WO2025168043A1 - Dérivé cyclique fusionné, son procédé de préparation et son utilisation - Google Patents

Dérivé cyclique fusionné, son procédé de préparation et son utilisation

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Publication number
WO2025168043A1
WO2025168043A1 PCT/CN2025/076167 CN2025076167W WO2025168043A1 WO 2025168043 A1 WO2025168043 A1 WO 2025168043A1 CN 2025076167 W CN2025076167 W CN 2025076167W WO 2025168043 A1 WO2025168043 A1 WO 2025168043A1
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Prior art keywords
alkyl
compound
alkoxy
deuterium
halogen
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PCT/CN2025/076167
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English (en)
Chinese (zh)
Inventor
万泽红
冯加权
石俊杰
邹元海
田振
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nhwa Pharmaceutical Corp
Shujing Biopharma Co Ltd
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Nhwa Pharmaceutical Corp
Shujing Biopharma Co Ltd
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Publication of WO2025168043A1 publication Critical patent/WO2025168043A1/fr
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Anticipated expiration legal-status Critical

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Classifications

    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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

Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a cyclic derivative, a preparation method and use thereof.
  • Commonly used analgesics are primarily nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids.
  • NSAIDs have a weak analgesic effect and a ceiling effect.
  • Opioid analgesics are also commonly addictive and suffer from severe abuse. Overall, the analgesic market still has significant unmet demand.
  • Voltage-gated sodium channels are multi-subunit transmembrane glycoproteins expressed on the cell membrane, composed of ⁇ and ⁇ subunits.
  • the ⁇ subunit is a functional unit composed of four homologous transmembrane domains, each of which contains six transmembrane hydrophobic ⁇ helices (S1-S6).
  • S1-S4 constitute the voltage receptor, which can regulate the hydrophilicity of the sodium ion channel between S5 and S6, causing cell depolarization or hyperpolarization, and completing the signal transmission across the membrane.
  • NaV1.1 to 1.9 In the human body, there are nine different subtypes of ⁇ subunits, named NaV1.1 to 1.9. Their abnormal inactivation or activation is associated with a variety of neurological, cardiovascular, and muscular diseases. Among them, the subtypes related to pain are mainly NaV1.3, NaV1.7, NaV1.8, and NaV1.9. NaV1.7 is present in sympathetic ganglion neurons and peripheral sensory neurons. NaV1.8 and NaV1.9 are expressed only in peripheral sensory neurons. Abnormal activation of these channels can cause analgesia or allodynia, providing potential targets for non-addictive analgesia.
  • NaV1.8 is a tetrodotoxin-insensitive sodium channel primarily expressed on nociceptive neurons. It plays a key role in pain signaling in the peripheral nervous system and is a primary selective target for pain treatment. Because NaV1.8 is primarily distributed in pain-sensing neurons, the use of selective NaV1.8 inhibitors is unlikely to result in the common adverse reactions of non-selective NaV inhibitors. More importantly, NaV1.8 does not participate in central nervous system-related activities, so NaV1.8 inhibitors do not have the addictive potential of opioids and will not affect motor function.
  • Vertex Pharmaceuticals' VX-548 is making the most progress.
  • VX-548 is an oral, selective NaV1.8 inhibitor developed by Vertex Pharmaceuticals. Compared to other NaV ion channels, it is highly selective for NaV1.8 and selectively inhibits it. Compared to opioids, this drug provides better analgesia while avoiding side effects such as addiction.
  • Vertex Pharmaceuticals announced the latest data from a Phase III clinical trial of VX-548 for the treatment of moderate to severe acute pain. The study achieved the primary endpoints of NPRS and SPID48, showing significant improvement compared to placebo.
  • the technical problem to be solved by the present invention is that there are relatively few types of existing NaV1.8 blockers.
  • the present invention provides a paracyclic derivative, a preparation method and its use.
  • This type of compound has good NaV1.8 inhibitory activity and can be used to treat and/or prevent diseases mediated by NaV1.8 inhibitors, such as pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain and visceral pain, cough, pathological cough, multiple sclerosis, Chuck-Male-Doucet syndrome, incontinence or arrhythmia, etc., providing a new option for the treatment of such diseases or alleviating their severity.
  • diseases mediated by NaV1.8 inhibitors such as pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain and visceral pain, cough, pathological cough, multiple sclerosis, Chuck-Male-Doucet syndrome
  • the object of the present invention is to provide a compound represented by general formula (I), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof,
  • X is O or S
  • Ring B is a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S;
  • R b is each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, or C 1-6 haloalkoxy;
  • R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, or C1-6 haloalkoxy;
  • Ring C is a C 6-10 aryl group or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;
  • R c is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy; wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted by one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo;
  • Ring A is a C 6-10 aryl group, a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, a 5-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, or
  • each Ra is independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, -( CH2 ) nORaa , -( CH2 )nNRaaRbb, -( CH2 ) nC (O) Raa , -( CH2 ) nC ( O ) ORaa , -( CH2 ) nC (O) NRaaRbb , -( CH2 ) nS (O) NRaaRbb , -( CH2 ) nC ( O) NRbb ( CH2 ) n1OP (O)( ORaa ) 2 , -( CH2 ) nOP (O ) ( ORaa ) 2.
