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WO2024251133A1 - 作为α5-GABAA受体调节剂的杂环化合物及其用途 - Google Patents

作为α5-GABAA受体调节剂的杂环化合物及其用途 Download PDF

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Publication number
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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French (fr)
Inventor
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

本发明提供了式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；该化合物对α5-GABAA受体具有调节功能，

Description

作为α5-GABAA受体调节剂的杂环化合物及其用途
本发明要求享有：
于2023年6月5日向中国国家知识产权局提交的，专利申请号为202310662536.9，名称为“作为α5-GABAA受体调节剂的杂环化合物及其用途”的在先申请的优先权；
于2024年5月24日向中国国家知识产权局提交的，专利申请号为202410658952.6，名称为“作为α5-GABAA受体调节剂的杂环化合物及其用途”的在先申请的优先权；
所述在先申请的全文通过引用的方式结合于本发明中。
技术领域
本发明属于医药领域，具体地，本发明涉及到α5-GABAA受体调节剂的杂环化合物及用途。
背景技术
GABAA受体与多种疾病相关，是其可能的治疗靶点，这也促进了对于GABAA受体不同亚基的生理和药理作用的研究。例如，应用基因修饰小鼠研究表明，分布最广泛的α5亚基γ-氨基丁酸A受体(α5-GABAA受体)是苯二氮(benzodiazepines，BDZ)类药物产生镇静和遗忘作用的主要靶点，α2-GABAA受体和α3-GABAA受体则与药物发挥抗惊厥和抗焦虑作用相关。α5-GABAA受体是哺乳动物中枢神经系统的一种抑制性受体，主要分布在大脑海马组织，通过调控氯离子外向电流对海马神经元产生抑制性效应，其在大脑皮层表达水平非常低，在其他大脑区域几乎不表达。海马组织是司职学习和记忆等认知功能的主要部位，说明α5-GABAA受体可能与学习和记忆等认知功能相关。除BDZ类药物以外，还有多种药物如丙泊酚、依托咪酯、巴比妥类和神经固醇类药物都能通过激动GABAA受体的变构调节位点增强GABA的神经功能，从而产生相应的药理效应，在临床上起到麻醉、抗焦虑、镇静或抗癫痫的作用。但它们往往与GABAA受体多种亚基非特异性结合，导致许多不良反应如药物耐受、镇静、焦虑或惊厥的发生。因此，研究者们始终致力于研究和发现对某一GABAA受体亚基具有选择性和特异性作用的药物。
大量研究表明，α5-GABAA受体兴奋性的改变会对学习和记忆等认知功能产生影响，从而导致一些病症如术后认知功能障碍、疼痛、抑郁症、精神分裂症和唐氏综合征等的发生。而其变构调节剂则能治疗或改善这些病症。
考虑到α5-GABAA受体的在大脑海马组织中特异性分布和功能研究，包括罗氏在内的许多制药公司从事于α5-GABAA受体配体的研究，陆续有大量的化合物合成出来，特别是针对大脑海马组织的含α5-GABAA受体的反向激动剂，其中α5IA和MRK-016在动物疾病模型和人体试验中显示出良好的治疗认知类疾病的效果，特别是治疗阿尔茨海默氏病。普遍认为α5-GABAA受体的反向激动剂可以用来治疗认知类疾病，特别是治疗阿尔茨海默氏病。专利申请US20110224278A1披露含α5-GABAA受体的反向激动剂可用于治疗多梗塞性痴呆和中风相关疾病。
发明内容
本发明的目的是提供一类新的化合物，该类化合物具有α5-GABAA受体的调节活性，特别地，具有α5-GABAA受体的抑制活性。为此，本发明还提供了这些化合物及其药学上可接受的盐在制备和制造用于治疗、预防、或改善与α5-GABAA受体相关的疾病的药物组合物或药物中的用途，所述疾病如阿尔兹海默氏病、多梗塞性痴呆、疼痛和中风，或者在制备缓解疼痛药物中的用途。本发明还提供了用于制备式I化合物的方法，以及在此类方法中可用的中间体。
本发明的第一方面，提供了式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
其中，
X1为N或C；
X2为N、O、S或CR5；
虚线表示单键或双键；
m选自0、1、2、3、4或5；
环A不存在或选自苯环、5-6元杂芳环；其中，
当环A不存在时，m为1，R1与X1相连；
R1选自氢、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷氨基、C3-7环烷基或3-6元杂环烷基；所述C1-6烷基、C1-6烷氧基、C1-6烷氨基、C3-7环烷基或3-6元杂环烷基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C3-7环烷基；
R2选自氢、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C3-7环烷基、3-7元杂环烷基或5-6元杂芳基；所述C1-6烷基、C1-6烷氧基、C3-7环烷基、3-7元杂环烷基或5-6元杂芳基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C3- 7环烷基；
L选自-CH2-O-、-CH(R6)-O-或-C(＝O)-NRa-；
环B选自5-14元杂芳环；
n选自0、1、2、3、4、5、6、7或8；
环D不存在或选自4-6元杂环烷基、3-6元环烷基；
p为0、1、2、3、4、5、6或7；
R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基-C(＝O)Ra-C0-6烷基、 -C0-6烷基-C(＝O)ORa-C0-6烷基、-C0-6烷基-C(＝O)NRaRb-C0-6烷基、-C0-6烷基-NRaRb-C0-6烷基、-C0- 6烷基-NRaC(＝O)Rb-C0-6烷基、-C0-6烷基-NRaSO2Rb-C0-6烷基、-C0-6烷基-SO2Ra-C0-6烷基、-C0-6烷基-SO2NRaRb-C0-6烷基、C1-6烷基、C3-7环烷基、3-6元杂环烷基、6-10元杂芳基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基、6-10元杂芳基任选地被1-4个选自下列基团的取代基取代：氘、卤素、氧代、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
M不存在或选自O；
R5选自氢、氘、卤素、羟基、氰基、C1-6烷基、C1-6烷氧基或C3-7环烷基；所述C1-6烷基、C1- 6烷氧基或C3-7环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1- 6烷基、C3-7环烷基；
R6选自氘、卤素、C1-6烷基、C1-6烷氧基或C3-7环烷基；所述C1-6烷基、C1-6烷氧基或C3-7环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
Ra和Rb各自独立地选自氢、氘、卤素、羟基、氨基、-C0-6烷基-S(＝O)2-C0-6烷基、-C0-6烷基-P(＝O)2-C0-6烷基、C1-6烷基或3-6元杂环烷基，其中所述C1-6烷基任选地被1-3个选自下列基团的取代基取代：卤素、羟基、-OC1-6烷基、-NH2、-NHC1-6烷基、-OC(＝O)C1-6烷基或-N(C1-6烷基)C1-6烷基；且所述3-6元杂环烷基是含有0、1、2或3个N原子和0、1或2个选自O和S原子的单环。
在本发明一优选实施方案中，所述R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基-C(＝O)Ra、-C0-6烷基-C(＝O)ORa、-C0-6烷基-C(＝O)NRaRb、-C0-6烷基-NRaRb、-C0- 6烷基-NRaC(＝O)Rb、-C0-6烷基-NRaSO2Rb、-C0-6烷基-SO2Ra、-C0-6烷基-SO2NRaRb、C1-6烷基、C3- 7环烷基、3-6元杂环烷基、6-10元杂芳基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基、6-10元杂芳基任选地被1-4个选自下列基团的取代基取代：氘、卤素、氧代、羟基、氨基、氰基、C1-6烷基、C3-7环烷基。
