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WO2025167992A1 - Antagoniste de canal cationique non sélectif trpa1 et son utilisation - Google Patents

Antagoniste de canal cationique non sélectif trpa1 et son utilisation

Info

Publication number
WO2025167992A1
WO2025167992A1 PCT/CN2025/076019 CN2025076019W WO2025167992A1 WO 2025167992 A1 WO2025167992 A1 WO 2025167992A1 CN 2025076019 W CN2025076019 W CN 2025076019W WO 2025167992 A1 WO2025167992 A1 WO 2025167992A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
formula
ring
configuration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/076019
Other languages
English (en)
Chinese (zh)
Inventor
盛锡军
李莉娥
田峦鸢
徐雄彬
曲龙妹
汪淼
程鹏
廖宗权
孙俊
张敏
王强
杨小青
肖小丽
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.)
Yichang Humanwell Pharmaceutical Co Ltd
Original Assignee
Yichang Humanwell Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yichang Humanwell Pharmaceutical Co Ltd filed Critical Yichang Humanwell Pharmaceutical Co Ltd
Publication of WO2025167992A1 publication Critical patent/WO2025167992A1/fr
Pending legal-status Critical Current
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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • TRPA1 knockout of TRPA1 can alleviate the corresponding symptoms.
  • Drugs that antagonize TRPA1 or knockout of TRPA1 can prevent damage to the myelin sheath under hypoxic-ischemic conditions (Hamilton NB, et. Nature. 2016 Jan 28; 529(7587): 523–7.).
  • Reduced anxiety behavior was observed in TRPA1 knockout mice, and memory was improved in aged mice, indicating that TRPA1 is a potential target for the treatment of anxiety and dementia.
  • TRPA1 antagonists can alleviate the symptoms of overactive bladder and bladder inflammation (Chen Z, et. BMC Urol. 2016 Jun 17; 16(1): 33.). TRPA1 transcript levels are upregulated in colon tissues of patients with Crohn's disease and ulcerative colitis. Expression in CD4+ T cells and the effectiveness of antagonizing TRPA1 in animal colitis models further demonstrate its important role in these inflammatory diseases. Finally, inhibition of TRPA1 can alleviate myocardial ischemia-reperfusion injury and improve cardiac repair after myocardial infarction by promoting angiogenesis (Conklin DJ, et. Am J Physiol-Heart Circ Physiol. 2019 Apr; 316(4): H889–99.), indicating the potential therapeutic role of TRPA1 in heart diseases.
  • TRPA1 antagonists with different chemical structures have recently been disclosed for the treatment and/or prevention of TRPA1-related diseases and/or conditions, including WO2015155306A1, WO2017060488A1, WO2021074198A1, WO2022002780A1, WO2022002782A1, WO2022079091A1, WO2022219013A1, WO2022219015A1, WO2023150592A2 and WO2023215775A1; in addition, many companies are actively developing compounds that can antagonize TRPA1, such as GRC-17536 and LY-3526318 in clinical phase II, and CB-189625 and GDC6599 in clinical phase I. However, no drug targeting TRPA1 has been successfully marketed yet. Therefore, there is an urgent need for new TRPA1 antagonists or inhibitors suitable for treating the above-mentioned diseases.
  • the present invention provides a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;
  • X 1 , X 2 , X 3 and X 4 are N or CR 5 , and the number of N in X 1 , X 2 , X 3 and X 4 is 0, 1 or 2;
  • Ring B is selected from a 5-membered heteroaryl group, wherein the heteroaryl group is optionally substituted with 1 to 3 R a1 groups; wherein the heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, D, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl is optionally substituted with 1 to 3 R a3 ;
  • R 6 is each independently selected from H, halogen, cyano, hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3- 6 cycloalkyl, -C(O)NR b R c , -NR b R c , C 2-6 alkenyl, C 2-6 alkynyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with 1 to 3 R a5 ;
  • R 7 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl is optionally substituted with 1 to 3 R a6 ;
  • R 9 is selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NR b R c , -NR b R c , -NR d C(O)R e , -C(O)R e , -C(O)OR e , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with 1 to 3 R a8 ;
  • p is an integer selected from 0, 1, 2, 3, 4 and 5;
  • R b and R c are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, or R b and R c and the atoms to which they are attached together form a 5- to 7-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, 5- to 7-membered heterocycloalkyl is optionally substituted with 1 to 3 R a10 ;
  • R d and Re are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl is optionally substituted with 1 to 3 R a11 ;
  • Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 and Ra11 are each independently selected from halogen, cyano, hydroxy, amino, C1-3 haloalkyl or C1-3 alkyl;
  • the configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration;
  • Ring A is In one embodiment, Ring A is
  • Ring B is selected from one of the following structures:
  • Ring C is selected from one of the following structures:
  • Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is In another embodiment, Ring C is in another embodiment, Ring C is
  • Ring C is selected from one of the following structures:
  • Ring C is In one embodiment, Ring C is
  • each R is independently -OC 1-6 alkyl. In another embodiment, each R is independently -SC 1-6 alkyl. In another embodiment, each R is independently C 2-6 alkenyl. In another embodiment , each R is independently C 2-6 alkynyl .
