WO2024251133A1 - COMPOSÉ HÉTÉROCYCLIQUE EN TANT QUE MODULATEUR DU RÉCEPTEUR α5-GABAA ET SON UTILISATION - Google Patents

COMPOSÉ HÉTÉROCYCLIQUE EN TANT QUE MODULATEUR DU RÉCEPTEUR α5-GABAA ET SON UTILISATION Download PDF

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WO2024251133A1
WO2024251133A1 PCT/CN2024/097429 CN2024097429W WO2024251133A1 WO 2024251133 A1 WO2024251133 A1 WO 2024251133A1 CN 2024097429 W CN2024097429 W CN 2024097429W WO 2024251133 A1 WO2024251133 A1 WO 2024251133A1
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alkyl
cycloalkyl
6alkyl
ring
pain
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Chinese (zh)
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张学军
李金平
贾一民
朱海勇
江文
李杨
杨俊�
李莉娥
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • patent application number 202310662536.9 entitled “Heterocyclic compounds as ⁇ 5-GABAA receptor modulators and their uses”, filed with the State Intellectual Property Office of China on June 5, 2023;
  • the present invention belongs to the field of medicine, and in particular, relates to heterocyclic compounds of ⁇ 5-GABA A receptor modulators and uses thereof.
  • GABA A receptors are associated with a variety of diseases and are possible therapeutic targets, which has also promoted the study of the physiological and pharmacological effects of different subunits of GABA A receptors.
  • studies using genetically modified mice have shown that the most widely distributed ⁇ 5 subunit of the ⁇ -aminobutyric acid A receptor ( ⁇ 5-GABA A receptor) is a benzodiazepine
  • the ⁇ 5-GABA A receptor is the main target of benzodiazepines (BDZ) drugs to produce sedation and amnesia, while the ⁇ 2-GABA A receptor and ⁇ 3-GABA A receptor are related to the anticonvulsant and antianxiety effects of the drugs.
  • BDZ benzodiazepines
  • the ⁇ 5-GABA A receptor is an inhibitory receptor in the central nervous system of mammals, mainly distributed in the hippocampus of the brain, and produces an inhibitory effect on hippocampal neurons by regulating the outward current of chloride ions. Its expression level in the cerebral cortex is very low, and it is almost not expressed in other brain regions.
  • the hippocampus is the main site responsible for cognitive functions such as learning and memory, indicating that the ⁇ 5-GABA A receptor may be related to cognitive functions such as learning and memory.
  • BDZ drugs there are many drugs such as propofol, etomidate, barbiturates and neurosteroids that can enhance the neural function of GABA by stimulating the allosteric regulatory sites of GABA A receptors, thereby producing corresponding pharmacological effects, and clinically play an anesthetic, antianxiety, sedative or anti-epileptic role.
  • drugs such as propofol, etomidate, barbiturates and neurosteroids that can enhance the neural function of GABA by stimulating the allosteric regulatory sites of GABA A receptors, thereby producing corresponding pharmacological effects, and clinically play an anesthetic, antianxiety, sedative or anti-epileptic role.
  • they often bind non-specifically to multiple subunits of GABA A receptors, leading to many adverse reactions such as drug tolerance, sedation, anxiety or convulsions. Therefore, researchers have been committed to studying and discovering drugs that have selective and specific effects on a certain GABA A receptor subunit.
  • ⁇ 5-GABA A receptors Considering the specific distribution and functional research of ⁇ 5-GABA A receptors in the brain hippocampus, many pharmaceutical companies including Roche are engaged in the research of ⁇ 5-GABA A receptor ligands, and a large number of compounds have been synthesized, especially inverse agonists containing ⁇ 5-GABA A receptors for the brain hippocampus, among which ⁇ 5IA and MRK-016 have shown good effects in treating cognitive diseases in animal disease models and human trials, especially Alzheimer's disease. It is generally believed that inverse agonists of ⁇ 5-GABA A receptors can be used to treat cognitive diseases, especially Alzheimer's disease.
