WO2025218764A1 - Composé utilisé en tant qu'inhibiteur de canal sodique dépendant de la tension et son utilisation - Google Patents

Composé utilisé en tant qu'inhibiteur de canal sodique dépendant de la tension et son utilisation

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Publication number
WO2025218764A1
WO2025218764A1 PCT/CN2025/089704 CN2025089704W WO2025218764A1 WO 2025218764 A1 WO2025218764 A1 WO 2025218764A1 CN 2025089704 W CN2025089704 W CN 2025089704W WO 2025218764 A1 WO2025218764 A1 WO 2025218764A1
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Prior art keywords
compound
mmol
alkyl
reaction
solution
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PCT/CN2025/089704
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English (en)
Chinese (zh)
Inventor
刘希乐
张鹏涛
杨文谦
王慧
赖庆莹
高翠
李捍雄
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Apichope Bio Pharmaceutical Co Ltd
Guangzhou Runlin Pharmaceutical Technology Co Ltd
Guangzhou Unirise Pharmaceutical Co Ltd
Guangzhou Apichope Pharmaceutical Co Ltd
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Apichope Bio Pharmaceutical Co Ltd
Guangzhou Runlin Pharmaceutical Technology Co Ltd
Guangzhou Unirise Pharmaceutical Co Ltd
Guangzhou Apichope Pharmaceutical Co Ltd
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Publication of WO2025218764A1 publication Critical patent/WO2025218764A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Definitions

  • the present invention relates to the technical field of chemical medicine, and in particular to a compound used as a voltage-gated sodium channel inhibitor and its application.
  • action potentials nerve impulses
  • DRG dorsal root ganglion
  • the generation and conduction of action potentials in neurons depend on voltage-gated sodium ion channels (NaV) on the cell membrane. When the cell membrane depolarizes, the sodium ion channels are activated, the channels open, causing an influx of sodium ions, further depolarizing the cell membrane, and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity can help treat and relieve pain.
  • NaV sodium ion channels
  • NaV1.8 is primarily expressed in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglia (DRG), and small DRG neurons expressing NaV1.8 include pain receptors involved in pain signaling.
  • NaV1.8 mediates large-amplitude action potentials in small neurons of the dorsal root ganglia, which are required for rapid repetitive action potentials in pain receptors and spontaneous activity of damaged neurons.
  • Knockdown of NaV1.8 in rats has been achieved using antisense DNA or small interfering RNA and achieved almost complete reversal of neuropathic pain in spinal nerve ligation and chronic constriction injury models.
  • NaV1.8 channels are considered promising targets for analgesics and are expected to play a role in conditions where pain exceeds their usefulness, such as neuropathic pain, inflammatory pain, and postoperative/spontaneous pain. Moreover, since NaV 1.8 is primarily limited to neurons that sense pain, selective NaV 1.8 inhibitors may avoid the adverse events commonly seen with non-selective NaV blockers.
  • NaV1.8 channels are also believed to be involved in diseases such as multiple sclerosis, arrhythmias, cough, and pruritus.
  • Multiple sclerosis is an inflammatory demyelinating disease originating in the central nervous system, and its exact pathogenesis remains to be elucidated.
  • Purkinje fibers in the cerebellum of normal people do not express NaV1.8 channels, but NaV1.8 expression is upregulated in the cerebellum of patients with multiple sclerosis.
  • NaV1.8 has been shown to be expressed in cardiac nerves such as Purkinje fibers and is considered a potential therapeutic target for cardiovascular diseases such as arrhythmias.
  • NaV1.8 is expressed in the vagal plexus associated with coughing.
  • NaV1.8 phosphorylation levels and expression levels increase, participating in the cough reflex.
  • itch factors such as histamine released by lymphocytes and mast cells can activate NaV1.8 channels. Knocking out NaV1.8 in mice can effectively alleviate histamine- and endothelin-induced itch behavior.
  • NaV1.8 selective inhibitors At present, NaV1.8 selective inhibitors, VERTEX's VX-150 and Suzetrigine have achieved positive results in clinical trials for patients with acute pain, diabetic peripheral neuropathy, etc., but there are currently no products targeting this target on the market.
  • the development of highly selective voltage-gated sodium channel NaV 1.8 inhibitors is of great clinical significance.
  • the present invention provides a compound, or a pharmaceutical composition thereof, that is a selective inhibitor of NaV1.8.
  • the present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and/or condition by inhibiting NaV1.8.
  • the present invention further describes a method for synthesizing the compound.
  • the compound of the present invention exhibits excellent biological activity and pharmacokinetic properties.
  • a compound which is a compound as shown in formula (X), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound shown in formula (X),
  • Ring A is phenyl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl;
  • Each R e is independently D, F, Cl, Br, I, CN, hydroxy, nitro, -N(R a ) 2 , -(C 1-6 alkylene)N(R a ) 2 , -S(O)( ⁇ NH)C 1-6 alkyl, -C(O)OR a , -C(O)N(R a ) 2 , -(C 1-6 alkylene)C(O)N(R a ) 2 , -C(O)R a , -S(O) 2 NR a , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy,
  • each Ra is independently H, D, hydroxy, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, oxo and C1-3 alkyl; R1 , R2 , R3, R4 and R5 are each independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocyclyl,
  • 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, nitro, amino, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl and C 1-3 alkoxy;
  • R 3 and R 5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • L 1 is a bond, O or S
  • L2 is a bond, C1-6 alkylene or -( C1-6 alkylene) -C1-6 alkoxy, wherein the C1-6 alkylene and C1-6 alkoxy may be independently optionally substituted with 1 or 3 substituents selected from D, F, Cl, Br, I, oxo and hydroxy;
  • R7 and R8 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocyclyl, and the C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro and C1-3 alkoxy.
  • n 0, 1, 2 or 3.
  • ring A can be phenyl, pyridazine, pyrazine, pyridine or pyrimidine.
  • it is a compound of formula (I), (II) or (III), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I), (II) or (III),
  • R9 and R10 are each independently H, D, F, Cl, Br, I, CN, amino, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy;
  • R 11 , R 12 and R 13 are each independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, -N(R a ) 2 , -(C 1-6 alkylene)N(R a ) 2 , -S(O)( ⁇ NH)C 1-6 alkyl, -C(O)OR a , -C(O)N(R a ) 2 , -(C 1-6 alkylene)C(O)N(R a ) 2 , -C(O)R a , -S(O) 2 NR a , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C 1-6 alkylene, C 1-6 alkyl
  • Each Ra is independently H, D, hydroxy, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl or 3-6 membered heterocyclyl, and the C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, oxo and C1-3 alkyl.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, D, F, Cl, Br, I, hydroxy, methyl, ethyl, CH 2 F, CHF 2 , CF 3 , -CH 2 OCH 3 or -CH 2 OH.
