods for treating a disease or disorder in an individual in need, the methods comprising administering to the individual a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the disease or disorder is pain.

[0373] This document discloses a method for treating sodium channel-mediated diseases or disorders in individuals in need, the method comprising administering to the individual a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0374] This article also discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the preparation of medicaments for modulating sodium ion channels in individuals in need.

[0375] This document also discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the preparation of medicaments for inhibiting sodium ion channels in individuals of need.

[0376] This document also discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the preparation of medicaments for inhibiting voltage-gated sodium channels in individuals of need.

[0377] This document also discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the preparation of medicaments for the treatment of diseases or disorders in individuals in need.

[0378] This document also discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the preparation of medicaments for the treatment of sodium channel-mediated diseases or disorders in individuals in need.

[0379] As disclosed herein, the compounds are used as inhibitors of voltage-gated sodium or calcium channels, preferably N-type calcium channels. In some embodiments, the compounds and pharmaceutical compositions disclosed herein are Na... V 1.l、Na V 1.2, Na V 1.3, Na V 1.4, Na V 1.5, Na V 1.6, Na V 1.7, Na V 1.8, Na V 1.9 or Ca V 2.2 One or more inhibitors, and therefore not wishing to be bound by any particular theory, said compounds and compositions are specifically intended for the treatment of diseases or disorders involving Na. V 1.l、NaV 1.2, Na V 1.3, Na V 1.4, Na V 1.5, Na V 1.6, Na V 1.7, Na V 1.8, Na V 1.9 or Ca V 2.2 One or more of the following: activation or overactivation. When a specific disease or disorder involves Na... V 1.l、Na V 1.2, Na V 1.3, Na V 1.4, Na V 1.5, Na V 1.6, Na V 1.7, Na V 1.8, Na V 1.9 or Ca V When one or more of the conditions in 2.2 are activated or overactivated, the disease or disorder may also be referred to as "Na". V 1.l、Na V 1.2, Na V 1.3, Na V 1.4, Na V 1.5, Na V 1.6, Na V 1.7, Na V 1.8, Na V 1.9-Mediated disease or disorder" or "Ca V 2,2-mediated diseases or disorders. Therefore, in another aspect, the present invention provides a method for treating diseases or disorders, wherein the disease state relates to Na… V 1.l、Na V 1.2, Na V 1.3, Na V 1.4, Na V 1.5, Na V 1.6, Na V 1.7, Na V 1.8, Na V 1.9 or Ca V One or more of the activations or overactivations described in 2.2.

[0380] In some embodiments, the compounds disclosed herein are used as Na V 1.8 inhibitor. In some embodiments, the compounds disclosed herein are used as Na V 1.8 and Ca V2.2 Inhibitors. In some embodiments, the compounds disclosed herein are used as Ca V 2.2 Inhibitors. In some embodiments, the compounds disclosed herein are used as Na V 1.8 and TTX-sensitive ion channels (e.g., Na+) V 1.3 or Na V 1.7) dual inhibitors.

[0381] In some embodiments, the compounds disclosed herein are used to treat diseases or disorders, including but not limited to chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from bursa resection, hernia repair, or abdominoplasty), visceral pain, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, pathological cough, or arrhythmia.

[0382] In some implementations, bowel pain includes pain from inflammatory bowel disease, Crohn's disease, or interstitial cystitis.

[0383] In some implementations, neuropathic pain includes postherpetic neuralgia, neuropathy, idiopathic neuropathy, or diabetic neuropathy.

[0384] In some implementations, neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, oral burn syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain following spinal cord injury, fine fiber neuropathy, idiopathic fine fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache.

[0385] In some implementations, musculoskeletal pain includes osteoarthritis pain. In other implementations, musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, hip pain, or dental pain.

[0386] In some implementations, inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0387] In some implementations, idiopathic pain includes fibromyalgia pain.

[0388] In some implementations, acute pain includes acute postoperative pain.

[0389] In some implementations, postoperative pain includes pain from cystectomy, hernia repair, or laparotomy.

[0390] In some implementations, visceral pain includes visceral pain resulting from laparotomy.

[0391] In some embodiments, the disease or disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease includes multiple sclerosis. In some embodiments, the neurodegenerative disease includes Pitt Hopkins Syndrome (PTHS).

[0392] In some embodiments, the compounds disclosed herein are used to treat diseases or disorders, including but not limited to acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, and breakthrough pain. Pain, postoperative pain (e.g., pain after bursal cystectomy, hernia repair, or laparotomy), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal abnormalities.

[0393] In some embodiments, the compounds disclosed herein are used to treat diseases or disorders including, but not limited to, femoral head cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headaches; migraines; tension headaches; cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Sharma-Tutan neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome. pain syndrome; phantom pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical lower back pain; neck pain; tendinitis; injury pain; movement pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain; heart pain; pelvic pain; renal colic; acute obstetric pain; labor pain; cesarean section pain; acute inflammatory pain; hip pain; traumatic pain; acute intermittent pain; endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behcet's disease pain; adiposis Dolorosa; Phlebitis pain; Guillain-Barrepain; Painful legs and moving toes; Haglund's syndrome; Erythromelalgia pain; Fabry's disease pain; Bladder and urogenital disorders; Urinary incontinence; Pathological cough; Overactive bladder; Bladder pain syndrome; Interstitial cystitis (IC); Prostatitis; Complex Regional Pain Syndrome (CRPS) Type I; Complex Regional Pain Syndrome (CRPS) Type II;Widespread pain, paroxysmal extreme pain, pain caused by itching, tinnitus, or angina.

[0394] dose

[0395] In some embodiments, a composition containing one or more compounds described herein is administered for a therapeutic treatment. In some therapeutic applications, the composition is administered to a patient who already has a disease or condition in an amount sufficient to cure or at least partially suppress at least one symptom of said disease or condition. The effective amount for this purpose depends on the severity and course of said disease or condition, prior therapy, the patient's health status, weight and response to the drug, and the judgment of the treating physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0396] Application route

[0397] Suitable 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, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0398] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection into an organ, typically in the form of a reservoir formulation or a sustained-release formulation. In certain embodiments, long-acting formulations are administered via implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In these embodiments, the liposomes target the organ and are selectively absorbed by it. In still other embodiments, the compounds described herein are provided in the form of a rapid-release formulation, a prolonged-release formulation, or a medium-release formulation.

[0399] Pharmaceutical Compositions / Formulations

[0400] In accordance with standard pharmaceutical practice, the compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as a pharmaceutical composition to an individual in need. In some embodiments, the compounds described herein are administered to animals.

[0401] On the other hand, this document provides pharmaceutical compositions comprising the compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. A suitable formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in the following literature: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., editors, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0402] Example

[0403] For illustrative purposes, the following examples are included. The examples provided herein describe the compounds disclosed herein and the synthesis of intermediates for the preparation of said compounds. However, it should be understood that these examples are not limiting of this disclosure, but are merely illustrative of methods for implementing this disclosure. Those skilled in the art will recognize that the described chemical reactions can be readily adapted to prepare many other compounds of this disclosure, and alternative methods for preparing the compounds of this disclosure are considered to be within the scope of this disclosure. For example, compounds not specifically implemented in this disclosure can be successfully synthesized by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by using other suitable reagents and building blocks known in the art instead of those described, and / or by conventionally adjusting the reaction conditions. Furthermore, those skilled in the art will understand that the various steps described herein or in separate batches of the compounds can be combined. Alternatively, other reactions disclosed herein or other reactions known in the art will be considered suitable for preparing other compounds of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure, which is determined by the appended claims.

[0404] Example 1: Synthesis of an exemplary compound

[0405] Example 1.1

[0406]

[0407] Step 1: At 25 °C, TEA (0.400 mL, 2.82 mmol) and T3P (50%, in ethyl acetate, 1.80 g, 2.82 mmol) were added to a solution of 1-1 (200 mg, 0.560 mmol) and 1-2 (100 mg, 0.560 mmol) in ethyl acetate (1.00 mL). The mixture was stirred at 50 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether = 1 / 4, to give compound 1. MS (ESI) m / z (M +H) + = 514.0.

[0408] Step 2: Separation of compound 1 (23.0 mg, 0.045 mmol) by SFC (column: RegisPack-(R,R)WHELK, 5 μm particle size, 100 x 4.6 mm; mobile phase A: supercritical CO2, mobile phase B: MeOH (containing 0.1% NH3) .H2O); A:B = 60:40; Flow rate: 2 mL / min; Nozzle pressure: 2000 psi; Column temperature: 35°C °C; wavelength: 210 nm), to obtain compounds 1a and 1b.

[0409] SFC Analysis Method: Instrument: Waters UPCC system equipped with PDA detector; Column: RegisPack-WHELK_RR_100x4.6mm_5μm; Mobile phase: CO2 : MeOH (0.1% NH3H2O) = 60:40; Run time: 6.0 min; Flow rate: 2.0 mL / min; Nozzle pressure: 2000 psi; Column temperature: 35 °C; Wavelength: 210 nm; Compound 1a: Rt = 3.898 min; Compound 1b: Rt = 1.960 min.

[0410] Compound 1a, MS (ESI) m / z (M + H) + = 514.2. 1 H NMR (400 MHz, CD3OD) δ 8.46(d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 7.89 (d, J = 5.6 Hz, 1H), 7.15 – 7.08 (m,1H), 7.03 – 6.91 (m, 1H), 5.08 (d, J = 10.4 Hz, 1H), 4.36 – 4.27 (m, 1H), 4.00 (d, J = 2.4 Hz, 3H), 2.91 – 2.83 (m, 1H), 2.82 – 2.77 (m, 1H), 1.66 (s, 3H), 0.87 – 0.78 (m, 5H), 0.70 – 0.63 (s, 2H).

[0411] Compound 1b, MS (ESI) m / z (M + H) + = 514.2. 1H NMR (400 MHz, CD3OD) δ 8.46(d, J = 5.6 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 5.6, 2.0 Hz,1H), 7.15 – 7.07 (m, 1H), 7.03 – 6.91 (m, 1H), 5.08 (d, J = 10.4 Hz, 1H), 4.37 – 4.28 (m, 1H), 4.00 (d, J = 2.0 Hz, 3H), 2.90 – 2.84 (m, 1H), 2.82 –2.75 (m, 1H), 1.66 (s, 3H), 0.87 – 0.78 (m, 5H), 0.72 – 0.61 (m, 2H).

[0412] Example 1.2

[0413]

[0414] Step 1: At 25 °C, bis(tert-butylphosphine)palladium (0.200 g, 0.448 mmol) and KOH (0.800 g, 13.4 mmol) were added to a mixture of 3-1 (1.00 g, 4.48 mmol) and bis(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)methane (2.40 g, 8.97 mmol) in THF / H2O (10 / 2 mL). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether = 1 / 10, to give 3-2. 1 H NMR (400 MHz, CDCl3) δ 6.80 – 6.62 (m, 2H), 3.86 (d, J = 2.0 Hz, 3H), 2.11 (s, 2H), 1.17 (s, 12H).

[0415] Step 2: At 25 ℃ and under N2, to ( relEthyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (racemic mixture) (3.00 g, 8.06 mmol) and 3-2 (2.52 g, 8.87 mmol) in dioxane / H2O (50 / 10 mL) were added to a mixture of Pd(dppf)Cl2 (590 mg, 0.806 mmol) and K2CO3 (3.34 g, 24.2 mmol). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether = 1 / 10, to give 3-3. MS (ESI) m / z (M + Na) + = 417.2.

[0416] Step 3: At 25 °C, Pd / C (10 wt%, 432 mg) was added to the mixture of 3-3 in MeOH (20.0 mL). The mixture was stirred at 25 °C under a H2 (50 psi) atmosphere for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 3-4. MS (ESI) m / z (M + Na) + = 419.2.

[0417] Step 4: Add 3-4 (1.00 g, 2.52 mmol) to the solution in 2-methyltetrahydrofuran (20.0 mL) t -BuOK (566 mg, 5.05 mmol). The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched with aqueous HCl (2.00 mol / L, 20.0 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, and concentrated under reduced pressure to give 3-5. MS (ESI) m / z (M + H) + = 369.2.

[0418] Step 5: To a solution of 3-5 (900 mg, 2.44 mmol) and 4-aminopyridine amide (503 mg, 3.67 mmol) in ethyl acetate (30.0 mL), TEA (1.00 mL, 7.33 mmol) and propylphosphonic anhydride (50%, in ethyl acetate, 2.33 g, 3.67 mmol) were added. The reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was quenched with water (60 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by preparative-HPLC to give compound 3. MS (ESI) m / z (M + H) + = 488.2.

[0419] Step 6: Separate compound 3 (300 mg, 0.616 mmol) by SFC (column: RegisPack-(R,R)WHELK, 5 μm particle size, 100 x 4.6 mm; mobile phase A: supercritical CO2, mobile phase B: MeOH (containing 0.1% NH3) . H2O); A:B = 60:40; Flow rate: 2 mL / min; Nozzle pressure: 2000 psi; Column temperature: 35°C °C; wavelength: 210 nm), to obtain compounds 3a-3d.

[0420] Analytical Methods: Instrumentation: Waters UPCC system equipped with a PDA detector; Column: RegisPack-WHELK_RR_100x4.6mm_5μm; Mobile Phase: CO2 : MeOH = 60:40; Run Time: 5.0 min; Flow Rate: 2.0 mL / min; Nozzle Pressure: 2000 psi; Column Temperature: 35 °C; Wavelength: 210 nm; Compound 3a: Rt = 1.989 min; Compound 3b: Rt = 2.021 min; Compound 3c: Rt = 3.105 min; Compound 3d: Rt = 2.427 min.

[0421] Compound 3a, MS (ESI) m / z (M + H) + = 488.2. 11H NMR (400 MHz, CD3OD) δ 8.48 (d, J = 5.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 5.6, 2.0 Hz, 1H), 7.02 – 6.97 (m, 1H), 6.84 – 6.71 (m, 1H), 4.41 (d, J = 8.4 Hz, 1H), 3.98 (d, J = 2.4 Hz, 3H), 3.29 – 3.15 (m, 1H), 2.94 (dd, J = 14.0, 6.4 Hz, 1H), 2.80 (dd, J = 14.0, 9.6 Hz, 1H), 2.61 – 2.51 (m, 1H), 1.55 (s, 3H), 1.26 - 1.16 (m, 3H).

[0422] Compound 3b, MS (ESI) m / z (M + H) + = 488.2. 1 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J = 5.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 5.6, 2.0 Hz, 1H), 7.02 – 6.97 (m, 1H), 6.84 – 6.71 (m, 1H), 4.41 (d, J = 8.4 Hz, 1H), 3.9 (d, J = 2.4 Hz, 3H),  3.29 – 3.15 (m, 1H), 2.94 (dd, J = 14.0, 6.4 Hz, 1H), 2.80 (dd, J = 14.0, 9.6 Hz, 1H), 2.61 – 2.51 (m, 1H), 1.55 (s, 3H), 1.26 - 1.16 (m, 3H).