  • R aa , R bb and R cc are each independently hydrogen, deuterium, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo;
  • x is an integer from 0 to 6;
  • y is an integer from 0 to 6;
  • n1 is an integer from 0 to 3.
  • X is O or S, preferably O.
  • the ring B is a C 3-8 cycloalkyl group or a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group or a tetrahydropyranyl group.
  • each of the R b groups is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; preferably hydrogen or C 1-3 alkyl; more preferably hydrogen or methyl.
  • R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy; preferably hydrogen or C1-3 alkyl; more preferably hydrogen, methyl, ethyl or isopropyl.
  • the ring C is a C 6-10 aryl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; preferably a phenyl group or a pyridyl group, more preferably the following groups:
  • each R c is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally further substituted with one or more deuterium or halogen; preferably hydrogen, deuterium, halogen, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally further substituted with one or more deuterium or halogen; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCD 2 F, -CD 3 , -OCD 3 or -OCDF 2 .
  • each R c is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy or C 1-6 haloalkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy or C 1-3 haloalkoxy; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, -CD 3 , -OCD 3 or -OCDF 2 .
  • said Raa , Rbb and Rcc are each independently hydrogen, deuterium, hydroxyl, C1-6 alkyl or C1-6 alkoxy, wherein said C1-6 alkyl or C1-6 alkoxy is optionally further substituted with one or more hydroxyl groups; preferably hydrogen, hydroxyl, C1-6 alkyl or C1-6 alkoxy, wherein said C1-6 alkyl or C1-6 alkoxy is optionally further substituted with one or more hydroxyl groups; more preferably hydrogen, hydroxyl, methyl, methoxy, -CH2OH or -CH2CH (OH)( CH2OH ).
  • the general formula (I) further has a structure represented by the general formula (II):
  • R b is each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, or C 1-6 haloalkoxy;
  • R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, or C1-6 haloalkoxy;
  • Ring C is a C 6-10 aryl group or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;
  • R c is each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, or C 1-6 haloalkoxy;
  • Ring A is a C 6-10 aryl group, a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, or a 5-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S;
  • R aa and R bb are each independently hydrogen, deuterium, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo;
  • x is an integer from 0 to 6;
  • y is an integer from 0 to 6;
  • z is an integer from 0 to 6;
  • Ring B is a C3-8 cycloalkyl group or a 3-6 membered heterocyclyl group containing 1-3 heteroatoms selected from N, O, and S; preferably, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or tetrahydropyranyl.
  • Each of the Rb groups is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy; preferably, hydrogen or C1-3 alkyl; more preferably, hydrogen or methyl.
  • R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy; preferably hydrogen or C1-3 alkyl; more preferably hydrogen, methyl, ethyl or isopropyl;
  • the R c are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy or C 1-3 haloalkoxy; preferably hydrogen, halogen, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen, fluorine, methyl, ethyl, deuterated methyl, deuterated ethyl, methoxy, ethoxy, deuterated methoxy or deuterated ethoxy.
  • the ring A is a C 6-10 aryl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, or a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably a phenyl group, a pyridyl group, a dihydropyridyl group, a pyridonyl group or a pyridine-N-oxide group; more preferably the following groups:
  • said Raa and Rbb are each independently hydrogen, deuterium, hydroxyl, C1-6 alkyl or C1-6 alkoxyl, wherein said C1-6 alkyl or C1-6 alkoxyl is optionally further substituted with one or more hydroxyl groups; preferably hydrogen, hydroxyl, C1-6 alkyl or C1-6 alkoxyl, wherein said C1-6 alkyl or C1-6 alkoxyl is optionally further substituted with one or more hydroxyl groups; more preferably hydrogen, hydroxyl, methyl, methoxyl, -CH2OH or -CH2CH (OH)( CH2OH ).
  • R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy;
  • R 3 , R 4 and R 5 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • x is an integer from 0 to 6;
  • the ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, or a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably a pyridyl group, a dihydropyridyl group or a pyridine-N-oxide group; more preferably the following groups:
  • said R aa and R bb are each independently hydrogen, deuterium, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted by one or more hydroxy groups, preferably hydrogen or C 1-6 alkyl substituted by one or more hydroxy groups; more preferably hydrogen, -CH 2 OH or -CH 2 CH(OH)(CH 2 OH).
  • x is an integer of 0-4; preferably 1, 2 or 3.
  • n is an integer from 0 to 1; preferably 0.
  • the general formula (III) further has a structure represented by the general formula (IV):
  • n is an integer of 0-3; and ring A, R 1 , R 3 , R 4 , R 5 , Ra , Raa , R bb , x and n are as described above.
  • m is 3, and the remaining ring A, R 1 , R 3 , R 4 , R 5 , Ra , Raa , R bb , x and n are as described above.
  • the general formula (III) further has a structure represented by the general formula (IV-A) or the general formula (IV-B):
  • n is an integer of 0-3; and ring A, R 1 , R 3 , R 4 , R 5 , Ra , Raa , R bb , x and n are as described above.
  • the Ra may also independently be -( CH2 ) nS (O) NRaaRbb or -( CH2 ) nC (O) NRbb ( CH2 ) n1OP (O)( ORaa ) 2 , preferably -S(O) NH2 or -C(O)NH- CH2 -OP(O)(OH) 2.