  • R 9 , R 10 and R 11 are each independently H, D, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, methoxy, trifluoromethyl or trifluoromethoxy;
  • R 12 and R 13 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, methyl, ethyl, CH 2 F, CHF 2, -OCH 3 , -OCH 2 CH 3 , -C(O)NH 2 , -C(O)NHOH, -C(O)NHOCH 3 , -CH 2 OH, -CH(OH)CH 2 OH, -C(O)NHCH 3 , -CH(OH)(CH 3 ) 2 , -S(O)( ⁇ NH)CH 3 , -S(O) 2 NH 2 ,
  • R 7 and R 8 are each independently H, D, F, Cl, Br, I, hydroxy, methyl, ethyl, CH 2 F, CHF 2 or CF 3 .
  • said C 1-3 alkyl, C 1-3 alkylthio and C 2-6 alkynyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, oxo and hydroxy;
  • L 1 is a bond, O or S
  • L 2 is a bond, C 1-3 alkylene or -(C 1-3 alkylene)-C 1-3 alkoxy;
  • R 6 is CN, -S(O)CH 3 , -S(O) 2 CH 3 , -P(O)(CH 3 ) 2,
  • the compounds disclosed herein have a structure represented by formula (IV) or (V):
  • R c is a C 2-6 alkynyl group, which may be independently and optionally substituted by 1, 2 , 3, 4, 5 or 6 substituents selected from D, F, Cl, Br, I, hydroxyl, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl.
  • it is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug having one of the following structures:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the present invention discloses the use of the compound and pharmaceutical composition in the preparation of a medicament for treating a disease responsive to inhibition of the voltage-gated sodium channel NaV1.8, wherein the disease is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Chuck-Mare-Douglas syndrome, incontinence, pathological cough, or cardiac arrhythmia.
  • substituents When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.
  • alkyl as used herein includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2
  • alkylene refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-3 carbon atoms; and in yet other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2- ) , isopropylene (-CH( CH3 ) CH2- ), and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C ⁇ C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), propargyl ( -CH2C ⁇ CH ), and the like.
  • halogen refers to F, Cl, Br or I.
  • unsaturated means that the moiety contains one or more degrees of unsaturation.
  • alkoxy refers to an alkyl group, as defined herein, attached to the rest of the molecule through an oxygen atom.
  • the alkoxy group is a C 1-4 alkoxy group; examples include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.
  • the alkoxy group may be independently unsubstituted or substituted with one or more substituents as described herein.
  • alkylthio refers to an alkyl group, as defined herein, attached to the remainder of the molecule through a sulfur atom.
  • the alkylthio group is a C 1-4 alkylthio group; examples include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio.
  • the alkylthio group may independently be unsubstituted or substituted with one or more substituents described herein.
  • alkylamino refers to an alkyl group, as defined herein, attached to the remainder of the compound molecule via a nitrogen atom.
  • the alkylamino group is a C1-4 alkylamino group; such examples include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino.
  • the alkylamino group may be independently unsubstituted or substituted with one or more substituents as described herein.
  • cycloalkyl refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic carbon ring system containing 3-12 carbon atoms, which may be saturated or contain one or more unsaturated bonds, but never aromatic.
  • Cycloalkyl or “cycloalkane” may also include bridged and spirocyclic rings.
  • the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; and in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms.
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.
  • the cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably herein and refer to saturated or partially unsaturated monocyclic, bicyclic, or tricyclic rings containing 3-12 ring atoms, never aromatic, in which at least one ring atom is a heteroatom.
  • Heterocyclyl or “heterocycle” may also include bridged heterocycles and spiro heterocycles.
  • heterocyclyl or “heterocycle” contains 3-10 ring atoms; in one embodiment, “heterocyclyl” or “heterocycle” contains 3-8 ring atoms; in another embodiment, “heterocyclyl” or “heterocycle” contains 5-8 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 3-6 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 5-6 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 4-6 ring atoms.
  • heterocyclyl may be carbon or nitrogen radicals, and heteroatoms have the meanings described herein.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxany
  • heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group may be optionally substituted with one or more substituents described herein.
  • aryl refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.
  • heteroaryl refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • the 5-10 heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom can be further oxidized.
  • heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazole 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,2,5
  • oxadiazole, pyrazinyl, 1,3,5-triazinyl also include the following bicyclic rings, but are in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, indolinyl, isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.
  • haloalkyl or haloalkoxy refers to an alkyl or alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
  • halocycloalkyl refers to a cycloalkyl group substituted with one or more halogen atoms. Examples include, but are not limited to, 1,1-difluorocyclopropane, 1-chloro-2-fluorocyclopropane, and the like.
  • a substituent group is attached to a ring by a bond to form a ring system, which indicates that the substituent group can be substituted at any substitutable position on the ring.
  • formula (a) indicates that the substituent group R can be substituted at any substitutable position on the pyridine ring.
  • a wavy line intersecting a bond in a chemical structure represents the point in the chemical structure at which the atom to which the wavy bond is attached is attached to the remainder of the molecule or to the remainder of a fragment of a molecule.
  • the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of such enantiomers, diastereomers, geometric isomers, or conformational isomers thereof, are within the scope of the present invention.
  • the structural formulas and compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present invention are also within the scope of the present invention. Furthermore, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.
  • Methodabolite refers to a product obtained by metabolism in vivo of a specific compound described herein, or a pharmaceutically acceptable salt, analog, or derivative thereof, which exhibits similar activity in vivo or in vitro as the compound of formula (I).
  • the metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage.
  • the present invention includes metabolites of a compound, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.
  • the definitions and conventions used in this invention are generally those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
  • the compounds of this invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of this invention.
  • racemic mixture A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereospecificity during chemical reactions.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomers that lacks optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers i.e., prototropic tautomers
  • Valence tautomers include interconversions by reorganization of bonding electrons.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977.
  • salts formed with non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange.
  • salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any compound containing a nitrogen group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization.
  • Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates, and aromatic sulfonates.
  • the "hydrate” of the present invention refers to an association compound formed when the solvent molecule is water.
  • solvate of the present invention refers to an association formed between one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • Esters herein refer to esters of compounds of formula (I) containing hydroxy groups that are hydrolyzable in vivo. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol.
  • examples of in vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl groups.
  • nitrogen oxide refers to a compound containing several amine functional groups in which one or more nitrogen atoms are oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings.
  • the corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages 1977).
  • N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), for example, by reacting the amine compound with m-chloroperbenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).
  • MCPBA m-chloroperbenzoic acid
  • prodrug refers to a compound that is converted in vivo to a compound represented by formula (I). Such conversion is affected by hydrolysis of the prodrug in the blood or by enzymatic conversion of the prodrug to the parent structure in the blood or tissues.
  • the prodrug compound of the present invention may be an ester.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters.
  • a compound of the present invention contains a hydroxyl group, it can be acylated to obtain a prodrug form.
  • prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of a hydroxyl group on the parent.
  • phosphate esters such as these phosphate ester compounds that are obtained by phosphorylation of a hydroxyl group on the parent.
  • the compounds of the present invention can be prepared by the methods described herein, wherein the substituents are as defined herein unless otherwise specified.
  • the following reaction schemes and examples are provided to further illustrate the present invention.
  • MS mass spectrometry
  • compound 1-3 (7.72 g, 38.2 mmol) was dissolved in acetonitrile (80 mL). Carbonyldiimidazole (6.50 g, 40.08 mmol) was added at 0°C. After stirring the mixture for 1 hour, potassium carbonate (6.59 g, 47.7 mmol) and compound 1-2 (26.6 g, 38.2 mmol, 22.4% content) were added sequentially. The reaction solution was warmed to 35°C and stirred for 10 hours.
  • compound 1-10 (2.6 g, 7.06 mmol) was added to 40 mL of dichloromethane. After cooling to -30°C, trimethylsilyl cyanide (2.8 mL, 21.2 mmol) was slowly added to the reaction solution. After stirring for 5 minutes, boron trifluoride etherate (7.8 mL, 28.2 mmol) was added dropwise. The reaction solution was stirred at -30-0°C for 2 hours. After completion of the reaction, potassium hydroxide aqueous solution (2 mol/L, 100 mL) was slowly added dropwise. The mixture was extracted with dichloromethane (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-11.
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by reverse-phase column chromatography (mobile phase A: water (0.1% formic acid) - B: acetonitrile; elution gradient: B: 70%-80%; elution over 15 minutes) to obtain compound 1-12.
  • boron tribromide (0.30 mL, 0.32 mmol) was slowly added dropwise to a solution of compound 1-17 (100 mg, 0.21 mmol) in 2 mL of dichloromethane at zero degrees Celsius. After the addition was complete, the mixture was stirred at zero degrees Celsius for 2 hours. After completion of the reaction, the reaction solution was poured into 50 mL of saturated aqueous sodium bicarbonate solution to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL x 2).
  • 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (6.19 mg, 0.01 mmol), cuprous iodide (3.22 mg, 0.02 mmol), and triethylamine (25.66 mg, 0.25 mmol) were added sequentially to 0.5 mL of DMF solvent containing compound 3-1 (50 mg, 0.08 mmol) and triisopropylsilyl acetylene (0.1 mL, 0.25 mmol).
  • the reaction mixture was heated to 100°C and stirred for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered through a short silica gel (washed with ethyl acetate). The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by reverse phase column chromatography (0.1% formic acid system) to obtain compound 3-2.
  • compound 4-1 (3.00 g, 18.4 mmol) was added dropwise to a 50 mL DMF solution containing 1,2-dibromoethane (14.5 g, 77.2 mmol) and triethylamine (5.60 mL, 40.5 mmol). The mixture was stirred at 20°C for 16 hours. After the reaction was completed, the reaction solution was poured into 100 mL of water and the mixture was extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 4-2.
  • compound 4-2 (58.8 mg, 0.22 mmol) was added to a 2 mL DMF solution of compound 1-18 (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol).
  • the reaction mixture was heated to 60°C and stirred for 6.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by reverse-phase column chromatography (0.1% formic acid) to obtain compound 4-3.
  • pyridine p-toluenesulfonate (0.27 mg) and paraformaldehyde (6.37 mg, 0.21 mmol) were added sequentially to a 3 mL dichloromethane solution of compound 4-4 (55 mg, 0.11 mmol), and the reaction solution was heated to 40 ° C and stirred for 4 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL ⁇ 2).
  • tert-butyldimethylsilyl chloride 865 mg, 5.74 mmol was added to a 5 mL DMF solution of compound 5-1 (300 mg, 2.87 mmol) and imidazole (586 mg, 8.61 mmol), and the reaction solution was stirred at 20°C for 3 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 5-2.
  • tributyl cyanomethylene phosphate (176.54 mg, 0.77 mmol) and compound 12-2 (95.28 mg, 0.73 mmol) were added sequentially to a solution of compound 1-18 (80 mg, 0.15 mmol) in 2 mL of dioxane.
  • the reaction was stirred at 40°C for 16 hours. After completion, the reaction was quenched with 10 mL of water and extracted with ethyl acetate (10 mL x 3).
  • tetrabutylammonium fluoride (235 ⁇ L, 0.23 mmol, 1 M THF solution) was added to a solution of compound 12-3 (60 mg, 0.08 mmol) in 2 mL of tetrahydrofuran, and the reaction mixture was stirred at 22.5°C for 1.5 hours. After completion of the reaction, the mixture was quenched with 40 mL of water and extracted with ethyl acetate (20 mL ⁇ 3).
  • n-butyllithium (6.8 mL, 17.12 mmol, 2.5 M) was slowly added dropwise to a solution of compound 15-1 (1 g, 14.27 mmol) in tetrahydrofuran (10 mL) at -78°C.
  • the reaction solution was stirred at -78°C for 1 hour, then paraformaldehyde (2.06 g, 22.83 mmol) was added.
  • the reaction solution was slowly warmed to 25°C and stirred for 16 hours. After completion of the reaction, the reaction solution was cooled to 0°C and quenched with saturated aqueous ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • tributyl cyanomethylene phosphate (116.90 mg, 0.48 mmol) and compound 15-2 (48.49 mg, 0.48 mmol) were added sequentially to a solution of compound 1-18 (50 mg, 0.10 mmol) in dioxane (2 mL).