[0423] Compound 3c, MS (ESI) m / z (M + H) + = 488.2. 1H NMR (400 MHz, CD3OD) δ 8.10(d, J = 5.6 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.06 – 7.01 (m, 1H), 6.98 –6.84 (m, 1H), 6.74 (dd, J = 5.6, 2.4 Hz, 1H), 4.46 (d, J = 7.6 Hz, 1H), 3.98 (d, J = 2.0 Hz, 3H), 3.08 (d, J = 7.6 Hz, 1H), 2.94 (dd, J = 7.6, 3.2 Hz,2H), 2.60 – 2.44 (m, 1H), 1.65 (s, 3H), 1.22 – 1.14 (m, 3H).

[0424] Compound 3d, MS (ESI) m / z (M + H) + = 488.2. 1 H NMR (400 MHz, CD3OD) δ 8.10(d, J = 5.6 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.06 – 7.01 (m, 1H), 6.98 –6.84 (m, 1H), 6.74 (dd, J = 5.6, 2.4 Hz, 1H), 4.46 (d, J = 7.6 Hz, 1H), 3.98 (d, J = 2.0 Hz, 3H), 3.08 (d, J = 7.6 Hz, 1H), 2.94 (dd, J = 7.6, 3.2 Hz,2H), 2.60 – 2.44 (m, 1H), 1.65 (s, 3H), 1.22 – 1.14 (m, 3H).

[0425] Example 1.4

[0426]

[0427] Step 1: At 25 °C, K₂CO₃ (2.52 g, 19.0 mmol) was added to a solution of guanidine hydrochloride (604 mg, 6.33 mmol) in ACN (10.0 mL). The mixture was stirred at 25 °C for 30 min. 9-1 (900 mg, 6.33 mmol) was added to the mixture, and the mixture was stirred at 100 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with methanol / dichloromethane = 1 / 10 to give 9-2. MS (ESI) m / z (M + H) + = 182.0.

[0428] Step 2: At 25 °C, add NH3 to a solution of 9-2 (200 mg, 1.10 mmol) in MeOH (10.0 mL). . H2O (1.00 mL) and Pd / C (10 wt%, 11.7 mg). The mixture was stirred at 25 °C under a H2 (15 psi) atmosphere for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 9-3. MS (ESI) m / z (M + H) + = 152.0.

[0429] Step 3: HATU (1.51 g, 3.97 mmol) was added to a solution of 9-3 (200 mg, 1.32 mmol), 1-1 (racemic mixture, 469 mg, 1.32 mmol), and DIEA (0.69 mL, 3.97 mmol) in DMF (5.0 mL). The mixture was stirred at 50 °C for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with methanol / dichloromethane = 1 / 20, to give compound 9. MS (ESI) m / z (M + H) + = 488.0.

[0430] Step 4: Separation of compound 9 (300 mg, 0.62 mmol) by SFC (column: RegisPack-(R,R)WHELK, 5 μm particle size, 100 x 4.6 mm; mobile phase A: supercritical CO2, mobile phase B: methanol (containing 0.1% NH3) .H2O); A:B = 60:40; Flow rate: 2 mL / min; Nozzle pressure: 2000 psi; Column temperature: 35°C °C; wavelength: 210 nm), to obtain compounds 9a and 9b.

[0431] Analytical methods: Instrumentation: Waters UPCC system equipped with a PDA detector; Column: RegisPack-WHELK_RR_100x4.6mm_5μm; Mobile phase: CO2: MeOH(0.1%NH3H2O) = 60:40; Run time: 6.0 min; Flow rate: 2.0 mL / min; Nozzle pressure: 2000 psi; Column temperature: 35 °C; Wavelength: 210 nm; Compound 9a: Rt = 1.798 min; Compound 9b: Rt = 2.391 min.

[0432] Compound 9a, MS (ESI) m / z (M + H) + = 488.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.44 (s, 1H), 8.27 (s, 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.17 –6.98 (m, 2H), 6.28 – 6.12 (m, 4H), 4.74 (d, J = 10.0 Hz, 1H), 4.15 – 4.11 (m,1H), 3.94 (d, J = 2.0 Hz, 3H), 2.77 – 2.68 (m, 1H), 1.55 (s, 3H), 0.72 – 0.67(m, 3H).

[0433] Compound 9b, MS (ESI) m / z (M + H) + = 488.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.44 (s, 1H), 8.27 (s, 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.17 –6.98 (m, 2H), 6.28 – 6.12 (m, 4H), 4.74 (d, J = 10.0 Hz, 1H), 4.15 – 4.11 (m,1H), 3.94 (d, J = 2.0 Hz, 3H), 2.77 – 2.68 (m, 1H), 1.55 (s, 3H), 0.72 – 0.67(m, 3H).

[0434] Example 1.5

[0435]

[0436] Step 1: To a solution of 11-1 (1.00 g, 6.57 mmol) and Boc2O (1.83 mL, 7.89 mmol) in DCM (10 mL), TEA (2.75 mL, 19.7 mmol) and DMAP (0.80 mg, 0.657 mmol) were added. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether = 1 / 1, to give 11-2. MS (ESI) m / z (M + H) + = 253.4.

[0437] Step 2: At 0 °C, sodium hydride (60 wt%, 95 mg, 3.96 mmol) and methyl iodide (1.41 g, 9.91 mmol) were added to a solution of 11-2 (500 mg, 1.98 mmol) in THF (5.0 mL). The reaction mixture was then heated to 25 °C. The mixture was stirred at °C for 4 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether = 1 / 1, to give 11-3. MS (ESI) m / z (M + H) + = 267.4.

[0438] Step 3: At 25 °C, TFA (110 mg, 1.13 mmol) was added to a solution of 11-3 (300 mg, 1.13 mmol) in DCM (5.0 mL). The reaction mixture was then stirred at 25 °C for 2 hours. The reaction mixture was concentrated to give 11-4. MS (ESI) m / z (M + H) + = 167.2.

[0439] Step 4: The solution of 11-4 (120 mg, 0.722 mmol) in NH3 (7.00 mol / L, in MeOH, 10.0 mL, 70.0 mmol) was stirred at 25 °C for 18 hours. The mixture was concentrated under reduced pressure to obtain 11-5. MS (ESI) m / z (M+ H) + = 152.2.

[0440] Step 5: To a solution of 1-1 (racemic mixture, 100 mg, 0.565 mmol) and 11-5 (120 mg, 2.82 mmol) in ethyl acetate (2.0 mL), TEA (285 mg, 2.82 mmol) and propylphosphonic anhydride (50%, in ethyl acetate, 898 mg, 1.41 mmol) were added. The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether = 1 / 1, to give compound 11. MS (ESI) m / z (M + H) + = 488.4.

[0441] Step 6: Separate compound 11 (40 mg, 0.082 mmol) by SFC (column: ChiralPak AD-H, 5 μm particle size, 250 x 30 mm; mobile phase A: supercritical CO2, mobile phase B: isopropanol (containing 0.1% NH3) . H2O); A:B = 60:40; Flow rate: 120 mL / min; Nozzle pressure: 100 Bar; Column temperature: 38°C °C; wavelength: 220 nm), to obtain compounds 11a and 11b.

[0442] SFC Analysis Method: Instrument: Waters UPCC system equipped with a PDA detector; Column: Daicel ChiralPAK-IH 100x3.0mm 3μm; Mobile phase: CO2 : IPA = 85:15; Run time: 7.0 min; Flow rate: 2.0 mL / min; Nozzle pressure: 2000 psi; Column temperature: 35 °C; Wavelength: 210 nm (Compound 11a: Rt = 1.627 min, Compound 11b: Rt = 3.893 min)

[0443] Compound 11a, MS (ESI) m / z (M + H) + = 488.2. 1 H NMR (400 MHz, CD3OD) δ 8.15(d, J = 6.0 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.27 – 7.22 (m, 1H), 7.03 –6.94 (m, 1H), 6.71 – 6.67 (m, 1H), 5.19 (d, J = 10.8 Hz, 1H), 4.25 – 4.19 (m,1H), 3.97 (d, J = 2.4 Hz, 3H), 2.84 (s, 3H), 2.82 – 2.76 (m, 1H), 1.74 (s,3H), 0.85 – 0.79 (m, 3H).

[0444] Compound 11b, MS (ESI) m / z (M + H) + = 488.2. 1 H NMR (400 MHz, CD3OD) δ 8.15(d, J = 6.0 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.27 – 7.22 (m, 1H), 7.03 –6.94 (m, 1H), 6.71 – 6.67 (m, 1H), 5.19 (d, J = 10.8 Hz, 1H), 4.25 – 4.19 (m,1H), 3.97 (d, J = 2.4 Hz, 3H), 2.84 (s, 3H), 2.82 – 2.76 (m, 1H), 1.74 (s,3H), 0.85 – 0.79 (m, 3H).

[0445] Example 1.7

[0446]

[0447] Step 1: Pd2(dba)3 (168 mg, 0.18 mmol) and Xantphos (106 mg, 0.18 mmol) were added to a mixture of 15-1 (500 mg, 1.83 mmol), iminodimethyl-16-sulfonone (341 mg, 3.66 mmol), and Cs2CO3 (1.78 g, 5.49 mmol) in dioxane (20 mL). The reaction mixture was then heated in 100 mL of water. o C. Stir under a nitrogen atmosphere for 12 hours. Concentrate the reaction mixture to obtain the residue. Purify the residue by rapid silica gel column chromatography, eluting with a solution of 7% MeOH in DCM to give 15-2. MS (ESI) m / z (M + H) + 286.2.

[0448] Step 2: Add TFA (1 mL) to the solution of 15-2 (100 mg, 0.35 mmol) in DCM (2 mL). Stir the reaction mixture at 25 °C for 2 hr. Concentrate the reaction mixture to obtain 15-3, which is used directly in the next step without further purification. MS (ESI) m / z (M + H) + 186.2.

[0449] Step 3: Compound 15 was prepared using (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid and 15-3 as starting materials, following a similar method as described in Example 1.1.

[0450] Compound 15, MS (ESI) m / z (M + H) + 522.2. 1HNMR: (400 MHz, MeOD) δ 7.99(d, J = 6.0 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 6.0, 1.6 Hz,1H), 7.12 – 7.06 (m, 1H), 7.02 – 6.93 (m, 1H), 5.04 (d, J = 10.4 Hz, 1H), 4.31 (dd, J = 10.4, 8.0 Hz, 1H), 3.99 (d, J = 2.4 Hz, 3H), 3.40 (s, 6H), 2.85– 2.72 (m, 1H), 1.64 (s, 3H), 0.84 – 0.76 (m, 3H).

[0451] Example 1.8

[0452]

[0453] Step 1: Add cesium carbonate (22.83 g, 70.10 mmol) and 1,2-dibromoethane (6.58 g, 35.00 mmol) to a solution of 16-1 (5 g, 23.36 mmol) in DMF (50 ml), and incubate the mixture at 60 °C. o Stir at C for 2 hours. Add H2O (50 mL), and mix with EA (50 mL). 3) Extract the mixture. The combined organic phases were washed with brine, dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the residue, which was purified by rapid column chromatography (0-20% EA in PE) to give 16-2. 1 H NMR (400 MHz, DMSO) δ7.83 – 7.52 (m, 2H), 7.30 (dd, J = 10.0, 8.8 Hz, 1H), 1.69(dd, J = 8.0, 5.2 Hz, 2H), 1.51 (dd, J = 8.0, 5.2 Hz, 2H).

[0454] Step 2: To a solution of 16-2 (4.8 g, 19.99 mmol), cesium carbonate (19.54 g, 60.00 mmol), tert-butyl carbamate (7.03 g, 60.00 mmol) in dioxane (10 mL), add (9,9-dimethyl-9H-xanthon-4,5-diyl)bis(diphenylphosphine) (1.157 g, 1.999 mmol) and Pd2(dba)3 (100 mg, 19.99 mmol). Heat the mixture in 100 mL of water. o Stir at C for 12 hours. Concentrate the mixture under vacuum to obtain a residue, which is then purified by rapid column chromatography (0-30% EA in PE) to obtain 16-3.

[0455] Step 3: The solution of 16-3 (100 mg, 0.362 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at 25°C for 2 hours. The mixture was concentrated under vacuum to obtain 16-4, which was used for the next step without further purification. MS (ESI) m / z (M+H) + 177.2.

[0456] Step 4: Add TEA (0.131 ml, 0.94 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (599 mg, 0.94 mmol) to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (80 mg, 0.23 mmol) and 16-4 (33.2 mg, 0.19 mmol) in ethyl acetate (5 mL). Stir the mixture at 25 °C for 2 hours. The reaction mixture was concentrated under vacuum to obtain a residue, which was then purified by silica gel column chromatography (0-30% EA in PE) to give 16-5 μL MS (ESI). m / z (M +H) + 513.0.

[0457] Step 5: Hydroxylamine hydrochloride (40.7 mg, 0.58 mmol) and TEA (0.163 mL, 1.17 mmol) were added to a solution of 16-5 (100 mg, 0.20 mmol) in EtOH (5 mL), and the mixture was stirred at 80 °C for 12 hr. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by rapid column chromatography (0-50% and 50-80% EA solutions in PE) to give compound 16.

[0458] Compound 16: MS (ESI) m / z (M + H) + 546.2. 1 H NMR (400 MHz, CD3OD) δ 7.61(dd, J = 6.4, 2.8 Hz, 1H), 7.49 – 7.40 (m, 1H), 7.15 – 7.08 (m, 1H), 7.02 –6.88 (m, 2H), 5.03 (d, J = 10.4 Hz, 1H), 4.28 (dd, J = 10.4, 8.0 Hz, 1H), 3.99 (d, J = 2.4 Hz, 3H), 2.85 – 2.71 (m, 1H), 1.65 (s, 3H), 1.35 (q, J = 4.6Hz, 2H), 1.05 (q, J = 4.6 Hz, 2H), 0.89 – 0.70 (m, 3H).

[0459] Example 1.9

[0460]

[0461] Step 1: Add TEA (0.034 mL, 0.25 mmol) and T3P (156 mg, 0.25 mmol) to a solution of 17-1 (racemic mixture) (30 mg, 0.082 mmol), 5-amino-2-fluorobenzyl nitrile (17-2, 16.72 mg, 0.123 mmol) in EA (5 mL) and incubate the mixture at 25°C. o Stir at C for 12 hours. Concentrate the mixture under vacuum to obtain a residue, which is then purified by rapid column chromatography (0-5% MeOH solution in DCM) to give 17-3 MS (ESI). m / z (M +H)+ 485.2

[0462] Step 2: To a mixture of 17-3 (racemic mixture) (40 mg, 0.083 mmol) in EtOH (5 mL), add TEA (0.035 mL, 0.25 mmol) and hydroxylamine hydrochloride (17.21 mg, 0.25 mmol). Stir the mixture at 80 °C for 12 hours. Concentrate the mixture under vacuum to obtain a residue, which is then purified by rapid column chromatography (0-5% MeOH in DCM) to give 17-3. MS (ESI). m / z (M + H) + 518.2. 1 H NMR: (400 MHz, CD3OD) δ 7.80 –7.60 (m, 2H), 7.25 – 7.08 (m, 2H), 6.98 (dd, J = 16.8, 9.2 Hz, 1H), 5.04 (d, J = 7.6 Hz, 1H), 4.31 (d, J = 7.6 Hz, 1H), 3.96 (d, J = 2.0 Hz, 3H), 2.5 –2.43 (m, 1H), 2.41 – 2.29 (m, 1H), 2.24 – 2.15 (m, 1H), 1.95 – 1.77 (m, 1H), 0.90 (s, 3H).