  • the R c or the corresponding position can also be independently a C 1-6 alkyl group or a C 1-6 alkoxy group optionally further substituted with one or more deuterium or halogen; preferably a C 1-3 alkyl group or a C 1-3 alkoxy group optionally further substituted with one or more deuterium or halogen; more preferably -OCD 2 F or -OCDF 2.
  • the general formula (I) further has a structure represented by the general formula (V):
  • X is O or S; preferably O;
  • R1 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy or C1-6 haloalkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy; more preferably hydrogen, methyl, ethyl or isopropyl;
  • R b is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy or C 1-6 haloalkoxy; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen or methyl;
  • Ring C is a C 6-10 aryl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; preferably a phenyl group or a pyridyl group; more preferably the following groups:
  • R c is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally further substituted with one or more deuterium or halogen; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCD 2 F, -CD 3 , -OC
  • Ring A is a C 6-10 aryl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S, or
  • each Ra is independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, -( CH2 ) nORaa , -( CH2 )nNRaaRbb, -( CH2 ) nC (O) Raa , -( CH2 ) nC ( O ) ORaa , -( CH2 ) nC (O) NRaaRbb , -( CH2 ) nS (O) NRaaRbb , -( CH2 ) nC ( O) NRbb ( CH2 ) n1OP (O)( ORaa ) 2 , -( CH2 ) nOP (O ) ( ORaa ) 2 , -( CH2
  • R aa , R bb and R cc are each independently hydrogen, deuterium, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, methyl, methoxy, -CH 2 OH or -CH 2 CH(OH)(CH 2 OH);
  • x is an integer from 0 to 6; preferably an integer from 0 to 4; more preferably 1, 2 or 3;
  • y is an integer of 0-6; preferably an integer of 0-4; more preferably 1, 2 or 3;
  • z is an integer from 0 to 6; preferably an integer from 0 to 4; more preferably 1, 2 or 3;
  • n is an integer of 0-3; preferably an integer of 0-2; more preferably 0 or 1;
  • R 1 , R 3 , R 4 , R 5 , R 7 and p are as described above.
  • the present invention also provides a method for preparing the compound represented by general formula (II), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising:
  • Ring A, Ring B, Ring C, R 1 , R 2 , Ra, R b , R c , x , y and z are as described above.
  • the present invention also provides a method for preparing the compound represented by general formula (III), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising:
  • the present invention also provides a method for preparing a compound represented by general formula (IV), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising:
  • the preparation method can be obtained by synthesizing commercially available raw materials through known methods.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above-mentioned general formula, its stereoisomers, its tautomers or pharmaceutically acceptable salts, and at least one pharmaceutical excipient selected from pharmaceutically acceptable carriers, diluents and excipients.
  • the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, wherein oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present application can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions.
  • Carriers used in tablet formulations typically include lactose and corn starch, and lubricants such as magnesium stearate may also be added.
  • Diluents used in capsule formulations typically include lactose and dried corn starch.
  • Aqueous suspension formulations typically combine the active ingredient with a suitable emulsifier and suspending agent. If desired, sweeteners, flavorings, or coloring agents may be added to these oral formulations.
  • Tablets include, but are not limited to, lozenges, sublingual tablets, buccal patches, chewable tablets, dispersible tablets, effervescent tablets, rapid-release, sustained-release, or controlled-release tablets, and enteric-coated tablets.
  • the compounds of the present application can be prepared into different topical preparations according to the different affected areas or organs, as described below.
  • the compounds of the present invention may be formulated as a micronized suspension or solution in an isotonic, sterile saline solution of a defined pH, with or without the addition of a preservative such as benzyl alkanoate chloride.
  • the compounds may also be formulated in an ointment such as petrolatum.
  • the compounds of the present invention may be formulated into suitable ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers for ointments include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water;
  • carriers for lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the present invention also provides a use of the compounds represented by the general formulae, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in the preparation of drugs for preventing and/or treating diseases mediated by voltage-gated sodium channel inhibitors.
  • the voltage-gated sodium channel is NaV1.8.
  • the present invention also provides a use of the compounds represented by the general formulae, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in the preparation of drugs for preventing and/or treating pain, cough, multiple sclerosis, Chuck-Male-Dodds syndrome, incontinence, arrhythmia or alleviating their severity.
  • the present invention also relates to a method for treating diseases mediated by voltage-gated sodium channel inhibitors, which comprises administering a therapeutically effective amount of the compound of the present invention, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof to a mammal.
  • the present invention also relates to a method for treating pain, cough, multiple sclerosis, Chuck-Mare-Dodds syndrome, incontinence, arrhythmia or alleviating the severity thereof, which comprises administering to a mammal a therapeutically effective amount of a compound of the present invention, its stereoisomers, its tautomers or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for treating a disease mediated by a voltage-gated sodium channel inhibitor in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pain is selected from one or more of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, and visceral pain.
  • the cough is a pathological cough.
  • alkyl refers to a saturated, linear or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., a " C1-20 alkyl group.”
  • the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms (i.e., a C1-8 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., a C1-6 alkyl group), and further preferably an alkyl group having 1 to 3 carbon atoms (i.e., a C1-3 alkyl group).
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., a monocyclic cycloalkyl) or a polycyclic hydrocarbon substituent (i.e., a polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., a C3-20 cycloalkyl.