  • the reaction mixture was stirred at 40°C for 12 hours. After completion of the reaction, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (20 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Example 15 The crude product was purified by reverse phase preparative chromatography (Column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; water (NH 4 HCO 3 )-ACN; Begin B: 40, End B: 70; Gradient Time (min): 10; 100% B Hold Time (min): 4, Flow Rate (ml/min): 25) to obtain Example 15.
  • tert-butyldiphenylsilyl chloride (21.57 g, 78.47 mmol) was added to a solution of compound 16-1 (5 g, 71.34 mmol), 4-dimethylaminopyridine (0.87 g, 7.13 mmol), and triethylamine (19.8 mL, 142.67 mmol) in dichloromethane (50 mL).
  • dichloromethane 50 mL
  • the reaction mixture was warmed to 25°C and stirred for 12 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride (50 mL). The aqueous phase was extracted with dichloromethane (50 mL ⁇ 3).
  • tributyl cyanomethylene phosphate (236.44 mg, 0.98 mmol) was added to a solution of 1-18 (150 mg, 0.33 mmol) and compound 16-3 (1105.38 mg, 3.27 mmol) in 1,4-dioxane (1.5 mL). The reaction was stirred at 25°C for 12 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was purified by reverse phase column (0.1% formic acid system) to obtain compound 16-4.
  • tert-butyldiphenylsilyl chloride (8.63 g, 31.39 mmol) was added to a solution of compound 17-1 (2 g, 28.53 mmol), 4-dimethylaminopyridine (0.35 g, 2.85 mmol), and triethylamine (7.9 mL, 57.07 mmol) in dichloromethane (20 mL). The reaction was stirred at 25°C for 12 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride (20 mL). The aqueous phase was extracted with dichloromethane (15 mL x 3).
  • Example 18 The crude product was then purified by reverse phase preparative purification (Column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; Condition: water (NH 4 HCO 3 )-ACN; Begin B: 43, End B: 73; Gradient Time (min): 15; 100% B Hold Time (min): 4, Flow Rate (ml/min): 25) to obtain Example 18.
  • n-butyllithium (14.1 mL, 35.2 mmol, 2.5 M) was slowly added dropwise to a solution of compound 19-1 (5.00 g, 29.4 mmol) in tetrahydrofuran (150 mL) at -40°C.
  • the reaction solution was stirred at -40°C for 0.5 hours, and then chloroformate (3.3 mL, 43.2 mmol) was added dropwise.
  • the mixture was stirred at -40°C for 2 hours.
  • the reaction solution was slowly added dropwise to a saturated aqueous ammonium chloride solution (50 mL) precooled to 0°C.
  • the aqueous phase was extracted with ethyl acetate (150 mL x 2).
  • lithium aluminum deuteride (0.29 g, 7.01 mmol) was slowly added portionwise to a solution of compound 19-2 (2.00 g, 8.76 mmol) in tetrahydrofuran (100 mL) at -70 ° C.
  • the mixture was stirred at -70 ° C for 2 hours, warmed to 0 ° C, and quenched by slowly adding 1 mL of deuterated water dropwise. After stirring for 10 minutes, the mixture was warmed to 25 ° C.
  • compound 19-4 (183 mg, 0.65 mmol) was added to a solution of compound 1-18 (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol) in N-N, dimethylformamide (2 mL), and the reaction solution was stirred at 60 ° C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with 20 mL of water. The aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the crude product, which was separated and purified by reverse phase preparative (0.1% FA/ACN, 80% to 90% over 10 min) to obtain compound 19-5.
  • Example 19 Under nitrogen atmosphere, 3 mL of hydrochloric acid/methanol (2 M) solution containing compound 19-5 (60.0 mg, 0.09 mmol) was stirred at 25°C for 0.5 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain the crude product, which was separated and purified by reverse phase preparation (column: Waters Xbridge 150 ⁇ 25mm ⁇ 5um, 30% to 60% over 10 min) to obtain Example 19.
  • compound 1-15 (200 mg, 0.54 mmol) was added to methanol (2 mL), and the mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated to dryness to obtain compound 21-1.
  • Propargyl bromide (0.34 g, 2.82 mmol) was added to a suspension of compound 21-2 (1.00 g, 2.82 mmol) and potassium carbonate (1.95 g, 14.1 L) in DMF (10 mL). The mixture was stirred at 60°C for 2 hours. The reaction mixture was filtered, and the filtrate was purified by reverse-phase column chromatography (0.1% formic acid) to obtain compound 21-3.
  • di-tert-butyl dicarbonate (2.8 mL, 13.1 mmol) and triethylamine (1.8 mL, 13.1 mmol) were added to a solution of compound 21-7 (1.00 g, 6.57 mmol) and 4-dimethylaminopyridine (0.40 g, 3.29 mmol) in 10 mL of dichloromethane.
  • the reaction was stirred at 26°C for 16 hours.
  • Additional di-tert-butyl dicarbonate (2.8 mL, 13.1 mmol) was added, and the reaction mixture was warmed to 40°C and stirred for another 16 hours.
  • compound 21-5 (70.0 mg, 0.18 mmol) was added to a 0.5 mL dichloromethane solution of compound 21-6 (148 mg, 0.88 mmol) and triethylamine (0.1 mL, 0.88 mmol), and the reaction solution was stirred at 25°C for 1.5 hours. After the reaction was completed, the reaction solution was quenched with 20 mL of water, and the aqueous phase was extracted with dichloromethane (10 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by reverse phase preparative (0.1% FA/ACN, 50% to 60% over 5 min) to obtain compound 21-10.
  • Example 21 Under nitrogen atmosphere, compound 21-10 (70.0 mg, 0.13 mmol) was added to 10 mL of ammonia methanol (7 M). The reaction solution was stirred at 25 ° C for 16 hours and then concentrated to obtain the crude product. The crude product was separated and purified by reverse phase preparation (column: Waters Xbridge 150 ⁇ 25mm ⁇ 5um, 32% to 62% over 11min) to obtain Example 21.