在本发明一优选实施方案中，所述选自
较佳地，所述选自
在本发明一优选实施方案中，所述化合物选自如下结构：
其中，环A、环B、环D、R1、R2、R3、R4、L、M、p、m和n的定义如本发明第一方面所述。
在本发明一优选实施方案中，所述环A不存在或选自苯环或6元杂芳环；所述6元杂芳环含有1、2、3个杂原子；
m为0、1、2、3、4或5；
R1选自氢、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基、C3-7卤代环烷基、C1-6烷氧基、C1-6卤代烷氧基；
所述杂原子选自N、O、S；当杂原子为多个时，所述杂原子相同或不同。
在本发明一优选实施方案中，所述环A不存在或选自苯环、吡啶、嘧啶、哒嗪、吡嗪或三嗪。
在本发明一优选实施方案中，所述环A不存在或选自苯环或吡啶。
在本发明一优选实施方案中，所述环A选自*端与X1连接。
在本发明一优选实施方案中，选自例如
在本发明一优选实施方案中，环A不存在时，m为1，R1与X1相连。
在本发明一优选实施方案中，所述化合物选自如下结构：
其中，环B、环D、R1、R2、R3、R4、L、M、m、n和p的定义如本发明第一方面所述。
在本发明一优选实施方案中，所述化合物选自如下结构：
其中，环B、环D、R1、R2、R3、R4、L、M、n和p的定义如本发明第一方面所述。
在本发明一优选实施方案中，所述化合物选自如下结构：
其中，环A、环B、环D、R1、R2、R3、R4、M、m、n和p的定义如本发明第一方面所述。
在本发明一优选实施方案中，所述化合物选自如下结构：
其中，环B、R1、R2、R3、m和n的定义如本发明第一方面所述；
当M不存在时，环D、R4和p同时不存在；
当M选自O时，环D、R4和p的定义如本发明第一方面所述。在本发明一优选实施方案中，所述环B选自含有1、2、3、4或5个杂原子的5-14元杂芳环；
较佳地，所述杂原子选自N、O、S；当杂原子为多个时，所述杂原子相同或不同；
较佳地，环B选自吖啶基、咔唑基、噌啉基、喹喔啉基、喹唑啉基、吡唑基、吲哚基、异吲哚基、苯并三唑基、呋喃基、噻吩基、吡啶并吗啉基、吡啶并哌啶基、吡啶并吡咯烷基、苯并噻吩基、苯并呋喃基、苯并二噁烷、苯并二氧杂苯、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、四氢萘啶、咪唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉基、噻唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、三嗪基、四嗪基、四唑基、呫吨基、吩嗪基、吩噻嗪基、吩噁嗪基、氮杂卓基、氧杂卓基、硫杂卓基、六氢吡嗪并吡啶并噁嗪、6,7,8,9-四氢吡啶并[2',3':4,5]咪唑并[1,2-a]吡嗪等；
更佳地，环B选自吡啶、嘧啶、哒嗪、四氢萘啶、吡啶并哌啶、
在本发明一优选实施方案中，所述环B选自吡啶、嘧啶、哒嗪、四氢萘啶、吡啶并哌啶、
在本发明一优选实施方案中，所述环B选自 *端与L连接。
在本发明一优选实施方案中，选自 *端与L连接。
在本发明一优选实施方案中，所述L选自-CH2-O-、-CH(R6)-O-或-C(＝O)-NRaRb-；
所述R6选自C1-3烷基或C3-5环烷基；所述C1-3烷基或C3-5环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
较佳地，L选自-CH2-O-、-CH(CH3)-O-或-C(＝O)-NH2-。
在本发明一优选实施方案中，所述L选自-CH2-O-、-CH(CH3)-O-或-C(＝O)-NH2-。
在本发明一优选实施方案中，所述L选自-CH2-O-、-CH(R6)-O-或-C(＝O)-NRa-；
所述R6选自C1-3烷基或C3-5环烷基；所述C1-3烷基或C3-5环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基。
在本发明一优选实施方案中，所述L选自-CH2-O-、-CH(CH3)-O-或-C(＝O)-NH-。
在本发明一优选实施方案中，所述L选自(如)、*端与连接。
在本发明一优选实施方案中，所述环D不存在或选自含有1-3个杂原子的4-6元杂环烷基、3-6元环烷基；
较佳地，所述杂原子选自N、O、S；当杂原子为多个时，所述杂原子相同或不同。
在本发明一优选实施方案中，所述环D不存在或选自环丙基、环丁基、环戊基、氮杂环丁烷、吡咯烷、哌啶、哌嗪。
在本发明一优选实施方案中，所述环D选自
在本发明一优选实施方案中，选自
在本发明一优选实施方案中，所述R1选自氢、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基、C1-6烷氧基；所述C1-6烷基、C3-7环烷基、C1-6烷氧基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
m选自0、1、2、3、4或5；
较佳地，R1选自F、甲基、环丙基、甲氧基、三氟甲基、二氟甲基、一氟甲基。
在本发明一优选实施方案中，所述R1选自卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、卤代烷基。
在本发明一优选实施方案中，所述R1选自F、甲基、环丙基、甲氧基、三氟甲基、二氟甲基、一氟甲基。
在本发明一优选实施方案中，所述R2选自卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基；所述C1-6烷基、C3-7环烷基、C1-6烷氧基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
较佳地，R2选自甲基。
在本发明一优选实施方案中，所述R3选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基 -C(＝O)Ra-C0-6烷基、-C0-6烷基-C(＝O)ORa-C0-6烷基、-C0-6烷基-C(＝O)NRaRb-C0-6烷基、C1-6烷基、C3-7环烷基、3-6元杂环烷基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基任选地被1-4个选自下列基团的取代基取代：氘、卤素、氧代、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
n选自0、1、2、3、4、5、6、7或8；
较佳地，R3选自氢、卤素、氧代、-C(＝O)Ra、-C(＝O)NRaRb-C0-3烷基、C1-3烷基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷、哌啶、哌嗪、哌啶酮、哌嗪酮。
在本发明一优选实施方案中，所述R3选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基-C(＝O)Ra、-C0-6烷基-C(＝O)ORa、-C0-6烷基-C(＝O)NRaRb、C1-6烷基、C3-7环烷基、3-6元杂环烷基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基任选地被1-4个选自下列基团的取代基取代：氘、卤素、氧代、羟基、氨基、氰基、C1-6烷基、C3-7环烷基。
在本发明一优选实施方案中，所述R3选自氢、卤素、氧代、-C(＝O)Ra、-C(＝O)NRaRb、C1- 3烷基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷、哌啶、哌嗪、哌啶酮、哌嗪酮。
在本发明一优选实施方案中，所述R3选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2-C0-3烷基、甲基、哌嗪酮；n选自0或1。
在本发明一优选实施方案中，所述R3选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2、-C(＝O)NH-C1-3烷基、甲基、哌嗪酮；n选自0或1。
在本发明一优选实施方案中，所述R3选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2、-C(＝O)NH-C1-3烷基、甲基、哌嗪酮、甲基取代的哌嗪酮。