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., a C3-12 cycloalkyl), more preferably a cycloalkyl group having 3 to 8 carbon atoms (i.e., a C3-8 cycloalkyl), further preferably a cycloalkyl group having 3 to 6 carbon atoms (i.e., a C3-6 cycloalkyl), most preferably a cycloalkyl group having 3 to 5 carbon atoms (i.e., a C3-5 cycloalkyl), or alternatively, a cycloalkyl group having 5 to 6 carbon atoms (i.e., a C3-5 cycloalkyl).
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl.
  • Non-limiting examples of polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls. The cycloalkyls may be optionally substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment.
  • the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, or haloalkoxy.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., a monocyclic heterocyclyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., a polycyclic heterocyclyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3-20 membered heterocyclyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, P(O) m , and S(O) n (wherein m and n are integers from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon.
  • the heterocyclyl group preferably has 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclyl), wherein 1-4 heteroatoms are selected from N, O and S atoms, more preferably has 3 to 8 ring atoms (i.e., a 3-8-membered heterocyclyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, further preferably has 3 to 6 ring atoms (i.e., a 3-6-membered heterocyclyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, and most preferably has 5 to 6 ring atoms (i.e., a 5-6-membered heterocyclyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms.
  • 3 to 12 ring atoms i.e., a 3-12-membered heterocyclyl
  • Non-limiting examples of the monocyclic heterocyclic group include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, dihydropyridinyl dihydropyridazinyl etc.
  • Non-limiting examples of the polycyclic heterocyclic group include: spiroheterocyclic group, fused heterocyclic group and bridged heterocyclic group.
  • the heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy or haloalkoxy.
  • aryl refers to an all-carbon monocyclic group (i.e., a monocyclic aryl) or a fused polycyclic group (i.e., a polycyclic aryl) having a conjugated ⁇ electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., a C 6-14 aryl).
  • the aryl is preferably an aryl having 6 to 12 carbon atoms (i.e., a C 6-12 aryl), more preferably an aryl having 6 to 10 carbon atoms (i.e., a C 6-10 aryl), further preferably a phenyl or naphthyl, most preferably a phenyl.
  • the monocyclic aryl is, for example, a phenyl.
  • Non-limiting examples of the polycyclic aryl include: naphthyl, anthracenyl, phenanthrenyl, etc.
  • the aryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy or haloalkoxy.
  • heteroaryl refers to a monocyclic heteroaryl group (i.e., a monocyclic heteroaryl group) or a fused polycyclic heteroaryl group (i.e., a polycyclic heteroaryl group) having a conjugated ⁇ electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5-14-membered heteroaryl group), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, N(O)r, P(O) m , and S(O) n (wherein r, m, and n are integers from 0 to 2), preferably heteroatoms selected from nitrogen, oxygen, or sulfur, excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon.
  • 5 to 14 e.g., 5, 6, 7, 8, 9,
  • the heteroaryl group is preferably a 5-10-membered heteroaryl group containing 1-4 heteroatoms selected from N, O, or S.
  • the monocyclic heteroaryl group is preferably a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S.
  • Non-limiting examples include: furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, pyridine-N-oxide
  • the polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, a C 6-10 aryl group or a C
  • the heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy or haloalkoxy.
  • halo or "halogen” or “halo” is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl,
  • deuterated alkyl refers to an alkyl group substituted by one or more deuterium, wherein alkyl is as defined above.
  • the deuterated alkyl group may be further substituted by one or more halogens.
  • alkoxy refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkoxy).
  • the alkoxy is preferably an alkoxy having 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably an alkoxy having 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), and most preferably an alkoxy having 1 to 3 carbon atoms (i.e., C 1-3 alkoxy).
  • Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro, and oxo.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • halomethoxy include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy.
  • haloethoxy include: 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2- Chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1
  • deuterated alkoxy refers to an alkoxy group substituted by one or more deuterium groups, wherein alkoxy is as defined above.
  • the deuterated alkoxy group may be further substituted by one or more halogen groups.
  • nitro refers to -NO2 .
  • cyano refers to -CN.
  • CDI carbonyldiimidazole.
  • Pd-C platinum-carbon.
  • DIBAL-H diisobutylaluminum hydride.
  • TMSCN trimethylsilyl cyanide.
  • MeOH refers to methanol.
  • EtOH refers to ethanol.
  • DMF N,N-dimethylformamide.
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • DIEA refers to N,N-diisopropylethylamine.
  • THF tetrahydrofuran.
  • DMSO dimethyl sulfoxide.
  • MeCN or “ACN” refers to acetonitrile.
  • DMAP 4-dimethylaminopyridine.
  • DCM dichloromethane.
  • mCPBA meta-chloroperbenzoic acid.
  • TEA triethylamine.
  • TMSCl trimethylchlorosilane.
  • DIPEA refers to N,N-diisopropylethylamine.
  • IPA refers to isopropyl alcohol.
  • NMP refers to N-methylpyrrolidone.
  • EA refers to ethyl acetate.
  • PE refers to petroleum ether.
  • FA refers to formic acid.
  • the expression mn refers to a range from m to n and subranges consisting of individual point values therein and individual point values.