  • the mixture was separated by SFC (Column: DAICEL CHIRALCEL OX (250 mm ⁇ 30 mm ⁇ 10 um); Condition: CO2 - EtOH (0.1% NH3H2O ); B%: 15-15; Gradient Time (min): 6.2; 100% B Hold Time (min): 0; Flow Rate (ml/min): 150) to obtain two single isomers.
  • cyanomethylenetri-n-butylphosphine (7.15 g, 29.64 mmol) was added to a solution of compound 21-2 (2.10 g, 5.93 mmol) and compound 12-2 (3.86 g, 29.64 mmol) in 80 mL of dioxane.
  • the reaction mixture was heated to 40°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched by the addition of 100 mL of water. The aqueous phase was extracted with ethyl acetate (50 mL x 2).
  • iodobenzene diacetate 216.7 mg, 0.67 mmol
  • a 4 mL methanol solution of compound 24-5 160 mg, 0.32 mmol
  • ammonium acetate 39.27 mg, 0.51 mmol
  • the product was diluted with 20 mL of water and concentrated under reduced pressure to remove the low-boiling solvent.
  • the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2).
  • Example 26 After completion of the reaction, the crude product was concentrated and purified via reverse phase preparative chromatography (Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; mobile phase: water (FA)-ACN; B%: 45%-75%, 25 min) and secondary reverse phase preparative chromatography (Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; mobile phase: water (NH 4 HCO 3 )-ACN; B%: 42%-72%, 25 min) to afford Example 26.
  • reverse phase preparative chromatography Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; mobile phase: water (FA)-ACN; B%: 45%-75%, 25 min
  • secondary reverse phase preparative chromatography Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; mobile phase: water (NH 4 HCO 3 )-ACN; B%: 42%-72%, 25 min
  • Example 29 The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by reverse phase preparative chromatography (Column Waters Xbridge 150*25 mm*5 ⁇ m; mobile phase: water (NH 3 H 2 O)-ACN; B%: 38%-68%, 12 min) to obtain Example 29.
  • tert-butyldimethylsilyl chloride 865 mg, 5.74 mmol was added to a solution of compound 32-1 (300 mg, 2.87 mmol) and imidazole (586 mg, 8.61 mmol) in 5 mL of N,N-dimethylformamide.
  • the reaction mixture was allowed to react at 20°C for 3 hours. After completion, the reaction was quenched with 50 mL of water and extracted with ethyl acetate (25 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (eluted with petroleum ether) to afford compound 32-2.
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 120.62 mg, 0.32 mmol
  • N,N-diisopropylethylamine 69.9 ⁇ L, 0.42 mmol
  • compound 34-4 64.93 mg, 0.25 mmol
  • the reaction solution was stirred at 25°C for 16 hours. After completion of the reaction, the mixture was quenched with 40 mL of water and extracted with ethyl acetate (30 mL ⁇ 3).
  • reaction mixture was cooled to room temperature, diluted with 30 mL of water, and extracted with ethyl acetate (15 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then isolated and purified by reverse phase preparative (0.1% FA/ACN, 80% to 90% over 5 min) to obtain compound 35-2.
  • compound 36-1 35.34 mg, 0.25 mmol was added to a 2 mL dichloromethane solution containing compound 21-5 (100 mg, 0.25 mmol) and triethylamine (105.1 ⁇ L, 0.76 mmol).
  • the reaction mixture was allowed to react at 25°C for 1 hour. After completion, 3 mL of water was added to dilute and quench the reaction. The aqueous phase was extracted with dichloromethane (10 mL ⁇ 3).
  • the mixture was separated by SFC (Column DAICEL CHIRALPAK AD (250 ⁇ 50 mm ⁇ 10 um); Condition: CO2 - EtOH (0.1% NH3H2O ); B%: 20-20; Gradient Time (min): 3.6; 100% B Hold Time (min): 0; Flow Rate (ml/min): 120) to obtain two single isomers.
  • Example 39 The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by reverse phase preparative chromatography (Column Waters Xbridge 150*25 mm*5 ⁇ m; mobile phase: water (NH 3 H 2 O)-ACN; B%: 38%-68%, 12 min) to obtain Example 39.
  • dimethylphosphine oxide (676.69 mg, 8.67 mmol), potassium phosphate (3.07 g, 14.45 mmol), tris(dibenzylideneacetone)dipalladium (317.58 mg, 0.35 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (401.34 mg, 0.69 mmol) were added to a solution of compound 42-1 (1.0 g, 5.78 mmol) in 20 mL of N,N-dimethylformamide. The reaction mixture was heated to 140°C and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered.
  • Example 46 Under nitrogen atmosphere, sodium methoxide in methanol (0.01 mL, 0.05 mmol) was added to Example 44 (100 mg, 0.21 mmol) in 5 mL of methanol. The reaction was stirred at room temperature for 2 hours, followed by the addition of ammonium chloride (23 mg, 0.42 mmol), and the temperature was raised to 40°C and stirring continued for 12 hours. The reaction was concentrated, and the crude product was purified via reverse elution (Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; flow rate: 25 mL/min; gradient: 23%-53% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to afford Example 46.
  • Example 44 100 mg, 0.21 mmol was dissolved in 2 mL of 1,4-dioxane, and triethylamine (0.058 mL, 0.42 mmol) and dimethylamine hydrochloride (33.87 mg, 0.42 mmol) were added sequentially.
  • the reaction solution was heated to 90°C and stirred for 16 hours.
  • the reaction solution was concentrated, and the crude product was purified via reverse elution (Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; flow rate: 25 mL/min; gradient: 24%-54% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give Example 47.
  • compound 48-2 (370 mg, 1.25 mmol) was dissolved in THF (1 mL) at -50°C.
  • a solution of n-butyllithium in n-hexane (1.0 mL, 2.50 mmol) was slowly added, and the mixture was stirred for 0.5 hours.
  • a solution of deuterated iodomethane (370 mg, 2.55 mmol) in THF (1 mL) was added, and the mixture was stirred for 1 hour.
  • the reaction mixture was quenched by pouring it into a saturated aqueous solution of ammonium chloride (100 mL), and the mixture was extracted with ethyl acetate (100 mL x 3).
  • the organic phase was combined with saturated brine (100 mL), washed once, dried over anhydrous sodium sulfate, filtered, and dried to obtain compound 48-3.