  • Patent application US20110224278A1 discloses that inverse agonists containing ⁇ 5-GABA A receptors can be used to treat multi-infarct dementia and stroke-related diseases.
  • the object of the present invention is to provide a new class of compounds having the modulating activity of ⁇ 5-GABA A receptors, in particular, the inhibitory activity of ⁇ 5-GABA A receptors.
  • the present invention also provides the use of these compounds and their pharmaceutically acceptable salts in the preparation and manufacture of pharmaceutical compositions or drugs for treating, preventing, or improving diseases associated with ⁇ 5-GABA A receptors, such as Alzheimer's disease, multi-infarct dementia, pain and stroke, or in the preparation of pain relief drugs.
  • the present invention also provides a method for preparing a compound of formula I, and an intermediate useful in such a method.
  • X1 is N or C
  • X 2 is N, O, S or CR 5 ;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • Ring A does not exist or is selected from a benzene ring, a 5-6 membered heteroaromatic ring; wherein,
  • R 1 is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-7 cycloalkyl or 3-6 membered heterocycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-7 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl;
  • R2 is selected from hydrogen, halogen, hydroxyl, amino, cyano, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl; the C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted with 1-4 substituents selected from the following groups: deuterium, halogen , hydroxyl, amino, cyano, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl ;
  • Ring B is selected from 5-14 membered heteroaromatic rings
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • Ring D is absent or selected from 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl;
  • p 0, 1, 2, 3, 4, 5, 6 or 7;
  • M is absent or selected from O
  • R 5 is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 3-7 cycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy or C 3-7 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl , amino, cyano, C 1-6 alkyl, C 3-7 cycloalkyl ;
  • R 6 is selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-7 cycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy or C 3-7 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-7 cycloalkyl;
  • the compound is selected from the following structures:
  • ring A, ring B, ring D, R 1 , R 2 , R 3 , R 4 , L, M, p, m and n are defined as described in the first aspect of the present invention.
  • the ring A is absent or selected from a benzene ring or a 6-membered heteroaromatic ring; the 6-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms;
  • n 0, 1, 2, 3, 4 or 5;
  • R 1 is selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;
  • the heteroatom is selected from N, O, and S. When there are multiple heteroatoms, the heteroatoms are the same or different.
  • the ring A is absent or is selected from a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine or triazine.
  • the ring A is absent or selected from a benzene ring or pyridine.
  • the ring A is selected from * terminal is connected to X1 .
  • ring A when ring A is absent, m is 1, and R 1 is linked to X 1 .
  • the compound is selected from the following structures:
  • ring B, ring D, R 1 , R 2 , R 3 , R 4 , L, M, m, n and p are as defined in the first aspect of the present invention.
  • the compound is selected from the following structures:
  • ring B, ring D, R 1 , R 2 , R 3 , R 4 , L, M, n and p are as defined in the first aspect of the present invention.
  • the compound is selected from the following structures:
  • ring A, ring B, ring D, R 1 , R 2 , R 3 , R 4 , M, m, n and p are defined as described in the first aspect of the present invention.
  • the compound is selected from the following structures:
  • ring B, R 1 , R 2 , R 3 , m and n are as defined in the first aspect of the present invention.
  • the definitions of ring D, R 4 and p are as described in the first aspect of the present invention.
  • the ring B is selected from a 5-14 membered heteroaromatic ring containing 1, 2, 3, 4 or 5 heteroatoms;
  • the heteroatom is selected from N, O, and S; when there are multiple heteroatoms, the heteroatoms are the same or different;
  • ring B is selected from acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, benzotriazolyl, furanyl, thienyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxabenzophenone, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, tetrahydronaphthyridine, imidazolyl, pyrazinyl , pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazo
  • ring B is selected from pyridine, pyrimidine, pyridazine, tetrahydronaphthyridine, pyridopiperidine,
  • the ring B is selected from pyridine, pyrimidine, pyridazine, tetrahydronaphthyridine, pyridopiperidine,
  • the ring B is selected from * terminal is connected to L.