  • the expression “ C2 - C8 " or “ C2-8 " encompasses a range of 2-8 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C2 - C5 , C3 - C4 , C2 - C6 , C3 - C6 , C4 - C6 , C4 - C7 , C4- C8 , etc., as well as C2 , C3 , C4 , C5 , C6 , C7 , C8, etc.
  • C3 - C10 or " C3-10” should be understood in a similar manner, e.g., to encompass any subranges and point values contained therein, such as C3 - C9 , C6 - C9 , C6 - C8 , C6 - C7 , C7 - C10 , C7 - C9 , C7 - C8 , C8-C9, etc. , as well as C3 , C4 , C5 , C6 , C7 , C8 , C9, C10 , etc.
  • C 1 -C 6 or "C 1-6” encompasses a range of 1-6 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , etc., as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc.
  • the expression "three to ten yuan” should be understood to include any sub-ranges therein and each point value, such as three to five yuan, three to six yuan, three to seven yuan, three to eight yuan, four to five yuan, four to six yuan, four to seven yuan, four to eight yuan, five to seven yuan, five to eight yuan, six to seven yuan, six to eight yuan, nine to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc.
  • Other similar expressions herein should also be understood in a similar manner.
  • cycloalkyl optionally substituted with alkyl means that alkyl may but need not be present, and the description includes both the case where the cycloalkyl is substituted with alkyl and the case where the cycloalkyl is not substituted with alkyl.
  • substituted and “substituted” refer to one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom being replaced by a selection from the designated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds. When a substituent is described as not being present, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When each carbon atom in a group is described as optionally substituted by a heteroatom, the proviso is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.
  • variable e.g., R
  • labeled variables e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , etc.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All such isomers and mixtures thereof are within the scope of the present invention. In certain embodiments, preferred compounds are those isomers that exhibit superior biological activity.
  • Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.
  • the terms “enantiomers” or “optical isomers” refer to stereoisomers that are mirror images of one another.
  • the terms “cis-trans isomers” or “geometric isomers” arise from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.
  • diastereomers refers to stereoisomers with two or more chiral centers that are not mirror images of each other.
  • tautomers or “tautomeric forms” refer to isomers of different functional groups that are in dynamic equilibrium at room temperature and readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers, include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations.
  • Valence tautomers are interconversions that occur by reorganization of some of the bonding electrons. Keto-enol tautomerization is exemplified by the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the compounds of the present invention include all suitable isotopic derivatives of their compounds.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom having the same atomic number but different atomic masses.
  • isotopes that can be incorporated into the disclosed compounds include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as, respectively, 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I , etc., preferably deuterium.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the deuterium replacement may be partial or complete, wherein partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • pharmaceutically acceptable refers to a substance that is, within the scope of normal medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.
  • composition refers to a composition containing one or more compounds described herein, or their physiologically/pharmaceutically acceptable salts or prodrugs, as well as other components, such as a physiologically/pharmaceutically acceptable carrier.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.
  • pharmaceutically acceptable carrier refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carriers” include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.
  • administration refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.
  • treating includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention.
  • Treatment also includes achieving a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated.
  • a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed.
  • a prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or when a patient develops one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.
  • active ingredient refers to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition.
  • neuropsychiatric disorder refers to a general term encompassing neurological and/or psychiatric disorders.
  • the terms "effective amount,” “therapeutically effective amount,” or “prophylactically effective amount” refer to a sufficient amount of the drug or pharmaceutical agent to achieve the desired effect with acceptable side effects.
  • the determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.
  • room temperature refers to a temperature from 10-40°C. In some embodiments, “room temperature” refers to a temperature from 15-30°C; in other embodiments, “room temperature” refers to a temperature from 18-25°C.
  • the present invention discloses a class of voltage-gated sodium channel NaV1.8 inhibitor compounds with a novel structure. These compounds have excellent NaV1.8 inhibitory activity and can be used to treat and/or prevent diseases mediated by NaV1.8 inhibitors, such as pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain and visceral pain, cough, pathological cough, multiple sclerosis, Chuck-Marie-Doucet syndrome, incontinence, or arrhythmias, providing a new option for treating or alleviating the severity of such diseases.
  • diseases mediated by NaV1.8 inhibitors such as pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain and visceral pain, cough, pathological cough, multiple sclerosis, Chuck-Marie-Doucet syndrome, incontinence, or arrhythmias, providing a new option for treating or alleviating the severity of such diseases.
  • the compound of this invention has good blocking effect to NaV1.8.
  • the compounds of this invention have good pharmacokinetic properties (such as suitable half-life and duration of action, good blood drug concentration, area under the drug curve and/or bioavailability).
  • the compounds of this invention have improved in vivo pharmacodynamic effects, and/or improved safety (lower toxicity and/or less side effect), and/or good patient compliance, and/or are less likely to produce more excellent drug properties such as tolerance.
  • the results of the NaV1.8 blocking activity experiments of the present disclosure show that the compounds of the present invention have a significant blocking effect on NaV1.8 and are effective NaV1.8 inhibitors.
  • the results of the rat pharmacokinetic experiments show that the compounds of the present invention exhibit good drug metabolism properties, have a suitable half-life t1 /2 , and have good metabolic parameters such as maximum plasma concentration Cmax and area under the concentration-time curve AUC (0-t) .