  • triphenylphosphine 70 mg, 0.11 mmol
  • compound 1-18 50 mg, 0.11 mmol
  • compound 48-4 10 mg, 0.13 mmol
  • THF 1.5 mL
  • Diisopropyl azodicarboxylate 30 mg, 0.15 mmol
  • Ethyl acetate 20 mL was added to the reaction solution, and the mixture was washed with water (10 mL x 2) and saturated brine (10 mL) once.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product, which was purified via reverse PCR (Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; flow rate: 25 mL/min; gradient: 48%-78% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 48.
  • reverse PCR Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; flow rate: 25 mL/min; gradient: 48%-78% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile
  • trifluoromethanesulfonic anhydride (4.409 g, 15.63 mmol) was added to a solution of triethylamine (3.163 g, 31.26 mmol) and compound 50-2 (4.130 g, 10.42 mmol) in 40 mL of dichloromethane at 0°C.
  • the reaction mixture was allowed to react at 0°C for 2 hours. After completion of the reaction, the reaction mixture was poured into 100 mL of water, and the aqueous phase was extracted with dichloromethane (50 mL x 3).
  • N,N-dimethylformamide (2.3 ⁇ L, 0.03 mmol) and oxalyl chloride (114.52 mg, 0.90 mmol) were added sequentially to 4 mL of dichloromethane solvent containing compound 50-7 (118 mg, 0.30 mmol).
  • the reaction solution was reacted at 25°C for 1 hour to obtain a solution containing compound 50-8, which was directly used in the next reaction.
  • Example 51 The crude product was purified by reverse phase preparative purification (Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; flow rate: 25 mL/min; gradient: 52%-72% Bover 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 51.
  • reverse phase preparative purification Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; flow rate: 25 mL/min; gradient: 52%-72% Bover 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile
  • the crude product was purified by reverse transpiration (Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; flow rate: 25 mL/min; gradient: 45%-75% B over 15 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 52.
  • reverse transpiration Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; flow rate: 25 mL/min; gradient: 45%-75% B over 15 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile
  • trifluoromethanesulfonic anhydride 83.5 ⁇ L, 0.50 mmol was added to a solution of compound 58-1 (280 mg, 0.61 mmol) in 4 mL of dichloromethane at 0°C.
  • the reaction mixture was stirred at 0°C for 2 hours. After completion, the reaction was quenched by the addition of 20 mL of water and extracted with dichloromethane (30 mL x 2).
  • tetrabutylammonium fluoride tetrahydrofuran solution (0.17 mL, 0.17 mmol) was added to a 1 mL THF solution of compound 60-4 (50 mg, 0.09 mmol), and the reaction solution was reacted at 25 degrees for 1 hour. After completion of the reaction, 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered.
  • Example 60 The filtrate was concentrated to obtain the crude product, which was purified by reverse phase preparation ((Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 um); flow rate: 25 mL/min; gradient: 42%-72% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 60.
  • reverse phase preparation (Phenomenex luna C18 150 ⁇ 25 mm ⁇ 10 um); flow rate: 25 mL/min; gradient: 42%-72% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 60.
  • CHO cells stably expressing human NaV1.8 were cultured in Ham's F-12 medium containing 10% fetal bovine serum, 10 ⁇ g/mL blasticidin, 200 ⁇ g/mL hygromycin B, and 100 ⁇ g/mL zeocin.
  • the cell culture temperature was 37°C and the carbon dioxide concentration was 5%.
  • the old culture medium was removed and the cells were washed once with PBS. Then, 0.25%-Trypsin-EDTA solution was added and incubated at 37°C. When the cells were observed to fall off from the bottom of the dish, an appropriate amount of complete culture medium preheated at 37°C was added.
  • the cells were blown off from the bottom of the dish, they were transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes to collect the cells. The cells were then seeded into 6 cm cell culture dishes (2.5 ⁇ 10 5 cells/dish, 5 mL culture medium) for expansion or maintenance culture. To maintain the electrophysiological activity of the cells, the cell density must not be lower than 80%.
  • trypsin-EDTA solution was added to CHO cells stably expressing human NaV1.8 to detach the cells and count them. 6.5 ⁇ 10 3 cells were attached to coverslips and cultured in 24-well plates (final volume 500 ⁇ L). The cells were tested 18 hours later.
  • Test compounds were prepared in dimethyl sulfoxide (DMSO) to a 100 mM stock solution. The solution was then diluted to various working concentrations in an extracellular solution containing 100 nM tetrodotoxin (TTX) (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, pH adjusted to 7.4 with NaOH). The DMSO concentration in each working solution was 0.1%. The working solutions were sonicated for 20 min prior to testing.
  • TTX tetrodotoxin
  • Patch clamp testing First, a recording electrode is drawn from a glass capillary using a microelectrode puller. The electrode, filled with intracellular solution (50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, 20mM EGTA, adjusted to pH 7.2 with CsOH), is then loaded into a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to bring the recording electrode into contact with the cell. Negative pressure is applied to create a G ⁇ seal. Fast capacitance compensation is then applied, followed by continued negative pressure to rupture the cell membrane and establish whole-cell recording mode. Finally, slow capacitance compensation is performed and the relevant parameters are recorded. No leakage compensation is performed.
  • intracellular solution 50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, 20mM EGTA, adjusted to pH 7.2 with CsOH
  • the drug is administered, and each drug concentration is acted on for 5 minutes (or the current is stable) before the next concentration is detected.
  • the coverslip with cells is placed in a recording bath under an inverted microscope, and the blank control external solution and the test compound working solution are flowed through the recording bath from low concentration to high concentration in sequence by gravity perfusion to act on the cells.
  • a peristaltic pump is used for liquid exchange during recording.
  • the current detected in the external solution without compound for each cell serves as its own control group.
  • Each concentration is independently repeated 2 times. All electrophysiological tests are carried out at room temperature. Specifically, 2 concentrations (preliminary screening) or 5 concentrations (IC 50 value calculation) are set for each test compound.
  • the inhibitory activity of the test compound on NaV1.8 sodium channels is determined by calculating the relative percentage of the peak current generated after the test compound treats the cells and the peak current generated by the control group cells.
  • Voltage stimulation protocol for whole-cell patch-clamp recording of NaV1.8 sodium currents After whole-cell patch-clamp formation, the cell is voltage-clamped at -120 mV. The voltage is first stepped from -130 mV to -10 mV in 10 mV steps and held for 5 seconds. A depolarizing pulse of 0 mV is then applied to obtain the half-inactivation voltage (Vhalf). The resting and half-inactivated states of sodium current are monitored using a double-pulse protocol. A first depolarizing pulse (TP1) is applied to 0 mV for 50 ms to measure the resting sodium current. The voltage is then adjusted to Vhalf and held for 5 seconds.