  • each R is independently a 5- to 7-membered heterocyclyl. In another embodiment, each R is independently -C(O) NRbRc . In another embodiment, each R is independently -NRbRc . In another embodiment, each R is independently -P (O) RbRc . In another embodiment, each R is independently -S (O) 2NRbRc . In another embodiment, each R is independently -C(O)Re . In another embodiment, each R is independently -C(O) ORe . In another embodiment, each R is independently -S (NH)(O) Re .
  • R a2 is independently halogen.
  • R 1 , R 2 , R 3 and R 4 are each independently H. In another embodiment, at least one of R 1 , R 2 , R 3 and R 4 is D. In another embodiment, at least one of R 1 , R 2 , R 3 and R 4 is C 1-3 alkyl. In another embodiment, at least one of R 1 , R 2 , R 3 and R 4 is halogen.
  • R 1 , R 2 , R 3 and R 4 are each independently H, D, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or -C 1-3 alkylene-C 3-6 cycloalkyl.
  • X is N or CH.
  • each R is independently C 2-6 alkynyl.
  • the C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with 1 to 3 R a4 .
  • each R 5 is independently H, halogen, cyano, hydroxy, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C(O)NR b R c , -NR b R c , C 2-6 alkenyl, or C 2-6 alkynyl.
  • R 5 is H, halogen, or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 to 3 halogens.
  • each R 5 is independently H, halogen or C 1-6 alkyl.
  • R 7 is H, C 1-6 alkyl, C 3-6 cycloalkyl, or -C 1-3 alkylene-C 3-6 cycloalkyl.
  • R 8 is H, halogen, or C 1-6 alkyl.
  • R 9 is H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NR b R c , -NR b R c , -NR d C(O)R e , -C(O)R e or -C(O)OR e .
  • R 9 is H, halogen, or C 1-6 alkyl.
  • the C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -OC 1-6 alkyl, or -SC 1-6 alkyl is optionally substituted with 1 to 3 instances of R a9 .
  • R 10 is H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C(O)NR b R c , -NR b R c , -OC 1-6 alkyl, or -SC 1-6 alkyl.
  • p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4. In another embodiment, p is 5.
  • p is 1 or 2.
  • n is 0. In another embodiment, m is 1. In another embodiment, m is 2.
  • m is 0 or 1.
  • n is 0. In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3.
  • n is 0 or 1.
  • R and R are each independently H. In another embodiment, R and R are each independently C 1-3 alkyl. In another embodiment, R and R are each independently -C 1-3 alkylene-C 3-6 cycloalkyl. In another embodiment, R and R and the atoms to which they are attached together form a 5- to 7-membered heterocycloalkyl. In another embodiment, either R and R is H and the other is selected from C 1-3 alkyl, -C 1-3 alkylene-C 3-6 cycloalkyl.
  • R b and R c are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl or -C 1-3 alkylene-C 3-6 cycloalkyl; preferably, R b and R c are each independently H or C 1-6 alkyl.
  • R d and Re are each independently H. In another embodiment, R d and Re are each independently C 1-3 alkyl. In another embodiment, R d and Re are each independently -C 1-3 alkylene-C 3-6 cycloalkyl. In another embodiment, either R d and Re is H and the other is selected from C 1-3 alkyl, -C 1-3 alkylene-C 3-6 cycloalkyl.
  • R d and Re are each independently H, C 1-6 alkyl or -C 1-3 alkylene-C 3-6 cycloalkyl, preferably H or C 1-6 alkyl.
  • Ra1 , Ra2 , Ra3, Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 , and Ra11 are halogen.
  • Ra1 , Ra2 , Ra3, Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 , and Ra11 are cyano.
  • Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 , and Ra11 are hydroxy .
  • Ra1 , Ra2 , Ra3 , Ra4, Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 , and Ra11 are amino.
  • Ra1 , Ra2 , Ra3, Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 , and Ra11 are C1-3 alkyl.
  • Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8, Ra9 , Ra10, and Ra11 are C1-3 haloalkyl .
  • Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 , and Ra11 are halogen or C1-3 alkyl.
  • the configuration of the carbon atom at the * position is R. In another embodiment, the configuration of the carbon atom at the * position is S; preferably, the configuration of the carbon atom at the * position is R.
  • the 5-membered heteroaryl group may be one of the following structures:
  • the 5-membered heteroaryl group is N-membered heteroaryl group
  • the C 6-14 aryl group may be a C 6-10 aryl group, such as a phenyl group or a naphthyl group, preferably a phenyl group.
  • the 5- to 14-membered heteroaryl group may be one of the following structures:
  • the heterocyclic group is a heterocycloalkyl group
  • the heterocycloalkyl group does not contain an unsaturated bond
  • the heterocyclic group is a heterocycloalkenyl group
  • the heterocycloalkenyl group contains 1, 2, 3 or 4 unsaturated bonds, and the heterocycloalkenyl group is not aromatic.
  • the 5- to 14-membered heterocyclic group may independently be a monocyclic or polycyclic ring; the polycyclic ring may be a paracyclic ring; the polycyclic ring may be a bicyclic or tricyclic ring; preferably, the 5- to 14-membered heterocyclic group may be a 5- to 6-membered monocyclic heterocyclic group or a 9- to 10-membered bicyclic heterocyclic group.
  • the halogen may independently be fluorine, chlorine, bromine or iodine.
  • the C 3-6 cycloalkyl group may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the -OC 1-6 alkyl group may independently be -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-isobutyl or -O-tert-butyl.
  • the -S- 1-6 alkyl group may independently be -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-isobutyl or -S-tert-butyl.
  • the C 2-6 alkenyl group may independently be a C 2-4 alkenyl group, such as ethenyl, propenyl or butenyl.
  • the heterocyclic group in the 5- to 7-membered heterocyclic group, can independently be a heterocycloalkyl group or a heterocycloalkenyl group;
  • the C 1-3 alkyl group may independently be methyl, ethyl, n-propyl or isopropyl.
  • n is an integer selected from 0, 1, 2 and 3.
  • Ring A is selected from:
  • n is an integer selected from 0, 1, 2 and 3.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (I) has the structural characteristics of the general formula (II-1):
  • R, p, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring B, * and ring C are as defined above.
  • the present invention provides a compound represented by the above general formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (II-2):
  • R, p, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , * and ring C are as defined above.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (II-3):
  • R is a halogen
  • P is 0, 1, or 2;
  • X is N or CH, preferably N
  • R5 is H, halogen or C1-6 alkyl
  • R 6 is H, C 1-6 alkyl or -NH 2 ;
  • the configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (II-4):
  • R is a halogen
  • P is 0, 1, or 2;
  • X is N or CH, preferably N
  • R5 is H, halogen or C1-6 alkyl
  • R 6 is H, C 1-6 alkyl or -NH 2 ;
  • R 7 is H, C 1-6 alkyl or -C 1-3 alkylene-C 3-6 cycloalkyl
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (III-1):
  • R, p, X, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , ring B, * and ring C are as defined above.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (III-2):
  • R, p, X, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , * and ring C in general formula (III-2) are as defined above.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (III-3):
  • R is halogen
  • P is 0, 1, or 2;
  • n 0 or 1
  • R5 is H, halogen or C1-6 alkyl
  • R 6 is H, C 1-6 alkyl or -NH 2 ;
  • the configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration;
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (IV-1):
  • R, p, X, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , ring B, * and ring C are as defined above.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (IV-2):
  • R, p, X, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , * and ring C in general formula (IV-2) are as defined above.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (IV-3):
  • R is a halogen
  • P is 0, 1, or 2;
  • n 0 or 1
  • R5 is H, halogen or C1-6 alkyl
  • R 6 is H, C 1-6 alkyl or -NH 2 ;
  • the configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (IV-4):
  • R is halogen
  • P is 0, 1, or 2;
  • n 0 or 1
  • R5 is H, halogen or C1-6 alkyl
  • R 6 is H, C 1-6 alkyl or -NH 2 ;
  • the configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the structural characteristics of formula (IV-5):
  • R is halogen, C 1-6 alkyl, C 3-6 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted by 1 to 3 R a2 ;
  • R a2 is independently halogen
  • P is 0, 1, or 2;
  • R 5 is H, halogen, C 1-6 alkyl or cyano
  • the configuration of the carbon atom at the position is R configuration, S configuration, or a mixture of R configuration and S configuration;
  • ring C is
  • R, p, X, R 1 , R 2 , R 3 , R 4 , R 6 , R 8 , R 9 , Ring B, * and Ring C are as defined above.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (V-2):
  • R, p, X, R 1 , R 2 , R 3 , R 4 , R 6 , R 8 , R 9 , * and ring C are as defined above.