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shifts are given in parts per million (ppm). NMR measurements were performed using an AVANCE III 400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), and deuterated chloroform (CDCl 3 ) as solvents, with tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass spectrometry
  • the thin layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used for TLC was 0.2mm ⁇ 0.03mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.
  • Dissolve compound a-1 (25 g, 210 mmol) in water (500 mL) and heat to 100°C.
  • Dissolve ferric chloride (68.5 g, 422 mmol) in 150 mL of water and slowly add to the reaction mixture. Continue the reaction at 100°C for 1 hour. After TLC, cool to room temperature and adjust the pH to approximately 7 with saturated ammonium sulfate. Extract three times with ethyl acetate. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product, compound a-2 (18.5 g, 88% yield), which is used directly in the next step.
  • Step 9 Synthesis of Compound 1 To compound 1-9 was added 10 mL of 7 M amine methanol solution, stirred at room temperature overnight for 16 h, and filtered to obtain compound 1 (48 mg, yield 85%).
  • Triethylamine (370 mg, 2.74 mmol), 4-dimethylaminopyridine (6 mg, 0.04 mmol), and 4-amino-2-pyridinylmethyl-2-(benzyloxy)pyridin-4-amine (251 mg, 1.25 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5% to 50%) to afford compound 4-1 (170 mg, 74.7% yield) as a white solid.
  • Chromatographic column DAICELCHIRALPAK IH; column size: 250*50 10 ⁇ m; mobile phase A: supercritical CO 2 ; mobile phase B: IPA (7.0 mol/L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214 nm; flow rate: 140 mL/min; column temperature: RT.
  • Compound 47-1 was prepared using a similar route to compound 46, substituting the corresponding reactants.
  • Compound 47-1 (380 mg, 0.73 mmol) was dissolved in 15 mL of tetrahydrofuran, and 10% palladium on carbon (38 mg) was added. The mixture was stirred overnight under an atmospheric pressure of hydrogen. The mixture was filtered through celite, concentrated, and separated by column chromatography (EtOH in EA: 0% to 5%) to afford compound 47 (180 mg, 59% yield).
  • Compound 51-1 was prepared using a similar route to compound 46, substituting the corresponding reactants.
  • Compound 51-1 250 mg, 0.62 mmol
  • m-chloroperbenzoic acid 427.9 mg, 2.48 mmol
  • the mixture was stirred at room temperature overnight.
  • concentration the product was separated by column chromatography (EtOH in EA: 0% to 14%) to afford compound 51 (103 mg, 39% yield).
  • Phenylacetic acid (2.1 g, 13.14 mmol) and carbonyldiimidazole (2.1 g, 13.14 mmol) were dissolved in acetonitrile (20 mL) and reacted at 0°C under nitrogen for 0.5 h.
  • Compound 10-1 (1 g, 8.76 mmol) and cesium carbonate (5.71 g, 17.52 mmol) were then added sequentially, and the temperature was slowly raised to 80°C and allowed to react overnight.
  • Ethyl acetate was added to dilute the mixture, and the mixture was washed with water and saturated brine in sequence. The organic phase was dried and then spin-dried.
  • the crude product was purified by column chromatography (EA in PE: 1% to 20%) to obtain 61-1 (0.65 g, yield 35.76%) as a white solid.
  • compound 67-8 (100 mg, 35.6% yield) was prepared. 10 mL of 7 M amine methanol solution was added to compound 67-8 (100 mg), stirred overnight, and filtered to obtain compound 67 (79 mg, 80% yield).
  • Chromatographic column DAICELCHIRALPAK IH; column size: 250*50 10 ⁇ m; mobile phase A: supercritical CO 2 ; mobile phase B: IPA (7.0 mol/L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214 nm; flow rate: 140 mL/min; column temperature: RT.
  • Oxalyl chloride (6.83 g, 53.8 mmol) was dissolved in dichloromethane (150 mL), the system was purged with nitrogen, and cooled to -70°C.
  • Dimethyl sulfoxide (4.1 g, 62.1 mmol) was slowly added, and the reaction system was stirred at -70°C for 10 minutes.
  • Compound 81-2 (6.7 g, 41.4 mmol) was slowly added dropwise to the reaction system, and the reaction system was stirred at -70°C for 30 minutes. Finally, triethylamine (12.5 g, 124.2 mmol) was added, and the reaction system was stirred at -70°C to room temperature.
  • Step 8 Synthesis of Compound 81-10
  • Compound 85-8 was prepared using compound 85-2 as the starting material and referring to the synthetic route of compound 10. 10 mL of 7 M amine methanol solution was added to compound 85-8 (92 mg), stirred overnight, and filtered to obtain compound 85 (58 mg, yield 65%).
  • Compound 86-1 was prepared by referring to the synthetic route of compound 85.
  • Compound 86-1 (365 mg, 0.88 mmol) was dissolved in methanol (15 mL), and sodium methoxide (50 mg, 0.88 mmol) was added. The mixture was stirred at room temperature overnight, followed by the addition of ammonium chloride (95 mg, 1.76 mmol). The temperature was raised to 70°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 10 mmol/L ammonium bicarbonate; organic phase: acetonitrile) and lyophilized to afford compound 86 (22 mg, 6% yield).