在本发明一优选实施方案中，所述R3选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2、甲基、
在本发明一优选实施方案中，n选自0或1。
在本发明一优选实施方案中，所述R4选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基-C(＝O)Ra-C0-6烷基、-C0-6烷基-C(＝O)ORa-C0-6烷基、-C0-6烷基-C(＝O)NRaRb-C0-6烷基、C1-6烷基、C3-7环烷基、3-6元杂环烷基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
p为0、1、2、3、4、5、6或7；
较佳地，R4选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2-C0-3烷基、甲基；
p选自0、1或2。
在本发明一优选实施方案中，所述R4选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基-C(＝O)Ra、-C0-6烷基-C(＝O)ORa、-C0-6烷基-C(＝O)NRaRb、C1-6烷基、C3-7环烷基、3-6元杂环烷基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
在本发明一优选实施方案中，所述R4选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2、-C(＝O)NH-C1-3烷基、甲基；p选自0、1或2。
在本发明一优选实施方案中，所述R4选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2、甲基。
在本发明一优选实施方案中，所述p选自0、1或2。
在本发明一优选实施方案中，所述化合物包括：
本发明第二方面，一种药物组合物，包括如第一方面所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。
本发明第三方面，如第一方面所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途，或第二方面所述的药物组合物的用途，所述用途包括：
调节α5-GABAA受体；
和/或，预防和/或治疗α5-GABAA受体相关的疾病；
和/或，制备用于调节α5-GABAA受体，和/或预防和/或治疗α5-GABAA受体相关的疾病的药物、药物组合物或制剂。
提供了如第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第二方面所述药物组合物预期可用于疼痛、阿尔兹海默氏病、多梗塞性痴呆或中风。
应该提及的疼痛是神经病理性疼痛、炎性疼痛或癌症痛。
应该提及的疼痛选自头痛，面部痛，颈痛，肩痛，背痛，胸痛，腹痛，腰痛，下肢痛，肌肉与骨骼疼痛，血管疼痛，痛风，关节炎疼痛，内脏疼痛，感染性疾病导致的疼痛，多骨疼痛，镰刀细胞贫血，自身免疫性疾病，多发性硬化或炎症有关的疼痛，损伤或手术引起的慢性疼痛，伤害感受性疼痛，疼痛性糖尿病，三叉神经痛，腰部或子宫颈神经根病痛，舌咽神经痛，自主神经反射性疼痛，反射性交感神经营养不良，神经根撕脱，癌症，化学损伤，毒素，营养缺乏，病毒或细菌感染，退行性骨关节病有关的疼痛。
应该提及的感染性疾病选自艾滋病或带状疱疹后神经痛。
本发明第四方面，提供一种调节α5-GABAA受体相关的疾病的方法，包括给予患者预防或治疗有效量的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第二方面所述的药物组合物。
在一些实施方案中，提供一种预防和/或治疗α5-GABAA受体相关疾病的方法，包括给予患者预防或治疗有效量的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第二方面所述的药物组合物。
所述疾病选自疼痛、阿尔兹海默氏病、多梗塞性痴呆或中风。
应该提及的疼痛选自神经病理性疼痛、炎性疼痛或癌症痛。
应该提及的疼痛选自头痛、面部痛、颈痛、肩痛、背痛、胸痛、腹痛、腰痛、下肢痛、肌肉与骨骼疼痛、血管疼痛、痛风、关节炎疼痛、内脏疼痛、感染性疾病导致的疼、多骨疼痛、镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛、损伤或手术引起的慢性疼痛、伤害感受性疼痛、疼痛性糖尿病、三叉神经痛、腰部或子宫颈神经根病痛、舌咽神经痛、自主神经反射性疼痛、反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染、退行性骨关节病有关的疼痛。
应该提及的感染性疾病选自AIDS或带状疱疹后神经痛。
本发明第五方面，如第一方面所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第二方面所述的药物组合物用作药物。
本发明第六方面，如第一方面所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第二方面所述的药物组合物用于：
调节α5-GABAA受体；
用于预防和/或治疗α5-GABAA受体相关的疾病。
所述疾病选自疼痛、阿尔兹海默氏病、多梗塞性痴呆或中风。
应该提及的疼痛选自神经病理性疼痛、炎性疼痛或癌症痛。
应该提及的疼痛选自头痛、面部痛、颈痛、肩痛、背痛、胸痛、腹痛、腰痛、下肢痛、肌肉与骨骼疼痛、血管疼痛、痛风、关节炎疼痛、内脏疼痛、感染性疾病导致的疼、多骨疼痛、镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛、损伤或手术引起的慢性疼痛、伤害感受性疼痛、疼痛性糖尿病、三叉神经痛、腰部或子宫颈神经根病痛、舌咽神经痛、自主神经反射性疼痛、反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染、退行性骨关节病有关的疼痛。
应该提及的感染性疾病选自AIDS或带状疱疹后神经痛。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
有益效果
本发明人经过广泛而深入地研究，意外地开发了一种化合物或其药学上可接受的盐及制备方法和用途。
本发明提供了式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，所述式I化合物对α5-GABAA受体具有显著的调节作用，可以治疗由α5-GABAA受体介导的疾病或病症，表现出优良的药代动力学性质，具备较高的安全性和成药性质。
本发明提供了制备I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的方法及中间体，所述方法操作简单、收率高、纯度高，可用于医药工业化生产。
术语定义与说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。如本文所用， 表示基团的连接位点。如本文所用，“R1”、“R1”和“R1”的含义相同，可相互替换。对于R2等其它其他符号，类似定义的含义相同。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～14的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9、10、11、12、13和14的每一个整数。
在本申请中，当指明取代基的数目时，术语“一个或多个”是指一个取代至取代的最多可能的数目，即取代一个氢至所有的氢均被取代基取代。当指明取代基的数目时，术语“1-4个”是指1、2、3或4个取代，即1、2、3或4个氢被取代基取代。
在本申请中，“饱和的、部分饱和的或不饱和的”包括被氢饱和的取代基、完全被氢不饱和的取代基和部分被氢饱和的取代基。
在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘。
在本申请中，在单独或作为其他取代基一部分时，术语"羟基"表示-OH。
在本申请中，在单独或作为其他取代基一部分时，术语"氰基"表示-CN。
在本申请中，在单独或作为其他取代基一部分时，术语"氨基"表示-NH2。
在本申请中，在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基，叔丁基，戊基，异戊基，新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。。