[0463] Step 3: Separation of compound 17 by SFC (instrument: Waters PrepSFC 150Mgm, column: Regis WhelkO1(R,R), 250 × 50mm ID, 10µm, mobile phase: A, CO2, B, MeOH, gradient: B 40%, flow rate: 140mL / min, column temperature: 40℃, wavelength: 210nm, cycle time: 13 min, sample preparation: dissolve the compound in 20 ml MeOH, injection: 5 ml per injection), to obtain compound 17a and compound 17b.

[0464] SFC Analysis Method: Instrument: Waters UPCC system equipped with PDA detector; Column: Regis WHELK(R,R)_150x4.6 mm_5μm; Column temperature: 35℃; Flow rate: 2.0 ml / min; Wavelength: 210 nm; Injection volume: 5 µl; Sample concentration: 2.0 mg / ml; Run time: 8.0 min; Diluent: MEOH; Critical conditions (CO2): P (2000 psi), T (35℃); Mobile phase: CO2 : MeOH = 75 : 2.

[0465] Compound 17a(t) R = 4.423 min):

[0466] MS (ESI) m / z (M + H) + 518.4. 1 H NMR: (400 MHz, CD3OD) δ 7.80 – 7.60(m, 2H), 7.16 – 6.90 (m, 3H), 5.04 (d, J = 7.6 Hz, 1H), 4.31 (d, J = 7.6 Hz, 1H), 3.96 (d, J = 2.0 Hz, 3H), 2.53 – 2.43 (m, 1H), 2.41 – 2.29 (m, 1H), 2.27 – 2.17 (m, 1H), 1.95 – 1.81 (m, 1H), 0.89 (s, 3H).

[0467] Compound 17b(t) R = 4.990 min):

[0468] MS (ESI) m / z (M + H) + 518.2. 1 H NMR: (400 MHz, CD3OD) δ 7.76 – 7.63(m, 2H), 7.16 – 6.94 (m, 3H), 5.04 (d, J = 7.6 Hz, 1H), 4.31 (d, J = 7.6 Hz, 1H), 3.96 (d, J= 2.0 Hz, 3H), 2.5 – 2.43 (m, 1H), 2.41 – 2.29 (m, 1H), 2.24 – 2.15 (m, 1H), 1.95 – 1.77 (m, 1H), 0.89 (s, 3H).

[0469] Example 1.10

[0470]

[0471] Step 1: Separate compound 17-1 by SFC (column: Regis WhelkO1(R,R), 250) 50mm ID, 10µm; Mobile phase A: supercritical CO2, Mobile phase B: MeOH; A:B = 75:25, Flow rate: 120 mL / min; Nozzle pressure: 100 Bar; Column temperature: 38°C o C; wavelength: 210 nm), yielding single isomers of 18-1a and 18-1b.

[0472] SFC Analysis Method: Instrument: Waters UPCC system equipped with PDA detector; Column: Regis WHELK(R,R)_150x4.6 mm_5μm; Column temperature: 35℃; Flow rate: 2.0 ml / min; Wavelength: 210 nm; Injection volume: 10 µl; Sample concentration: 2.0 mg / ml; Run time: 5.0 min; Diluent: MEOH; Critical conditions (CO2): P (2000 psi), T (35℃); Mobile phase: CO2 : MeOH = 90 : 10.

[0473] 18-1a: t R = 1.902 min, 18-1b: t R = 2.524 min.

[0474] Step 2: To a solution of 18-1a (50.0 mg, 0.137 mmol) and 4-aminopyridinecarboxynitrile (32.5 mg, 0.27 mmol) in EtOAc (3 mL), TEA (69.1 mg, 0.68 mmol) and T3P (50%, in EtOAc) (217 mg, 0.68 mmol) were added. The reaction mixture was stirred at 50 °C for 2 hr. The reaction mixture was concentrated to obtain a residue, which was purified by rapid silica gel column chromatography, eluting with 3% MeOH in DCM to give 18-2a. MS (ESI) m / z (M +H) +468.4

[0475] Step 3: Add m-CPBA (195 mg, 0.96 mmol) to a solution of 18-2a (45.0 mg, 0.096 mmol) in DCE (3 mL). Stir the reaction mixture at 70 °C for 12 hr. Concentrate the reaction mixture to obtain a residue, which is then purified by rapid silica gel column chromatography, eluting with 3% MeOH in DCM to give 18-3a. MS (ESI) m / z (M + H) + 484.4 [M+H] +

[0476] Step 4: TEA (36.6 mg, 0.36 mmol) was added to a solution of 18-3a (35.0 mg, 0.072 mmol) and hydroxylamine hydrochloride (25.2 mg, 0.36 mmol) in EtOH (3 mL). The reaction mixture was then stirred at 80 °C for 12 hr. The reaction mixture was concentrated to obtain a residue, which was purified by reverse-phase chromatography (40% ACN in H2O containing 0.5% FA) to give compound 18a.

[0477] Compound 18a: MS (ESI) m / z (M + H) + 517.2. 1 H NMR: (400 MHz, CD3OD) δ8.226 – 8.18 (m, 2H), 7.94 (dd, J = 7.2, 3.2 Hz, 1H), 7.13 – 7.03 (m, 1H),7.03 – 6.94 (m, 1H), 5.09 (d, J = 7.6 Hz, 1H), 4.33 (d, J = 7.6 Hz, 1H), 3.98(d, J = 2.0 Hz, 3H), 2.54 – 2.42 (m, 1H), 2.39 – 2.29 (m, 1H), 2.26 – 2.15(m, 1H), 1.94 – 1.84 (m, 1H), 0.90 (d, J = 1.2 Hz, 3H).

[0478] Compound 18b was prepared using a similar method as described above, using raw material 18-1b.

[0479] Compound 18b: MS (ESI) m / z (M + H) + 517.2.1 H NMR: (400 MHz, CD3OD) δ8.26 – 8.17 (m, 2H), 7.93 (dd, J = 7.2, 3.2 Hz, 1H), 7.09 – 6.94 (m, 2H), 5.08 (d, J = 7.6 Hz, 1H), 4.32 (d, J = 7.6 Hz, 1H), 3.97 (d, J = 2.0 Hz, 3H),2.50 -2.40 (m, 1H), 2.39 – 2.30 (m, 1H), 2.25 – 2.13 (m, 1H), 1.93 – 1.82 (m,1H), 0.89 (s, 3H).

[0480] Example 1.12

[0481]

[0482] In 0 o C. Trimethylaluminum (21.7 mg, 0.301 mmol) was added to a solution of ammonium chloride (14.6 mg, 0.273 mmol) in toluene (3 mL). The reaction system was heated at 25 °C. o Stir at C for 1 h. Then, slowly add compound 16-5 (70.0 mg, 0.137 mmol) to the resulting solution, and incubate the mixture at 80 °C. o Stir at C for 12 hours. Quench the reaction mixture with MeOH (1 mL). Stir the resulting slurry vigorously for 30 min. Filter the reaction mixture through a silica gel pad and wash with MeOH. Concentrate the filtrate under vacuum to give compound 20.

[0483] Compound 20: MS (ESI) m / z (M + H) + 530.2. 1 H NMR: (400 MHz, CD3OD) δ7.77 (dd, J = 6.4, 2.8 Hz, 1H), 7.52-7.47 (m, 1H), 7.18-7.12 (m, 2H), 7.01-6.94 (m, 1H), 5.06 (d, J = 10.8 Hz, 1H), 4.32-4.26 (m, 1H), 4.00 (d, J= 2.4Hz, 3H), 2.84-2.69 (m, 1H), 1.72-1.68 (m, 2H), 1.66 (s, 3H), 1.52- 1.47 (m, 2H), 0.86-0.76 (m, 3H).

[0484] Example 1.13

[0485]

[0486] Step 1: At 0 °C, NaH (152 mg, 3.81 mmol, 60% w / w) and (R)-4-methyl-1,3,2-dioxane-2,2-dioxide (386 mg, 2.79 mmol) were added to a mixture of 21-1 (500 mg, 2.54 mmol) in DMF (15 mL), and the reaction mixture was stirred at 25 °C for 2 hr. Water (10 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by rapid silica gel column chromatography, eluting with a solution of 30% EtOAc in PE, to give 21-2. MS (ESI) m / z (M + H) + 237.2.

[0487] Step 2: To a mixture of Xantphos (61.0 mg, 0.105 mmol), Cs₂CO₃ (1.03 g, 3.16 mmol), and 21-2 (250 mg, 1.054 mmol) in dioxane (10 mL), tert-butyl carbamate (247 mg, 2.109 mmol) and Pd₂(dba)₃ (97 mg, 0.105 mmol) were added, and the reaction mixture was stirred at 100 °C for 12 hr. Water (50 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel column chromatography, eluting with a solution of 30% EtOAc in PE to give 21-3. MS (ESI) m / z (M + H) + 274.2

[0488] Compound 21 was prepared using a method similar to that described in Example 1.8.

[0489] Compound 21: MS (ESI) m / z (M + H) + 543.2, t R =1.754 min. 1 H NMR: (400 MHz, CD3OD) δ 8.25 (d, J = 5.6 Hz, 1H),, 7.66 – 7.61 (m, 1H), 7.58 – 7.48 (m, 1H), 7.15 – 7.07 (m, 1H), 7.04 – 6.91 (m, 1H), 5.03 (d, J = 10.4 Hz, 1H), 4.36 –4.27 (m, 1H), 4.02 – 3.96 (m, 3H), 2.81 – 2.73 (m, 1H), 2.00 – 1.80 (m, 1H),1.64 (s, 3H), 1.28 – 1.21 (m, 2H), 1.18 (d, J = 6.4 Hz, 3H), 0.84 – 0.76 (m,3H).

[0490] Example 1.14

[0491]

[0492] Step 1: PdCl2 (dppf) (0.663 g, 0.906 mmol) was added to a solution of 22-1 (racemic mixture, 7 g, 18.12 mmol), bis(pinacol)diboron (18.41 g, 72.5 mmol), and potassium acetate (5.34 g, 54.4 mmol) in 1,4-dioxane (80 mL). The reaction mixture was then stirred at 80 °C under N2 for 18 hr. The resulting mixture was concentrated to obtain a residue, which was purified by rapid silica gel column chromatography, eluting with a solution of 0–30% EtOAc in PE to give 22-2 (racemic mixture).

[0493] Step 2: Add NaBH4 (3.30 g, 87 mmol) to the mixture of 22-3 (10 g, 43.7 mmol) in MeOH (100 mL). Then stir the reaction mixture at 0 °C under a nitrogen atmosphere for 2 hr. Add water (100 mL) to the reaction mixture. Extract the resulting mixture with EtOAc (20 mL x 3). Wash the combined organic phases with water (100 mL) and brine (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate to give 22-4.

[0494] Step 3: Add TFA (8.00 mL, 104 mmol) to a mixture of 22-4 (8 g, 34.6 mmol) and triethylsilane (33.2 mL, 208 mmol) in DCM (100 mL). Then, stir the reaction mixture at 25 °C under a nitrogen atmosphere for 2 hr. Adjust the pH of the reaction mixture to 8 with saturated NaHCO3 (aqueous solution). Add water (200 mL) to the reaction mixture. Extract the resulting mixture with EtOAc (50 mL x 3). Wash the combined organic phases with water (200 mL) and brine (200 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain the residue. The residue was purified by rapid silica gel column chromatography, eluting with a solution of 0–10% EtOAc in PE, to give 22–5. ¹H NMR (400 MHz, CDCl₃) δ 7.18–7.12 (m, 1H), 6.69–6.63 (m, 1H), 3.01–2.92 (m, 2H), 2.92–2.84 (m, 2H), 2.11–2.00 (m, 2H).

[0495] Step 4: To a solution of 22-5 (1 g, 4.65 mmol) and 22-2 (racemic mixture, 2.032 g, 5.58 mmol) in 1,4-dioxane (10 mL), water (2 mL), PdCl2 (dppf) (0.340 g, 0.465 mmol), and potassium carbonate (1.928 g, 13.95 mmol) were added. The mixture was stirred at 0 °C under a nitrogen atmosphere for 3 hr. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 100 / 1 - 1 / 10) to give 22-6 (racemic mixture). MS (ESI) m / z (M + H) + 373.2.

[0496] Step 5: Add Pd / C (200 mg, 10% w / w) and Pd(OH)₂ (200 mg, 20% w / w) to the mixture of 2-6 (racemic mixture, 1 g, 2.69 mmol) in EtOH (20 mL). Then, stir the reaction mixture at 30 °C under a H₂ atmosphere (3 atm) for 72 hr. Filter the reaction solution, concentrate the filtrate, and obtain the residue. Purify the residue by rapid silica gel column chromatography, eluting with a solution of 0-30% EtOAc in PE, to give 22-7 (racemic mixture). MS (ESI) m / z (M +H) + 375.2.

[0497] Step 6: Add KOH (180 mg, 3.21 mmol) to a solution of 22-7 (racemic mixture, 400 mg, 1.068 mmol) in EtOH (10 mL), and then stir the reaction mixture at 25 °C for 18 hr. Acidify the reaction mixture to pH = 4 with 1 N HCl. Add water (20 mL) to the reaction mixture. Extract the resulting mixture with EtOAc (5 mL x 3). Wash the combined organic phases with water (20 mL) and brine (20 mL), dry with anhydrous sodium sulfate, filter and concentrate to give 22-8 (racemic mixture).

[0498] Step 7: To a solution of 22-8 (racemic mixture, 350 mg, 1.011 mmol), 4-aminopyridinecarboxynitrile (144 mg, 1.213 mmol), and TEA (1 mL, 7.17 mmol) in ethyl acetate (2 mL), T3P (50%, in EA) (1 mL, 1.011 mmol) was added, and the reaction mixture was stirred at 50 °C for 2 hr. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The resulting mixture was extracted with EtOAc (5 mL x 3). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel column chromatography, eluting with a solution of 50 to 100% EtOAc in PE to give 22-9 (racemic mixture). MS (ESI) m / z (M +H) + 448.2.

[0499] Step 8: Add m-CPBA (454 mg, 2.235 mmol) to the mixture of 22-9 (racemic mixture, 100 mg, 0.223 mmol) in DCE (10 mL). Then stir the reaction mixture at 70 °C for 12 hr. Concentrate the reaction mixture to obtain the residue. Purify the residue by rapid silica gel column chromatography, eluting with a solution of 10% MeOH in DCM to give 22-10 (racemic mixture). MS (ESI) m / z (M + H) + 464.4.

[0500] Step 9: Add TEA (0.027 ml, 0.194 mmol) to a solution of 22-10 (racemic mixture, 30 mg, 0.065 mmol) and hydroxylamine (4.28 mg, 0.129 mmol) in EtOH (5 ml), and then stir the reaction mixture at 80 °C for 4 hr. Purify the residue by reverse-phase (50% ACN in H2O (0.5% FA)) to give compound 22 (racemic mixture).

[0501] Compound 22: MS (ESI) m / z (M + H) + 497.2. 1 H NMR (400 MHz, DMSO- d 6 ) δ10.78 – 10.67 (m, 1H), 10.14 (s, 1H), 8.22 – 8.16 (m, 2H), 7.72 – 7.60 (m,1H), 7.22 – 7.09 (m, 1H), 7.00 – 6.90 (m, 1H), 6.80 – 6.75 (m, 2H), 5.08 (d,J = 10.4 Hz, 1H), 4.11 – 4.03 (m, 1H), 2.95 – 2.86 (m, 4H), 2.79 – 2.75 (m,1H), 2.15 – 2.00 (m, 2H), 1.60 (s, 3H), 0.69 (s, 3H).