  • the present invention provides a compound represented by the above general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has the structural characteristics of formula (V-3):
  • R is a halogen
  • P is 0, 1, or 2;
  • R 6 is H, C 1-6 alkyl or -NH 2 ;
  • R 8 is H, halogen or C 1-6 alkyl
  • R 9 is H, halogen or C 1-6 alkyl
  • the configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.
  • the compound represented by formula (I) has the structural characteristics of formula (VI):
  • ring A is
  • Ring C, R, p, n, R 5 , R 6 and * are as defined above.
  • P is 0, 1, or 2;
  • R 5 is H, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1 to 3 halogens;
  • the configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.
  • the compound represented by formula (I) has the structural characteristics of formula (VI):
  • ring A is
  • R is halogen, C 1-6 alkyl or C 3-6 cycloalkyl
  • P is 0, 1, or 2;
  • n 0, 1, or 2;
  • preferred compounds of the present invention include, but are not limited to, the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
  • the present invention also provides any intermediate described in the present invention.
  • the present invention further provides a method for preparing the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, the preparation method comprising the following steps:
  • Y 1 and Y 2 in formula (I-1) to (I-4) represent leaving groups, such as bromine, chloride or sulfonate, and other groups in formula (I-1) to (I-4) and formula (I) are as defined above.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.
  • the compound of the present invention is provided in the pharmaceutical composition in an effective amount.
  • the compound of the present invention is provided in a therapeutically effective amount.
  • the compound of the present invention is provided in a prophylactic effective amount.
  • the present invention also provides use of the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating diseases and/or disorders associated with TRPA1.
  • the disease and/or disorder associated with TRPAl is pain, respiratory disease, fibrotic disease, urinary system disease, autoimmune disease, central nervous system (CNS) disease, inflammatory disease, gastrointestinal disease or cardiovascular disease.
  • the pain is postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, or inflammation-induced pain.
  • the respiratory disease is asthma, cough, chronic obstructive pulmonary disease or sleep apnea.
  • the present invention also provides a use of a compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating a disease and/or disorder;
  • the disease and/or disorder is pain, respiratory disease, fibrotic disease, urinary system disease, autoimmune disease, central nervous system (CNS) disease, inflammatory disease, gastrointestinal disease or cardiovascular disease.
  • the pain is postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, or inflammation-induced pain.
  • the respiratory disease is asthma, cough, chronic obstructive pulmonary disease or sleep apnea.
  • Halogen refers to a fluorine, chlorine, bromine or iodine atom.
  • Alkyl refers to a straight-chain or branched monovalent saturated hydrocarbon group.
  • C 1-6 alkyl refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms
  • C 1-3 alkyl refers to a straight or branched saturated hydrocarbon group having 1 to 3 carbon atoms.
  • the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, and n-hexyl.
  • the alkyl group in the present application is preferably a C 1-3 alkyl group.
  • C 1-3 haloalkyl refers to the above-mentioned "C 1-3 alkyl” substituted by one or more halogen groups.
  • exemplary haloalkyl groups include, but are not limited to, -CF 3 , -CH 2 F, -CHF 2 , -CH F CH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl, -CHCl 2 , and the like.
  • C3-6 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 6 ring carbon atoms and zero heteroatoms. In some embodiments, C3 - C5 cycloalkyl is preferred, more preferably C3 cycloalkyl.
  • Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, wherein the alkenyl group contains at least one carbon-carbon double bond.
  • Non-limiting examples of " C2-6 alkenyl” include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, and the like.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, said alkynyl group containing at least one carbon-carbon triple bond.
  • Non-limiting examples of “C 2-6 alkynyl” include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • C6-14 aryl refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic arrangement) having 6-14 ring carbon atoms and zero heteroatoms.