在本申请中，在单独或作为其他取代基一部分时，术语“Cα-β烷基”是指在支链或线性关系或这三者的任意组合中包含最小α个和最大β个碳原子的烷基，其中α和β表示整数，亦可 用“Cα-Cβ烷基”的形式表示。在该部分描述的烷基还可以含有一个或两个双键或三键。C0烷基的指定表示直连键。C1-6烷基的实例包括但不限于以下：
在本申请中，单独或以组合的“苯并基团”是指二价基团C4H4＝，其中一个表示是-CH＝CH-CH＝CH-，当邻位附接到另一环时形成苯状环，例如四氢萘、吲哚等。
在本申请中，在单独或作为其他取代基一部分时，术语“Cα-β卤代烷基”是指如上所述的烷基，其中，任意数量(至少一个)的附接到烷基链的氢原子被氟、氯、溴或碘替代。
在本申请中，在单独或作为其他取代基一部分时，术语“烷氧基”是指基团-O-RQ，其中，RQ为如上文所定义的“烷基”。
在本申请中，在单独或作为其他取代基一部分时，术语“氧代”是指亚甲基上的两个氢被氧取代，也即亚甲基被羰基替代，表示＝O。
在本申请中，在单独或作为其他取代基一部分时，术语“硫代”是指亚甲基上的两个氢被硫取代，表示＝S。
在本申请中，在单独或作为其他取代基一部分时，术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”、“Cm-Cn环烷基”或者“Cm-n环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-15元环烷基”或者“C3-C15环烷基”是指含有3至15，3至9，3至7，3至6或3至5个碳原子的环状烷基，它可能包含1至4个环。“5-8元环烷基”则含有5-8个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基，环丁基，环戊基，环己基和金刚烷基，或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中，环烷基可以是与芳基或杂芳基稠合的环烷基。术语“C3-C6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环系统。例如环丙基、环丁基、环戊基、环己基。
在本申请中，在单独或作为其他取代基一部分时，术语“杂环烷基”或“杂环基”是指其中一个或多个(在一些实施方案中为1至3个)碳原子被杂原子取代的环烷基，所述杂原子例如但不限于N、O、S和P。“杂环烷基”或“杂环基”可以是饱和的或不饱和的，但不是芳族的。“杂环烷基”或“杂环基”也可以是含有1、2或3个环，包括桥环及螺环结构。术语“3-8元杂环基”或“3-8元杂环烷基”应理解为表示具有3至8个原子的单环、双环或三环，其中杂原子优选自N、O和S，应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻，例如3-6元杂环烷基或3-7元杂环烷基。杂环烷基的实例包括但不限于：四氢异喹啉基、四氢喹啉基、四氢吡喃基、四氢呋喃基、四氢噻喃基。
在本申请中，在单独或作为其他取代基一部分时，术语“Cα-β环烯基”是指有α至β个原子，具有双键、但不具有芳香性的单环基团。环烯基的示例为：环丙烯、环丁烯、环己烯、环丁二烯、环戊二烯、环庚三烯、环辛四烯等。
在本申请中，在单独或作为其他取代基一部分时，术语“杂烯环”是指具有杂原子的单环基团(该单环基团具有双键、但不具有芳香性)，优选含有1个、2个或3个独立选自N、O和S的环杂原子的单环。杂环烯基的示例为：二氢呋喃基、二氢噻吩基、二氢吡咯基、二氧杂环戊烯基、二氢咪唑基、二氢吡唑基、二氢噻唑基、二氢异噻唑基、二氢噁二唑基、二氢噻二唑基、二氢三唑基、二氢四唑基、四氢吡啶基、3,4-二氢-2H-吡喃、吡喃基、噻喃基、二氢吡啶 基、二氢吡嗪基、二氢嘧啶基、噁嗪基、二氢四唑基等。术语“杂烯环”可以和术语“杂环烯基”交换使用。
在本申请中，在单独或作为其他取代基一部分时，术语“芳基”或者“芳环”是指含有6-14个、优选6-10碳原子并具有至少一个芳环或其中至少一个环为芳环的多稠合环的单价芳族碳环环系。芳基的实例包括但不限于苯基、萘基、联苯基或茚满基等。
在本申请中，在单独或作为其他取代基一部分时，术语“5-14元杂芳环”或“5-14元杂芳基”表示具有5、6、7、8、9、10、11、12、13或14个环原子的稳定单环、双环或三环，其中至少一个环是芳族的并且至少一个环含有1-5个独立选自N、O和S的杂原子。应该理解的是，当杂芳基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。5-14元杂芳基可通过杂原子或碳原子连接到分子的其余部分。在该定义的范围内的5-14元杂芳基包括但不限于吖啶基、咔唑基、噌啉基、喹喔啉基、喹唑啉基、吡唑基、吲哚基、异吲哚基、1H,3H-1-氧代异吲哚基、苯并三唑基、呋喃基、噻吩基、吡啶并吗啉基、吡啶并哌啶基、吡啶并吡咯烷基、苯并噻吩基、苯并呋喃基、苯并二噁烷、苯并二氧杂苯、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、咪唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉基、噻唑基、异噻唑基、1,2,3—三唑基、1,2,4—三唑基、1,2,4-噁二唑基、1,2,4-噻二唑基、1,3,5-三嗪基、1,2,4-三嗪基、1,2,4,5-四嗪基、四唑基、呫吨基、吩嗪基、吩噻嗪基、吩噁嗪基、氮杂卓基、氧杂卓基和硫杂卓基等。术语“5-10元杂芳环”或“5-10元杂芳基”应当理解为具有5至10个原子的单环、双环或三环，其中至少一个环是芳族并且至少含有1-5个独立选自N、O和S的杂原子。5-10元杂芳环的实例包括但不限于呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、噻二唑基，吡啶并吗啉基、吡啶并哌啶基、吡啶并吡咯烷基等。
在本申请中，在单独或作为其他取代基一部分时，术语“单环”意指可以为饱和的、不饱和的或部分饱和的只有一个环的基团，可以为碳环(所有环原子为碳原子)或杂环(除了碳原子之外，环原子包括例如1、2或3个杂原子，例如N、O或S)。
在本申请中，在单独或作为其他取代基一部分时，术语“双环”意指具有两个连接环的基团。双环可以为碳环(所有环原子为碳原子)或杂环(除了碳原子之外，环原子包括例如1、2或3个杂原子，例如N、O或S)。这两个环都可以是脂肪族的(例如萘烷和降冰片烷)，或可以是芳香族(例如萘)，或脂肪族和芳香族的组合(例如四氢化萘)。双环包括(a)螺环化合物，其中两个环只共享一个单原子(螺原子，其通常为季碳)。螺环化合物的实例包括但不限于：
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
(b)稠合的双环化合物，其中两个环共享两个相邻原子。换句话说，环共享一个共价键，即桥头原子直接连接(例如α-崖柏烯和萘烷)。稠合的双环的实例包括但不限于：
和(c)桥联的双环化合物，其中两个环共享三个或更多个原子，并通过包含至少一个原子的桥将两个桥头原子隔开。例如，降冰片烷，也称为双环[2.2.1]庚烷，可以被认为是一对环戊烷环，每个环共享它们的五个碳原子中的三个。桥联的双环的实例包括但不限于：
在本申请中，在单独或作为其他取代基一部分时，NRaRa基团可以以的形式存在，或者也可以包括其中两个Ra基团一起形成环，该环任选地包含N、O或S原子，并且也可以包括以下基团，例如：
在本申请中，在单独或作为其他取代基一部分时，基团N(Cα-β烷基)Cα-β烷基(其中α和β如上文定义)包括其中两个Cα-β烷基基团一起形成环(任选地包含N、O或S原子)的取代基，并且包括以下基团，例如：
在本申请中，术语“惰性溶剂”包括但不限于：甲苯、苯、水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃二氯甲烷、三氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
本文提供的化合物，包括可用于制备本文提供的化合物的中间体，其含有反应性官能团(例如但不限于羧基，羟基和氨基部分)，还包括其保护的衍生物。“受保护的衍生物”是其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物。合适的羧基部分保护基包括苄基，叔丁基等，以及同位素等。合适的氨基和酰氨基保护基包括乙酰基，三氟乙酰基，叔丁氧基羰基，苄氧基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团是本领域普通技术人员所熟知的。