  • Selected from * terminal is connected to L.
  • the R 6 is selected from C 1-3 alkyl or C 3-5 cycloalkyl; the C 1-3 alkyl or C 3-5 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-7 cycloalkyl;
  • the R 6 is selected from C 1-3 alkyl or C 3-5 cycloalkyl; the C 1-3 alkyl or C 3-5 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-7 cycloalkyl.
  • said L is selected from (like ), *End and connect.
  • the ring D is absent or selected from 4-6 membered heterocycloalkyl and 3-6 membered cycloalkyl containing 1-3 heteroatoms;
  • the heteroatom is selected from N, O, and S; when there are multiple heteroatoms, the heteroatoms are the same or different.
  • the ring D is absent or is selected from cyclopropyl, cyclobutyl, cyclopentyl, azetidine, pyrrolidine, piperidine, and piperazine.
  • the ring D is selected from
  • the R 1 is selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy; the C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy is optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-7 cycloalkyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 1 is selected from F, methyl, cyclopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl.
  • R 1 is selected from halogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, and haloalkyl.
  • the R 1 is selected from F, methyl, cyclopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl.
  • the R 2 is selected from halogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy; the C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy is optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-7 cycloalkyl;
  • R2 is selected from methyl.
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • n is selected from 0 or 1.
  • p 0, 1, 2, 3, 4, 5, 6 or 7;
  • p is selected from 0, 1 or 2.
  • said p is selected from 0, 1 or 2.
  • the compound comprises:
  • the second aspect of the present invention is a pharmaceutical composition, comprising the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.
  • the use of the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of the pharmaceutical composition as described in the second aspect includes:
  • preparing a drug, pharmaceutical composition or preparation for regulating ⁇ 5-GABA A receptor and/or preventing and/or treating ⁇ 5-GABA A receptor-related diseases.
  • a compound of formula I as described in the first aspect its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, which is expected to be used for pain, Alzheimer's disease, multi-infarct dementia or stroke.
  • Pain that should be mentioned is neuropathic pain, inflammatory pain or cancer pain.
  • the pain that should be mentioned is selected from the group consisting of headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, low back pain, lower limb pain, musculoskeletal pain, vascular pain, gout, arthritis pain, visceral pain, pain caused by infectious diseases, polyostotic pain, sickle cell anemia, autoimmune diseases, pain associated with multiple sclerosis or inflammation, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins, nutritional deficiencies, viral or bacterial infections, pain associated with degenerative osteoarthritis.
  • Infectious diseases that should be mentioned are selected from AIDS or postherpetic neuralgia.
  • the present invention provides a method for regulating ⁇ 5-GABA A receptor-related diseases, comprising administering to a patient a preventive or therapeutically effective amount of a compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of the second aspect.
  • a method for preventing and/or treating ⁇ 5-GABA A receptor-related diseases comprising administering to a patient a preventive or therapeutically effective amount of a compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of the second aspect.
  • Pain which should be mentioned is selected from neuropathic pain, inflammatory pain or cancer pain.
  • the pain that should be mentioned is selected from the group consisting of headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, low back pain, lower limb pain, musculoskeletal pain, vascular pain, gout, arthritis pain, visceral pain, pain caused by infectious diseases, polyostotic pain, sickle cell anemia, autoimmune diseases, pain associated with multiple sclerosis or inflammation, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins, nutritional deficiencies, viral or bacterial infections, and pain associated with degenerative osteoarthritis.
  • Infectious diseases which should be mentioned are selected from AIDS or postherpetic neuralgia.
  • the compound represented by formula I as described in the first aspect its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect is used as a drug.
  • the compound represented by formula I as described in the first aspect its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect is used for:
  • the pain that should be mentioned is selected from the group consisting of headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, low back pain, lower limb pain, musculoskeletal pain, vascular pain, gout, arthritis pain, visceral pain, pain caused by infectious diseases, polyostotic pain, sickle cell anemia, autoimmune diseases, pain associated with multiple sclerosis or inflammation, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins, nutritional deficiencies, viral or bacterial infections, and pain associated with degenerative osteoarthritis.