  • the aryl group has six ring carbon atoms ("C6 aryl”; e.g., phenyl).
  • the aryl group has ten ring carbon atoms ("C10 aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl).
  • 5 to 14 membered heteroaryl refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as long as valence permits.
  • Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring.
  • 5 to 10 membered heteroaryl groups are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 5- to 6-membered heteroaryl groups are particularly preferred and are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • a "5-membered heteroaryl” is a 5-membered monocyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • 5- to 14-membered heterocyclyl refers to a 5- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, preferably nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, or 3.
  • 5- to 7-membered heterocyclyl groups are particularly preferred, which are 5- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, 5- to 6-membered heterocyclyl groups are 5- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms.
  • Steps refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.
  • “Pharmaceutically acceptable salts” refer to pharmaceutically acceptable organic or inorganic salts, as defined above, of the compounds of the present invention, which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which may be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice.
  • substituents and/or their variants are permissible only if such combinations result in stable compounds.
  • Cyano refers to -CN.
  • Hydrophill refers to -OH.
  • therapeutically effective amount refers to an amount administered to a patient that is sufficient to effectively treat a disease.
  • the therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
  • pharmaceutical excipients refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient (API). These substances are generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).
  • treat refers to eliminating the cause or alleviating the symptoms of a disease.
  • prevent refers to reducing the risk of developing a disease.
  • patient refers to any animal, typically a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.
  • the positive progress of the present invention is that the compounds of the present invention have better inhibitory activity against TRPA1, or have more excellent pharmacodynamic and/or pharmacokinetic properties, are safe, and can be used to treat and/or prevent diseases related to TRPA1.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • High performance liquid chromatography was determined by a Waters high performance liquid preparative chromatograph using a YMC-Triart-C18 EXRS (20 mm ⁇ 100 mm ⁇ 5 ⁇ m) column.
  • the thin layer chromatography silica gel plate used was West Asia Reagent GF254 silica gel plate.
  • DCM dichloromethane
  • RT room temperature
  • EtOH ethanol
  • KOH potassium hydroxide
  • H 2 SO 4 sulfuric acid
  • NH 3 H 2 O aqueous ammonia
  • dioxane 1,4-dioxane
  • HC(OEt) 3 triethyl orthoformate
  • Zn(CN) 2 represents zinc cyanide
  • Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium
  • dppf 1,1-bis(diphenylphosphino)ferrocene
  • Tetrabutylammonium tribromide represents tetrabutylammonium tribromide
  • DCE represents 1,2-dichloroethane
  • LiHMDS represents lithium bis(trimethylsilylamide)
  • THF represents tetrahydrofuran
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • LDA lithium diiso
  • mM represents the concentration unit mmol/L
  • M represents the concentration unit mol/L
  • K2CO3 represents potassium carbonate
  • DMA represents N,N-dimethylacetamide
  • NaBH4 represents sodium borohydride
  • MeOH represents methanol
  • MeCN represents acetonitrile
  • TLC thin layer chromatography
  • 1H NMR hydrogen nuclear magnetic resonance spectroscopy
  • LC-MS liquid chromatography-mass spectrometry
  • DMSO represents dimethyl sulfoxide
  • EDTA represents ethylenediaminetetraacetic acid
  • DMEM stands for Dulbecco's Modified Eagle Medium, which is a widely used basal culture medium
  • HEPES represents N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid.
  • the compounds are named according to the conventional naming rules in the art, and commercial
  • intermediate 1-1 120 mg, 0.80 mmol
  • intermediate a1 (261 mg, 0.96 mmol)
  • acetonitrile 3 mL
  • anhydrous potassium carbonate 221 mg, 1.60 mmol
  • the reaction system was stirred at room temperature for 14 hours. TLC confirmed that the starting materials had essentially reacted completely.
  • the reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was evaporated on a rotary evaporator under reduced pressure to remove the solvent.
  • the crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 174 mg of a yellow solid, a yield of 56.31%.
  • intermediate 2-1 100 mg, 0.69 mmol
  • intermediate a1 225 mg, 0.83 mmol
  • N,N-dimethylacetamide 2 mL
  • anhydrous potassium carbonate 190 mg, 1.38 mmol
  • the reaction system was stirred at 40°C for 14 hours. TLC indicated that the starting materials had essentially reacted completely.
  • the reaction solution was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure.