在本申请中，术语“任选地被…取代”或“任选的被…取代”是指指定的基团是未取代的或者是被一个或多个独立选自可能的取代基所取代的。例如，“芳基任选地被1-4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1-6烷基”表示芳基未被取代或被1、2、3或4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1-6烷基，且该描述同时包括被取代的芳基 与未被取代的芳基。
在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
在本申请中，术语“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
在本申请中，术语“胺盐”是指用酸中和烷基伯胺、仲胺或叔胺得到的产物。所述酸包括本申请中所述的无机酸或有机酸。
在本申请中，术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。
在本申请中，术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
在本申请中，术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(2H)，氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
在本申请中，术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。
具体实施方式
下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
本申请具有如下定义：
符号或单位：
IC50：半数抑制浓度，指达到最大抑制效果一半时的浓度
M：mol/L，例如正丁基锂(14.56mL，29.1mmol，2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液
N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液
RT：保留时间
试剂：
PE：石油醚
EA：乙酸乙酯，也叫EtOAc
DMF：N,N-二甲基甲酰胺
DIPEA：N,N-二异丙基乙胺
RuPhos-Pd-G3：甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)或(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯基)]钯(II)甲磺酸盐
试验方法：
LCMS：液质联用色谱
TLC：薄层色谱法
实施例1：目标化合物I-1的制备
4-(6-(1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙氧基)哒嗪-3-基)哌嗪-2-酮
目标化合物I-1的合成路线如下所示：
第一步：1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-甲酸的合成
将1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-甲酸乙酯(3.0g，10.67mmol)溶于无水四氢呋喃(20mL)和甲醇(5mL)，然后称取一水合氢氧化锂(1.34g,32.0mmol)溶于水(10 mL)中，并加入到上述溶液中。加完后，反应液在室温下反应16小时。TLC(PE:EA(V/V)＝3:1)显示反应完全。反应液用乙酸乙酯(20mL×3)萃取，合并有机相，用水(15mL×2)洗涤，水相合并，并用2N盐酸调节pH到3，然后用乙酸乙酯(30mL×3)萃取，合并有机相，饱和食盐水(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩旋干，得到1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-甲酸(2.80g，粗品)，直接用于下一步。
第二步：1-(4-(二氟甲基)苯基)-N-甲氧基-N,4-二甲基-1H-1,2,3-三唑-5-甲酰胺的合成
冰浴条件下，将1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-甲酸(2.80g，11.06mmol)溶于无水乙腈(30mL)中，然后称取N,O-二甲基羟胺盐酸盐(1.29g,13.27mmol)和N,N-二异丙基乙胺(7.15g,55.29mmol)，再在该条件下缓慢滴入1-丙基磷酸酐(11.95g,50％in EtOAc,16.59mmol)。加完后，反应液在室温下反应16小时。TLC(PE:EA＝1:1)显示反应完全。向反应液中加入水(20mL),反应液用乙酸乙酯(30mL×3)萃取，合并有机相，分别用水(20mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩旋干，粗品通过正相硅胶柱层析分离(PE/EtOAc(V/V)＝1:0-1:1)得到1-(4-(二氟甲基)苯基)-N-甲氧基-N,4-二甲基-1H-1,2,3-三唑-5-甲酰胺(2.70g，收率：82.41％)。
第三步：1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙-1-酮的合成
冰浴条件，氮气保护下，将1-(4-(二氟甲基)苯基)-N-甲氧基-N,4-二甲基-1H-1,2,3-三唑-5-甲酰胺(1.40g，4.73mmol)溶于无水四氢呋喃(5mL)，随后加入甲基溴化镁的四氢呋喃溶液(1.13g,1M,9.45mmol)，加完后升至室温并在室温下反应4小时。TLC(PE:EA(V/V)＝3:1)显示反应完全。向反应液中加入饱和氯化铵的水溶液(15mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗1次，并用无水硫酸钠干燥，过滤，减压浓缩旋干，粗品通过正相硅胶柱层析分离(PE/EtOAc(V/V)＝1:0-1:1)得到1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙-1-酮(1.10g，收率：92.66％)。
第四步：1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙-1-醇的合成
冰浴条件下，称取1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙-1-酮(1.10g，4.38mmol)溶于甲醇(10mL)，然后分批次加入硼氢化钠(331.28mg，8.76mmol)。加完后，反应液在室温条件下反应2小时。TLC(PE:EA(V/V)＝3:1)显示反应完全。向反应液中加入饱和氯化铵溶液(20mL)，用乙酸乙酯(20mL×3)萃取，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，减压浓缩旋干，粗品通过正相硅胶柱层析分离(PE/EtOAc(V/V)＝1:0-1:1)得到1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙-1-醇(1.0g，收率：90.19％)。
第五步：3-氯-6-(1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙氧基)哒嗪的合成
冰浴条件，氮气保护下，称取1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙-1-醇(1.00g，4.38mmol)溶于四氢呋喃(10mL)，然后分批次加入氢化钠(236.90mg，60％，5.92mmol)。加完后，反应液在冰浴条件下反应30分钟，再加入3,6-二氯哒嗪(882.36mg，5.92mmol)，室温条件下反应10小时。TLC(PE:EA(V/V)＝1:1)显示反应完全。向反应液中加入饱和氯化铵溶液(20mL)，用乙酸乙酯(20mL×3)萃取，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，减压浓缩旋干，粗品通过正相硅胶柱层析分离(PE/EtOAc(V/V)＝1:0-1:1)得到3-氯-6-(1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙氧基)哒嗪(1.33g，收率：92.09％)。