  • Infectious diseases which should be mentioned are selected from AIDS or postherpetic neuralgia.
  • the present inventors have unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, a preparation method and use thereof through extensive and in-depth research.
  • the present invention provides a compound represented by formula I, and its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.
  • the compound represented by formula I has a significant regulatory effect on ⁇ 5-GABA A receptors, can treat diseases or conditions mediated by ⁇ 5-GABA A receptors, exhibits excellent pharmacokinetic properties, and has high safety and drugability.
  • the present invention provides a method for preparing the compound shown in I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and intermediates.
  • the method is simple to operate, high in yield and purity, and can be used for industrial production of medicines.
  • the manufacturer's instructions for the use of the kit can be used, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH 2 O is equivalent to OCH 2 .
  • saturated, partially saturated or unsaturated includes substituents saturated with hydrogen, substituents completely unsaturated with hydrogen and substituents partially saturated with hydrogen.
  • halogen by itself or as part of another substituent refers to fluorine, chlorine, bromine, iodine.
  • amino by itself or as part of another substituent means -NH2 .
  • alkyl when used alone or as part of other substituents means a straight or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.
  • Alkyl groups may be unsubstituted or substituted with one or more suitable substituents.
  • Alkyl groups may also be isotopic isomers of natural abundance alkyl groups that are rich in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium). .
  • C ⁇ - ⁇ alkyl when used alone or as part of other substituents refers to an alkyl group containing a minimum of ⁇ and a maximum of ⁇ carbon atoms in a branched or linear relationship or any combination of the three, wherein ⁇ and ⁇ represent integers and may also be
  • the alkyl groups described in this section may also contain one or two double or triple bonds.
  • the designation of C 0 alkyl groups indicates a direct bond.
  • Examples of C 1-6 alkyl groups include, but are not limited to, the following :
  • C ⁇ - ⁇ haloalkyl when alone or as part of another substituent refers to an alkyl group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine.
  • alkoxy by itself or as part of another substituent refers to the group -ORQ , wherein RQ is an "alkyl” as defined above.
  • cycloalkyl refers to a cyclic alkyl group.
  • mn-membered cycloalkyl C m -C n cycloalkyl
  • C mn cycloalkyl should be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms.
  • 3-15-membered cycloalkyl or "C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 7, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings.
  • "5-8-membered cycloalkyl” contains 5-8 carbon atoms. Including monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings.
  • unsubstituted cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring.
  • Cycloalkyl groups may be substituted by one or more substituents.
  • cycloalkyl groups may be cycloalkyl groups fused to aryl or heteroaryl groups.
  • C 3 -C 6 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • heterocycloalkyl or “heterocyclyl” refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as but not limited to N, O, S and P, when alone or as part of other substituents.
  • heterocycloalkyl or “heterocyclyl” can be saturated or unsaturated, but not aromatic.
  • Heterocycloalkyl” or “heterocyclyl” can also contain 1, 2 or 3 rings, including bridged rings and spirocyclic structures.
  • 3-8 membered heterocyclyl or “3-8 membered heterocycloalkyl” should be understood to mean a monocyclic, bicyclic or tricyclic ring having 3 to 8 atoms, wherein the heteroatoms are preferably selected from N, O and S. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other, such as 3-6 membered heterocycloalkyl or 3-7 membered heterocycloalkyl.
  • heterocycloalkyl examples include, but are not limited to, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl.
  • C ⁇ - ⁇ cycloalkenyl when used alone or as part of other substituents refers to a monocyclic group having ⁇ to ⁇ atoms, a double bond, but not aromatic.
  • Examples of cycloalkenyl groups are: cyclopropene, cyclobutene, cyclohexene, cyclobutadiene, cyclopentadiene, cycloheptatriene, cyclooctatetraene, etc.
  • heteroalkene ring when used alone or as part of another substituent refers to a monocyclic group with heteroatoms (the monocyclic group has a double bond but is not aromatic), preferably a monocyclic ring containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S.