[0502] The single isomers of 22a and 22b can be separated from compound 22 by the following SFC: (Column: ChiralPak IKDaicel Chemical Industries, Ltd, 250) 40 mm ID, 10 μm; Mobile phase A: supercritical CO2, Mobile phase B: EtOH (0.1% NH3H2O); A:B = 60:40, Flow rate: 140 mL / min; Nozzle pressure: 100 Bar; Column temperature: 38 °C; Wavelength: 220 nm, Rt = 6.1 min, 7.4 min).

[0503] Compound 22a:

[0504] SFC Analysis Method: Instrument: Waters UPCC system equipped with a PDA detector; Column: Daicel ChiralPaK IK 250x4.6 mm_5μm; Column Temperature: 35℃; Flow Rate: 2.0 ml / min; Wavelength: 210 nm; Injection Volume: 5 µl; Sample Concentration: 2.0 mg / ml; Run Time: 8.0 min; Diluent: MEOH; Critical Conditions (CO2): P (2000 psi), T (35℃); Mobile Phase: CO2 : MeOH (0.1% DEA) = 60:40. R = 4.185 min.

[0505] MS (ESI) m / z (M + H) + 497.2. 1 H NMR (400 MHz, MeOD) δ 8.19 (d, J =7.2 Hz, 1H), 8.12 (d, J = 3.2 Hz, 1H), 7.87 (dd, J = 7.2, 3.2 Hz, 1H), 7.14(dd, J = 8.4, 4.6 Hz, 1H), 6.85 (t, J = 8.4 Hz, 1H), 5.08 (d, J = 10.4 Hz,1H), 4.13 (dd, J = 10.4, 8.0 Hz, 1H), 3.05 – 2.83 (m, 4H), 2.83 – 2.70 (m,1H), 2.19 – 2.10 (m, 2H), 1.65 (s, 3H), 0.84 – 0.74 (m, 3H).

[0506] Compound 22b:

[0507] SFC Analysis Method: Instrument: Waters UPCC system equipped with a PDA detector; Column: Daicel ChiralPaK IK 250x4.6 mm_5μm; Column Temperature: 35℃; Flow Rate: 2.0 ml / min; Wavelength: 210 nm; Injection Volume: 5 µl; Sample Concentration: 2.0 mg / ml; Run Time: 8.0 min; Diluent: MEOH; Critical Conditions (CO2): P (2000 psi), T (35℃); Mobile Phase: CO2 : MeOH (0.1% DEA) = 60:40. R = 5.064 min.

[0508] MS (ESI) m / z (M + H) + 497.2. 1 HNMR: (400 MHz, MeOD) δ 8.19 (d, J =7.2 Hz, 1H), 8.12 (d, J = 3.2 Hz, 1H), 7.87 (dd, J = 7.2, 3.2 Hz, 1H), 7.14(dd, J = 8.4, 4.6 Hz, 1H), 6.85 (t, J = 8.4 Hz, 1H), 5.08 (d, J = 10.4 Hz,1H), 4.13 (dd, J = 10.4, 8.0 Hz, 1H), 3.05 – 2.83 (m, 4H), 2.83 – 2.70 (m,1H), 2.19 – 2.10 (m, 2H), 1.65 (s, 3H), 0.84 – 0.74 (m, 3H).

[0509] Example 1.15

[0510]

[0511] Following a similar method to that described in Example 1.14, 23-2 and 23-3 can be prepared using raw material 23-1.

[0512] Et3N (0.04 mL, 0.25 mmol) was added to a mixture of 23-3 (racemic mixture, 25.0 mg, 0.05 mmol) and hydroxylamine hydrochloride (17.9 mg, 0.25 mmol) in EtOH (3 mL). The reaction mixture was then stirred at 80 °C for 3 hr. The reaction mixture was concentrated to give the residue. The residue was purified by reverse-phase reaction (0.5% FA solution in H2O / ACN = 50 / 50) to give compound 23 (racemic mixture).

[0513] Compound 23: MS (ESI) m / z (M + H) + 517.2 [M+H] + . 1 H NMR (400 MHz, CD3OD)δ 8.40 (d, J = 5.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.70 – 7.68 (m, 1H),7.54 – 7.48 (m, 1H), 7.07 (t, J = 8.8 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.20 – 4.13 (m, 1H), 3.22 – 3.10 (m, 1H), 3.04 – 2.95 (m, 1H), 2.86 – 2.76(m, 1H), 2.72 – 2.55 (m, 2H), 1.66 (s, 3H), 0.87 – 0.77 (m, 3H).

[0514] To a solution of 23-3 (racemic mixture, 100 mg, 0.20 mmol) in DCE (3 mL), m-CPBA (420 mg, 2.06 mmol) was added. The reaction mixture was then stirred at 70 °C for 12 hr. The reaction mixture was concentrated to obtain a residue, which was purified by rapid silica gel column chromatography, eluting with 5% MeOH in DCM, to give 2-cyano-4,5-dimethyl-3-(1,1,7-trifluoro-2,3-dihydro-1H-inden-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-formamide)1-oxopyridine (racemic mixture).

[0515] TEA (0.1 mL, 0.75 mmol) was added to a mixture of 2-cyano-4,5-dimethyl-3-(1,1,7-trifluoro-2,3-dihydro-1H-inden-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxypyridine (racemic mixture, 75.0 mg, 0.15 mmol) and hydroxylamine hydrochloride (52.2 mg, 0.75 mmol) in EtOH (5 mL). The reaction mixture was then stirred at 80 °C for 12 hr. The reaction mixture was concentrated to give a residue. The residue was purified by reverse-phase reaction (0.5% FA solution in H2O / ACN = 60 / 40) to give compound 24.

[0516] Compound 24: MS (ESI) m / z (M + H) + 533.2 [M+H] + 1 H NMR (400 MHz, CD3OD) δ8.19 (d, J = 6.4 Hz, 1H), 8.14 (d, J = 3.2 Hz, 1H), 7.88 – 7.85 (m, 1H), 7.53– 7.50 (m, 1H), 7.07 (t, J = 8.8 Hz, 1H), 5.13 (d, J = 10.4 Hz, 1H), 4.19 –4.13 (m, 1H), 3.18 – 3.09 (m, 1H), 3.09 – 2.95 (m, 1H), 2.86 – 2.78 (m, 1H),2.69 – 2.52 (m, 2H), 1.66 (s, 3H), 0.88 – 0.74 (m, 3H).

[0517] Compound 24 was separated by SFC (column: ChiralPak AD-H Daicel Chemical Industries, Ltd, 250). 30 mm ID, 5 μm; Mobile phase A: supercritical CO2, Mobile phase B: EtOH (0.1% NH3H2O); A:B = 75:25, Flow rate: 140 mL / min; Nozzle pressure: 100 Bar; Column temperature: 38 °C; Wavelength: 220 nm), to obtain single isomers of compounds 24a and 24b.

[0518] Compound 24a:

[0519] SFC Analysis Method: Instrument: Waters UPCC system equipped with a PDA detector; Column: Daicel_ChiralCel_OD 100x3 mm_3μm; Column Temperature: 35℃; Flow Rate: 2.0 ml / min; Wavelength: 210 nm; Injection Volume: 5 µl; Sample Concentration: 2.0 mg / ml; Run Time: 4.0 min; Diluent: MEOH; Critical Conditions (CO2): P (2000 psi), T (35℃); Mobile Phase: CO2 : MeOH = 85 : 15. R = 1.476 min

[0520] MS (ESI) m / z (M + H) + 533.2 1 H NMR: (400 MHz, CD3OD) δ 8.20 (d, J =7.2 Hz, 1H), 8.14 (d, J = 3.2 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.54 – 7.50 (m,1H), 7.08 (t, J = 8.8 Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H), 4.20 – 4.12 (m,1H), 3.21 – 3.09 (m, 1H), 3.09 – 2.96 (m, 1H), 2.84 – 2.75 (m, 1H), 2.72 –2.54 (m, 2H), 1.67 (s, 3H), 0.86 – 0.78 (m, 3H).

[0521] Compound 24b:

[0522] SFC Analysis Method: Instrument: Waters UPCC system equipped with a PDA detector; Column: Daicel_ChiralCel_OD 100x3 mm_3μm; Column Temperature: 35℃; Flow Rate: 2.0 ml / min; Wavelength: 210 nm; Injection Volume: 5 µl; Sample Concentration: 2.0 mg / ml; Run Time: 4.0 min; Diluent: MEOH; Critical Conditions (CO2): P (2000 psi), T (35℃); Mobile Phase: CO2 : MeOH = 85 : 15. R = 2.204 min

[0523] MS (ESI) m / z (M + H) + 533.2 1H NMR: (400 MHz, CD3OD) δ 8.19 (d, J =7.2 Hz, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.90 – 7.86 (m, 1H), 7.54 – 7.50 (m,1H), 7.07 (t, J = 8.8 Hz, 1H), 5.13 (d, J = 10.4 Hz, 1H), 4.22 – 4.12 (m,1H), 3.21 – 3.09 (m, 1H), 3.09 – 2.95 (m, 1H), 2.85 – 2.79 (m, 1H), 2.72 –2.56 (m, 2H), 1.66 (s, 3H), 0.86 – 0.78 (m, 3H).

[0524] Compounds 23a and 23b can be prepared using a method similar to that described above.

[0525] Example 1.16

[0526]

[0527] Step 1: Iodobenzene diacetate (3.81 g, 11.8 mmol) was added in a single batch to a mixture of 25-1 (1.00 g, 5.91 mmol) and ammonium acetate (0.683 g, 8.87 mmol) in EtOH (10 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 12 h. The mixture was directly concentrated to obtain a residue, which was purified by silica gel column chromatography (PE:EA = 5:1 to 1:3) to give 25-2. MS (ESI) m / z (M + H) + 201.1; 1 H NMR (400 MHz, DMSO-d6) δ8.65 (t, J = 2.0 Hz, 1H), 8.54 – 8.44 (m, 1H), 8.40 – 8.30 (m, 1H), 7.91 (t, J = 8.0 Hz, 1H), 4.62 (s, 1H), 3.18 (d, J = 0.8 Hz, 3H).

[0528] Step 2: At 0 °C, add EDCI (211 mg, 1.099 mmol), DMAP (268 mg, 2.20 mmol), and 25-2 (200 mg, 1.00 mmol) to a solution of tetrahydrofuran-2-carboxylic acid (128 mg, 1.10 mmol) in CH2Cl2 (2 ml). Then, stir the reaction suspension at 25 °C under a N2 atmosphere for 12 hr. Dilute the reaction suspension with water (5 mL) and EtOAc (4 mL). 3) Extraction. The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give 25–3 μL MS (ESI). m / z (M + H) + 299.1.

[0529] Step 3: Add Pd(OH)₂ / C (50 mg) to a solution of 25-3 (450 mg, 1.51 mmol) in MeOH (20 mL). Then, stir the reaction suspension at 25 °C under a H₂ atmosphere (45 psi) for 2 hours. Filter the reaction suspension and concentrate under reduced pressure to obtain 25-4. LCMS: MS (ESI) m / z (M + H) + 269.1; 1 H NMR (400 MHz, DMSO-d6) δ 7.26 (t, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H),6.89 - 6.80 (m, 1H), 5.73 (s, 2H), 4.30 - 4.21 (m, 1H), 3.86 - 3.69 (m, 2H),3.37 - 3.34 (m, 3H), 2.18 - 2.06 (m, 1H), 1.96 - 1.71 (m, 3H).

[0530] Step 4: DIEA (0.044 mL, 0.254 mmol) was added to a solution of 25-4 (25.0 mg, 0.093 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (30 mg, 0.085 mmol) in DCM (1 mL), followed by dropwise addition of T4P (9.15 mg, 0.127 mmol). The mixture was stirred at 25 °C under a N2 atmosphere for 2 h. The sample was then analyzed by preparative HPLC (column: Boston Prime C18 150). 30mm 5 μm; mobile phase: [water (NH3H2O-NH4HCO3)-MeCN]; B%: 44%-74%, 9 min) to purify the reaction suspension to obtain compound 25 (a mixture of 4 isomers).

[0531] Compound 25: MS (ESI) m / z (M + H) + 605.3; 1 H NMR (400 MHz, CD3OD) δ 8.46- 8.34 (m, 1H), 7.90 - 7.78 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.68 - 7.54(m, 1H), 7.20 - 7.07 (m, 1H), 7.05 - 6.92 (m, 1H), 5.11 - 5.05 (m, 1H), 4.45– 4.37 (m, 1H), 4.36 - 4.27 (m, 1H), 4.00 (s, 3H), 4.00 - 3.81 (m, 2H), 3.39 (s, 3H), 2.85 - 2.70 (m, 1H), 2.31 - 2.17 (m, 1H), 2.09 - 1.95 (m, 1H), 1.95- 1.79 (m, 2H), 1.67 (s, 3H), 0.87 - 0.75 (m, 3H).

[0532] Example 1.17

[0533]

[0534] Compound 26-2 can be prepared using (tert-butoxycarbonyl)proline as a starting material, following a similar method as described in Example 1.16.

[0535] The mixture of 26-2 (20 mg, 28 µmol) in HCl / dioxane (1 mL, 2 M) was stirred at 25 °C for 1 h. The combined reaction mixture was concentrated under reduced pressure to give the residue. Preparative HPLC was performed (column: Boston Prime C18150). 30mm 5 μm; mobile phase: [water (NH3H2O-NH4HCO3)-ACN]; B%: 46%-86%, 9 min) to purify the crude product and obtain compound 26 (a mixture of 4 isomers).

[0536] Compound 26: MS (ESI) m / z (M + H) + 604.1; 1 H NMR (400 MHz, CD3OD) δ: 8.46- 8.36 (m, 1H), 7.89 - 7.80 (m, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.64 - 7.58(m, 1H), 7.17 - 7.10 (m, 1H), 7.04 - 6.94 (m, 1H), 5.08 (d, J = 10.8 Hz, 1H),4.36 - 4.26 (m, 1H), 4.00 (d, J = 2.0 Hz, 3H), 3.74 – 3.65 (m, 1H), 3.40 (s,3H), 3.18 – 2.93 (m, 1H), 2.88 – 2.72 (m, 2H), 2.23 – 2.07 (m, 1H), 1.98 –1.84 (m, 1H), 1.81 - 1.68 (m, 2H), 1.67 (s, 3H), 0.85 - 0.78 (m, 3H).

[0537] Example 1.18

[0538]

[0539] Step 1: To a mixture of 23-2 (racemic mixture, 50 mg, 0.13 mmol), pyridine-4-amine (24.6 mg, 0.26 mmol), and Et3N (0.50 mL, 3.59 mmol) in EA (5 mL), T3P (50%, in EA) (0.5 mL, 0.13 mmol) was added. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to obtain a residue, which was purified by rapid silica gel column chromatography, eluting with 5% MeOH in DCM to give 27-1 (racemic mixture). MS (ESI) m / z (M +H) + 459.2.

[0540] Step 2: Add m-CPBA (26 mg, 0.151 mmol) to a solution of 27-1 (23 mg, 0.05 mmol) in DCM (5 mL). Stir the mixture at 25 °C for 18 hr. Concentrate the reaction mixture to obtain a residue, which is then purified by rapid silica gel column chromatography, eluting with a solution of 4% MeOH in DCM to give compound 27.