第六步：4-(6-(1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙氧基)哒嗪-3-基)哌嗪-2-酮的合成
氩气保护下，将3-氯-6-(1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙氧基)哒嗪 (1.33g,3.64mmol)和2-哌嗪酮(364.06mg,3.64mmol)溶解于二氧六环(15mL)中，依次加入2-双环已基膦-2',6'-二异丙氧基联苯(169.68mg,0.364mmol)、碳酸铯(1.18g,3.64mmol)和甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(304.12mg,0.364mmol)，加完后，反应液升温至100℃，并在该条件下搅拌16小时。LCMS监测反应完毕。反应液经二氯甲烷(50mL)稀释、过滤，滤液减压浓缩。残余物利用反相高效液相色谱制备(柱子column:SunFileTM Prep C18 OBDTM 5μm 30mm×150mm)；溶剂：A＝乙腈，B＝水；梯度：1％-25％，8分钟)纯化得到4-(6-(1-(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)乙氧基)哒嗪-3-基)哌嗪-2-酮(600.0mg，收率：38.42％)。
1H NMR(400MHz,DMSO-d6)：δ8.14-8.10(m,1H),7.82(dd,4H,J1＝8.0Hz,J2＝20.0Hz),7.38(d,1H,J＝12.0Hz),7.18-7.04(m,2H),6.15-6.10(m,1H),3.95(s,2H),3.66-3.63(m,2H),3.28-3.25(m,2H),2.36(s,3H),1.60(d,3H,J＝8.0Hz)。
LC-MS,M/Z(ESI):430.1[M+H]+
实施例2：目标化合物I-7的制备
1-(3-((6-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)哒嗪-3-基)氧基)氮杂环丁烷-1-基)乙烷-1-酮
目标化合物I-7的合成路线如下所示：
第一步：(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲醇的合成
在0℃下，向1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-甲酸乙酯(2.60g,9.24mmol)的四氢呋喃(30mL)溶液滴加2.5M四氢铝锂溶液(5.2mL)，并将反应液在0℃下搅拌0.5小时。反应结束后，在氮气氛围下，滴加水(0.5mL)，15％氢氧化钠溶液(0.5mL)和水(1.5mL)。淬灭后的混合液用无水硫酸钠干燥，过滤浓缩得到(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲醇(2.06g,8.61mmol)。
LC-MS,M/Z(ESI):240.0[M+H]+
第二步：3-氯-6-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)哒嗪的合成
在0℃和氮气保护下，向(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲醇(250mg,1.05mmol)和3,6-二氯哒嗪(156mg,1.05mmol)的四氢呋喃(3mL)溶液中缓慢加入钠氢(84.0mg,2.10mmol,60％)，并将反应液在25℃下搅拌2小时。反应结束后，将反应液用饱和氯化铵(20mL)水溶液淬灭，乙酸乙酯(20mL)萃取三次，有机相经过无水硫酸钠干燥后过滤浓缩得到3-氯-6-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)哒嗪(350mg，粗品)。
LC-MS,M/Z(ESI):351.9[M+H]+
第三步：1-(3-((6-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)哒嗪-3-基)氧基)氮杂环丁烷-1-基)乙烷-1-酮的合成
在0℃和氮气保护下，向1-(3-羟基氮杂环丁烷-1-基)乙烷-1-酮(115mg,995μmol)的四氢呋喃(4mL)和N-甲基吡咯烷酮(2mL)溶液中加入钠氢(119mg,2.98mmol,60％)，然后将3-氯-6-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)哒嗪(350mg，995μmol)加入到反应混合液中。反应液在氮气氛围下80℃下搅拌1小时。反应结束后，将反应液用水(20mL)淬灭，乙酸乙酯(20mL)萃取三次，有机相使用无水硫酸钠干燥后过滤浓缩得到粗品。粗品经高效液相色谱制备纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相:溶剂A＝水+0.1％甲酸，B＝乙腈；梯度:25％-55％,10min)得到1-(3-((6-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)哒嗪-3-基)氧基)氮杂环丁烷-1-基)乙烷-1-酮(80.0mg,182μmol)。
LC-MS,M/Z(ESI):431.1[M+H]+
1H NMR(400MHz,CDCl3)δ7.71-7.66(m,4H),7.06(d,J＝9.2,1H),7.00(d,J＝9.2,1H),6.73(t,J＝56Hz,1H),5.44-5.49(m,3H),4.49-4.47(m,1H),4.44-4.42(m,1H),4.19-4.11(m,2H),2.51(s,3H),1.92(s,3H).
实施例3：目标化合物I-9的制备
1-(4-(二氟甲基)苯基)-4-甲基-N-(6-(4-甲基-3-氧代哌嗪-1-基)哒嗪-3-基)-1H-1,2,3-三唑-5-甲酰胺
目标化合物I-9的合成路线如下所示：
第一步：4-(6-氨基哒嗪-3-基)-1-甲基哌嗪-2-酮的合成
在25℃下，将6-氯哒嗪-3-胺(200mg,1.54mmol)和1-甲基哌嗪-2-酮(212mg,1.85mmol)混合在一起，然后在150℃下搅拌2小时。反应结束后，将反应液冷却至室温，然后加入甲基叔丁基醚(5mL)搅拌0.5小时，过滤得到4-(6-氨基哒嗪-3-基)-1-甲基哌嗪-2-酮(200mg，粗品)。
LC-MS,M/Z(ESI):208.0[M+H]+
第二步：1-(4-(二氟甲基)苯基)-4-甲基-N-(6-(4-甲基-3-氧代哌嗪-1-基)哒嗪-3-基)-1H-1,2,3-三唑-5-甲酰胺的合成
在室温下，向1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-甲酸(170mg,672μmol)的二氯甲烷(3.00mL)溶液中加入一滴N,N-二甲基甲酰胺和草酰氯(128mg,1.01mmol)，将反应液在25℃下搅拌0.5小时。反应结束后，直接浓缩得到粗品，粗品用二氯甲烷(2mL)分散，然后将分散液在零度下缓慢滴加到4-(6-氨基哒嗪-3-基)-1-甲基哌嗪-2-酮(146mg,705μmol)和N,N-二异丙基乙胺(260mg,2.01mmol)的二氯甲烷(3mL)溶液中，反应液继续在25℃下搅拌0.5小时。反应结束后，直接浓缩得到粗品。粗品经高效液相色谱制备纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相:溶剂A＝水+0.1％甲酸，B＝乙腈；梯度:25％-45％,10min)得到1-(4-(二氟甲基)苯基)-4-甲基-N-(6-(4-甲基-3-氧代哌嗪-1-基)哒嗪-3-基)-1H-1,2,3-三唑-5-甲酰胺(81.7mg,177μmol)。
LC-MS,M/Z(ESI):443.2[M+H]+
1H NMR(400MHz,CDCl3)δ10.3(s,1H),8.31(d,J＝8Hz,1H),7.67-7.62(m,4H),6.94(d,J＝9.6Hz,H),6.72(t,J＝56.4Hz,1H),4.03(s,2H),3.77(t,J＝5.6Hz,2H),3.43(t,J＝5.6Hz,1H),3.03(s,3H),2.57(s,3).