  • intermediate 3-1 100 mg, 0.69 mmol
  • intermediate a1 225 mg, 0.83 mmol
  • N,N-dimethylacetamide 2 mL
  • anhydrous potassium carbonate 190 mg, 1.38 mmol
  • the reaction system was stirred at 40°C for 14 hours. TLC indicated that the starting materials had essentially reacted completely.
  • the reaction solution was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure.
  • the solvent was removed by rotary evaporation under reduced pressure.
  • the crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:40) to obtain 48 mg of a yellow solid, with a yield of 31.79%.
  • intermediate a4 120 mg, 0.74 mmol
  • N,N-dimethylformamide 1.5 mL
  • intermediate a1 (245 mg, 0.90 mmol)
  • anhydrous potassium carbonate 207 mg, 1.50 mmol
  • the reaction system was stirred at 40°C for 12 hours. TLC indicated that the reaction of the starting materials was essentially complete.
  • the reaction solution was cooled to room temperature and diluted with water (3 mL). Extraction was performed with ethyl acetate (3 mL ⁇ 3) and the layers separated. The combined organic phases were washed with saturated brine (6 mL ⁇ 2), dried over anhydrous sodium sulfate, and filtered.
  • the solvent was removed by rotary evaporation under reduced pressure.
  • the crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:50) to obtain 84 mg of a white solid, with a yield of 41.94%.
  • the solvent was removed by rotary evaporation under reduced pressure.
  • the crude product was purified by column chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:30) to obtain 73 mg of a white solid, with a yield of 14.41%.
  • intermediate a4 100 mg, 0.62 mmol
  • N,N-dimethylformamide 1.2 mL
  • intermediate a5 202 mg, 0.74 mmol
  • anhydrous potassium carbonate 17.1 mg, 1.24 mmol
  • intermediate a4 100 mg, 0.62 mmol
  • N,N-dimethylformamide 1.2 mL
  • intermediate a6 190 mg, 0.74 mmol
  • anhydrous potassium carbonate 17.1 mg, 1.24 mmol
  • intermediate a4 80 mg, 0.50 mmol
  • N,N-dimethylformamide 1 mL
  • intermediate a2 176 mg, 0.60 mmol
  • anhydrous potassium carbonate 138 mg, 1.00 mmol
  • the reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted.
  • the reaction solution was cooled to room temperature and diluted with water (5 mL).
  • the mixture was extracted with ethyl acetate (3 mL ⁇ 3).
  • the organic phases were combined, washed with saturated brine (5 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator.
  • intermediate a7 (40 mg, 0.21 mmol), N,N-dimethylformamide (2 mL), intermediate a1 (60 mg, 0.22 mmol), and anhydrous potassium carbonate (55 mg, 0.40 mmol).
  • the reaction system was stirred at room temperature for 12 hours. TLC indicated that the starting materials were essentially reacted.
  • the reaction solution was diluted with water (6 mL) and extracted with ethyl acetate (5 mL ⁇ 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator.
  • intermediate a4 (135 mg, 0.84 mmol), N,N-dimethylformamide (5 mL), intermediate a8 (234 mg, 0.84 mmol), and anhydrous potassium carbonate (173 mg, 1.26 mmol).
  • the reaction system was stirred at room temperature for 12 hours. TLC indicated that the starting materials were essentially reacted.
  • the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator.
  • intermediate a4 80 mg, 0.50 mmol
  • intermediate a9 184 mg, 0.60 mmol
  • anhydrous potassium carbonate 104 mg, 0.75 mmol.
  • the reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely.
  • the reaction solution was cooled to room temperature and diluted with water (8 mL).
  • the mixture was extracted with ethyl acetate (8 mL ⁇ 3).
  • the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure.
  • intermediate a4 80 mg, 0.50 mmol
  • intermediate a10 165 mg, 0.60 mmol
  • anhydrous potassium carbonate 104 mg, 0.75 mmol
  • the reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely.
  • the reaction solution was cooled to room temperature and diluted with water (8 mL).
  • the mixture was extracted with ethyl acetate (8 mL ⁇ 3).
  • the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure.
  • intermediate a4 100 mg, 0.62 mmol
  • N,N-dimethylformamide 5 mL
  • intermediate a11 199 mg, 0.68 mmol
  • anhydrous potassium carbonate 129 mg, 0.93 mmol
  • the reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely.
  • the reaction solution was cooled to room temperature and diluted with water (20 mL).