[0541] Compound 27: MS (ESI) m / z (M + H) + 475.2. 1 H NMR (400 MHz, DMSO) δ 8.24– 8.19 (m, 2H), 7.88 – 7.82 (m, 2H), 7.52 (dd, J = 8.4, 4.4 Hz, 1H), 7.07 (t,J = 8.8 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.15 (dd, J = 10.4, 8.0 Hz, 1H), 3.20 – 2.96 (m, 2H), 2.86 – 2.70 (m, 1H), 2.70 – 2.50 (m, 2H), 1.66 (s, 3H), 0.87 – 0.74 (m, 3H).

[0542] Compounds 27a and 27b can be separated by SFC using a method similar to that described in Example 1.15.

[0543] The following molecules can be prepared using a method similar to that described in Example 1.18.

[0544]

[0545] Example 1.19 Preparation of compound 30a

[0546]

[0547] Step 1: To a solution of compound 30a-1 (20.0 g, 79.6 mmol) in mesitylene (350 mL), add 30a-2 (20.3 g, 119 mmol), DMAP (973 mg, 7.97 mmol), allyl(chloro)palladium (582 mg, 1.59 mmol), and BINAP (2.98 g, 4.78 mmol). Stir the mixture at 140 °C for 12 hr. Cool the mixture to room temperature, filter to obtain the filtrate, and purify by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 100 / 5) to give compound 30a-3. 1 HNMR (400 MHz, CDCl3) δ 7.34 (dd, J = 4.7, 8.3 Hz, 1H), 6.98 (t, J =8.6 Hz, 1H), 4.23 - 4.11 (m, 2H), 3.57 (s, 2H), 3.03 (tt, J = 3.2, 6.7 Hz,2H), 2.77 - 2.55 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0548] Step 2: Add NaOH (3 M, 100 mL) to a solution of compound 30a-3 (26.0 g, 100 mmol) in MeOH (90 mL) and THF (160 mL). Stir the mixture at 25 °C for 2 hours. Dilute the mixture with H2O (300 mL) and dilute with DCM (100 mL). 3) Extraction. Adjust the pH of the mixture to 1 with an aqueous HCl solution (3 M), and then extract with DCM (100 mL). 3) Extraction. The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to give compound 30a-4. 1 HNMR (400MHz, CDCl3) δ 7.34 (br dd, J= 4.6, 8.1 Hz, 1H), 7.07 - 6.94 (m, 1H), 3.62 (s, 2H), 3.26 - 2.96 (m, 2H), 2.78 - 2.54 (m, 2H).

[0549] Step 3: At 0 °C, add CDI (17.0 g, 104 mmol) to a solution of 30a-4 (23.0 g, 99.9 mmol) in ACN (230 mL). Stir the mixture at 25 °C for 2 hr. Add compound 30a-5 (53.13 g, 108.91 mmol) and K2CO3 (17.2 g, 124 mmol), and stir the mixture at 50 °C for 12 hr. Wash the mixture with H2O (250 mL) and MTBE (100 mL). 3) Extraction. The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was ground with IPA (90 mL) and H2O (200 mL) at 25 °C for 30 min to give compound 30a-6. 1 HNMR (400 MHz, CDCl3) δ 7.30 (dd, J = 4.6, 8.4 Hz, 1H), 7.10 (t, J = 8.6 Hz,1H), 2.94 (br s, 2H), 2.72 - 2.50 (m, 2H), 2.09 (s, 3H), 1.78 (d, J = 0.6 Hz, 3H).

[0550] Step 4: At -40 °C, add NiCl2 to a solution of 30a-6 (21.0 g, 59.9 mmol) in MeOH (200 mL) and THF (100 mL). 6H₂O (71.2 g, 299 mmol). After addition, NaBH₄ (36.2 g, 959 mmol) was added in portions over 30 min at -40 °C. The resulting mixture was stirred at -40 °C for 2 hr. The reaction mixture was quenched with NH₄Cl (300 mL) at -40 °C and then extracted with DCM (500 mL). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 30a-7.1 H NMR (400 MHz, CDCl3) δ 7.38 (dd, J =4.6, 8.4 Hz, 1H), 7.08 (t, J = 8.7 Hz, 1H), 4.32 (d, J = 9.3 Hz, 1H), 3.17 -2.97 (m, 1H), 2.95 - 2.82 (m, 2H), 2.77 - 2.58 (m, 2H), 1.74 (s, 3H), 0.80(qd, J = 2.3, 7.4 Hz, 3H).

[0551] Step 5: At -30 °C and under a N2 atmosphere, DIBAL-H (1 M, 34.6 mL) was added to a solution of compound 30a-7 (11.5 g, 32.6 mmol) in toluene (150 mL), and the reaction was allowed to proceed for 10 min. The mixture was then stirred at -30 °C and under a N2 atmosphere for 30 min. An aqueous solution of potassium sodium tartrate (42.7 g in 200 mL) was added at 0 °C and under a N2 atmosphere, and the reaction was allowed to proceed for 30 min. The mixture was then warmed to 25 °C and stirred for 2.5 hr, and MTBE (100 mL) was added. 1) Extraction. The organic layer was concentrated to obtain compound 30a-8.

[0552] Step 6: To a solution of compound 30a-8 (12.5 g, 35.2 mmol) in toluene (125 mL), TEA (3.71 g, 36.6 mmol, 5.11 mL) and DMAP (43.1 mg, 352 μmol) were added. Then, Ac₂O (3.67 g, 35.9 mmol, 3.38 mL) was added at 15 °C under a N₂ atmosphere. The mixture was then stirred at 25 °C for 2 hr. The mixture was washed with NH₄Cl aqueous solution (150 mL) and MTBE (50 mL). 1) Extraction. The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to give compound 30a-9.

[0553] Step 7: At -30 °C and under N2, add TMSCN (2.25 g, 22.7 mmol) to a solution of compound 30a-9 (6.00 g, 15.1 mmol) in toluene (60 mL), and then add BF3 dropwise at -30 °C. Et₂O (2.15 g, 15.1 mmol). The mixture was stirred at -20 °C for 2 hours. The reaction mixture was quenched at -20 to 0 °C with a 2 M, 30 mL aqueous solution of KOH. The solution was then quenched with toluene (60 mL). 3) Extract the mixture. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 30a-10.

[0554] Step 8: Add KOH (2 M, 3.44 mL) to a solution of compound 30a-10 (500 mg, 1.38 mmol) in EtOH (3.44 mL). Stir the mixture at 100 °C for 2 hours. Adjust the pH of the mixture to 1 with an aqueous HCl solution (2 M) and then add MTBE (5 mL). 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 30a-11. 1 H NMR (400 MHz, CDCl3-) d 6 ) δ 7.40 – 7.25 (m, 1H), 7.03 (t, J = 8.4 Hz, 1H), 4.97 (d, J = 10.0Hz, 1 H), 3.89 (t, J = 9.2 Hz, 1 H), 3.08 – 3.10 (m, 1H), 2.95 – 2.83 (m,1H), 2.75 – 2.55 (m, 3H), 1.60 (s, 3H), 0.85 – 0.75 (m, 3H).

[0555] Step 9: At 0 °C, add (COCl)₂ (99.60 mg, 784.73 μmol) dropwise to a solution of 30a-11 (150 mg, 392.37 μmol) in DCM (5 mL), followed by the addition of DMF (573.59 μg, 7.85 μmol) at 0 °C. Stir the resulting mixture at 0 °C for 1 hr. Then concentrate the mixture to obtain the residue. At 0 °C, add the residue (1 mL) in DCM to a solution of 30a-12 (49.87 mg, 340.25 μmol) and TEA (124.99 mg, 1.24 mmol) in DCM (2 mL). Stir the resulting mixture at 0 °C under a N₂ atmosphere for 30 min. Partition the reaction mixture between NH₄Cl (5 mL aqueous solution) and DCM (5 mL). The organic phase was separated, washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO₂, DCM: MeOH = 10:1) to give compound 30a. MS (ESI) m / z (M + H) + 475.3. 1 H NMR (400 MHz, CDCl3) δ ppm 8.96 (s, 1H), 8.65 (s, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.67 (d, J=8.8 Hz,1H), 7.60 – 7.40 (m, 1H), 7.25 – 7.15 (m, 1H), 7.08 (t, J 1.66 (s, 3H), 0.90 – 0.75 (m, 3H).

[0556] The following molecules can be prepared using methods similar to those described above.

[0557]

[0558]

[0559] Example 1.19

[0560]

[0561] Step 1: Add K₂CO₃ (32.6 g, 236 mmol) to a mixture of 32-1 (10 g, 79 mmol) and methyl 2,4-dibromobutyrate (20.45 g, 79 mmol) in acetonitrile (120 mL). Heat the mixture at 60 °C. o Stirred at C for 16 hours. The reaction mixture was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 32-2 MS (ESI). m / z (M + H) + 226.0.

[0562] A mixture of 32-2 (1 g, 4.44 mmol) and NH3-MeOH (7 mol / L) (20 mL, 140 mmol) was prepared at 30 °C. o Stir at C for 16 hours. Filter and concentrate the reaction mixture to obtain the residue. Purify the residue by rapid silica gel column chromatography, eluting with a solution of 50-55% EtOAc in PE to give 32-3. MS (ESI). m / z (M + H) + 211.0.

[0563] Step 2: Dissolve 32-3 (1.5 g, 7.14 mmol) and Burgess reagent (6.80 g, 28.5 mmol) in THF (100 mL) at 25°C. o Stir at C for 2 hours. Quench the mixture with H₂O (100 mL) and extract with EA (100 mL x 2). Wash the combined organic phases with brine, dry with anhydrous sodium sulfate, and concentrate under vacuum to give 32-4. MS (ESI) m / z (M + H) + 193.2

[0564] Step 3: In 0 o C, 4,4'-bipyridine (4.06 mg, 0.026 mmol) was added to a solution of 32-5 (500 mg, 2.60 mmol) and tetrahydroxydiboron (1166 mg, 13.01 mmol) in DMF (20 mL), and the mixture was heated at 0... oStir at C for 5 min. Quench the mixture with H2O (20 mL) and extract with EA (50 mL x 3). Wash the combined organic phases with brine and dry with anhydrous sodium sulfate, then concentrate under vacuum to give the residue. Purify the residue by rapid column chromatography (0-5% MeOH solution in DCM) to give 32-5 MS (ESI). m / z (M + H) + 163.2.

[0565] Step 4: To a mixture of 32-5 (50 mg, 0.308 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (98 mg, 0.277 mmol) in ethyl acetate (5 mL), add TEA (0.215 mL, 1.541 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphonane 2,4,6-trioxide (589 mg, 0.925 mmol), and heat the mixture at 25°C. o Stirring at C for 2 h. The mixture was then concentrated under vacuum to obtain a residue. The residue was purified by rapid column chromatography (0-5% MeOH solution in DCM) to obtain 32-6. MS (ESI) m / z (M + H) + 499.2. 1 H NMR: (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.12 –7.08 (m, 1H), 7.01 – 6.90 (m, 1H), 5.08 (d, J = 10.8 Hz, 1H), 4.26 (dd, J =10.8, 8.0 Hz, 1H), 3.98 (d, J = 2.4 Hz, 3H), 2.76 (t, J = 7.6 Hz, 1H), 2.14(s, 3H), 1.76 (dt, J = 3.6, 2.4 Hz, 4H), 1.64 (s, 3H), 0.84 – 0.77 (m, 3H).

[0566] Step 5: Add TEA (0.063 mL, 0.451 mmol) to a solution of 32-6 (45 mg, 0.090 mmol) and hydroxylamine hydrochloride (18.82 mg, 0.271 mmol) in ethanol (5 mL), and incubate the mixture at 80 °C. o Stirred at C for 12 h. The mixture was concentrated under vacuum to obtain a residue. The residue was purified by rapid column chromatography (0-5% of MeOH in DCM) to give compound 32.

[0567] Compound 32: MS (ESI) m / z (M + H) + 532.2. 1 H NMR: (400 MHz, CD3OD) δ7.88 (s, 1H), 7.17 – 7.05 (m, 1H), 7.03 – 6.90 (m, 1H), 5.07 (d, J = 10.6 Hz, 1H), 4.25 (dd, J = 10.6, 8.0 Hz, 1H), 3.97 (d, J = 2.4 Hz, 3H), 2.83 – 2.69(m, 1H), 2.11 (s, 3H), 1.64 (s, 3H), 1.50 – 1.39 (m, 2H), 1.37 – 1.27 (m,2H), 0.85 – 0.75(m, 3H).

[0568] Example 1.20

[0569]

[0570] Step 1: Add a solution of 33-1 (9 g, 61.6 mmol) in acetonitrile (50 mL) to a 100-mL round-bottom flask. Then, add potassium tert-butoxide (7.74 g, 69.0 mmol) in portions at room temperature. Stir the resulting solution at room temperature for 1.5 h. Collect the solid formed by filtration to obtain 33-2. 1 H NMR (400 MHz, DMSO- d 6) δ 4.09 (s, 1H), 4.01 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H).

[0571] Step 2: At 0 °C, sulfuric acid (3.47 mL, 65.2 mmol) was added dropwise to a mixture of methylhydrazine (8.43 g, 73.2 mmol) in MeOH (120 mL). The mixture was stirred at 25 °C for 0.5 h, and then 33-2 (9.2 g, 65.2 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 20.5 h. After completion, the mixture was diluted with EtOAc (100 mL) and washed with water (100 mL x 2). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:THF = 2:1) to give compound 33-3. LCMS: MS (ESI) m / z (M + H) + 170.1; 1 H NMR (400 MHz, CDCl3) δ = 6.09 (s, 1H),4.37 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 3.34 (s, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0572] Step 3: Under a nitrogen atmosphere and at 0 °C, T4P (763 mg, 1.06 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (250 mg, 0.706 mmol), 33-3 (131 mg, 0.776 mmol), and DIEA (0.37 mL, 2.12 mmol) in DCM (5 mL). The reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated to obtain a residue, which was purified by rapid silica gel chromatography and eluted with PE / EA (2:1) to give compound 33-4. MS (ESI) m / z (M + H) + 506.2.

[0573] Step 4: Treat the suspension of ammonium chloride (58.2 mg, 1.09 mmol) in toluene (2 ml) dropwise with trimethylaluminum (0.495 ml, 0.989 mmol). After stirring for 30 min, add 33-4 (100 mg, 0.198 mmol) in toluene (2 ml). Heat the resulting solution at 90 °C for 16 h, then cool to 0 °C, add MeOH (0.080 ml, 1.978 mmol), warm the reaction mixture to room temperature, and stir for 30 min. Add methanol, and filter the suspension through a Celite filter. Concentrate the combined reaction mixture under reduced pressure to obtain the residue. Purify the crude product by preparative HPLC (column: Boston Prime C18 150). 30mm 5 μm; mobile phase: [water(FA)-ACN]; B%: 22%-52%, 9 min), to obtain compound 33.

[0574] Compound 33: MS (ESI) m / z (M + H) + 476.2; 1 H NMR (400 MHz, CD3OD) δ 7.20 -7.12 (m, 1H), 7.04 - 6.95 (m, 1H), 6.96 (s, 1H), 5.16 (d, J = 10.8 Hz, 1H), 4.29 (dd, J = 10.8, 8.0 Hz, 1H), 4.00 (d, J = 2.4 Hz, 3H), 3.80 (s, 3H), 2.86– 2.72 (m, 1H), 1.68 (s, 3H), 0.87 - 0.80 (m, 3H).