  • TP1 first depolarizing pulse
  • the voltage is then returned to -120 mV and held for 20 ms.
  • a second depolarizing pulse (TP2) is applied to 0 mV for 50 ms to measure the half-inactivated sodium current.
  • the voltage is returned to the clamping voltage of -120 mV. Data are collected repeatedly every 20 ms to observe the effects of drugs on the peak sodium currents in the two distinct states.
  • the inhibitory activity of the example compounds on Na V 1.8 channels was determined by the above test.
  • the inhibition rate and IC 50 at a concentration of 1 nM are shown in Tables 1 and 2.
  • mice Six male SD rats weighing 200-300 g were divided into two groups. One group received a single oral dose of 5 mg/kg, and the other group received a single tail vein dose of 1 mg/kg. The animals that received oral administration fasted overnight and resumed eating 4 hours after administration. The animals that received intravenous administration were free to eat. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. After pretreatment, the plasma samples were detected by LC/MS/MS in MRM mode, and a suitable standard curve was established to quantify the target compound in the plasma sample to obtain the drug concentration-time curve. The pharmacokinetic parameters were calculated using the non-atrioventricular membrane model of WinNonlin software. The experimental results are shown in the following table:
  • mice Six male C57BL/6 mice weighing 20-30 g were divided into two groups. One group received a single dose of 5 mg/kg via the tail vein, and the other group received a single oral dose of 1 mg/kg. Both groups of animals had free access to food. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After pretreatment, the plasma samples were detected by LC/MS/MS in MRM mode, and a suitable standard curve was established to quantify the target compound in the plasma sample to obtain the drug concentration-time curve. The pharmacokinetic parameters were calculated using the non-compartmental model of WinNonlin software. The experimental results are shown in the following table:
  • the experimental results show that the compounds of the present invention have high blood concentrations and high exposure in mice, and have pharmacokinetic advantages.
  • mice Six male beagle dogs weighing 9-11 kg were divided into two groups. One group received a single dose of 0.5 mg/kg via the tail vein, and the other group received a single oral dose of 1 mg/kg. The animals in the intravenous administration group were free to eat, while the animals in the oral administration group fasted overnight and resumed eating 4 hours after administration. Blood was collected from the intravenous administration group at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 and 48 hours after administration, and from the oral administration group at 0.25, 0.5, 1, 2, 4, 8, 24, 32 and 48 hours after administration.
  • the plasma samples were detected by LC/MS/MS in MRM mode, and a suitable standard curve was established to quantify the target compound in the plasma sample to obtain the drug concentration-time curve.
  • the pharmacokinetic parameters were calculated using the non-compartmental model of WinNonlin software. The experimental results are shown in the following table:
  • the plasma samples were detected by LC/MS/MS in MRM mode, and a suitable standard curve was established to quantify the target compound in the plasma sample to obtain the drug concentration-time curve.
  • the pharmacokinetic parameters were calculated using the non-compartmental model of WinNonlin software. The experimental results are shown in the following table:
  • CYP450 isoenzyme-specific probe substrates were incubated with human liver microsomes and various concentrations of the compound. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the concentrations of metabolites produced by the probe substrates were quantitatively measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The IC50 values were then calculated. The experimental results are shown in the following table:
  • the experimental results show that the compounds of the present invention have weak inhibition on cytochrome P450 isoenzymes and low risk of drug-drug interaction.
  • Experimental Example 10 Plasma protein binding rate of the compound of the present invention.
  • Experimental Method Take a 10mM stock solution in DMSO and dilute it to a 1mM working solution. Add 3 ⁇ L of the working solution of the test substance to 597 ⁇ L of pre-incubated plasma and mix thoroughly. The final concentration of the test substance in plasma is 5 ⁇ M. The final organic solvent content of the incubation system is 0.5%. After mixing, immediately transfer 50 ⁇ L of the incubation system to a new 96-well plate as the zero-point sample and treat it in the same manner as the pre-incubated samples.
  • mice Male SD rats and male C57 BL/6J mice were used to establish a plantar incision pain model, and the analgesic effect of the disclosed compounds was evaluated by measuring the changes in the mechanical pain threshold of the animals.
  • Example 3 Example 12 and Example 24.
  • 5% DMSO, 10% solutol, and 85% saline were added in sequence and vortexed to mix until clear.
  • mice After adaptive feeding, C57 BL/6J mice were divided into the following groups:
  • Plantar incision pain modeling The experimental animals were anesthetized and fixed on the operating table in a prone position. The soles of the hind limbs were flattened upwards, fixed with surgical tape, and disinfected. A longitudinal incision was made at the heel of the sole of the foot with a sterilized blade to cut the skin fascia toward the toe end. Insert one end of the curved forceps under the lateral edge of the flexor digitorum brevis and push the forceps into the inner side of the muscle to lift the flexor digitorum brevis. Make a longitudinal incision in the muscle with a blade, making sure to cut the muscle belly in half and remove the skin. Use 7-0 sutures for suturing and disinfection. The animals were returned to their original place and recovered from the surgery overnight. Oral gavage was performed, and mechanical pain measurement was performed 3 hours after the animals were administered.
  • Mechanical pain measurement Place the experimental animal on a mechanical pain metal grid and let it rest for 30-60 minutes. The test begins when the animal stops looking around, exploring, and becomes relatively quiet. Once the experimental animal is quiet, slowly and gently stimulate the sole of the hind limb to be tested with a Von-Frey fiber, causing the fiber to bend. The animal's paw withdrawal reaction is observed for 2-3 seconds. The animal is stimulated one by one in ascending order of fiber weight. Each fiber weight is stimulated five times continuously, with at least 10 seconds between each stimulation. If fewer than three positive reactions occur, repeat the above procedure with a larger fiber. The first time three or more positive reactions occur, the fiber used is considered the pain threshold for that animal (each animal is tested twice, and the average is taken).
  • Fiber weight rat 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0 (g), cut-off value is 15.0g; mouse 0.16, 0.40, 0.60, 1.00, 1.40, 2.00 (g), cut-off value is 2.00g.
  • SPSS data statistical software version R26.0.0.0 was used to analyze the mean and standard error. Based on the SPSS statistical results, Graph Pad (version 8.0.2) software was used to draw images, and one-way ANOVA and t-test were used to test the data.