  • heterocycloalkenyl groups are: dihydrofuranyl, dihydrothiophenyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, 3,4-dihydro-2H-pyran, pyranyl, thiopyranyl, dihydropyridine
  • heteroalkene ring may be used interchangeably with the term “heterocycloalkenyl”.
  • aryl or "aromatic ring” refers to a monovalent aromatic carbocyclic ring system containing 6-14, preferably 6-10 carbon atoms and having at least one aromatic ring or multiple fused rings in which at least one ring is an aromatic ring, when used alone or as part of other substituents.
  • aryl include, but are not limited to, phenyl, naphthyl, biphenyl or indanyl, etc.
  • the term "5-14 membered heteroaromatic ring” or “5-14 membered heteroaryl” when alone or as part of other substituents means a stable monocyclic, bicyclic or tricyclic ring having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, wherein at least one ring is aromatic and at least one ring contains 1-5 heteroatoms independently selected from N, O and S. It should be understood that when the total number of S atoms and O atoms in the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other.
  • the 5-14 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • 5-14 membered heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H,3H-1-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxine, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzotriazolyl, benzothiophene, benzofuranyl, benzodioxane, benzodioxine, quinolinyl, isoquinolinyl,
  • 1,2,4-triazolyl 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,4,5-tetrazinyl, tetrazolyl, xanthenyl, phenazinyl, phenothiazinyl, phenoxazinyl, aza-zepinyl, oxa-zepinyl and thia-zepinyl.
  • 5-10 membered heteroaromatic ring or “5-10 membered heteroaryl” is understood as a monocyclic, bicyclic or tricyclic ring having 5 to 10 atoms, wherein at least one ring is aromatic and contains at least 1 to 5 heteroatoms independently selected from N, O and S.
  • 5-10 membered heteroaromatic rings include, but are not limited to, furanyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, and the like.
  • the term "monocyclic" when alone or as part of other substituents means a group having only one ring, which may be saturated, unsaturated or partially saturated, and may be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S).
  • bicyclic means a group having two connected rings, either alone or as part of other substituents.
  • Bicyclic rings can be carbocyclic rings (all ring atoms are carbon atoms) or heterocyclic rings (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings can be aliphatic (e.g., decalin and norbornane), or can be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin).
  • Bicyclic rings include (a) spirocyclic compounds, in which the two rings share only one single atom (spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:
  • Non-limiting examples include:
  • bridged bicyclic compounds wherein the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising at least one atom.
  • norbornane also known as bicyclo[2.2.1]heptane
  • bridged bicyclic rings include, but are not limited to:
  • the NR a R a group when alone or as part of another substituent, can be In the form of, or may include two Ra groups together to form a ring, the ring optionally contains N, O or S atoms, and may also include the following groups, for example:
  • the group N(C ⁇ - ⁇ alkyl)C ⁇ - ⁇ alkyl when alone or as part of other substituents includes substituents in which two C ⁇ - ⁇ alkyl groups together form a ring (optionally containing N, O or S atoms), and includes the following groups, for example:
  • inert solvent includes, but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.
  • Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as but not limited to carboxyl, hydroxyl and amino moieties), and also include protected derivatives thereof.
  • "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups).
  • Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., and isotopes, etc.
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc.
  • Suitable hydroxyl protecting groups include benzyl, etc. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • the term "optionally substituted by" or “optionally substituted by" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from possible substituents.
  • aryl is optionally substituted by 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C 1-6 alkyl” means that aryl is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C 1-6 alkyl, and the description also includes substituted aryl. With unsubstituted aryl.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or organic acid that retains the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or organic base that retains the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.
  • amine salt refers to the product obtained by neutralizing an alkyl primary amine, a secondary amine or a tertiary amine with an acid.
  • the acid includes the inorganic acid or organic acid described in the present application.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in molecules, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
  • the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule.
  • the prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to a functional group isomer resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer generally produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form is predominant; whereas in phenols, the enol form is predominant.