[0575] Example 1.21

[0576]

[0577] Step 1: A mixture of 34-1 (19.4 g, 122.36 mmol), 34-2 (19.34 g, 144.39 mmol), Pd(dppf)Cl2 (5.00 g, 6.12 mmol), and Cs2CO3 (79.74 g, 244.73 mmol) in 2-MeTHF (230 mL) and H2O (23 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C under N2 atmosphere for 12 hr. The reaction mixture was partitioned between NH4Cl (150 mL) and EtOAc (300 mL). The organic layer was separated, washed with 400 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1–10 / 1) to give compound 34-3. 1 H NMR (400 MHz, CDCl3) δ ppm9.39 (d, J = 2.5 Hz, 1H), 8.44 (dd, J = 2.6, 8.6 Hz, 1H), 7.49 (d, J = 8.6Hz, 1H), 6.91 (dd, J = 10.8, 17.4 Hz, 1H), 6.46 (d, J = 17.4 Hz, 1H), 5.75(d, J = 10.8 Hz, 1H).

[0578] Step 2: Degas the mixture of 34-3 (9 g, 59.95 mmol), OsO4 (304.80 mg, 1.20 mmol), and NMO (21.07 g, 179.84 mmol) in acetone (90 mL) and H2O (45 mL), purging it three times with N2. Then, stir the mixture at 25 °C under N2 atmosphere for 4 hr. Partition the reaction mixture between EtOAc (100 mL) and water (150 mL). Separate the organic phase, wash with brine (100 mL), dry with Na2SO4, filter, and concentrate under reduced pressure to obtain 34-4, which was used directly in the next step without further purification.

[0579] Step 3: Degas the mixture of 34-4 (6.9 g, 37.47 mmol), 34-5 (4.68 g, 44.96 mmol), and ZrCl4 (873.18 mg, 3.75 mmol) in THF (140 mL) and purge three times with N2. Then, stir the mixture at 25 °C under N2 atmosphere for 12 hours. Pour the combined reaction mixture into water (50 mL), extract with ethyl acetate (100 mL), dry with Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1–3 / 1) to obtain 34-6. 1 H NMR (400 MHz, DMSO- d 6) δ ppm 9.32 (d, J =2.4 Hz, 1H), 8.62 (dd, J = 2.6, 8.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 5.27(t, J = 6.5 Hz, 1H), 4.45 (dd, J = 7.2, 8.3 Hz, 1H), 3.91 (dd, J = 6.0, 8.4Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H).

[0580] Step 4: Under a nitrogen atmosphere, add Pd / C (3 g, 10% purity) in THF (30 mL) and MeOH (30 mL) to a solution of 34-6 (3 g, 13.38 mmol) in THF (30 mL). Degas the suspension and purge it three times with H2. Stir the mixture at 25 °C for 12 hours under a H2 (15 Psi) atmosphere. Filter the reaction mixture and concentrate under reduced pressure to give 34-7, which is used for the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6) δ ppm 7.87 (d, J =2.4 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.92 (dd, J = 2.7, 8.3 Hz, 1H), 5.30(s, 2H), 4.92 (t, J = 6.9 Hz, 1H), 4.21 (dd, J = 6.5, 8.0 Hz, 1H), 3.79 (t, J= 7.7 Hz, 1H), 1.40 (s, 3H), 1.36 (s, 6H).

[0581] Step 5: At 0 °C under a N2 atmosphere, (COCl)₂ (33.2 mg, 261 μmol) was added to a solution of 30a-11 (50.0 mg, 130 μmol) and DMF (191 μg, 2.62 μmol) in DCM (1 mL), and then stirred at 25 °C for 1 hr. The reaction mixture was concentrated to give a yellow oily residue, which was added at 0 °C under a N2 atmosphere to a solution of compound 34-7 (25.2 mg, 129 μmol) in TEA (18.3 mg, 181 μmol) / DCM (1 mL). The mixture was then stirred at 0 °C for 15 min. Water (20 mL) was added, followed by DCM (20 mL). 3) Extract the mixture. The combined organic layers were dried with Na₂SO₄, filtered, and concentrated to obtain the residue, which was then analyzed by preparative-TLC (petroleum ether:ethyl acetate = 1:1, P1 R). f = 0.42) Purification yielded compound 34-8. MS (ESI) m / z (M + H) + 559.2.

[0582] Step 6: A solution of 34-8 (6.01 mg, 10.7 μmol) in HCl / EtOAc (2 M, 1 mL) was stirred at 25 °C for 0.5 hr. NaHCO3 (aq. 40 mL) was added and mixed with DCM (10 mL). 3) Extract the mixture. Combine the organic layers and dry with Na2SO4, filter and concentrate to obtain the residue, which is purified by preparative-TLC (dichloromethane:methanol = 10:1) to give compound 34. MS (ESI) m / z (M + H) + 519.2. 1 H NMR: (400 MHz, CDCl3) δ 8.60 (s,1 H) 8.39 (s, 1 H) 8.05 - 8.17 (m, 1 H) 7.51 (dd, J = 8.38, 4.50 Hz, 1 H) 7.33 (d, J = 8.38 Hz, 1 H) 7.08 (t, J = 8.69 Hz, 1 H) 5.11 (d, J= 10.51 Hz,1 H) 4.81 (s, 1 H) 3.88 - 3.97 (m, 2 H) 3.40 - 3.60 (m, 1 H) 3.01 - 3.15 (m,1 H) 2.75 - 2.95 (m, 1 H) 2.60 - 2.72 (m, 3 H) 1.69 (s, 3 H) 0.80 - 0.84 (m, 3 H)

[0583] Step 7: At 0 °C, add m-CPBA (10.0 mg, 46.3 μmol, 80.0% purity) to a solution of 34-8 (7.00 mg, 12.5 μmol) in DCM (0.5 mL), and then stir at 25 °C for 1 hr. Quench the reaction mixture with Na2SO3 aqueous solution (10 mL) and then with DCM (10 mL). 3) Extraction. The organic layers were combined and dried over Na₂SO₄, filtered, and concentrated to give compound 35-1. MS (ESI) m / z (M + H) + 575.2.

[0584] Step 8: Stir the solution of 35-1 (7.00 mg, 12.1 μmol) in HCl / EtOAc (2 M, 1 mL) at 25°C for 0.5 hr. Add 40 mL of NaHCO3 aqueous solution to the reaction mixture and stir with DCM (10 mL). 3) Extraction. The organic layers were combined, dried with Na₂SO₄, filtered, and concentrated to obtain the residue, which was purified by preparative TLC (dichloromethane:methanol = 10:1) to give compound 35. MS (ESI) m / z (M + H) + 535.2 1 H NMR (400 MHz, CDCl3) δ 8.54 - 8.72 (m, 2 H) 7.30-7.60 (m, 3 H) 6.98 (t, J = 8.38 Hz, 1 H) 4.87 -5.09 (m, 2 H) 3.74 - 3.97 (m, 3 H) 2.92 - 3.07 (m, 1 H) 2.72 - 2.88 (m, 1 H)2.46 - 2.65 (m, 3 H) 1.59 (s, 3 H) 0.72 (d, J = 6.50 Hz, 3 H).

[0585]

[0586] By preparing a type-SFC (column: DAICL CHIRALCEL OD (250mm)) column (30 mm, 10 μm); mobile phase: [CO2-MeOH(0.1%NH3H2O)]; B%: 25%, isocratic elution mode) can prepare the R-isomer and S-isomer of 34-7. Two peaks (P1 and P2) can be obtained.

[0587] 34-7-P1: SFC Analysis Method: Column: Chiralpak IK-3 50 x 4.6 mm ID, 3 μm; Mobile Phase: Phase A (hexane), Phase B (IPA); Isocratic Elution: B in A, 15%; Flow Rate: 1 mL / min; Detector: PDA; Column Temperature: 35°C; Run Time: 10.0 min. R : 5.102 min.

[0588] 1 H NMR (400 MHz, DMSO) δ 7.86 (d, J = 2.50 Hz, 1 H) 7.11 (s, 1 H) 6.92(dd, J = 8.32, 2.69 Hz, 1 H) 5.30 (s, 2 H) 4.92 (t, J = 6.94 Hz, 1 H) 4.21(dd, J = 8.00, 6.50 Hz, 1 H) 3.79 (t, J = 7.75 Hz, 1 H) 1.40 (s, 3 H) 1.36 (s, 3 H)

[0589] 34-7-P2: SFC Analytical Method: Column: Chiralpak IK-3 50 x 4.6 mm ID, 3 μm; Mobile Phase: Phase A (hexane), Phase B (IPA); Isocratic Elution: Phase A of Phase B, 15%; Flow Rate: 1 mL / min; Detector: PDA; Column Temperature: 35°C; Run Time: 10.0 min. R 7.580 min

[0590] 1 H NMR: (400 MHz, DMSO) δ7.87 (d, J=2.63 Hz, 1 H) 7.12 (d, J=8.38 Hz,1 H) 6.92 (dd, J=8.32, 2.69 Hz, 1 H) 5.30 (s, 2 H) 4.92 (t, J=6.94 Hz, 1 H)4.21 (dd, J=8.00, 6.38 Hz, 1 H) 3.79 (t, J=7.69 Hz, 1 H) 1.40 (s, 3 H) 1.36 (s, 3 H)

[0591] Compounds 35a and 35b were prepared using 34-7-P1 and 34-7-P2 as raw materials, respectively, as described above.

[0592] 35a: MS (ESI) m / z (M + H) + 535.2. 1 H NMR (400 MHz, CDCl3) δ 8.84 (s,1 H) 8.69 (s, 1 H) 7.42 - 7.59 (m, 2 H) 7.20 - 7.40 (m, 1 H) 6.90 - 7.20 (m,1 H) 4.95 - 5.20 (m, 2 H) 3.84 - 4.00 (m , 2 H) 3.67 - 3.84 (m, 1 H) 2.98 -3.16 (m, 1 H) 2.81 - 2.96 (m, 1 H) 2.54 - 2.74 (m, 3 H) 1.65 (s, 3 H) 0.79 (s, 3 H).

[0593] 35b: MS (ESI) m / z (M + H) + 535.2. 1 H NMR (400 MHz, CDCl3) δ 8.94 (s,1 H) 8.69 (s, 1 H) 7.42 - 7.54 (m, 2 H) 7.26 - 7.40 (m, 1 H) 7.03 (t, J =8.50 Hz, 1 H) 5.07 (d, J= 10.38 Hz, 2 H) 3.85 - 4.02 (m, 2 H) 3.65 - 3.78(m, 1 H) 3.00 - 3.16 (m, 1 H) 2.78 - 2.93 (m, 1 H) 2.55 - 2.72 (m, 3 H) 1.64(s, 3 H) 0.77 (d, J = 5.88 Hz, 3 H)

[0594] The following molecules can be prepared using a method similar to that described above. Compounds 36a and 36b were prepared using 34-7-P1 and 34-7-P2 as starting materials, respectively, according to the method described above. Compounds 37a and 37b were prepared using 34-7-P1 and 34-7-P2 as starting materials, respectively, according to the method described above.

[0595]

[0596]

[0597] Example 1.22

[0598]

[0599] Step 1: At 25 °C, (Boc)₂O (5.85 mL, 25.2 mmol) and 4-dimethylaminopyridine (2.1 g, 16.79 mmol) were added to a solution of 42-1 (2.0 g, 16.79 mmol) in DCM (20 mL). After addition, the resulting mixture was stirred at 25 °C for 1.5 hr. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue, which was purified by column chromatography (SiO₂, PE: EtOAc = 10:10⁻⁵:1) to give 42-2. MS (ESI) m / z 320.3 (M+H) + .

[0600] Step 2: At -78 °C, tetraisopropoxytitanium (6.2 g, 21.92 mmol) was added to a solution of 42-2 (3.5 g, 10.96 mmol) in THF (40 mL). After addition, the mixture was stirred at -78 °C for 0.5 hr. Ethyl magnesium bromide (43.8 mL, 43.8 mmol) was added dropwise, and the mixture was stirred at -78 °C for 1.5 hr. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by rapid silica gel chromatography (SiO2, PE: EtOAc = 5:1 to 3:1) to give 42-3. MS (ESI) m / z 250.4 (M+H) + .

[0601] Step 3: At 0 °C, sodium bicarbonate (0.7 g, 8.82 mmol) and Cbz-Cl (6.62 mmol) were added to a solution of 42-3 (1.1 g, 4.41 mmol) in DCM (20 mL). After addition, the resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into water (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue, which was purified by rapid silica gel chromatography (SiO2, PE:EtOAc = 3:1 to 2:1) to give 42-4. MS (ESI) m / z 384.4 (M+H) + . 1 H NMR (400 MHz, methanol-) d 4) δ 8.15 (d, J = 5.7 Hz, 1H), 7.66 – 7.10 (m, 7H), 5.11 (s, 2H), 1.55 –1.48 (m, 11H), 1.30 – 1.20 (m, 2H).

[0602] Step 4: At 25 °C, TFA (1.0 mL, 13.04 mmol) was added to a solution of 42-4 (200.0 mg, 0.52 mmol) in DCM (5 mL). After addition, the resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 42-5, which was used for the next step without further purification. MS (ESI) m / z 284.4 (M+H) + .

[0603] Step 5: Using 42-5 as a raw material, 42-6 can be prepared according to the method described in the above examples. MS (ESI) m / z 648.2 (M+H) + .

[0604] Step 6: At 25 °C, Pd / C (10.0 mg, 10% w / w) was added to a solution of 42-6 (20.0 mg, 0.03 mmol) in MeOH (5 mL). After addition, the resulting mixture was degassed and purged three times with H2 (15 psi), then stirred for 1 hr under H2 atmosphere. The resulting mixture was filtered through Celite, and the filter cake was washed with MeOH (20 mL). The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Welch Triart C18 250 × 21.2 mm × 10 μm; mobile phase: [water (0.1% TFA) - ACN]; B%: 40% - 60%, 20 min) to give compound 42. MS (ESI) m / z 514.4 (M+H) + . 1 H NMR (400 MHz, methanol-) d 4) δ 8.43 (d, J = 5.6 Hz, 1H), 7.54 –7.51 (m, 2H), 7.46 (dd, J = 5.6, 1.9 Hz, 1H), 7.07 (t, J = 8.8 Hz, 1H), 5.14(d, J = 10.5 Hz, 1H), 4.14 (dd, J = 10.5, 7.9 Hz, 1H), 3.18 – 3.09 (m, 1H), 3.08 – 3.01 (m, 1H), 2.85 – 2.75 (m, 1H), 2.70 – 2.57 (m, 2H), 1.67 – 1.65(m, 3H), 1.51 – 1.46 (m, 2H), 1.46 – 1.42 (m, 2H), 0.84 – 0.80 (m, 3H).

[0605] Example 2: The compounds disclosed herein affect sodium ion channel 1.8 (Na V 1.8) inhibitory activity

[0606] 1. Test Method: Patch-clamp technique was used to test the compound's effect on voltage-gated sodium channels 1.8 (Na).V 1.8) Influence of subtype current.

[0607] 2. Preparation and analysis of drug formulations

[0608] 2.1. Preparation method of stock solution of drug formulation

[0609] Control: Weigh an appropriate volume of DMSO as a stock solution.