  • a reverse-phase column aqueous phase: 10 mmol/L ammonium bicarbonate; organic phase: acetonitrile
  • Compound 106-8 was prepared by referring to the synthetic route of compound 85. To compound 106-8 (130 mg) was added 20 mL of 7 M amine methanol solution, stirred overnight, and filtered to obtain compound 106 (110 mg, yield 87%).
  • Chromatographic column DAICELCHIRALPAK IH; column size: 250*50 10 ⁇ m; mobile phase A: supercritical CO 2 ; mobile phase B: IPA (7.0 mol/L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214 nm; flow rate: 140 mL/min; column temperature: RT.
  • Chromatographic column DAICELCHIRALPAK IH; column size: 250*50 10 ⁇ m; mobile phase A: supercritical CO 2 ; mobile phase B: IPA (7.0 mol/L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214 nm; flow rate: 140 mL/min; column temperature: RT.
  • the remaining compounds of the present invention can be prepared using commercially available raw materials and referring to the synthetic routes of Examples 1-88 above.
  • Test Example 1 Blocking activity experiment of the compound of the present invention on voltage-gated sodium ion channel 1.8 (NaV1.8)
  • the patch clamp technique was used to detect the effects of the compounds of the present invention on NaV1.1-1.8 subtype currents.
  • Vehicle control Weigh an appropriate volume of DMSO as a stock solution.
  • control and test compound stock solutions were diluted into 10 mL of extracellular fluid as working solution and sonicated for 20 min.
  • control and test compound stock solutions were further diluted into the extracellular fluid to achieve the final concentration tested. Visual inspection for precipitation was performed before testing, and the final DMSO concentration in the extracellular fluid did not exceed 0.30%. Five concentration gradients were tested for each compound, with two replicates for each concentration, depending on the actual situation.
  • Cell passaging Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25%-Trypsin-EDTA solution and incubate at 37°C for 1.5 minutes. When the cells detach from the bottom of the dish, add 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and collect the cells by centrifugation at 1000 rpm for 5 minutes. For expansion or maintenance culture, inoculate the cells into 6 cm cell culture dishes, with 2.5*105 cells inoculated into each cell culture dish (final volume: 5 mL).
  • the cell density must not exceed 80%.
  • HEK-293 cell lines stably expressing hNav1.8/ ⁇ 1 sodium channel (WuXi Apptec, Nav1.8: AF117907; ⁇ 1: NM_001037) were used.
  • the cells were cultured in a cell culture incubator at 37°C and 5% carbon dioxide.
  • the culture medium conditions are shown in the table below.
  • HEK-293 cells can be used for patch clamp experiments after being cultured for at least two days and reaching a cell density of approximately 75%.
  • Cells were induced with tetracycline (Sangon Biotech, T0422) at a concentration of 1 ⁇ g/mL for 24 hours prior to testing.
  • Cells were dissociated using TrypLE digestion enzyme and resuspended in extracellular medium at room temperature for testing.
  • Extracellular solution was prepared at least one month in advance, and electrode solution was prepared in batches, aliquoted, and stored at -20°C until use.
  • the voltage stimulation protocol for whole-cell patch-clamp recordings of NaV channel currents was as follows: the cell membrane potential was first clamped at -130 mV. The voltage was then stepped to -40 mV or -20 mV in 10 mV steps for 8 seconds. The clamping voltage was maintained at -120 mV, and data were collected repeatedly every 20 seconds. The peak amplitude of the inward current was measured to determine the half-inactivation voltage.
  • the cell clamp potential was set at -120 mV. Resting and half-inactivation inhibition of sodium currents were measured using a double-pulse mode.
  • the double-pulse mode consisted of two 0 mV depolarizing test pulses (TP1 and TP2) lasting 50 ms.
  • the conditioning voltage between the two depolarizing pulses was set near the half-inactivation voltage (lasting 8 s).
  • the cell membrane potential was clamped to -120 mV for 20 ms to allow the channels in the inactivated state to recover without binding the compound. Data were collected repeatedly at intervals of 20 s, and the current peaks at the two test pulses were measured.
  • the drug is administered. After each drug concentration is applied for 5 minutes (or the current is stable), the next concentration is detected. Multiple concentrations are detected for each test compound.
  • the coverslip with cells is placed in the recording bath in an inverted microscope.
  • the test compound and the external solution without the compound are flowed through the recording chamber from low concentration to high concentration by gravity perfusion to act on the cells.
  • a vacuum pump is used for liquid exchange during the recording.
  • the current detected in the external solution without the compound for each cell serves as its own control group. Multiple cells are tested independently and repeatedly. All electrophysiological experiments are performed at room temperature.
  • Electrodes were pulled and heat-polished from borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co., UK) using a programmable microneedle puller (NARISHIGE PC-10 Puller, Japan).
  • the electrode tip resistance ranged from 2 to 5 M ⁇ .
  • the recorded cells were continuously perfused with extracellular fluid using a perfusion system (Warner Instrument Corporation, VC-6-PINCH, ⁇ 1 ml/min).
  • the system was mounted on the platform of an inverted microscope (Nikon ECLIPSE Ti, Japan), and the perfusion head was manually positioned under the microscope.