实施例4：目标化合物I-14的制备
2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-甲酰胺
目标化合物I-14的合成路线如下所示：
第一步：2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-甲酸叔丁酯的合成
在25℃下，将(1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲醇(300mg,1.25mmol)和2-氯-7,8-二氢-1,6-萘啶-6(5H)-甲酸叔丁酯(371mg,1.37mmol)溶于四氢呋喃(6mL)中，再分批加入叔丁醇钾(281mg,2.51mmol)，将反应体系在60℃下搅拌12小时。反应结束后，将反应液降至室温，并加入水(10mL)稀释。混合液用乙酸乙酯(30mL)萃取三次，合并的有机相用饱和氯化钠溶液(20mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-甲酸叔丁酯(520mg,粗品)。
LC-MS,M/Z(ESI):472.2[M+H]+
第二步：2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-5,6,7,8-四氢-1,6-萘啶的合成
在25℃下，将2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-甲酸叔丁酯(500mg,1.06mmol)溶于二氯甲烷(5mL)中，再加入三氟乙酸(5mL)，将反应液在25℃下搅拌0.5小时。反应结束后，将反应液浓缩得到粗品，粗品经反相高效液相色谱法进行分离纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相:溶剂A＝水 +0.1％甲酸，B＝乙腈；梯度:12％-42％,9min)后得到2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-5,6,7,8-四氢-1,6-萘啶(250mg,63.5％收率)。
LC-MS,M/Z(ESI):372.2[M+H]+
第三步：2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-甲酰胺的合成
在25℃下，将2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-5,6,7,8-四氢-1,6-萘啶(200mg,538μmol)溶于二氯甲烷(4mL)中，再加入三乙胺(218mg,2.15mmol)和三甲基硅异氰酸酯(186mg，1.63mmol)，反应液在25℃下搅拌1小时。反应结束后，将反应液倒入水(10mL)中稀释，再加入二氯甲烷(5mL)萃取三次，合并有机相用饱和氯化钠溶液(10mL)洗涤和无水硫酸钠干燥后，过滤得到粗品，粗品经反相高效液相色谱法进行分离纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相:溶剂A＝水+0.1％甲酸，B＝乙腈；梯度:30％-60％,9min)后得到2-((1-(4-(二氟甲基)苯基)-4-甲基-1H-1,2,3-三唑-5-基)甲氧基)-7,8-二氢-1,6-萘啶-6(5H)-甲酰胺(151mg,67.0％收率)。
LC-MS,M/Z(ESI):415.1[M+H]+
1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.4Hz,2H),7.67(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,1H),6.72(t,J＝56.4Hz,1H),6.60(d,J＝8.4Hz,1H),5.36(s,2H),4.68(br s,2H),4.52(s,2H),3.69(t,J＝6Hz,2H),2.88(t,J＝5.6Hz,2H),2.51(s,3H).
实施例5：下列化合物的制备参考以上化合物的制备方法得到。


测试例1：化合物对α5-GABAA受体的反向激动活性
本试验采用瞬时表达GABAA(α5β3γ2)受体的HEK-293细胞系。测试化合物的最终浓度均在当天配制，再溶于细胞外液。细胞外液为:140mM NaCl，5mM CsCl，2mM CaCl2·2H2O，1mM MgCl2·6H2O，5mM HEPES，10mM D-Glucose，NaOH调节pH＝7.4。细胞内液为：130mM CsCl，0.1mM CaCl2·2H2O，2mM MgCl2·6H2O，1.1mM EGTA，5mM Na2-ATP，10mM HEPES，CsOH调节pH＝7.2。测试化合物溶于二甲基亚砜(DMSO)，测试当天再溶于细胞外液，配制成100nM终浓度。
首先用微电极拉制仪将毛细玻璃管拉制成记录电极，再将充灌细胞内液的电极装入微电极夹持器，在倒置显微镜下操控微电极操纵器使电极浸入细胞外液并记录电极电阻(Rpip)。然后将电极缓慢接触到细胞表面，给予负压抽吸形成GΩ高阻封接。此时执行快电容补偿，继续给予负压吸破细胞膜，形成全细胞记录模式。最后进行慢电容补偿并记录串联电阻(Rs)等实验参数。不给予漏电补偿。当形成全细胞封接后，细胞膜电压钳制于-70mV在Gap-free模式下进行记录GABA受体电流。
检测受试物的反向激动作用时，依次给予细胞表面快速喷射EC50浓度GABA，EC50浓度GABA与受试物检测浓度的混合液以及饱和浓度GABA后电流的峰值。每次切换工作液后用细胞外液洗脱，待电流稳定再切换下一个工作液。试验数据由膜片钳放大器(HEKA，EPC 10)进行采集并储存于数据采集软件(HEKA，Patch Master)中。每个浓度至少使用2个细胞独立重复检测2次。所有电生理试验在室温下进行。试验时，测量给药前GABA激发的电流峰值(IGABA)，受试物检测浓度作用后的电流峰值(ICmpd)，受试物检测浓度与GABA的混合液作用后的电流峰值(IGABA+Cmpd)和饱和浓度GABA激发的电流峰值(IGABA saturated)。分析时计算受试物的拮抗作用，即(1-(ICmpd/IGABA)*100％)，反向激动作用，即(1-(IGABA+Cmpd)/(IGABA)*100％)。
表1.化合物(100nM)的α5-GABAA受体的反向激动活性数据
实验结果表明，本发明化合物具有较强的α5-GABAA受体的反向激动活性。
以上对本公开技术方案的实施方式进行了示例性的说明。应当理解，本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。

Claims (16)

  1. 一种如式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    其中，
    X1为N或C；
    X2为N、O、S或CR5；
    虚线表示单键或双键；
    m选自0、1、2、3、4或5；
    环A不存在或选自苯环、5-6元杂芳环；其中，当环A不存在时，m为1，R1与X1相连；
    R1选自氢、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷氨基、C3-7环烷基或3-6元杂环烷基；所述C1-6烷基、C1-6烷氧基、C1-6烷氨基、C3-7环烷基或3-6元杂环烷基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C3-7环烷基；
    R2选自氢、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C3-7环烷基、3-7元杂环烷基或5-6元杂芳基；所述C1-6烷基、C1-6烷氧基、C3-7环烷基、3-7元杂环烷基或5-6元杂芳基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C3-7环烷基；
    L选自-CH2-O-、-CH(R6)-O-或-C(＝O)-NRa-；
    环B选自5-14元杂芳环；
    n选自0、1、2、3、4、5、6、7或8；
    环D不存在或选自4-6元杂环烷基、3-6元环烷基；
    p为0、1、2、3、4、5、6或7；
    R3和R4各自独立地选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基-C(＝O)Ra-C0-6烷基、-C0-6烷基-C(＝O)ORa-C0-6烷基、-C0-6烷基-C(＝O)NRaRb-C0-6烷基、-C0-6烷基-NRaRb-C0-6烷基、-C0-6烷基-NRaC(＝O)Rb-C0-6烷基、-C0-6烷基-NRaSO2Rb-C0-6烷基、-C0-6烷基-SO2Ra-C0-6烷基、-C0-6烷基-SO2NRaRb-C0-6烷基、C1-6烷基、C3-7环烷基、3-6元杂环烷基、6-10元杂芳基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基、6-10元杂芳基任选地被1-4个选自下列基团的 取代基取代：氘、卤素、氧代、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    M不存在或选自O；
    R5选自氢、氘、卤素、羟基、氰基、C1-6烷基、C1-6烷氧基或C3-7环烷基；所述C1-6烷基、C1-6烷氧基或C3-7环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    R6选自氘、卤素、C1-6烷基、C1-6烷氧基或C3-7环烷基；所述C1-6烷基、C1-6烷氧基或C3- 7环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    Ra和Rb各自独立地选自氢、氘、卤素、羟基、氨基、-C0-6烷基-S(＝O)2-C0-6烷基、-C0-6烷基-P(＝O)2-C0-6烷基、C1-6烷基或3-6元杂环烷基，其中所述C1-6烷基任选地被1-3个选自下列基团的取代基取代：卤素、羟基、-OC1-6烷基、-NH2、-NHC1-6烷基、-OC(＝O)C1-6烷基或-N(C1-6烷基)C1-6烷基；且所述3-6元杂环烷基是含有0、1、2或3个N原子和0、1或2个选自O和S原子的单环。
  2. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述选自