  • the present invention encompasses all tautomeric forms of the compounds.
  • pharmaceutical composition refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.
  • solvate means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • prodrug refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds.
  • radioactive isotope labeled compounds may be used, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of the type of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.
  • treatment and other similar synonyms include the following meanings:
  • the reaction temperature of each step can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, etc.
  • the target compound can be separated and purified from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. In the case of not affecting the next step reaction, the target compound can also be directly used in the next step reaction without separation and purification.
  • IC 50 Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56 mL, 29.1 mmol, 2.5 M n-hexane solution
  • n-butyllithium n-hexane solution means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol/L
  • N equivalent concentration, for example, 2N hydrochloric acid means 2 mol/L hydrochloric acid solution
  • PE Petroleum ether
  • EA Ethyl acetate, also called EtOAc
  • DIPEA N,N-diisopropylethylamine
  • RuPhos-Pd-G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate or (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate
  • the synthetic route of the target compound I-1 is as follows:
  • Step 1 Synthesis of 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic acid
  • the reaction solution was extracted with ethyl acetate (20mL ⁇ 3), the organic phases were combined, washed with water (15mL ⁇ 2), the aqueous phases were combined, and the pH was adjusted to 3 with 2N hydrochloric acid, then extracted with ethyl acetate (30mL ⁇ 3), the organic phases were combined, washed with saturated brine (20mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic acid (2.80g, crude product), which was directly used in the next step.
  • Step 2 Synthesis of 1-(4-(difluoromethyl)phenyl)-N-methoxy-N,4-dimethyl-1H-1,2,3-triazole-5-carboxamide
  • Step 3 Synthesis of 1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethan-1-one
  • Step 4 Synthesis of 1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol
  • Step 5 Synthesis of 3-chloro-6-(1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethoxy)pyridazine
  • 3-chloro-6-(1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethoxy)pyridazine (1.33 g, 3.64 mmol) and 2-piperazinone (364.06 mg, 3.64 mmol) were dissolved in dioxane (15 mL), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (169.68 mg, 0.364 mmol), cesium carbonate (1.18 g, 3.64 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (304.12 mg, 0.364 mmol) were added in sequence.
  • reaction solution was heated to 100 ° C and stirred under this condition for 16 hours.
  • LCMS monitored the completion of the reaction.
  • the reaction solution was diluted with dichloromethane (50 mL), filtered, and the filtrate was concentrated under reduced pressure.
  • the synthetic route of the target compound I-7 is as follows:
  • Step 2 Synthesis of 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine
  • reaction solution was quenched with saturated ammonium chloride (20 mL) aqueous solution, extracted three times with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (350 mg, crude product).
  • Step 3 Synthesis of 1-(3-((6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)oxy)azetidin-1-yl)ethan-1-one
  • reaction solution was quenched with water (20 mL), extracted three times with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered and concentrated to obtain a crude product.
  • the synthetic route of the target compound I-9 is as follows:
  • 6-chloropyridazine-3-amine 200 mg, 1.54 mmol
  • 1-methylpiperazine-2-one 212 mg, 1.85 mmol
  • the reaction solution was cooled to room temperature, and then methyl tert-butyl ether (5 mL) was added and stirred for 0.5 hours, and 4-(6-aminopyridazine-3-yl)-1-methylpiperazine-2-one (200 mg, crude product) was obtained by filtration.
  • Step 2 Synthesis of 1-(4-(difluoromethyl)phenyl)-4-methyl-N-(6-(4-methyl-3-oxopiperazin-1-yl)pyridazin-3-yl)-1H-1,2,3-triazole-5-carboxamide
  • the synthetic route of the target compound I-14 is as follows:
  • Step 1 Synthesis of tert-butyl 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate
  • Step 2 Synthesis of 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine
  • tert-butyl 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 500 mg, 1.06 mmol was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added, and the reaction solution was stirred at 25°C for 0.5 hours.