  • the voltage was adjusted to Vhalf for 8 seconds (pre-pulse) to inactivate the sodium channels, and then the voltage was adjusted back to the -120mV holding potential for 20 milliseconds. Afterwards, the voltage was adjusted to 0mV for 20 milliseconds to open the sodium channels. The peak current induced under the 0mV pulse was used for data analysis. Finally, the voltage was adjusted back to the -120mV holding potential again. During the test period (control and test compound), this voltage control program was repeated continuously every 15 seconds.
  • I/Icontrol Bottom+(Top-Bottom)/(1+10 ⁇ (( LogIC50 -X)*HillSlope)), where X is the logarithm of the concentration, I/Icontrol is the normalized peak current amplitude, Top is 1, and Bottom is 0.
  • the current after each drug concentration was normalized to the blank control current.
  • the blockade ratio for each drug concentration was then calculated.
  • the mean and standard error were calculated for each concentration. All values were calculated using Microsoft Excel.
  • IC 50 half-maximal blocking activity
  • a + represents IC 50 value ⁇ 1 nM
  • A represents 1 nM ⁇ IC 50 value ⁇ 10 nM
  • B represents 10 nM ⁇ IC 50 value ⁇ 50 nM
  • C represents 50 nM ⁇ IC 50 value ⁇ 100 nM
  • D represents IC 50 value > 100 nM.
  • Test Example 2 In vivo pharmacokinetic study of the compound of the present invention in rats
  • the compound of the present invention was administered orally orally to male SD rats, and the blood concentration of the compound of the present invention in the rats was determined.
  • the PK parameters were calculated, and the pharmacokinetic evaluation of the compound of the present invention was performed.
  • Test sample Compounds of the present invention, homemade.
  • Drug preparation Calculate the preparation volume based on the weight of the sample to be tested, add 5-10% DMSO and 40% PEG 400. After the sample is fully dissolved, add 50-55% of 20% ⁇ -cyclodextrin aqueous solution, mix thoroughly and set aside.
  • SD rats were stratified by body weight and randomly divided into groups of three. All rats were fasted overnight before the experiment. Following oral gavage, 50 ⁇ L of blood was collected from the rat's jugular vein at 0, 0.167, 0.333, 0.5, 1 , 2, 4, 7, and 24 hours after administration. Blood was collected from the rat's jugular vein into a tube containing the anticoagulant sodium heparin. The tube was placed on wet ice and centrifuged at 4000 rpm for 10 minutes. Plasma was separated and stored frozen at -80°C until analysis.
  • LC-MS/MS High-performance liquid chromatography-tandem mass spectrometry
  • the compounds of the present invention Compared with known Nav1.8 inhibitors including VX-548, the compounds of the present invention have a suitable half-life t 1/2 , a good exposure AUC and a maximum blood concentration C max , and exhibit good pharmacokinetic properties.

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Abstract

La présente invention concerne un dérivé cyclique fusionné, son procédé de préparation et son utilisation. Plus particulièrement, l'invention concerne un composé tel que représenté dans la formule générale (I), un stéréoisomère de celui-ci, un tautomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, et son procédé de préparation, utilisé pour prévenir et/ou traiter des maladies associées médiées par un inhibiteur de canal sodique voltage-dépendant.
PCT/CN2025/076167 2024-02-08 2025-02-07 Dérivé cyclique fusionné, son procédé de préparation et son utilisation Pending WO2025168043A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996015099A1 (fr) * 1994-11-09 1996-05-23 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation de ces composes
CN114945566A (zh) * 2019-12-06 2022-08-26 沃泰克斯药物股份有限公司 作为钠通道调节剂的取代四氢呋喃
WO2022256842A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuranes à substitution hydroxy et (halo)alkoxy utiles en tant que modulateurs de canaux sodiques
WO2022256622A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hétéro)aryl) tétrahydrofuran carboxamides utilisés en tant que modulateurs de canaux sodiques
WO2022256676A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de tétrahydrofurane substitués utiles en tant que modulateurs de canaux sodiques
WO2022256679A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2022256702A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuran-2-carboxamides substitués utiles en tant que modulateurs de canaux sodiques
WO2024046253A1 (fr) * 2022-08-28 2024-03-07 上海汇伦医药股份有限公司 Régulateur de canal sodique et son utilisation
WO2024217528A1 (fr) * 2023-04-20 2024-10-24 西藏海思科制药有限公司 Composé hétérocyclique et son utilisation en médecine

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996015099A1 (fr) * 1994-11-09 1996-05-23 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation de ces composes
CN114945566A (zh) * 2019-12-06 2022-08-26 沃泰克斯药物股份有限公司 作为钠通道调节剂的取代四氢呋喃
WO2022256842A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuranes à substitution hydroxy et (halo)alkoxy utiles en tant que modulateurs de canaux sodiques
WO2022256622A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hétéro)aryl) tétrahydrofuran carboxamides utilisés en tant que modulateurs de canaux sodiques
WO2022256676A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de tétrahydrofurane substitués utiles en tant que modulateurs de canaux sodiques
WO2022256679A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2022256702A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuran-2-carboxamides substitués utiles en tant que modulateurs de canaux sodiques
WO2024046253A1 (fr) * 2022-08-28 2024-03-07 上海汇伦医药股份有限公司 Régulateur de canal sodique et son utilisation
WO2024217528A1 (fr) * 2023-04-20 2024-10-24 西藏海思科制药有限公司 Composé hétérocyclique et son utilisation en médecine

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