    较佳地，所述选自
  3. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环A不存在或选自苯环或6元杂芳环；所述6元杂芳环含有1、2、3个杂原子；
    m为0、1、2、3、4或5；
    R1选自氢、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基、C3-7卤代环烷基、C1-6烷氧基、C1-6卤代烷氧基；
    较佳地，所述杂原子选自N、O、S；当杂原子为多个时，所述杂原子相同或不同；
    较佳地，环A不存在或选自苯环、吡啶、嘧啶、哒嗪、吡嗪或三嗪；
    较佳地，所述环A选自*端与X1连接；
    较佳地，选自例如
    当环A不存在时，m为1，R1与X1相连；
    更佳地，环A不存在或选自苯环或吡啶。
  4. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：
    其中，环B、环D、R1、R2、R3、R4、L、M、m、n和p具有权利要求1所述的定义。
  5. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：

    其中，环A、环B、环D、R1、R2、R3、R4、M、m、n和p具有权利要求1所述的定义。
  6. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：
    其中，环B、R1、R2、R3、m和n具有权利要求1所述的定义；
    当M不存在时，环D、R4和p同时不存在；
    当M选自O时，环D、R4和p具有权利要求1所述的定义。
  7. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环B选自含有1、2、3、4或5个杂原子的5-14元杂芳环；
    较佳地，所述杂原子选自N、O、S；当杂原子为多个时，所述杂原子相同或不同；
    较佳地，环B选自吖啶基、咔唑基、噌啉基、喹喔啉基、喹唑啉基、吡唑基、吲哚基、异吲哚基、1H,3H-1-氧代异吲哚基、苯并三唑基、呋喃基、噻吩基、吡啶并吗啉基、吡啶并哌啶基、吡啶并吡咯烷基、苯并噻吩基、苯并呋喃基、苯并二噁烷、苯并二氧杂苯、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、四氢萘啶、咪唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉基、噻唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、三嗪基、四嗪基、四唑基、呫吨基、吩嗪基、吩噻嗪基、吩噁嗪基、氮杂卓基、氧杂卓基、硫杂卓基、六氢吡嗪并吡啶并噁嗪、6,7,8,9-四氢吡啶并[2',3':4,5]咪唑并[1,2-a]吡嗪等；
    更佳地，环B选自吡啶、嘧啶、哒嗪、四氢萘啶、吡啶并哌啶、
    较佳地，所述环B选自*端与L连接；
    较佳地，选自 *端与L连接。
  8. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述L选自-CH2-O-、-CH(R6)-O-或-C(＝O)-NRa-；
    所述R6选自C1-3烷基或C3-5环烷基；所述C1-3烷基或C3-5环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    较佳地，所述L选自-CH2-O-、-CH(R6)-O-或-C(＝O)-NRa-；
    所述R6选自C1-3烷基或C3-5环烷基；所述C1-3烷基或C3-5环烷基任选地被1-4个选自下列基团的取代基取代：卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    较佳地，所述L选自-CH2-O-、-CH(CH3)-O-或-C(＝O)-NH-；
    较佳地，所述L选自(如)、*端与连接。
  9. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环D不存在或选自含有1-3个杂原子的4-6元杂环烷基、3-6元环烷基；
    较佳地，所述杂原子选自N、O、S；当杂原子为多个时，所述杂原子相同或不同；
    较佳地，所述环D不存在或选自环丙基、环丁基、环戊基、氮杂环丁烷、吡咯烷、哌啶、哌嗪；
    较佳地，所述环D选自
    较佳地，选自
  10. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R1选自氢、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基、C1-6烷氧基；所述C1-6烷基、C3-7环烷基、C1-6烷氧基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    m选自0、1、2、3、4或5；
    较佳地，所述R1选自卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、卤代烷基；
    较佳地，R1选自F、甲基、环丙基、甲氧基、三氟甲基、二氟甲基、一氟甲基。
  11. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R2选自卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基；所述C1-6烷基、C3-7环烷基、C1-6烷氧基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    较佳地，R2选自甲基。
  12. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R3选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基-C(＝O)Ra-C0-6烷基、-C0-6烷基-C(＝O)ORa-C0-6烷基、-C0-6烷基-C(＝O)NRaRb-C0-6烷基、C1-6烷基、C3-7环烷基、3-6元杂环烷基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基任选地被1-4个选自下列基团的取代基取代：氘、卤素、氧代、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    n选自0、1、2、3、4、5、6、7或8；
    较佳地，R3选自氢、卤素、氧代、-C(＝O)Ra、-C(＝O)NRaRb、C1-3烷基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷、哌啶、哌嗪、哌啶酮、哌嗪酮；
    更佳地，R3选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2、-C(＝O)NH-C1-3烷基、甲基、哌嗪酮、甲基取代的哌嗪酮；
    较佳地，所述R3选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2、甲基、
    n选自0或1。
  13. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述R4选自氢、卤素、羟基、氨基、氰基、氧代、-C0-6烷基-C(＝O)Ra-C0-6烷基、-C0-6烷基-C(＝O)ORa-C0-6烷基、-C0-6烷基-C(＝O)NRaRb- C0-6烷基、C1-6烷基、C3-7环烷基、3-6元杂环烷基；所述C1-6烷基、C3-7环烷基、3-6元杂环烷基任选地被1-4个选自下列基团的取代基取代：氘、卤素、羟基、氨基、氰基、C1-6烷基、C3-7环烷基；
    p为0、1、2、3、4、5、6或7；
    较佳地，R4选自氢、氧代、-C(＝O)-CH3、-C(＝O)NH2、-C(＝O)NH-C1-3烷基、甲基；
    p选自0、1或2。
  14. 如权利要求1所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物包括：

  15. 一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1-14中所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。
  16. 如权利要求1-14中所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途，或权利要求15所述的药物组合物的用途，所述用途包括：
    调节α5-GABAA受体；
    和/或，预防和/或治疗α5-GABAA受体相关的疾病；
    和/或，制备用于调节α5-GABAA受体，和/或预防和/或治疗α5-GABAA受体相关的疾病的药物、药物组合物或制剂；
    较佳地，所述α5-GABAA受体相关的疾病包括：疼痛、阿尔兹海默氏病、多梗塞性痴呆或中风；
    较佳地，所述疼痛是神经病理性疼痛、炎性疼痛或癌症痛；
    较佳地，所述疼痛选自头痛，面部痛，颈痛，肩痛，背痛，胸痛，腹痛，腰痛，下肢痛，肌肉与骨骼疼痛，血管疼痛，痛风，关节炎疼痛，内脏疼痛，感染性疾病导致的疼痛，多骨疼痛，镰刀细胞贫血，自身免疫性疾病，多发性硬化或炎症有关的疼痛，损伤或手术引起的慢性疼痛，伤害感受性疼痛，疼痛性糖尿病，三叉神经痛，腰部或子宫颈神经根病痛，舌咽神经痛，自主神经反射性疼痛，反射性交感神经营养不良，神经根撕脱，癌症，化学损伤，毒素，营养缺乏，病毒或细菌感染，退行性骨关节病有关的疼痛；
    较佳地，所述感染性疾病选自艾滋病或带状疱疹后神经痛。
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WO2023185704A1 (zh) * 2022-03-28 2023-10-05 上海赛默罗生物科技有限公司 异噁唑-杂环类衍生物、药物组合物和用途
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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