  • Step 3 Synthesis of 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide
  • Example 5 The following compounds were prepared by referring to the preparation methods of the above compounds.
  • Test Example 1 Inverse agonist activity of compounds on ⁇ 5-GABAA receptors
  • This test uses a HEK-293 cell line that transiently expresses GABAA ( ⁇ 5 ⁇ 3 ⁇ 2) receptors.
  • the final concentration of the test compound was prepared on the same day and then dissolved in the extracellular solution.
  • the extracellular solution is: 140mM NaCl, 5mM CsCl, 2mM CaCl 2 ⁇ 2H 2 O, 1mM MgCl 2 ⁇ 6H 2 O, 5mM HEPES, 10mM D-Glucose, and NaOH is used to adjust the pH to 7.4.
  • the intracellular solution is: 130mM CsCl, 0.1mM CaCl 2 ⁇ 2H 2 O, 2mM MgCl 2 ⁇ 6H 2 O, 1.1mM EGTA, 5mM Na2-ATP, 10mM HEPES, and CsOH is used to adjust the pH to 7.2.
  • the test compound was dissolved in dimethyl sulfoxide (DMSO) and dissolved in the extracellular solution on the day of the test to a final concentration of 100nM.
  • DMSO dimethyl sulfoxide
  • the peak current after the EC50 concentration of GABA, the mixture of EC50 concentration of GABA and the test substance detection concentration, and the saturated concentration of GABA were given to the cell surface in sequence.
  • the cells were eluted with extracellular solution, and the next working solution was switched after the current stabilized.
  • the experimental data were collected by a patch clamp amplifier (HEKA, EPC 10) and stored in the data acquisition software (HEKA, Patch Master). At least 2 cells were used for each concentration and the test was repeated twice independently. All electrophysiological experiments were performed at room temperature.
  • the peak current stimulated by GABA before administration (I GABA )
  • the peak current after the test substance detection concentration (I Cmpd )
  • the peak current after the test substance detection concentration and the mixture of GABA (I GABA+Cmpd )
  • the peak current stimulated by saturated concentration of GABA (I GABA saturated ) were measured.
  • the antagonistic effect of the test substance was calculated, i.e., (1-( ICmpd / IGABA )*100%)
  • the inverse agonistic effect was calculated, i.e., (1-( IGABA+Cmpd )/( IGABA )*100%).
  • the experimental results show that the compound of the present invention has strong inverse agonist activity of ⁇ 5-GABAA receptor.

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Abstract

La présente invention concerne un composé hétérocyclique représenté par la formule I, ou un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. Le composé a une fonction de modulation du récepteur α5-GABAA,
PCT/CN2024/097429 2023-06-05 2024-06-05 COMPOSÉ HÉTÉROCYCLIQUE EN TANT QUE MODULATEUR DU RÉCEPTEUR α5-GABAA ET SON UTILISATION Ceased WO2024251133A1 (fr)

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CN109923113A (zh) * 2016-12-08 2019-06-21 豪夫迈·罗氏有限公司 作为GABA A α5 PAM的新型异噁唑基醚衍生物
CN112424197A (zh) * 2018-07-20 2021-02-26 勃林格殷格翰国际公司 作为gaba受体调节剂的二氟甲基-苯基三唑类
CN115703765A (zh) * 2021-08-12 2023-02-17 上海赛默罗生物科技有限公司 取代三唑类衍生物、其制备方法、药物组合物和用途
WO2023053015A1 (fr) * 2021-09-29 2023-04-06 Richter Gedeon Nyrt. DÉRIVÉS BICYCLIQUES D'AMINE SERVANT DE MODULATEURS DU RÉCEPTEUR GABAA α5
WO2023185704A1 (fr) * 2022-03-28 2023-10-05 上海赛默罗生物科技有限公司 Dérivé d'isoxazole hétérocyclique, composition pharmaceutique et utilisation
CN116854685A (zh) * 2022-03-28 2023-10-10 上海赛默罗生物科技有限公司 异噁唑-稠环类衍生物、药物组合物和用途

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