[0610] Test compound: Weigh an appropriate mass of the compound (actual amount = theoretical concentration × volume × molecular weight / purity), calculate the required volume of DMSO according to the formula, and then obtain the final required mass of DMSO. Then, dissolve the powder with the weighed DMSO. Calculate the actual stock solution concentration based on the final DMSO usage. Typically, the actual stock solution concentration differs slightly from the theoretical concentration.

[0611] 2.2. Preparation method and concentration of working solution for drug delivery formulation

[0612] In Na V Before the channel current test, the control and test compound stock solutions were diluted in 10 mL of extracellular fluid as working solutions and sonicated for 20 minutes.

[0613] 3. Experimental System

[0614] 3.1. Cell Culture

[0615] (1) Stable expression of Na V The specific information for the 1.8 channel CHO cell line is as follows: SCN10A: NM_006514.

[0616] (2) Cells were cultured in HAM'S / F-12 medium containing 10% fetal bovine serum and 10 μg / mL blastomycin, 200 μg / mL hygromycin B, and 100 μg / mL Zeocin in culture dishes. Cells were then incubated at 37°C in a humidified incubator. Grown at °C and 5% carbon dioxide.

[0617] (3) Cell passage: Remove the old culture medium and wash the cells once with PBS, then add 1 mL of 0.25% trypsin-EDTA solution and incubate at 37 °C for 1.5 minutes. Separate the cells from the bottom of the culture dish and add them to the culture medium at 37 °C. Preheat 5 mL of complete culture medium to °C. Slowly agitate the cell suspension with a pipette to separate aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect cells. For expansion or maintenance culture, seed cells in 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 Cells (final culture medium volume: 5 mL).

[0618] (4) In order to maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0619] (5) Patch-clamp detection: Before this experiment, cells were separated using 0.25% trypsin-EDTA and subjected to a 6.5 × 10⁻⁶ m² / g cell line. 3 Cells were seeded at a density per well in 24-well plates (final volume: 500 μL), and tetracycline was added. Cells were tested 18 hours later.

[0620] 3.2. Electrophysiological solutions

[0621] (1) Extracellular fluid: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2 6H₂O, 2 mM CaCl₂ 2H₂O, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH₂PO₄ 2H2O, using NaOH to achieve pH=7.4.

[0622] (2) Intracellular fluid: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM MEGTA, using CsOH to achieve pH=7.2.

[0623] 4. Testing Methods

[0624] 4.1. Instruments

[0625] The instruments used are shown in Table 6 below.

[0626] Table 6 Instrument Suppliers and Models

[0627]

[0628] 4.2. Patch clamp testing

[0629] Na+ was recorded using whole-cell patch-clamp technique at a holding potential of -120 mV. VThe current in the 1.8 channel was stepped from -110 mV to -20 mV in 10 mV increments for 0.3 s, and then a 0-mV depolarization pulse was applied to measure the peak amplitude of the internal current, thus obtaining the half-inactivation voltage (Vhalf).

[0630] A dual-pulse protocol was used to test the sodium current in both the resting and semi-inactivated states. First, the first test pulse (TP1) was repolarized to 0 mV for 50 ms to measure the resting sodium current. Then, between two depolarization pulses, the conditional voltage was adjusted to Vlhalf for 5 s, followed by a voltage recovery to -120 mV for 20 ms to allow the channel in the inactivated state to recover and not bind to the compound. The second test pulse (TP2) was then repolarized to 0 mV for 50 ms to measure the semi-inactivated sodium current. Finally, the voltage was restored to a holding potential of -120 mV. This protocol was repeated at 20-s intervals to observe the effect of the drug on the peak amplitude of the sodium current in both states.

[0631] Data was acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0632] First, a micropipette (P97, Sutter Instrument) was used to pull a glass pipette (BF150-86-10, Sutter Instrument) to manipulate the patch clamp. Then, a micropipette filled with intracellular solution was placed in a pipette holder and manipulated using a micromanipulator (Carm-CS, MCI Instruments) under an inverted microscope (M53, MShot). The pipette was lowered into the recording solution, and the resistance (Rpip) was recorded. After contact with the cell, a slight suction was applied to achieve a high-resistance seal (in the GΩ range). Rapid capacitance compensation was performed, and negative pressure was continued to rupture the membrane into whole-cell mode. Then, slow capacitance compensation was performed, and experimental parameters were recorded. No leak subtraction was performed.

[0633] Incubate the cells with the test sample for approximately 5 minutes, or until Na+ is absorbed. V1.8 The current reached a steady-state level. Multiple concentrations of the test sample were tested. A coverslip lined with cells was placed in the recording chamber under an inverted microscope. Control and test solutions were sequentially fed through the chamber from low to high concentration using a gravity-feed solution delivery system. During the experiment, the solution was withdrawn from the chamber using a peristaltic pump. The current detected in each cell in the compound-free extracellular fluid was used as its own blank control. Each concentration was measured twice independently. All tests were performed at room temperature.

[0634] 4.3. Data Analysis

[0635] In each recording, the current response to the test compound was normalized to the blank control, and the inhibition rate was calculated, i.e., inhibition rate % = (1- I 化合物 / I 对照 )×100%. Calculate the mean, standard error (SE), and standard deviation (SD) for each experimental group, and express the data as mean ± SE.

[0636] Computing IC 50 The value was calculated using the nonlinear regression equation Y=1 / (1+10^((LogIC)). 50 -X) × Hill slope)) fits the dose-response curve, where IC 50 This is the half-maximal inhibitory concentration (MCC). IC50 was performed using GraphPad Prism software. 50 Calculation and curve fitting.

[0637] In this embodiment, the compound reacts with Na at 1 nM or 10 nM. V 1.8 IC 50 Or the inhibition rate is shown in Table 7.

[0638] Table 7: Effects of compounds on Na at a certain concentration V 1.8 Restriction Rate

[0639]

[0640] It is evident that the compounds disclosed herein affect Na. V It has a significant inhibitory effect on the activity of the 1.8 channel.

[0641] Example 3: Pharmacokinetic Test Results of the Compounds Disclosed

[0642] In this experimental protocol, in vivo pharmacokinetics in mice / rats were assessed by a single intravenous injection or oral gavage.

[0643] Experimental methods and conditions: Male CD-1 mice or C57B6 / J mice with free access to food and water were used. The test compounds were administered intravenously and / orally by gavage. Blood samples were collected via the submandibular vein or other suitable vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous injection, or at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after oral administration, at a rate of 0.03 mL / time point. Samples were placed in tubes containing K2-EDTA and stored on ice until centrifugation. Within 1 hour of collection, blood samples were centrifuged at 6800 g for 6 minutes at 2–8°C to separate plasma for detection. Plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry (LC / MS / MS), and pharmacokinetic parameters were calculated based on the measured concentrations. Results are shown in Tables 8-1 and 8-2.

[0644] Experimental Methods and Conditions: Male Sprague-Dawley rats with free access to food and water were used. The test compounds were administered at 1 mg / kg (intravenous injection, solvent: 5% DMSO + 10% Solutol + 85% saline) and 5 mg / kg (gavage, solvent: 5% DMSO + 10% Solutol / 85% saline), respectively. Blood samples were collected via the submandibular vein or other suitable vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous injection, or at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after oral administration, at a rate of 0.02 mL / time point. Samples were placed in tubes containing K2-EDTA and stored on ice until centrifugation. Within 1 hour of collection, blood samples were centrifuged at 6800 g for 6 minutes at 2–8°C to separate plasma for detection. The plasma drug concentration was detected by liquid chromatography-tandem mass spectrometry (LC / MS / MS), and pharmacokinetic parameters were calculated based on the measured concentrations. The results are shown in Table 9.

[0645] Table 8-1: PK in CD-1 mice

[0646]

[0647] Table 8-2: In vivo PK in C57B6 / J mice

[0648]

[0649] Table 9: In vivo PK in rats

[0650]

[0651] Compound A is a reference molecule from WO2021113726A1 (Example 7), and compound B is a reference molecule from WO2024041613A1 (Example 43). The structures of compounds A / B and Examples 22 / 24a are shown below:

[0652]

[0653] A comparison of the pharmacokinetic properties of compounds 22 (dihydroindene core) and 24a (difluorodihydroindene core) shows the advantage of the difluorodihydroindene core of this disclosure (as exemplified in compound 24a): Mouse pharmacokinetic: AUC: 10332 ng hr / mL (compound 24a) vs 2490 (compound 22); F: 94% (compound 24a) vs 63% (compound 22).

[0654] The disclosed compounds exhibit favorable pharmacokinetic absorption / plasma exposure in rats and mice. The pharmacokinetic advantage of the compound with the difluorodihydroindene core compared to the reference monocyclic compounds A / B is as follows: Rat PK: AUC: 3232 ng hr / mL (compound 24a) vs 277 (compound A) vs 665 (compound B); F: 73% (compound 24a) vs 9% (compound A) vs 29% (compound B).

[0655] Example 4: Solubility assessment in PBS / FassiF / FessiF

[0656] medium:

[0657] Preparation of 50 mM phosphate buffer (PB) at pH 7.4: a. Preparation of 50 mM Na2HPO4: Dissolve 3.549 g of Na2HPO4 in 500 mL of water, and the pH is approximately 9.4. b. Preparation of 50 mM NaH2PO4: Dissolve 3.000 g of NaH2PO4 in 500 mL of water, and the pH is approximately 4.5. c. Preparation of 50 mM PB (pH 7.4): Add 15 mL of 50 mM Na2HPO4 to a 50 mL tube, and then adjust the pH to 7.4 ± 0.05 using 50 mM NaH2PO4.

[0658] Preparation of Fasted State Simulated Intestinal Fluid (FaSSIF): 0.056% (w / v) lecithin, 0.161% (w / v) sodium taurocholate, 0.39% (w / v) potassium dihydrogen phosphate, 0.77% (w / v) potassium chloride, deionized water, pH 6.5 ± 0.05.

[0659] Preparation of Fed-State Simulated Intestinal Fluid (FeSSIF): 0.282% (w / v) lecithin, 0.806% (w / v) sodium taurocholate, 0.865% (w / v) acetic acid, 1.52% (w / v) potassium chloride, deionized water, pH 5.0 ± 0.05.

[0660] method:

[0661] Step 1: Add 10 μL of DMSO stock solution of the test and control compounds to each well of a 96-well plate. Step 2: Add 490 μL of medium to each well of the 96-well plate. Step 3: Vortex the solubility sample for at least 2 minutes. Step 4: Shake the 96-well plate at 800 rpm for 24 hours at room temperature. Step 5: Centrifuge at 25°C for 10 minutes (e.g., 4000 rpm). Step 6: Transfer the supernatant to a filter plate, and then collect the filtrate into a new 96-well plate by centrifugation for at least 5 minutes. Step 7: Quantify the concentration of the filtrate using an LC-UV system.

[0662] In this embodiment, the solubility data of the compound are shown in Table 10.

[0663] Table 10: Compound Solubility

[0664]

[0665] It is evident that the compounds disclosed herein have improved PBS solubility.

[0666] Example 5: Evaluation of the analgesic effect of the compound in a mouse postoperative model

[0667] An in vivo mouse postoperative model (plantar incision pain model) was established using 6-8 week old male C57BL / 6J mice. Changes in mechanical pain threshold were measured to evaluate the analgesic effect of the compounds.

[0668] Mice were acclimatized to laboratory conditions for 7 days, with free access to food and water upon delivery. During the acclimatization period (days 5-7), animals were placed on a metal pain measurement grid for 40-60 minutes to allow for adaptation. During this process, the experimenter was allowed acclimatization contact with the animals (stroking them for 3-5 minutes) to reduce stress responses. After stroking adaptation, the animals were tested with von Frey filaments to obtain baseline values ​​for paw withdrawal threshold (PWT) in randomized groups, as listed in the table below. Foot incision pain modeling was then performed on mice (except the control group). Briefly, the mice were anesthetized and restrained with their hind legs facing upwards. A longitudinal incision was made at the heel, facing towards the toes, to cut through the skin and fascia. Forceps were inserted below the lateral edge of the flexor brevis muscle and pushed into the muscle. The muscle was lifted with forceps, cut in half with a blade, and the wound was sutured and disinfected.

[0669]

[0670] PWT was measured before administration and at 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. In short, mice were placed on a metal pain measurement grid and allowed to rest for 30 to 60 minutes before the test. The sole of the operated hind limb was gently stimulated with a von Frey filament, bending the filament for 2–3 seconds, while observing the animal's withdrawal response. A positive (×) response was indicated by lifting, avoiding, or licking the paw. Withdrawal responses due to body movement were not counted. A negative (○) response was indicated by observing any of the above. Mice were stimulated sequentially with filaments in ascending order of gram strength (filament strength: 0.16, 0.40, 0.60, 1.00, 1.40, 2.00 (g), with a cutoff value of 2.00 g), five times consecutively for each gram strength, with at least 10 seconds between each stimulation. If fewer than three positive responses were observed, the procedure was repeated with the next filament of a higher gram strength. When three or more positive reactions are observed for the first time, the filament is determined to be the claw retraction threshold of the animal (test each animal twice and take the average).

[0671]

[0672] Compared with the model group, PWT was significantly increased in the 24a group at 2 hours, 6 hours and 8 hours after administration, which was statistically significant (p<0.001).

[0673] .