  • Threshold elevation percentage (%) [( Gt - G0 )/ G0 ] x 100 (%), wherein Gt is the plantar pain threshold of animals in the drug-treated group, and G0 is the plantar pain threshold of animals in the vehicle group.
  • Example 3 The analgesic efficacy of Example 3, Example 12 and Example 24 in the rat plantar incision pain model is shown in Table 12.
  • the analgesic efficacy of Example 3, Example 12 and Example 24 in the mouse plantar incision pain model is shown in Table 13.
  • the baseline pain thresholds of rats before surgery were as follows: 3 hours after surgery, the pain threshold of Example 3 at 30 mg/kg was 7.1 ⁇ 0.2 g, a significant increase of 97.2% (p ⁇ 0.0001) compared to the pain threshold of the vehicle control group; the pain thresholds of Example 12 at 15 and 30 mg/kg were 7.0 ⁇ 0.3 g and 7.5 ⁇ 0.2 g, respectively, significantly increasing by 94.4% (p ⁇ 0.0001) and 108.3% (p ⁇ 0.0001) compared to the pain thresholds of the vehicle control group.
  • the pain threshold of Example 12 at 30 mg/kg was slightly higher than that at 15 mg/kg, and the analgesic effect was close to saturation; the pain threshold of Example 24 at 30 mg/kg was 8.1 ⁇ 0.3 g, a significant increase of 125% (p ⁇ 0.0001) compared to the pain threshold of the vehicle control group, and the analgesic effect was significantly higher than that of Example 3 at 30 mg/kg (p ⁇ 0.05).
  • the baseline pain thresholds of mice before surgery were as follows: 3 hours after surgery, the pain threshold of Example 3 at 60 mg/kg was 0.70 ⁇ 0.05 g, a significant increase of 94.4% (p ⁇ 0.01) compared to the pain threshold of the vehicle control group; the pain threshold of Example 12 at 60 mg/kg was 0.78 ⁇ 0.06 g, a significant increase of 116.7% (p ⁇ 0.001) compared to the pain threshold of the vehicle control group; and the pain thresholds of Example 24 at 30 and 15 mg/kg were 0.74 ⁇ 0.08 g and 0.54 ⁇ 0.04 g, respectively, significantly increasing by 105.6% (p ⁇ 0.001) and 50.0% compared to the pain threshold of the vehicle control group.
  • the pain threshold of Example 24 at 30 mg/kg was significantly higher than that at 15 mg/kg (p ⁇ 0.05), demonstrating a clear dose-dependent analgesic effect.
  • the mechanical allodynia test was used to evaluate the efficacy of the compounds in the mouse plantar incision pain model.
  • Example 61 The compound of Example 61 was added in sequence with 5% DMSO, 10% solutol, and 85% saline, and vortexed to mix until clear.
  • mice After adaptive breeding, C57 BL/6 mice were divided into the following groups:
  • Plantar incision pain modeling Use isoflurane to anesthetize the animal, and squeeze the animal's toes to confirm that the animal is fully anesthetized before surgery. Apply eye ointment to the animal's eyes to prevent the animal's cornea from drying out. Use iodine tincture and 70% ethanol to disinfect the sole of the left foot three times, and start the surgery after the skin is dry. Starting from 2mm from the heel, make an incision about 5mm long longitudinally toward the toe. After cutting the skin, lift the flexor digitorum brevis muscle and cause longitudinal blunt injury. Suture the wound and disinfect. After the animal is fully awake (free to move), put the animal back in the cage. 10 animals did not undergo mouse incision pain surgery, as a contrast.
  • mice were individually placed in a plexiglass box with a mesh bottom to ensure that the mouse's foot was accessible for testing. The mice were acclimated for 15 minutes before testing. After acclimation, the center of the sole of the left hind paw of the mouse was tested using a test fiber.
  • the test fiber included 8 test strengths: 2.36 (0.02g), 2.44 (0.04g), 2.83 (0.07g), 3.22 (0.16g), 3.61 (0.4g), 3.84 (0.6g), 4.08 (1g), and 4.17 (1.4g).
  • test fiber was pressed vertically against the skin and force was applied to bend the fiber for 6-8 seconds, with 5 seconds between each test.
  • a rapid withdrawal of the animal's foot was recorded as a pain response. If the animal withdraws its paw when the test fiber leaves its skin, it is also recorded as a pain response. If the animal moves or walks, it is not recorded as a pain response and the test should be repeated.
  • the test is initially performed using a force of 3.22 (0.16g). If the animal reacts to pain, the next test is performed using a test fiber of a lower force. If the animal does not react to pain, the next test is performed using a test fiber of a higher force. The maximum force of the test fiber is 4.17 (1.4g).
  • the test results are recorded in the table below. An X indicates a pain response and an O indicates no pain response.
  • Example 61 The analgesic efficacy of Example 61 in the mouse plantar incision pain model is shown in Table 14.
  • Example 61 At different times after administration, the compound of Example 61 had significant analgesic effect in the plantar incision pain model of mice, and had a clear dose-dependency.
  • the reference terms “one embodiment”, “some embodiments”, “example”, “specific example”, or “some examples” mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention.
  • the schematic representations of the above terms do not necessarily refer to the same embodiment or example.
  • the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.
  • those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

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Abstract

La présente invention concerne un inhibiteur sélectif de canal sodique dépendant de la tension Nav1.8 et son utilisation dans la préparation d'un médicament associé. Le médicament est utilisé pour traiter des maladies sensibles à l'inhibition du canal sodique dépendant de la tension NaV1.8, telles que la douleur chronique, l'entérodynie, la douleur neuropathique, la douleur musculo-squelettique, la douleur aiguë, la douleur inflammatoire, la douleur cancéreuse, la douleur idiopathique, la douleur post-opératoire, la douleur viscérale, la sclérose en plaques, le syndrome de Charcot-Marie-Tooth, l'incontinence, la toux pathologique ou l'arythmie. Plus particulièrement, la présente invention concerne un composé tel que représenté par la formule (X), et un isomère, un oxyde d'azote, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci.
PCT/CN2025/089704 2024-04-19 2025-04-18 Composé utilisé en tant qu'inhibiteur de canal sodique dépendant de la tension et son utilisation Pending WO2025218764A1 (fr)

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