  • the mixture was extracted with ethyl acetate (15 mL x 3).
  • the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure.
  • pyrrolo[2,3-D]pyrimidin-4(hydrogen)-one (19-1) (100 mg, 0.68 mmol), N,N-dimethylformamide (4 mL), intermediate a1 (224 mg, 0.82 mmol), and anhydrous potassium carbonate (141 mg, 1.02 mmol) were added sequentially.
  • the reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted completely.
  • the reaction solution was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (15 mL x 3).
  • aqueous phase was adjusted to a pH of approximately 7 with 1 M aqueous hydrochloric acid, resulting in the precipitation of a white solid.
  • the filtered solid was purified by slurrying with dichloromethane/methanol (200 mL, 1/20 volume ratio) to afford 514 mg of compound 21-5 as a yellow solid in a 61.70% yield.
  • LC-MS (ESI) m/z: 177.1 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) ⁇ 11.00 (s, 1H), 8.46-8.32 (m, 1H), 6.93-6.79 (m, 1H), 6.71-6.44 (m, 2H), 2.66 (s, 3H).
  • reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (8 mL ⁇ 3). The organic phases were combined, washed with saturated brine (8 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, concentrated, and mixed with silica gel. Purification was performed by silica gel chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 62 mg of the oily product in a yield of 15.62%.
  • the organic phases were combined, washed with saturated brine (6 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product.
  • the crude product was purified by silica gel chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) to obtain 95 mg of a white solid in a yield of 68.84%.
  • the organic phases were combined, washed with saturated brine (6 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product.
  • the crude product was purified by silica gel chromatography (mobile phase: methanol and dichloromethane, volume ratio 1:25) to obtain 20 mg of a white solid, with a yield of 12.20%.
  • intermediate 7-3 80 mg, 0.48 mmol
  • N,N-dimethylformamide 1 mL
  • intermediate a1-R 158 mg, 0.58 mmol
  • anhydrous potassium carbonate 132 mg, 0.96 mmol
  • the reaction system was stirred at 40°C for 12 hours. TLC indicated that the starting materials had essentially reacted.
  • the reaction solution was cooled to room temperature and diluted with water (3 mL).
  • the mixture was extracted with ethyl acetate (3 mL ⁇ 3) and separated.
  • the combined organic phases were washed with saturated brine (6 mL ⁇ 2), dried over anhydrous sodium sulfate, and filtered.
  • HEK-293 cell lines stably expressing human TRPA1 ion channels were cultured in DMEM (Hyclone, SH30243.01) medium containing 10% fetal bovine serum (AusGeneX, FBS500-S), 10 ⁇ g/mL Blasticidin S (Solarbio B9300), and 100 ⁇ g/mL Zeocin (Solarbio Z8020) at 37°C and a carbon dioxide concentration of 5%.
  • test compound was dissolved in 100% DMSO at a concentration of 10 mM, and then serial gradient dilution steps were performed in 100% DMSO. Ten different concentrations were prepared by three-fold dilution. Then, a 10x intermediate solution of the test compound was prepared by diluting it 1:100 with 1x Hank’s Balanced Salt Solution (HBSS) buffer containing 20 mM HEPES (preparation method: 1XHBSS and 1M HEPES were used to prepare HBSS containing 20 mM HEPES, where HBSS, Gibco, Cat.14025092; 1M HEPES, Solarbio, Cat.H1095).
  • HBSS Hank’s Balanced Salt Solution
  • the required cell suspension was calculated based on a density of 8000 cells per well.
  • the cells were plated into a black bottom transparent 384-well plate (Corning, Cat.3764). After culturing in the 384-well plate (final volume: 25 ⁇ L) for 12 hours, the test was performed.
  • HBSS Balanced Salt Solution
  • the prepared 10 ⁇ test substance intermediate solution was transferred to the corresponding 384-well plate (Nunc, 264573).
  • the detection concentration of A-967079 and the test substance was 10 ⁇ M, and three-fold serial dilution was performed.
  • agonist AITC EC 80 solution (25 ⁇ M) using a 5 ⁇ agonist intermediate solution. Transfer the prepared 5 ⁇ agonist intermediate solution to the corresponding 384-well compound plate.
  • the agonist AITC EC 80 working solution concentration is 5 ⁇ M.
  • Test Example 2 Pharmacokinetics of the compound of the present invention in rats after intravenous and oral administration
  • the test compound was prepared with 5% DMSO, 10% HS15 and 85% normal saline (vehicle).