Claims

1. Compound of formula (A): Equation (A), Or its pharmaceutically acceptable salt. in: X is -O-, -S-, or -N(R) a1 )-; Ring A is aryl or heteroaryl; Ring B is aryl, heteroaryl, or heterocyclic; L 1 It is a key, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -C(R) b1 )2-、-N(R a2 )-、-C(=O)N(R a2 )-、-N(R a2 )C(=O)-、-N(R a2 )C(=O)N(R a2 )-、-S(=O)N(R a2 )-、-N(R a2 )S(=O)-、-S(=O)2N(R a2 )-、-N(R a2 )S(=O)2-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R a2 )-、-N(R a2 )C(=O)O-、-N(R a2 )C(=NCN)-、-C(=NCN)N(R a2 -, -O-alkyl-, -alkyl-O-, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; L 2 It is -C(=O)N(R) a3 )-、-N(R a3 )C(=O)-、-C(=S)N(R a3 )-、-N(R a3 )C(=S)-、-S(=O)N(R a3 )-、-S(=O)2N(R a3 )-、-cycloalkyl-N(R a3 )-、-C(=O)N(R a3 )-cycloalkyl-,-C(=O)N(R a3 )-heterocyclic group-,-C(R b2 )2-N(R a3 )-, heterocyclic or heteroaryl, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted with one or more R; R 1 and R 2 Each is independently a halogen, -SF5, alkyl, alkynyl, or haloalkyl; R 3 and R 4 Each can be independently hydrogen, -SF5, halogen, cyano, alkyl, alkynyl, or -N(R) a4 )2; or R 1 and R 2 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted by one or more R groups; or R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted by one or more R groups; or R 1 and R 3 Together with the adjacent atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted with one or more R groups; or R 2 and R 3 Together with the adjacent atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted with one or more R groups; R 5 It is hydrogen, -SF5, halogen, or alkyl; R 6 Each is independently a halogen, -SF5, alkyl, haloalkoxy, alkoxy, cycloalkyl-O-, or halocycloalkyl-O-; Or two Rs 6 Together with intercalary atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each optionally being oxidized by one or more R atoms. 8 replace; R 7 Each of these can be independently halogenated, amino, oxo, -C(=O)-NH2, -C(=O)-NH-cycloalkyl, or -C(=NR)-NH2-cycloalkyl. a5 )-NR a6 R a7 -NHC(=NH)-NH2, -NHC(=O)-NH2, -C(=O)NHC(=NH)-NH2, -cycloalkyl-NH2, -CH(haloalkyl)-NH2, -cycloalkyl-C(=NR) a5 )-NR a6 R a7 -heterocyclic group-C(=NR) a5 )-NR a6 R a7 -S(=O)2R a9 -S(=O)2NR a6 R a7 S(=O)(=NH)R a10 -N=S(=O)(R a6 R a7 -S(=O)(R) a9 (=NR) a5 -SF5, haloalkyl, alkyl, alkoxy, cycloalkyl or heterocyclic, wherein the cycloalkyl portion of -C(=O)-NH-cycloalkyl and -cycloalkyl-NH2 is optionally substituted by one or more groups independently selected from halogen, hydroxyl, amino, cyano or alkyl; the haloalkyl, alkyl, alkoxy, cycloalkyl and heterocyclic groups are optionally substituted by one or more R; R 8 Each is independently selected from halogen, -SF5, hydroxyl, cyano, alkyl, alkoxy, or haloalkyl; Or two Rs 8 Together with the intervening atom, a cycloalkyl or heterocyclic group is formed, each of which is optionally substituted by one or more groups, the groups being independently selected from halogens, hydroxyl groups, -SF5 groups, cyano groups, alkyl groups, alkoxy groups, or haloalkyl groups; R a1 R a2 R a3 R a4 R a8 R b1 and R b2 Each is independently hydrogen, -SF5, alkyl, cycloalkyl, heterocyclic, or haloalkyl; R a5 R a6 R a7 and R a10 Each of these groups independently represents hydrogen, hydroxyl, -SF5, cyano, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, -C(=O)R a8 or -C(=O)OR a9 The alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, the groups being independently selected from halogen, hydroxy, amino or cyano; R is independently a halogen, -SF5, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC( =O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; or Two R atoms on the same atom together form an oxo group; R a9 It is an alkyl, cycloalkyl, or haloalkyl group; n is any integer from 0 to 5; and m is any integer from 0 to 5.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is -S- or -N(R) a1 )-, optional, R a1 It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein (a) R 1 and R 2 One of them is -CF3, and the other is a halogen or alkynyl group; or (b) R 1 and R 2 One of them is -CH3, and the other is an alkynyl group.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein (a) R 1 and R 2 One of them is -CF3, and the other is -F or ethynyl; or (b) R 1 and R 2 One of them is -CH3, and the other is ethynyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 It is an alkyl or halogen.

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 5 It is -CH3 or -F.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 One of them is hydrogen, and the other is an alkynyl group, halogen, cyano group, or -N(R) group. a4 )2, optional, R a4 Each is either hydrogen or alkyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 It is -O-, -C(R) b1 )2-、-N(R a2 )-、-C(=O)N(R a2 - or -N(R) a2 C(=O)-, optionally, R b1 Each is hydrogen, optionally, R a2 It is hydrogen or alkyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl or a 5-membered heterocyclic group.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein ring A is , , or .

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I): Formula (I), in: The ring C is a cycloalkyl, heterocyclic, aryl, or heteroaryl group; p is any integer from 0 to 3; and q is any integer from 0 to 4.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein... yes , , or .

13. The compound of any one of claims 11-12 or a pharmaceutically acceptable salt thereof, wherein R 8 Each is -F, and optionally, p is 1, and R 6 It is -OCH3.

14. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein yes , , , , , , or .

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II): Equation (II), in Ring D is a cycloalkyl, heterocyclic, aryl, or heteroaryl group; p is any integer from 0 to 3; and q is any integer from 0 to 4.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein ring D is dihydrofuranyl, tetrahydrofuranyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, dihydropyranyl, tetrahydropyranyl, spiroheptyl, spiroheptenyl, oxaspiroheptyl or oxaspiroheptenyl.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein... yes , , , , , , , , or .

18. The compound of any one of claims 15-17 or a pharmaceutically acceptable salt thereof, wherein q is 1, and R 8 It is -CH3; or q is 2, and both R are R. 8 All are -F.

19. The compound of any one of claims 15-18 or a pharmaceutically acceptable salt thereof, wherein p is 1 and R 6 Yes -F.

20. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein... yes , , , , , , , , , or .

21. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein L 2 It is -C(=O)N(R) a3 )-, and R a3 It is hydrogen or alkyl.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R a3 It is H or -CH3.

23. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein L 2 It is -N(R) a3 )C(=O)-、-C(=S)N(R a3 )-、-S(=O)N(R a3 )-、-S(=O)2N(R a3 )- or -cycloalkyl-N(R a3 )-.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R a3 It is hydrogen or alkyl.

25. The compound of claim 23 or 24 or a pharmaceutically acceptable salt thereof, wherein L 2 It is -NHC(=O)- -C(=S)NH- -S(=O)2NH- or L 2 of The end indicates the connection point with ring B.

26. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein L 2 It is a heterocyclic group or a heteroaryl group.

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein L 2 It is imidazole, triazole, or tetraazole.

28. The compound of claim 26 or 27 or a pharmaceutically acceptable salt thereof, wherein L 2 yes , , , , , or L 2 of The end indicates the connection point with ring B.

29. The compound of any one of claims 1 and 15-28 or a pharmaceutically acceptable salt thereof, wherein m is 0.

30. The compound of any one of claims 1 and 15-28 or a pharmaceutically acceptable salt thereof, wherein m is 1.

31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R 7 It is -cycloalkyl-NH2, -CH (haloalkyl)-NH2, -cycloalkyl-C (=NR) a5 )-NR a6 R a7 -C(=O)-NH-cycloalkyl, -N=S(=O)(R a6 R a7 ) or -S(=O)(R a9 (=NR) a5 ), wherein the cycloalkyl portion is optionally substituted by one or more groups, said groups being independently selected from halogen, hydroxyl, cyano or alkyl.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 7 yes , , , , , , , , , or .

33. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R 7 It is -C(=NR) a5 )-NR a6 R a7 .

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R a5 R a6 and R a7 Each of the groups is independently hydrogen, hydroxyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, or -alkoxy-cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, and -alkoxy-cycloalkyl are optionally substituted by one or more groups, which are independently selected from halogen, hydroxyl, amino, or cyano.

35. The compound of claim 33 or 34 or a pharmaceutically acceptable salt thereof, wherein R 7 yes , , , , , , , , , , , , , , , , , , or .

36. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 2.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein... (a) R 7 One of them is a halogen, and the other is -C (=NR) a5 )-NR a6 R a7 ; (b) R 7 One of them is an alkyl group, and the other is -C (=NR). a5 )-NR a6 R a7 ; (c) R 7 One of them is a halogen, and the other is a cycloalkyl-C (=NR) a5 )-NR a6 R a7 ;or (d) R 7 One of them is an alkyl group, and the other is a -cycloalkyl-C (=NR) a5 )-NR a6 R a7 .

38. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R a5 R a6 and R a7 Each of the groups is independently hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl, -alkoxy-cycloalkyl, wherein the alkyl, cycloalkyl, alkoxy, cycloalkoxy, -cycloalkoxy-alkyl, -alkyl-cycloalkyl, -cycloalkyl-alkyl and -alkoxy-cycloalkyl are optionally substituted by one or more groups, wherein the groups are independently selected from halogen, hydroxyl, amino or cyano.

39. The compound of any one of claims 36-38 or a pharmaceutically acceptable salt thereof, wherein R 7 One of them is fluorine or -CH3, and the other is... , , , , , , , , , , , , , , , , , , , , , , , , , , or .

40. The compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof, wherein ring B is an aryl group.

41. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl.

42. The compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof, wherein ring B is a heteroaryl group.

43. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein ring B is pyrazolyl, pyridinyl, 1-pyridinyl oxide, 1-pyridazinyl oxide, indazole, benzisoxazolyl, dihydrobenzisothiazolyl, 1,1-dihydrobenzisothiazolyl, imidazopyridazinyl, or naphridinyl.

44. The compound of any one of claims 23-25 ​​or a pharmaceutically acceptable salt thereof, wherein ring B is a heterocyclic group.

45. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein ring B is imidazoalkyl, oxazolidinyl, pyrrolidinyl, or piperazine.

46. ​​The compound of any one of claims 3-45 or a pharmaceutically acceptable salt thereof, wherein X is -O-.

47. The compound of any one of claims 1-2 and 5-46, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 One of them is -CF3, and the other is -CH3.

48. The compound of any one of claims 1-4 and 7-47, or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen.

49. The compound of any one of claims 1-6 and 8-48, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 One of them is hydrogen, and the other is -CH3.

50. The compound of any one of claims 1-7 and 9-49, or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key.

51. The compound of any one of claims 1-8 and 11-50, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

52. The compound of any one of claims 1-10 and 21-51, or a pharmaceutically acceptable salt thereof, wherein R 6 Each is independently either a halogen or an alkoxy group.

53. The compound of any one of claims 1-20 and 29-52, or a pharmaceutically acceptable salt thereof, wherein L 2 It is -C(=O)NH-.

54. The compound of any one of claims 1-28 and 46-53, or a pharmaceutically acceptable salt thereof, wherein m is 1, and R 7 It is -C(=O)NH2.

55. The compound of any one of claims 1-54 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted with one or more R groups.

56. The compound of any one of claims 1-54 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted with one or more R groups.

57. The compound of any one of claims 1-54 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Together with the adjacent atoms to which they are attached, they form cycloalkyl or heterocyclic groups, each of which is optionally substituted with one or more R.

58. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (B): Equation (B), in: Ring E is a cycloalkyl or heterocyclic group; q1 is any integer from 0 to 4.

59. The compound of claim 58 or a pharmaceutically acceptable salt thereof, wherein ring E is C 3-7 Cycloalkyl or 3 to 7-membered heterocyclic groups.

60. A compound of any one of claims 1-59 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or heteroaryl, optionally ring B is phenyl or pyridyl.

61. The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3 or 4, R 7 One of them is independently -C(=O)-NH-cycloalkyl, -C(=NR) a5 )-NR a6 R a7 -NHC(=NH)-NH2, -NHC(=O)-NH2, -C(=O)NHC(=NH)-NH2, -cycloalkyl-NH2, -CH(haloalkyl)-NH2, -cycloalkyl-C(=NR) a5 )-NR a6 R a7 or -heterocyclic group-C(=NR) a5 )-NR a6 R a7 In which the cycloalkyl portion of -C(=O)-NH-cycloalkyl and -cycloalkyl-NH2 is optionally substituted by one or more groups independently selected from halogen, hydroxyl, amino, cyano or alkyl, and the cycloalkyl and heterocyclic groups are optionally substituted by one or more R.

62. The compound of claim 61 or a pharmaceutically acceptable salt thereof, wherein R 7 yes , , , , , , , , , , , , , , , , , , , , , or .

63. The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein ring B is 1-pyridyl oxide or a 5-membered heteroaryl group.

64. The compound of claim 63 or a pharmaceutically acceptable salt thereof, wherein R 7 Independently, it is halogen, amino, oxo, -C(=O)-NH2, -C(=O)-NH-cycloalkyl, -C(=NR)-NH2-cycloalkyl, -C(=NR)-NH2-cycloalkyl, -C(=O ... a5 )-NR a6 R a7 -NHC(=NH)-NH2, -NHC(=O)-NH2, -C(=O)NHC(=NH)-NH2, -cycloalkyl-NH2, -CH(haloalkyl)-NH2, -cycloalkyl-C(=NR) a5 )-NR a6 R a7 -heterocyclic group-C(=NR) a5 )-NR a6 R a7 -S(=O)2R a9 -S(=O)2NR a6 R a7 S(=O)(=NH)R a10 The alkyl, alkyl, cycloalkyl, or heterocyclic group is a halogenated alkyl group, wherein the cycloalkyl portion of -C(=O)-NH-cycloalkyl and -cycloalkyl-NH2 is optionally substituted by one or more groups independently selected from halogen, hydroxyl, amino, cyano, or alkyl groups; the alkyl, alkyl, cycloalkyl, and heterocyclic group is optionally substituted by one or more R groups.

65. The compound of any one of claims 63-64 or a pharmaceutically acceptable salt thereof, wherein R 7 It is -CH3, -CF3, -CHF2, -S(=O)2CH3, -C(=O)-NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

66. The compound of any one of claims 1-59 or a pharmaceutically acceptable salt thereof, wherein ring B is Ring F is aryl or heteroaryl, ring G is aryl, heteroaryl, heterocyclic or cycloalkyl, R f and R g Each is R independently 7 q2 is any integer between 0 and 2, and q3 is any integer between 0 and 2. Optionally, ring G is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclic or C. 5-6 Cycloalkyl.

67. The compound of claim 66 or a pharmaceutically acceptable salt thereof, wherein ring B is , , , , , or Each of them is optionally controlled by one or more R 7 replace.

68. The compound of any one of claims 58-67 or a pharmaceutically acceptable salt thereof, wherein L 2 It is -C(=O)N(R) a3 )-、-C(=O)N(R a3 )-cycloalkyl- or -C(=O)N(R a3 )-heterocyclic-, wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more R.

69. The compound of any one of claims 58-67 or a pharmaceutically acceptable salt thereof, wherein L 2 It is -C(=O)NH- or .

70. The compound of any one of claims 58-68 or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key.

71. The compound of any one of claims 58-69 or a pharmaceutically acceptable salt thereof, wherein ring A is an aryl group.

72. The compound of any one of claims 58-70 or a pharmaceutically acceptable salt thereof, wherein ring A is R 6A R 6B and R 6C Each is independently hydrogen or R 6 , or R 6A and R 6B Together with their adjacent atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each optionally bound by one or more R groups. 8 replace, or R 6B and R 6C Together with their adjacent atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each optionally bound by one or more R groups. 8 replace.

73. The compound of any one of claims 58-72 or a pharmaceutically acceptable salt thereof, wherein ring A is , , , or .

74. The compound of any one of claims 58-73 or a pharmaceutically acceptable salt thereof, wherein R 1 It's CF3.

75. The compound of any one of claims 58-74 or a pharmaceutically acceptable salt thereof, wherein R 4 It is CH3.

76. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the compounds listed in Table 1 or Table 2.

77. A pharmaceutical composition comprising a compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

78. A method for inhibiting voltage-gated sodium channels in an individual, the method comprising administering to the individual a compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition of claim 77.

79. The method of claim 78, wherein the voltage-gated sodium channel is Na V 1.

8.

80. A method for treating a disease or disorder in an individual in need, the method comprising administering to the individual a compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition of claim 77.

81. The method of claim 80, wherein the disease or disorder is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, pathological cough, or arrhythmia; optionally, the disease or disorder is neuropathic pain selected from postherpetic neuralgia, neuropathy, idiopathic neuropathy, or diabetic neuropathy; optionally, the disease or disorder is musculoskeletal pain, such as osteoarthritis pain; optionally, the disease or disorder is acute pain, such as acute postoperative pain; optionally, the disease or disorder is postoperative pain selected from pain following bursal resection, hernia repair, or laparotomy.

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