  • the rat intravenous administration group had an intravenous dose of 1 mg/kg; the rat oral administration group fasted overnight before administration and had an oral dose of 5 mg/kg.
  • Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.
  • the blood samples were placed on ice and plasma was separated within 1 hour (centrifugation conditions 6000g, 3 minutes, 2-8°C). The separated plasma was stored at -80°C.
  • Test Example 3 Determination of the efficacy of the compound of the present invention in the citric acid-induced guinea pig cough model
  • a stopwatch was used to time the number of coughs in the guinea pig within 12 minutes of the nebulization (a cough was counted as one cough when the guinea pig opened its mouth and heard a loud cough). Guinea pigs that did not cough or coughed more than 35 times (continuous coughing with severe symptoms) were eliminated.
  • Guinea pigs that passed the screening were selected and randomly divided into vehicle control group (5% DMSO, 10% HS15 and 85% saline), 7-R group and 5-R group. They were given the corresponding drug solution by oral gavage at a dose of 10 mg/kg, and the vehicle control group was given an equal volume of vehicle.
  • vehicle control group 5% DMSO, 10% HS15 and 85% saline
  • the vehicle control group was given an equal volume of vehicle.
  • One hour before the drug was given the guinea pigs were placed in a YLS-8A cough and asthma induction instrument, and 0.5 mol/L citric acid solution was added as a cough induction solution.
  • the nebulizer was used at the maximum spray level (7 L/min) and the nebulizer was used to spray for 60 seconds to stimulate the guinea pigs to cough.
  • a stopwatch was used while the citric acid solution was introduced.
  • the cough latency s - the time when the guinea pig first
  • Quantitative data are expressed as mean ⁇ standard deviation.

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Abstract

L'invention concerne un antagoniste de canal cationique non sélectif TRPA1 et son utilisation. L'antagoniste de canal cationique non sélectif TRPA1 est un composé tel que représenté dans la formule (I), un stéréoisomère de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci, et peut être utilisé pour traiter et/ou prévenir diverses maladies ou états liés à TRPA1.
PCT/CN2025/076019 2024-02-08 2025-02-06 Antagoniste de canal cationique non sélectif trpa1 et son utilisation Pending WO2025167992A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017060488A1 (fr) * 2015-10-09 2017-04-13 Almirall, S.A. Nouveaux antagonistes de trpa1
WO2018109155A1 (fr) * 2016-12-16 2018-06-21 Galderma Research & Development Antagonistes de trpa1 destinés à être utilisés dans le traitement de la dermatite atopique
WO2019173790A1 (fr) * 2018-03-09 2019-09-12 Timothy Hla Composés à base de pyridinone et de pyridazinone et utilisations médicales associées
CN110461838A (zh) * 2017-03-07 2019-11-15 豪夫迈·罗氏有限公司 噁二唑瞬时受体电位通道抑制剂
CN114555601A (zh) * 2019-10-15 2022-05-27 勃林格殷格翰国际有限公司 新颖的四唑类
WO2023215775A1 (fr) * 2022-05-04 2023-11-09 D. E. Shaw Research, Llc Composés de pyridone en tant qu'inhibiteurs de trpa1

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017060488A1 (fr) * 2015-10-09 2017-04-13 Almirall, S.A. Nouveaux antagonistes de trpa1
WO2018109155A1 (fr) * 2016-12-16 2018-06-21 Galderma Research & Development Antagonistes de trpa1 destinés à être utilisés dans le traitement de la dermatite atopique
CN110461838A (zh) * 2017-03-07 2019-11-15 豪夫迈·罗氏有限公司 噁二唑瞬时受体电位通道抑制剂
WO2019173790A1 (fr) * 2018-03-09 2019-09-12 Timothy Hla Composés à base de pyridinone et de pyridazinone et utilisations médicales associées
CN114555601A (zh) * 2019-10-15 2022-05-27 勃林格殷格翰国际有限公司 新颖的四唑类
WO2023215775A1 (fr) * 2022-05-04 2023-11-09 D. E. Shaw Research, Llc Composés de pyridone en tant qu'inhibiteurs de trpa1

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Title
SCHENKEL, L. B. ET AL.: "Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, 4 March 2016 (2016-03-04), pages 2794 - 2809, XP055373392, DOI: 10.1021/acs.jmedchem.6b00039 *

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